Linee guida per la terapia del diabete mellito

Linee guida AACE/ACE

 AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS e AMERICAN COLLEGE OF ENDOCRINOLOGY –
LINEE GUIDA DI PRATICA CLINICA PER LO SVILUPPO DI UN PIANO DI TRATTAMENTO INTEGRATO DEL DIABETE MELLITO – 2015

Yehuda Handelsman, MD, FACP, FACE, FNLA1; Zachary T. Bloomgarden, MD, MACE2; George Grunberger, MD, FACP, FACE3; Guillermo Umpierrez, MD, FACP, FACE4; Robert S. Zimmerman, MD, FACE5; Timothy S. Bailey, MD, FACP, FACE, ECNU6; Lawrence Blonde, MD, FACP, FACE7; George A. Bray, MD, MACP, MACE8; A. Jay Cohen, MD, FACE, FAAP9; Samuel Dagogo-Jack, MD, DM, FRCP, FACE10; Jaime A. Davidson, MD, FACP, MACE11; Daniel Einhorn, MD, FACP, FACE12; Om P. Ganda, MD, FACE13; Alan J. Garber, MD, PhD, FACE14; W. Timothy Garvey, MD15; Robert R. Henry, MD16; Irl B. Hirsch, MD17; Edward S. Horton, MD, FACP, FACE18; Daniel L. Hurley, MD, FACE19; Paul S. Jellinger, MD, MACE20; Lois Jovanovič, MD, MACE21; Harold E. Lebovitz, MD, FACE22; Derek LeRoith, MD, PhD, FACE23; Philip Levy, MD, MACE24; Janet B. McGill, MD, MA, FACE25; Jeffrey I. Mechanick, MD, FACP, FACE, FACN, ECNU26; Jorge H. Mestman, MD27; Etie S. Moghissi, MD, FACP, FACE28; Eric A. Orzeck, MD, FACP, FACE29; Rachel Pessah-Pollack, MD, FACE30; Paul D. Rosenblit, MD, PhD, FACE, FNLA31; Aaron I. Vinik, MD, PhD, FCP, MACP, FACE32; Kathleen Wyne, MD, PhD, FNLA, FACE33; Farhad Zangeneh, MD, FACP, FACE34

Le linee guida per la pratica clinica dell’American Association of Clinical Endocrinologists/American College of Endocrinology sono dichiarazioni sviluppate sistematicamente per aiutare i professionisti in ambito sanitario nel processo decisionale medico in situazioni cliniche specifiche. La maggior parte del contenuto si basa su revisioni della letteratura. Nelle aree di incertezza è stato applicato il giudizio clinico.
Queste linee guida sono un documento operativo che riflette lo stato dell’arte al momento della pubblicazione. Visti i rapidi progressi attesi nel campo, saranno inevitabili revisioni periodiche. Invitiamo i professionisti medici a usare queste informazioni insieme al miglior giudizio clinico. Le raccomandazioni presentate potrebbero non essere adeguate in tutte le situazioni. Qualunque decisione del clinico sull’applicazione di queste linee guida deve essere presa alla luce delle risorse localmente disponibili e delle circostanze del singolo paziente.

ENDOCRINE PRACTICE Vol 21 (Suppl 1) April 2015

Gruppo di Lavoro AACE per il trattamento integrato del diabete mellito
Comitato Editoriale

Copresidenti
Yehuda Handelsman, MD, FACP, FACE, FNLA
Zachary T. Bloomgarden, MD, MACE
George Grunberger, MD, FACP, FACE
Guillermo Umpierrez, MD, FACP, FACE
Robert S. Zimmerman, MD, FACE

Membri del Gruppo di Lavoro
Timothy S. Bailey, MD, FACP, FACE, ECNU
Lawrence Blonde, MD, FACP, FACE
George A. Bray, MD, MACP, MACE
A. Jay Cohen, MD, FACE, FAAP
Samuel Dagogo-Jack, MD, DM, FRCP, FACE
Jaime A. Davidson, MD, FACP, MACE
Daniel Einhorn, MD, FACP, FACE
Om P. Ganda, MD, FACE
Alan J. Garber, MD, PhD, FACE
W. Timothy Garvey, MD
Robert R. Henry, MD
Irl B. Hirsch, MD
Edward S. Horton, MD, FACP, FACE
Daniel L. Hurley, MD, FACE
Paul S. Jellinger, MD, MACE
Lois Jovanovič, MD, MACE
Harold E. Lebovitz, MD, FACE
Derek LeRoith, MD, PhD, FACE
Philip Levy, MD, MACE
Janet B. McGill, MD, MA, FACE
Jeffrey I. Mechanick, MD, FACP, FACE, FACN, ECNU
Jorge H. Mestman, MD
Etie S. Moghissi, MD, FACP, FACE
Eric A. Orzeck, MD, FACP, FACE
Paul D. Rosenblit, MD, PhD, FACE, FNLA
Aaron I. Vinik, MD, PhD, FCP, MACP, FACE
Kathleen Wyne, MD, PhD, FNLA, FACE
Farhad Zangeneh, MD, FACP, FACE

Revisori
Lawrence Blonde, MD, FACP, FACE
Alan J. Garber, MD, PhD, FACE

Affiliazioni:

  • 1Medical Director & Principal Investigator, Metabolic Institute of America, President, American College of Endocrinology, Tarzana, California;
  • 2Clinical Professor, Mount Sinai School of Medicine, Editor, Journal of Diabetes, New York, New York;
  • 3Chairman, Grunberger Diabetes Institute, Clinical Professor, Internal Medicine and Molecular Medicine & Genetics, Wayne State University School of Medicine, Bloomfield Hills, Michigan;
  • 4Professor of Medicine, Emory University School of Medicine, Director, Endocrinology Section, Grady Health System, Atlanta, Georgia;
  • 5Vice Chairman Endocrinology, Director, Cleveland Clinic Diabetes Center, Cleveland Clinic, Cleveland, Ohio;
  • 6Clinical Associate Professor, UCSD School of Medicine, Director, AMCR Institute, Escondido, California;
  • 7Director, Ochsner Diabetes Clinical Research Unit, Department of Endocrinology, Diabetes and Metabolism, Ochsner Medical Center, New Orleans, Louisiana;
  • 8Boyd Professor and Professor of Medicine, Pennington Center, Louisiana State University, Baton Rouge, Louisiana;
  • 9Medical Director, The Endocrine Clinic, P.C., Memphis, Tennessee;
  • 10C. Mullins Professor & Director, Division of Endocrinology, Diabetes and Metabolism, University of Tennessee Health Science Center, Memphis, Tennessee;
  • 11Clinical Professor of Medicine, Division of Endocrinology, Touchstone Diabetes Center, The University of Texas, Southwestern Medical Center, Dallas, Texas;
  • 12Immediate Past President, American College of Endocrinology, Past-President, American Association of Clinical Endocrinologists, Medical Director, Scripps Whittier Diabetes Institute, Clinical Professor of Medicine, UCSD, Associate Editor, Journal of Diabetes, Diabetes and Endocrine Associates, La Jolla, California;
  • 13Senior Physician and Director, Lipid Clinic, Joslin Diabetes Center, Associate Clinical Professor of Medicine, Harvard Medical School, Boston, Massachusetts;
  • 14Professor, Departments of Medicine, Biochemistry, and Molecular Biology, and Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas;
  • 15Professor and Chair, Department of Nutrition Sciences, University of Alabama at Birmingham, Director, UAB Diabetes Research Center, Mountain Brook, Alabama;
  • 16Professor of Medicine, UCSD, Chief, Section of Diabetes, Endocrinology & Metabolism, VA San Diego Healthcare System, San Diego, California;
  • 17Professor of Medicine, University of Washington School of Medicine, Seattle, Washington;
  • 18Senior Investigator, Joslin Diabetes Center, Professor of Medicine, Harvard Medical School, Brookline, Massachusetts;
  • 19Assistant Professor of Medicine, Mayo Clinic, Rochester, Minnesota;
  • 20Professor of Clinical Medicine, University of Miami, Miller School of Medicine, Miami, Florida, The Center for Diabetes & Endocrine Care, Hollywood, Florida;
  • 21Physician Consultant, Sansum Diabetes Research Institute, Clinical Professor of Medicine, Keck School of Medicine of USC, Attending Physician, Santa Barbara County Health Care Services, Adjunct Professor Biomolecular Science and Engineering and Chemical Engineering, University of California Santa Barbara, Santa Barbara, California;
  • 22Professor of Medicine, State University of New York Health Science Center at Brooklyn, Staten Island, New York;
  • 23Director of Research, Division of Endocrinology, Diabetes and Bone Diseases, Mount Sinai School of Medicine, New York, New York;
  • 24Clinical Professor of Medicine, University of Arizona College of Medicine, Banner Good Samaritan Multispecialty Group, Phoenix, Arizona;
  • 25Professor of Medicine, Division of Endocrinology, Metabolism & Lipid Research, Washington University, St. Louis, Missouri;
  • 26Clinical Professor of Medicine, Director, Metabolic Support, Division of Endocrinology, Diabetes, and Bone Disease, Icahn School of Medicine at Mount Sinai, New York, New York;
  • 27Professor of Medicine and Obstetric and Gynecology, Keck School of Medicine of USC, Los Angeles, California;
  • 28Clinical Associate Professor, University of California Los Angeles, Marina Del Ray, California;
  • 29Endocrinology Associates, Houston, Texas;
  • 30Assistant Clinical Professor, Mount Sinai School of Medicine, New York, New York, ProHealth Care Associates, Division of Endocrinology, Lake Success, New York;
  • 31Clinical Professor, Medicine, Division of Endocrinology, Diabetes, Metabolism, University California Irvine School of Medicine, Irvine, California, Co-Director, Diabetes Out-Patient Clinic, UCI Medical Center, Orange, California, Director & Principal Investigator, Diabetes/Lipid Management & Research Center, Huntington Beach, California;
  • 32Professor of Medicine/Pathology/Neurobiology, Director of Research & Neuroendocrine Unit, EasternVirginia Medical Center, The Strelitz Diabetes Center, Norfolk, Virginia;
  • 33Weill Cornell Medical College, Houston Methodist Hospital, Houston, Texas;
  • 34Endocrine, Diabetes & Osteoporosis Clinic, Sterling, Virginia.

Corrispondenza: American Association of Clinical Endocrinologists, 245 Riverside Ave, Suite 200, Jacksonville, FL 32202.
E-mail: Questo indirizzo email è protetto dagli spambots. È necessario abilitare JavaScript per vederlo.. DOI:10.4158/EP15672.GL.
Per ristampe di questo articolo: www.aace.com/reprints.
Copyright © 2015 AACE.

La traduzione delle raccomandazioni operative è stata fatta da Enrico Papini (Albano Laziale) e Roberto Attanasio (MI).
Il testo è stato rivisto e discusso per il confronto con le altre linee guida e la contestualizzazione italiana da Giorgio Borretta (CN), Davide Brancato (PA), Marco Caputo (VR), Roberto Castello (VR), Elena Cimino (Monza), Ilaria Dalle Mule (Legnano), Rossella Dionisio (MI), Olga Disoteo (MI), Vito Giagulli (BA), Edoardo Guastamacchia (BA), Damiano Gullo (CT), Luigi Liparulo (CO), Valentina Lombardi (Sesto S. Giovanni), Pietro Lucotti (PV), Maurizio Nizzoli (FC), Maria Antonietta Pellegrini (UD), Barbara Pirali (Castellanza), Silvio Settembrini (NA), Vincenzo Triggiani (BA).

Abbreviazioni

A1C = emoglobina A1c
AACE = American Association of Clinical Endocrinologists
ACCORD = Action to Control Cardiovascular Risk in Diabetes
ACE = angiotensin-converting enzyme (enzima di conversione dell’angiotensina)
ADA = American Diabetes Association
ADVANCE = Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation
AER = albumin excretion rate (tasso di escrezione dell’albumina)
ApoB = apolipoproteina B
ARB = angiotensin II receptor blocker (bloccante del recettore dell’angiotensina II)
ASCVD = atherosclerotic cardiovascular disease (malattia cardiovascolare aterosclerotica)
BEL = best evidence level (miglior livello di evidenza)
BMI = body mass index (indice di massa corporea)
CDC = Centers for Disease Control and Prevention
CDE = certified diabetes educator (educatore certificato per il diabete)
CGM = continuous glucose monitoring (Holter glicemico)
CKD = chronic kidney disease (nefropatia cronica)
CPAP = continuous positive airway pressure (ventilazione a pressione positiva continua)
CPG = clinical practice guideline
CSI = continuous subcutaneous insulin infusion
CVD = cardiovascular disease (malattia cardiovascolare)
DCCT = Diabetes Control and Complications Trial
DKA = diabetic ketoacidosis (chetoacidosi diabetica)
DM = diabete mellito
DM1 = diabete tipo 1
DM2 = diabete tipo 2
DPP-4 = dipeptidil-peptidasi 4
DSME = diabetes self-management education (educazione all’auto-controllo del diabete)
DSPN = distal symmetric polyneuropathy (polineuropatia simmetrica distale)
EL = evidence level (livello di evidenza)
ESRD = end-stage renal disease (nefropatia terminale)
FDA = U.S. Food and Drug Administration
FPG = fasting plasma glucose (glicemia a digiuno)
GDM = gestational diabetes mellitus (diabete gestazionale)
GFR = glomerular filtration rate (velocità di filtrazione glomerulare)
GI = gastrointestinale
GLP-1 = glucagon-like peptide 1
HBV = hepatitis B virus (virus dell’epatite B)
HDL-C = high-density lipoprotein cholesterol (lipoproteina ad alta densità)
HR = hazard ratio (rapporto di rischio)
ICU = intensive care unit (unità di cure intensive)
IFG = impaired fasting glucose (alterata glicemia a digiuno)
IGT = impaired glucose tolerance (intolleranza al glucosio)
IRC = insufficienza renale cronica
ISF = insulin sensitivity factor (fattore di sensibilità all’insulina)
LDL-C = low-density lipoprotein cholesterol (lipoproteina a bassa densità)
LDL-P = low-density lipoprotein particles (particelle di lipoproteina a bassa densità)
LE = livello di evidenza
Look AHEAD = Look Action for Health in Diabetes
MDI = multiple daily injections (terapia multi-iniettiva)
MLE = miglior livello di evidenza
MNT = medical nutrition therapy (terapia nutrizionale medica)
NPH = neutra protamina Hagedorn
OGTT = oral glucose tolerance test (test di tolleranza orale al glucosio)
OSA = obstructive sleep apnea (apnea ostruttiva del sonno)
POC = point-of-care (punto di cura)
PPG = postprandial glucose (glicemia post-prandiale)
PTH = paratormone
Q = quesito clinico
R = raccomandazione
RAAS = renin-angiotensin-aldosterone system (sistema renina-angiotensina-aldosterone)
RCT = randomized controlled trial (studio randomizzato controllato)
SFN = small-fiber neuropathy (neuropatia delle piccole fibre)
SGLT2 = sodium glucose cotransporter 2 (cotrasportatore sodio-glucosio tipo 2)
SMBG = self-monitoring of blood glucose (auto-monitoraggio glicemico)
TZD = tiazolidinedione
UKPDS = United Kingdom Prospective Diabetes Study
VADT =Veterans Affairs Diabetes Trial


 

1. INTRODUZIONE

Queste linee guida per la pratica clinica (CPG) per il trattamento globale del diabete mellito (DM) sono un aggiornamento di quelle AACE del 2011 (1 [LE 4; NE]). Il mandato per questa CPG era fornire una guida pratica che incorporasse la valutazione integrata del rischio micro- e macro-vascolare (compresi, quindi, i fattori di rischio cardio-vascolare, come lipidi, ipertensione e coagulazione) piuttosto che focalizzarsi sul solo controllo glicemico.
Oltre agli aspetti già trattati nella precedente edizione 2011, questo aggiornamento offre nuove e approfondite informazioni su vaccinazioni, rischio oncologico e trattamento di obesità, disturbi del sonno e depressione nei diabetici, come pure sui problemi relativi agli operatori di veicoli commerciali o altre occupazioni a rischio di obesità e DM, in cui l’ipoglicemia può essere di rischio per gli altri. È stato inoltre eseguito un aggiornamento e sostanziale revisione dei capitoli relativi al trattamento di ipertensione, nefropatia, ipoglicemia e terapia ipoglicemizzante. Gli obiettivi del trattamento nel 2015 pongono l’accento sulla gestione individualizzata di calo ponderale, terapia dell’iperglicemia, dislipidemia e ipertensione. Sono inoltre incentivati piani di trattamento personalizzati che tengano conto della sicurezza oltre che della semplice efficacia.
Queste linee guida propugnano un approccio globale nella consulenza per il trattamento del DM e suggeriscono al clinico di andare al di là del semplice controllo glicemico. Questo approccio integrato si basa sull’evidenza che sebbene i parametri del controllo glicemico (emoglobina glicata - A1c -, escursioni glicemiche post-prandiali – PPG -, glicemia a digiuno – FPG - e variabilità glicemica) abbiano un impatto sul rischio di complicanze micro-vascolari, di malattia cardio-vascolare (CVD), di mortalità e di qualità della vita, anche gli altri fattori influenzino fortemente gli esiti clinici nelle persone affette da DM.
Obiettivi di questa CPG sono fornire:

  • una visione complessiva di un piano di cura globale per endocrinologi e altri clinici che si prendono cura dei pazienti diabetici;
  • una base di evidenze a supporto di soluzioni a problemi specifici della gestione del diabete;
  • un documento che possa essere implementato elettronicamente per guidare il processo decisionale clinico nei pazienti con DM.

Per questo è stato compilato un riassunto operativo di 67 raccomandazioni di pratica clinica organizzate in 24 domande a coprire l’intero spettro della gestione del DM. Le raccomandazioni forniscono risposte - brevi ma accurate - a ciascuna domanda, mentre l’evidenza a loro sostegno è contenuta nell’appendice organizzata sulla base della stessa lista di domande e corredata da esauriente bibliografia. La struttura è concisa e non presenta in modo enciclopedico le pubblicazioni pertinenti in letteratura, per evitare ridondanza e sovrapposizione con altri documenti relativi al DM (CPG e pubblicazioni basate sull’evidenza). Perciò sono citati molti lavori a livello di evidenza (LE) elevato (LE 1) come gli studi randomizzati e controllati (RCT) e le loro metanalisi, ma, per brevità, vengono più spesso indicate le pubblicazioni derivate (LE 4) che raggruppano fonti con evidenza primaria (LE 1,2,3). La CPG ha pertanto una funzione di sintesi, complementare dei testi esistenti e delle altre CPG già pubblicate (comprese, ovviamente, quelle di AACE).


 

2. METODI

Il Consiglio Direttivo AACE ha richiesto un aggiornamento delle CPG AACE sul DM del 2011 (1 [LE 4; NE]), giunte a scadenza nel 2014. La scelta dei copresidenti, degli estensori e dei revisori, come pure la logistica per la creazione di questa CPG basata sull’evidenza, sono state condotte in stretta conformità al protocollo AACE per la produzione standardizzata di CPG del 2010, aggiornato nel 2014 (2 [LE 4; CPG NE; Fig. 1; tabelle 1-4]; 3 [LE 4; CPG NE; tabelle 1-4]).
Tutti gli estensori sono soci AACE ed esperti accreditati nel campo della cura del DM. Questa CPG è stata rivista e approvata dagli estensori, da altri esperti invitati, dal Comitato AACE per le Pubblicazioni e dal Consiglio Direttivo AACE prima di essere inviata al processo di revisione esterno di Endocrine Practice. Tutti gli estensori hanno evidenziato i loro conflitti di interesse e attestato di non essere dipendenti di industrie.
Le citazioni bibliografiche nel testo comprendono il numero progressivo, un descrittore numerico (p.e., LE 1, 2, 3, o 4), e un descrittore semantico (tabella 1). Le raccomandazioni sono basate sulla qualità delle evidenze (tabella 2), tutte accuratamente vagliate (tabella 3). Questa CPG è organizzata in quesiti clinici specifici e rilevanti (etichettati come “Q”).
Le raccomandazioni (etichettate come “R1, R2, ecc.”) sono basate su importanza ed evidenza (gradi A, B, e C) o opinione di esperti se non esiste un’evidenza clinica conclusiva (grado D). Nel rissunto operativo viene fornito anche il miglior livello di evidenza (MLE), che corrisponde alla migliore evidenza riportata nell’appendice a seguire. La definizione delle evidenze è dettagliata nella figura 1 e tabella 1 (2 [LE 4; CPG NE; fig. 1; tabella 1-4]). Al grado di raccomandazione e al MLE possono essere aggiunti commenti che riguardano eventuali fattori soggettivi rilevanti che possono aver influenzato il processo di attribuzione dei punteggi (tabella 4). I dettagli relativi a ogni raccomandazione possono essere ritrovati nella corrispondente sezione dell’appendice. Quindi il processo che porta all’attribuzione di un punteggio e a una raccomandazione non è rigido, ma comprende una complessa integrazione da parte degli esperti di fattori oggettivi e soggettivi, intesi a riflettere un processo decisionale clinico ottimale per la vita reale e a migliorare la cura del paziente. Dove serve, sono fornite raccomandazioni multiple, in modo da lasciare una scelta al lettore.

Questo documento è concepito solo come linea guida. Le circostanze e le presentazioni dei pazienti reali possono variare e il trattamento clinico dell’individuo reale alla fine si deve basare su quello che rappresenta il miglior interesse per il singolo paziente, che comprende i contributi del paziente stesso e il giudizio clinico ponderato del clinico sul campo. 

Figura 1. Metodologia 2010 per le linee guida di pratica clinica (CPG) dell’AACE. Le attuali CPG AACE sono orientate per problemi, con conseguente accorciamento del tempo di produzione, ricerca sulla letteratura di ampiezza intermedia, enfasi sulle evidenze che interessano al paziente, maggiore trasparenza del meccanismo di attribuzione dei punteggi all’evidenza intuitiva, incorporazione di fattori soggettivi nella mappatura delle raccomandazioni basate sull’evidenza, approcci alternativi a cascata, meccanismo di revisione celere a più livelli.

 

*1 = evidenza forte; 2 = evidenza intermedia; 3 = evidenza debole; 4 = assenza di evidenza.
Tabella 1
Protocollo 2010 dell’American Association of Clinical Endocrinologists
per la produzione di linee guida per la pratica clinica
Prima tappa: attribuzione del punteggio alle evidenze *
(modificato da (1): Endocr Pract 2010;16:270-283)
Descrittore numerico (livello di evidenza) Descrittore semantico (metodologia di riferimento)
1 Metanalisi di studi randomizzati controllati (MRCT)
1 Studio randomizzato controllato (RCT)
2 Metanalisi di studi prospettici non randomizzati o studi caso-controllo (MNRCT)
2 Studio randomizzato non controllato (NRCT)
2 Studio prospettico di coorte (PCS)
2 Studio retrospettivo caso-controllo (RCCS)
3 Studio trasversale (ST)
3 Studio di sorveglianza (registri, sondaggi, studi epidemiologici) (SS)
3 Serie di casi consecutivi (CCS)
3 Case report singoli (SCR)
4 Assenza di evidenza (teoria, opinione, consenso, o revisione) (N-E)

 

Tabella 2
Protocollo 2010 dell’American Association of Clinical Endocrinologists
per la produzione di linee guida per la pratica clinica
Seconda tappa: analisi dell’evidenza e dei fattori soggettivi
(da (1): Endocr Pract 2010;16:270-283)
Disegno dello studio Analisi dei dati Interpretazione dei risultati
Correttezza delle premesse Intenzione di trattamento Generalizzabilità
Randomizzazione Statistiche appropriate Logica
Bias di selezione   Incompletezza
Appropriato uso del cieco   Validità
Uso di end-point surrogati (specialmente negli studi in campi inesplorati)    
Numerosità del campione (errore beta)    
Ipotesi nulla vs statistica Bayesiana    

 

Tabella 3
Protocollo 2010 dell’American Association of Clinical Endocrinologists
per la produzione di linee guida per la pratica clinica
Terza tappa: forza delle raccomandazioni;
come differenti livelli di evidenza possono portare alla stessa forza di raccomandazione *
(da (1): Endocr Pract 2010;16:270-283)
Miglior livello di evidenza Impatto dei fattori soggettivi Consenso dei 2/3 Aggiustamento Forza della raccomandazione
1 Nessuno Nessuno A
2 Positivo In su A
2 Nessuno Nessuno B
1 Negativo In giù B
3 Positivo In su B
3 Nessuno Nessuno C
2 Negativo in giù C
4 Positivo In su C
4 Nessuno Nessuno D
3 Negativo In giù D
1,2,3,4 NA No in giù D
*Partendo dalla colonna di sinistra, miglior livello di evidenza (MLE), fattori soggettivi e consenso portano alla forza della raccomandazione nella colonna di destra. Quando i fattori soggettivi hanno impatto scarso o assente, allora il MLE porta direttamente alla forza della raccomandazione. Quando i fattori soggettivi hanno un forte impatto, allora la forza della raccomandazione può essere aumentata (“impatto positivo”) o diminuita (“impatto negativo”). Se non si riesce a raggiungere il consenso dei 2/3 dei partecipanti, allora la forza della raccomandazione è D.
NA = non applicabile (indipendentemente dalla presenza o assenza di forti fattori soggettivi, l’assenza del consenso dei 2/3 dei partecipanti rende obbligatoria la forza della raccomandazione di grado D).

 

Tabella 4
Protocollo 2010 dell’American Association of Clinical Endocrinologists
per la produzione di linee guida per la pratica clinica
Quarta tappa: esempi di parametri che possono essere aggiunti alle raccomandazioni
(da (1): Endocr Pract 2010, 16: 270-283)
Costo-efficacia
Analisi rischio-beneficio
Lacune di evidenza
Preferenze alternative del medico (opinioni in dissenso)
Raccomandazioni in alternativa (“a cascata”)
Disponibilità di risorse
Fattori culturali
Rilevanza (evidenza che importa al paziente)

 


 

3. RIASSUNTO OPERATIVO DELLE RACCOMANDAZIONI

Per una più agevole consultazione, le raccomandazioni per il trattamento integrato del diabete sono organizzate in modo da rispondere alle seguenti domande:

  • Q 1. Come indagare e diagnosticare il Diabete Mellito (DM)?
  • Q 2. Come gestire il Prediabete?
  • Q 3. Quali sono gli obiettivi glicemici del trattamento del DM?
  • Q 4. Come raggiungere gli obiettivi glicemici nel diabete mellito tipo 2 (DM2)?
  • Q 5. Come gestire la glicemia nel diabete mellito tipo 1 (DM1)?
  • Q 6. Come gestire l’ipoglicemia?
  • Q 7. Come gestire l’ipertensione arteriosa nei diabetici?
  • Q 8. Come gestire la dislipidemia nei diabetici?
  • Q 9. Come gestire la nefropatia nei diabetici?
  • Q 10. Come gestire la retinopatia nei diabetici?
  • Q 11. Come diagnosticare e gestire la neuropatia diabetica?
  • Q 12. Come gestire la malattia cardiovascolare nei diabetici?
  • Q 13. Come gestire l’obesità nei diabetici?
  • Q 14. Qual è il ruolo della medicina del sonno nella cura dei diabetici?
  • Q 15. Come trattare il DM in ospedale?
  • Q 16. Come stabilire un piano di cura integrato per il DM nel bambino e nell’adolescente?
  • Q 17. Come trattare il diabete in gravidanza?
  • Q 18. Come e quando impiegare il monitoraggio glicemico?
  • Q 19. Come e quando impiegare i micro-infusori insulinici?
  • Q 20. Quali sono gli elementi essenziali per l’educazione e l’approccio di team alla cura del DM?
  • Q 21. Quali vaccinazioni effettuare nei diabetici?
  • Q 22. Come trattare la depressione nel contesto del DM?
  • Q 23. Qual è l’associazione fra DM e cancro?
  • Q 24. Quali sono le attività lavorative con necessità specifiche per la gestione del DM?

I lettori sono rimandati all’Appendice (sezione 4) per maggiori dettagli e per le evidenze a sostegno di ogni argomento.

Sono state segnalate ove necessario alcune integrazioni al documento originale derivate dall’aggiornamento 2016 delle raccomandazioni AACE (Garber AJ, et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm – 2016 Executive Summary. Endocr Pract 2016, 22: 84-113).

Alla fine del testo delle raccomandazioni operative AACE, per ogni query sono elencate, ove necessario, le integrazioni/raccomandazioni di AACE Chapter Italia.


 

Q 1. Come indagare e diagnosticare il DM?

R 1. Dalla normale tolleranza al glucosio al diabete mellito tipo 2 (DM2) si realizza un incremento continuo del rischio di eventi avversi per la salute.

  • Nei soggetti con i fattori di rischio elencati nella tabella 5, deve essere sempre considerato lo screening per DM (Grado C; MLE 3).
  • I soggetti con fattori di rischio per DM i cui valori glicemici siano risultati normali, devono essere rivalutati ogni tre anni. Lo screening dovrebbe essere più ravvicinato (possibilmente annuale) se coesistono 2 o più fattori di rischio (Grado C; MLE 3).
Tabella 5
Fattori di rischio per prediabete e DM2: criteri per la ricerca del DM negli adulti asintomatici
Età ≥ 45 anni (anche senza altri fattori di rischio)
CVD o anamnesi familiare di DM2
Sovrappeso o obesità a
Stile di vita sedentario
Gruppi etnici a rischio aumentato: Asiatici, Afro-Americani, Ispanici, Nativi Americani, isole del Pacifico
HDL-C < 35 mg/dL (0.90 mmol/L) e/o trigliceridi > 250 mg/dL (2.82 mmol/L)
IGT, IFG e/o sindrome metabolica
PCOS, acanthosis nigricans, NAFLD
Ipertensione arteriosa (PA > 140/90 mm Hg o terapia anti-ipertensiva in corso)
Anamnesi di diabete gestazionale o parto di un neonato con peso > 4 kg
Terapia anti-psicotica per schizofrenia e/o grave malattia bipolare
Esposizione cronica a glucocorticoidi
Disordini del sonno in presenza di intolleranza a glucosio (pregresso riscontro di A1C > 5.7% (39 mmol/mol), IGT, o IFG), compresi OSA, deprivazione cronica di sonno, e lavoro su turni notturni
Abbreviazioni: A1C = emoglobina A1C; PA = pressione arteriosa; CVD = malattia cardiovascolare; HDL-C = colesterolo-lipoproteina ad alta densità; IFG = alterata glicemia a digiuno; IGT = alterata tolleranza a glucosio; NAFLD = steatosi epatica non alcolica; OSA = apnea ostruttiva nel sonno; PCOS = sindrome dell’ovaio policistico.
a Test di screening da considerare in tutti gli adulti obesi (BMI ≥ 30 kg/m2) e in quelli sovrappeso (BMI 25-30 kg/m2) con altri fattori di rischio. Il livello di BMI a rischio può essere inferiore in alcuni gruppi etnici, in cui possono essere usati altri parametri (circonferenza vita e altri fattori).

 

R 2. Il DM è diagnosticato sulla base di uno dei seguenti criteri (tabella 6) (Grado B; MLE 3):

  • glicemia a digiuno (FPG) ≥ 126 mg/dL (7 mmol/L) (dopo digiuno di almeno 8 ore);
  • glicemia ≥ 200 mg/dL (11.1 mmol/L) due ore dopo carico orale (OGTT) con 75 g di glucosio (eseguito al mattino dopo almeno 8 ore di digiuno);
  • glicemia “random” ≥ 200 mg/dL (11.1 mmol/L) in associazione ai sintomi tipici di iperglicemia (poliuria, polidipsia, polifagia);
  • emoglobina glicata (A1c) ≥5% (48 mmol/mol).

Devono essere preferiti per la diagnosi i criteri basati sui valori glicemici (FPG o glicemia 2 ore dopo OGTT). Se l’esame (glicemia o A1c) risulta alterato, per confermare la diagnosi di DM il test deve essere ripetuto in un giorno successivo. Il riscontro di una glicemia random ≥ 200 mg/dL (11.1 mmol/L) non necessita di conferma se associato a sintomi di DM (Grado B; MLE 3).

Tabella 6
Interpretazione degli esami diagnostici per DM
Parametro Normalità Alto rischio di diabete Diabete
Glicemia a digiuno < 100 mg/dL (5.55 mmol/L) 100-125 mg/dL (5.55-7 mmol/L) (IFG) ≥ 126 mg/dL (7 mmol/L)
Glicemia a 2 h < 140 mg/dL (7.8 mmol/L) 140-199 mg/dL (7.8-11 mmol/L) (IGT) ≥ 200 mg/dL (11 mmol/L)
Glicemia random ≥ 200 mg/dL (11 mmol/L) + sintomi
A1C < 5.5% (37 mmol/mol) 5.5-6.4% (37-46 mmol/mol)
Screening del prediabete
≥ 6.5% (48 mmol/mol)
Secondario b
Abbreviazioni: A1C = emoglobina A1C; IFG = alterata glicemia a digiuno; IGT = alterata tolleranza a glucosio.
a A1C dovrebbe essere usata solo per lo screening del prediabete. La diagnosi di prediabete (sia IFG che IGT) deve essere confermata con il dosaggio della glicemia.
b Per la diagnosi di DM devono essere preferiti i criteri glicemici. In tutti i casi, per la diagnosi è necessaria la conferma in un’altra occasione ripetendo glicemia o A1C. Nel caso si usi la A1C per la diagnosi, misurare la glicemia nel follow-up per indirizzare il trattamento del DM.

 

R 3. La diagnosi di Prediabete è formulata in presenza di uno dei seguenti criteri (tab 6) (Grado B; MLE 2):

  • alterata glicemia a digiuno (IFG): glicemia a digiuno compresa fra 100 e 125 mg/dL (5.55 e 7 mmol/L);
  • alterata tolleranza al glucosio (IGT): glicemia 2 ore dopo OGTT compresa fra 140 e 199 mg/dL (7.8 e 11 mmol/L).

Valori di A1C compresi fra 5.5 e 6.4% (37 e 46 mmol/mol) devono essere seguiti da test diagnostici più specifici, basati sui valori glicemici (Grado D; MLE 4). La A1c ha quindi solo valore di screening per il Prediabete, la cui diagnosi definitiva deve essere confermata dalla documentazione di valori alterati di FPG o OGTT (Grado B; MLE 2).
La Sindrome Metabolica, definita secondo i criteri NCEP IV – Adult Treatment Panel III, è considerata equivalente alla condizione di Prediabete (Grado C; MLE 3).

R 4. Le gravide con fattori di rischio per DM devono essere valutate nel corso della prima visita ostetrica prenatale utilizzando i criteri diagnostici standard (Grado D; MLE 4).
Tutte le gravide, indipendentemente dalla presenza di fattori di rischio, devono essere valutate per diabete gestazionale (GDM) fra la 24° e la 28° settimana di gestazione. Lo screening deve essere effettuato mediante OGTT a 2 ore con 75 g di glucosio.
La diagnosi di GDM è posta sulla base dei seguenti criteri (Grado C; MLE 3):

  • FPG > 92 mg/dL (5.1 mmol/L);
  • glicemia 1 ora dopo carico > 180 mg/dL (10 mmol/L);
  • glicemia 2 ore dopo carico > 153 mg/dL (8.5 mmol/L).

R 5. Il DM è costituito da un gruppo eterogeneo di disordini metabolici caratterizzati da una secrezione insulinica insufficiente a mantenere normali livelli di glicemia.
Il DM2 è la forma più frequente di diabete, rappresenta oltre il 90% dei casi, ed è tipicamente associato a sovrappeso od obesità, anamnesi familiare di DM o anamnesi personale di GDM, o a Sindrome Metabolica.
Posta la diagnosi di DM, il DM2 è identificato sulla base di (Grado A; MLE 1):

  • storia clinica;
  • fenotipo del paziente;
  • assenza di auto-anticorpi specifici per DM1.

Nella maggior parte dei casi di DM2 sono presenti insulino-resistenza (caratterizzata da elevati livelli basali o post-prandiali di insulinemia o C-peptide), ipertrigliceridemia e/o bassi livelli di colesterolo HDL (HDL-C).

R 6. Il Diabete tipo 1 (DM1) è di regola caratterizzato dal deficit completo di insulina. La diagnosi di DM1 è confermata dalla determinazione degli anticorpi diretti contro la decarbossilasi dell’acido glutammico (GAD), le ß-cellule delle insule pancreatiche (tirosin-fosfatasi IA-2), il trasportatore dello zinco (Zn-T8) e/o l’insulina (Grado A; MLE 1).
Le rare forme di DM1 non associate a dimostrabile auto-immunità sono definite idiopatiche.
Il DM1 può presentarsi anche in alcuni soggetti sovrappeso od obesi. I livelli di insulina e C-peptide e la presenza (o assenza) dei marcatori autoimmuni consentono, in associazione alla presentazione clinica, di stabilire la corretta diagnosi differenziale fra DM1 e DM2 – soprattutto nei bambini e giovani adulti – e di mettere a punto un trattamento appropriato (Grado B; MLE 2).

R 7. I bambini e i giovani adulti con caratteri non tipici di presentazione, decorso o risposta alla terapia devono essere indagati per un possibile DM monogenico (precedentemente definito MODY). La probabilità di DM monogenico è più elevata in presenza di una storia familiare che mostri l’interessamento di tre generazioni, suggerendo così un’eredità autosomica dominante (Grado C; MLE 3).

 

Raccomandazioni AACE-Chapter Italia

R 1. Si concorda con l’elenco della popolazione a rischio da sottoporre a screening, con l’integrazione di ragazzi > 10 anni con BMI > 85° percentile + 2 tra le seguenti condizioni:

  1. familiarità di I o II grado per DM;
  2. madre con GDM;
  3. segni di insulino-resistenza o condizioni associate (ipertensione, dislipidemia, acanthosis nigricans, PCOS, basso peso alla nascita; appartenenza a gruppo etnico ad alto rischio).

R 2. Per porre diagnosi di DM, se c’è contraddizione tra i risultati di glicemia basale, glicemia dopo OGTT e HbA1c, deve essere ripetuta in una seconda occasione la determinazione del parametro alterato.

R 3. Premesso che è necessaria una standardizzazione del metodo di determinazione dell’HbA1c, la correlazione tra HbA1c e rischio di diabete è diretta e continua e non esiste un valore soglia (International Expert Committee. International Expert Committee report on the role of the A1C assay in the diagnosis of diabetes. Diabetes Care 2009, 32: 1327-34).
Il “prediabete” ha comunque un potenziale valore prognostico per malattie CV, con una relazione a “U” tra HbA1c e rischio di mortalità (Paprott R, et al. Association between hemoglobin A1c and all-cause mortality: results of the mortality follow-up of the German National Health Interview and Examination Survey 1998. Diabetes Care 2015, 38: 249-56.) e tra HbA1c e rischio di eventi CV (Goto A, et al. Hemoglobin a1c levels and the risk of cardiovascular disease in people without known diabetes: a population-based cohort study in Japan. Medicine (Baltimore) 2015, 94: e785).
Suggeriamo come intervallo per tale diagnosi valori di HbA1c fra 5.7 e 6.49%.

R 4. Si conferma la necessità della determinazione della glicemia a digiuno in tutte le gravide. Lo screening universale con OGTT appare auspicabile, ma si ricorda che, secondo i documenti di consenso nazionali, in Italia l’esecuzione di OGTT è raccomandata soltanto nelle gravide che presentano almeno un fattore di rischio.

R 5-6. Si ricorda che, secondo gli standard di cura italiani, il quadro clinico è spesso sufficiente per porre una corretta diagnosi differenziale.
Lo screening con anti-GAD alla diagnosi permette un’opportuna diagnosi differenziale nei soggetti di età giovane-adulta. Il suo impiego nelle età più avanzate deve essere valutato individualmente sulla base del quadro complessivo.
La determinazione del peptide C fornisce un complemento diagnostico alla diagnosi di DM, soprattutto in soggetti giovani e in sovrappeso.


 

Q 2. Come gestire il Prediabete?

R 8. L’insorgenza del DM2 può essere prevenuta o ritardata con un intervento terapeutico sulle persone con Prediabete (cfr tab 6 per i criteri glicemici) (Grado A, MLE 1). Per definire lo stato glicemico dei soggetti con diagnosi di Prediabete, si richiedono determinazioni frequenti di FPG e/o OGTT (Grado C; MLE 3). Devono essere trattati efficacemente e monitorati a intervalli regolari i fattori di rischio cardio-vascolare (CV), soprattutto ipertensione arteriosa e dislipidemia, e il sovrappeso (Grado C; MLE 3).

R 9. Le persone con Prediabete devono modificare il loro stile di vita, in particolare con (Grado B; MLE 3):

  • una riduzione del 5–10% del loro peso corporeo (in soggetti sovrappeso od obesi);
  • il regolare svolgimento di un’attività fisica moderata (ad esempio, camminare) per almeno 20’ al giorno.

I pazienti vanno inseriti in un programma strutturato dedicato alle modifiche dello stile di vita con la verifica dei risultati, perché il supporto comportamentale è di notevole beneficio per il calo ponderale e il suo mantenimento nel tempo (Grado B; MLE 3).

R 10. Nei pazienti a rischio intermedio-elevato di sviluppare DM (presenza di parenti di 1° grado con DM2), in aggiunta alle modifiche dello stile di vita deve essere considerato l’impiego di farmaci come metformina, acarbosio o glitazonici (TZD) (Grado A; MLE 1).

 

Q 2. Raccomandazioni AACE-Chapter Italia

R 8. È opportuno precisare l’effetto metabolico degli anti-ipertensivi (Owen JG, Reisin E. Anti-hypertensive drug treatment of patients with and the metabolic syndrome and obesity: a review of evidence, meta-analysis, post hoc and guidelines publications. Curr Hypertens Rep 2015, 17: 558.):

  • diuretici e ß-bloccanti: neutro, con tendenza al peggioramento;
  • ACE-inibitori, sartani o Ca-antagonisti: neutro o moderatamente favorevole.

R 9. Si sottolinea che la sedentarietà aumenta l’incidenza del diabete (HR = 1.91, IC95% 1.6-2.2). (Biswas A, et al. Sedentary time and its association with risk for disease incidence, mortality, and hospitalization in adults: a systematic review and meta-analysis. Ann Intern Med 2015, 162: 123-32).

R 10. Metformina, acarbose e glitazonici non hanno l’indicazione nelle condizioni di rischio per le malattie metaboliche e, pertanto, sarebbero prescritti “off-label” (legge 648/96) e non rimborsabili. Nei pazienti obesi possono essere considerati anche orlistat (Stevens JW, et al. Preventing the progression to type 2 diabetes mellitus in adults at high risk: a systematic review and network meta-analysis of lifestyle, pharmacological and surgical interventions. Diabetes Res Clin Pract 2015, 107: 320-31) e liraglutide 3 mg (Benefits of liraglutide treatment in overweight and obese older individuals with prediabetes. Diabetes Care 2013, 36: 3276-82).
Studi preliminari hanno dimostrato risultati interessanti
della chirurgia bariatrica (Garber AJ, et al. Diagnosis and management of prediabetes in the continuum of hyperglycemia: when do the risks of diabetes begin? A consensus statement from the American College of Endocrinology and the American Association of Clinical Endocrinologists. Endocr Pract 2008, 14: 933-46).


 

Q 3. Quali sono gli obiettivi glicemici del trattamento del DM?

Q 3.1. Obiettivi glicemici negli adulti ambulatoriali non in gravidanza

R 11. Gli obiettivi glicemici devono essere personalizzati sulla base di (Grado A; MLE 1):

  • aspettativa di vita,
  • durata di malattia,
  • presenza/assenza di complicanze micro- e macro-vascolari,
  • fattori di rischio CV,
  • comorbilità,
  • rischio di ipoglicemia,
  • stato psicologico del paziente.

Di regola, se raggiungibile senza rischi, l’obiettivo della terapia ipoglicemizzante è un livello di A1c ≤ 6.5% nei soggetti adulti non in gravidanza (tab 7) (Grado D; MLE 4).

Tabella 7
Obiettivi per il trattamento nella cura integrata del diabete
Parametro Obiettivi del trattamento Riferimenti bibliografici (livello di evidenza e disegno dello studio)
Glucosio
A1C

Individualizza in base a età, comorbilità, durata di malattia; in generale:

  • ≤ 6.5% (48 mmol/mol) nella maggior parte dei casi:
  • più vicino alla normalità nei soggetti più sani;
  • meno stringente nei “meno sani”
(4 [LE 4; NE])

Glicemia a digiuno < 110 mg/dL (6.1 mmol/L)
Glicemia post-prandiale a 2-h < 140 mg/dL (7.8 mmol/L)
Paziente ricoverato con iperglicemia 140-180 mg/dL (7.8-10 mmol/mol) (5 [LE 4; consenso NE])
Pressione: individualizza in base a età, comorbilità, durata di malattia; obiettivi generali:
Sistolica (mm Hg) ~ 130 (8 [LE 4; NE])
Diastolica (mm Hg) ~ 80
Lipidi
LDL-C Rischio moderato: < 100 mg/dL (2.6 mmol/L)
Rischio alto: < 70 mg/dL (1.8 mmol/L)
(4 [LE 4; NE])
Non-HDL-C Rischio moderato: < 130 mg/dL (3.4 mmol/L)
Rischio alto: < 100 mg/dL (2.6 mmol/L)
(4 [LE 4; NE])
Trigliceridi < 150 mg/dL (1.7 mmol/L)
Rapporto TC/HDL-C Rischio moderato: < 3.5
Rischio alto: < 3.0
ApoB (mg/dL) Rischio moderato: < 90
Rischio alto: < 80
Particelle LDL Rischio moderato: < 1200
Rischio alto: < 1000
Peso
Calo ponderale Ridurre il peso di almeno 5-10%;
evitare l’incremento ponderale
(4 [LE 4; NE])
Terapia anti-aggregante
Aspirina Nella prevenzione secondaria CVD o nella prevenzione primaria dei pazienti a rischio molto alto a (9 [LE 1; MRCT ma piccola numerosità campionaria e basso tasso di eventi]; 10 [LE 1; MRCT]; 11 [LE 1; MRCT]; 12 [LE 2; PCS])

Abbreviazioni: ApoB = apolipoproteina B; MLE = miglior livello di evidenza; CVD = malattia cardiovascolare; DM = diabete mellito; LE = livello di evidenza; HDL-C = colesterolo-lipoproteina ad alta densità; LDL = lipoproteina a bassa densità; MRCT = meta-analisi di studi controllati randomizzati; NE = assenza di evidenza (teoria, opinione, consenso, revisione, o studio preclinico); PCS = studio prospettico di coorte; TC = colesterolo totale.

a Rischio alto: DM senza malattia cardiovascolare; rischio molto alto: DM + CVD.

Per raggiungere questo livello di A1c, la FPG dovrebbe essere < 110 mg/dL (6.1 mmol/L) e la PPG a 2 ore dovrebbe essere < 140 mg/dL (7.8 mmol/L) (tab 7) (Grado B, MLE 2).
Negli adulti con DM2 di recente insorgenza e senza evidenza clinica di CVD, il controllo glicemico deve essere diretto a raggiungere livelli normali o pressoché normali di glicemia (Grado A; MLE 1). Questo obiettivo - che non deve esporre a rischio di ipoglicemia o altri eventi sfavorevoli - ha lo scopo di prevenire le complicanze micro- e macro-vascolari nel corso degli anni successivi. Rimane incerto l’effetto favorevole dello stretto controllo glicemico sul decorso delle complicanze CV già in atto, mentre è certamente ritardata la progressione delle complicanze micro-vascolari.
Nei pazienti con:

  • anamnesi di ipoglicemia severa,
  • ridotta aspettativa di vita,
  • nefropatia avanzata,
  • complicanze macro-vascolari,
  • comorbilità importanti,
  • DM di lunga durata,

in cui non si è riusciti a mantenere gli obiettivi di A1c nonostante tentativi intensivi, si ritiene adeguato un controllo meno stretto della glicemia (A1c compresa fra 7 e 8%, 53 e 64 mmol/mol) (Grado A; MLE 1). Anche in questi pazienti il trattamento deve comunque assicurare l’assenza dei sintomi associati a iperglicemia (poliuria, polidipsia e polifagia).

 

Q 3.2. Obiettivi glicemici negli adulti ricoverati (non in gravidanza)

R 12. Per i degenti in Terapia Intensiva è raccomandato il mantenimento della glicemia in un ambito compreso fra 140 e 180 mg/dL (7.8 e 10 mmol/L), posto che non implichi il rischio di eventi avversi (tab 7) (Grado D; MLE 4). Per i reparti non intensivi di Medicina o Chirurgia sono raccomandati valori di glicemia pre-prandiale < 140 mg/dL (7.8 mmol/L) e di glicemia “random” < 180 mg/dL (10 mmol/L) (Grado C; MLE 3).

 

Q 3.3. Obiettivi glicemici nelle gravide ambulatoriali

R 13. Nelle donne con GDM considerare i seguenti obiettivi glicemici (Grado D; MLE 4):

  • glicemia pre-prandiale ≤ 95 mg/dL (5.3 mmol/L);
  • glicemia 1 ora dopo il pasto ≤ 140 mg/dL (7.8 mmol/L);
  • glicemia 2 ore dopo il pasto ≤ 120 mg/dL (6.7 mmol/L).

Nelle gestanti con pre-esistente DM1 o DM2 gli obiettivi glicemici - se raggiungibili senza rischio di eventi avversi - sono (Grado D; MLE 4):

  • glicemia pre-prandiale, al momento di coricarsi e notturna: 60–99 mg/dL (3.3-5.5 mmol/L);
  • picco post-prandiale: 100–129 mg/dL (5.55-7.1 mmol/L);
  • A1c ≤ 6% (42 mmol/mol).

 

Q 3. Raccomandazioni AACE-Chapter Italia

È opportuno ricordare la differenza creata dall’AIFA tra appropriatezza prescrittiva e rimborsabilità di un farmaco.

R 11. I nuovi farmaci a rischio ipoglicemico basso o nullo consentono di mirare a obiettivi più stringenti e quindi concordiamo con il target ≤ 6.5% per la maggior parte dei pazienti. Suggeriamo di mantenere il target un po’ più alto (≤ 7%) nei pazienti che utilizzano ancora farmaci a rischio di ipoglicemia (glinidi, sulfaniluree e insulina) (Inzucchi SE, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the ADA and the EASD. Diabetes Care 2015, 38: 140-9).
Il
corrispondente obiettivo glicemico andrebbe innalzato in coerenza con l’evidenza scientifica (Wei N, et al. Empirically establishing blood glucose targets to achieve HbA1c goals. Diabetes Care 2014, 37: 1048-51): per ottenere HbA1c = 5.5-6.5%, bisogna mirare a glicemia basale = 122 mg/dL, mentre il target proposto per la post-prandiale è concorde con l’evidenza scientifica.

R 13. Siamo d‘accordo con AACE per i target glicemici del GDM e, come da linee guida nazionali, pensiamo che tali valori possano essere estesi anche agli altri tipi di DM in gravidanza.


 

Q 4. Come raggiungere gli obiettivi glicemici nel diabete mellito tipo 2?

Q 4.1. Come modificare lo stile di vita

R 14. In tutte le persone con Prediabete e DM - DM1, DM2, GDM e forme meno comuni di DM - è raccomandata la terapia medica nutrizionale (TMN).
La TMN deve essere personalizzata sulla base dell’anamnesi nutrizionale e gestita da un nutrizionista esperto, da un dietista diplomato o comunque da un medico con specifica competenza nell’ambito della nutrizione (Grado D; MLE 4).
La TMN è finalizzata a migliorare le condizioni complessive di salute, educando il paziente a una dieta che comprende alimenti vari e in quantità adeguate a gestire in modo appropriato peso, glicemia, quadro lipidico e pressione arteriosa (tabella 8).
Le raccomandazioni dietetiche devono tenere conto delle preferenze personali e culturali, della conoscenza e disponibilità degli alimenti, della motivazione e delle barriere al cambiamento del paziente.
Per i diabetici in terapia insulinica, gli aggiustamenti della posologia insulinica devono essere correlati con l’apporto di carboidrati, mediante l’addestramento al metodo del conteggio dei carboidrati.

Tabella 8
Raccomandazioni dell’American Association of Clinical Endocrinologists per una sana alimentazione nei pazienti diabetici
Argomento Raccomandazione Riferimenti bibliografici (livello di evidenza e disegno dello studio) 
Generalità sulle abitudini alimentari Fare pasti e spuntini regolari; evitare il digiuno per perdere peso
Assumere una dieta ricca di verdure (alto contenuto di fibre e anti-ossidanti, basso indice calorico/glicemico)
Verificare e comprendere le informazioni nutrizionali sule etichette
Discutere credenze e culture
Cuocere preferibilmente a temperatura medio-bassa
Mantenere a livello informale le discussioni medico-paziente
(71 [LE 3; SS]; 72 [LE 4; position NE]; 73 [LE 4; position NE]; 74 [LE 4; revisione NE]; 75 [LE 3; SS]; 76 [LE 1; RCT]; 86 [LE 3; SS])
Carboidrati

Spiegare i 3 tipi di carboidrati (zuccheri, amidi e fibre) e i rispettivi effetti sulla salute
Dettagliare i carboidrati salutari (frutta e verdure fresche, legumi, semi integrali) mirando ad assumerne 7-10 porzioni/die
I cibi a basso indice glicemico (< 55/100 = pane multicereali o di segale, avena integrale, riso integrale, legumi, lenticchie, ceci, patate dolci, mele, mango) possono facilitare il controllo glicemico, ma l’evidenza non è sufficiente per raccomandare formalmente l’istruzione dei pazienti sul fatto che gli zuccheri possono avere effetti sia positivi che negativi sulla salute

(73 [LE 4; position NE]; 77 [LE 4; revisione NE NE]; 78 [LE 4; revisione NE NE]; 79 [LE 4; revisione NE]; 80 [LE 4; NE revisione]; 81 [LE 4; revisione NE]; 89 [LE 4; revisione NE])
Grassi Dettagliare i grassi salutari (noci a basso contenuto di contaminanti/mercurio, avocado, alcuni oli vegetali, pesce)
Limitare i grassi saturi (burro, carni grasse rosse, oli tropicali, fast food) e i grassi trans; scegliere prodotti caseari scremati o a basso contenuto di grasso
(82 [LE 4; revisione NE]; 87 [LE 4; revisione NE]; 88 [LE 4; NE revisione])
 Proteine Assumere proteine da cibi con pochi grassi saturi (pesce, albume, fagioli); non è necessario evitare le proteine animali
Evitare o limitare le carni trattate in modo industriale
(73 [LE 4; position NE]; 83 [LE 2; MNRCT]; 85 [LE 2; PCS, i dati potrebbero non essere generalizzabili ai pazienti già diabetici])
Micronutrienti Non è necessaria una supplementazione di routine, perché una nutrizione sana di solito ne fornisce a sufficienza
In particolare non sono raccomandati, per il controllo glicemico, cromo, vanadio, magnesio, vitamine A, C, E, CoQ10
Supplementi vitaminici dovrebbero essere raccomandati nei pazienti a rischio di insufficienza o carenza
(84 [LE 4; CPG NE])
Abbreviazioni: MLE = miglior livello di evidenza; CPG = linea guida per la pratica clinica; LE = livello di evidenza; MNRCT = meta-analisi di studi prospettici non randomizzati o studi caso-controllo; NE = assenza di evidenza (teoria, opinione, consenso, revisione, o studio pre-clinico); PCS = studio prospettico di coorte; RCT = studio controllato randomizzato.

 

R 15. I pazienti devono svolgere almeno 150 minuti/settimana di esercizio fisico moderato, come camminare a passo svelto (< 15’/km) o svolgere un’attività equivalente (Grado B; MLE 2).
Le persone con DM2 devono inoltre svolgere esercizi per migliorare il tono muscolare e la flessibilità articolare (Grado B; MLE 2).
Deve essere eseguita una valutazione preliminare dei possibili limiti – o controindicazioni – all’attività fisica. L’esercizio fisico deve essere personalizzato, tenendo conto degli obiettivi e dei limiti propri di ciascun paziente. Il programma di attività fisica, inoltre, deve essere iniziato in modo progressivo e sotto adeguato controllo (Grado D; MLE 4).
Anche i pazienti con DM1 devono svolgere un regolare esercizio fisico dopo essere stati educati sugli effetti, acuti e cronici, dell’esercizio fisico sulla glicemia. Devono inoltre essere addestrati ad adeguare il dosaggio insulinico e l’apporto alimentare per il mantenimento del controllo glicemico prima, durante e dopo l’esercizio per prevenire episodi di ipo- o iperglicemia (Grado D; MLE 4).

 

Q 4.2. Terapia farmacologica ipoglicemizzante per DM2

R 16. Il trattamento farmacologico deve essere personalizzato sulla base delle caratteristiche di ciascun paziente (Grado D; MLE 4). Come sintetizzato nella tabella 9, gli agenti ipoglicemizzanti differiscono per il loro impatto su FPG, PPG, peso corporeo, secrezione e sensibilità insulinica, rischio di ipoglicemia e altri eventi avversi.
La scelta del farmaco deve essere basata su una valutazione complessiva del paziente, che comprende:

  • profilo glicemico ottenuto con auto-monitoraggio (SMBG),
  • A1C,
  • peso corporeo,
  • complicanze o comorbilità.

La minimizzazione dell’aumento di peso e del rischio di ipoglicemia ha un ruolo prioritario nella scelta del farmaco.

Tabella 10
Farmaci per il trattamento del DM2 a
Monoterapia Terapia duplice Terapia triplice
Metformina
GLP1-RA
SGLT2-I
DPP4-I
AGI
TZDb
SU/glinideb
Metformina (o altro farmaco di prima linea) +
GLP1-RA
SGLT2-I
DPP4-I
TZDb
Insulina basaleb
Colesevelam
BCR-QR
AGI

SU/glinideb
Farmaci di prima e seconda linea +
GLP1-RA
SGLT2-I
TZDb
Insulina basaleb
DPP4-I

Colesevelam
BCR-QR
AGI

SU/glinideb

Abbreviazioni: A1C = emoglobina A1C; AGI = inibitori α-glucosidasi; BCR-QR = bromocriptina a veloce rilascio; DPP4I = inibitori dipeptidil-peptidasi 4; GLP1RA = agonisti del recettore glucagon-like peptide 1; SGLT2I = inibitori del co-trasportatore 2 sodio-glucosio; SU = sulfaniluree; TZD = tiazolidinedioni.

a Intensificare la terapia se A1C supera gli obiettivi personalizzati. Il grassetto indica rischio lieve o assente di ipoglicemia o incremento ponderale, pochi eventi avversi e/o la possibilità di benefici al di là dell’effetto ipoglicemizzante.

b Usare con prudenza.

 

R 17. Gli effetti e il meccanismo di azione dei farmaci ipoglicemizzanti disponibili sono riportati in dettaglio nel documento di consenso AACE del 2015 sull’algoritmo per il trattamento globale del diabete (4).
Nei pazienti con A1c basale < 7.5% (59 mmol/mol), AACE raccomanda di iniziare la terapia con metformina, oppure con un agonista del recettore del glucagon-like peptide 1 (GLP-1), un inibitore della dipeptidil-peptidasi 4 (DPP-4), un inibitore del co-trasportatore sodio-glucosio (SGLT-2) o un inibitore delle alfa-glucosidasi (Grado C; MLE 3). TZD, sulfaniluree e glinidi possono essere presi in considerazione come alternative, ma devono essere impiegati con cautela per i possibili effetti collaterali (Grado C; MLE 3).
Nei pazienti con A1C iniziale > 7.5% (59 mmol/mol), il trattamento farmacologico deve essere iniziato con la combinazione di metformina (se non controindicata) con un secondo ipoglicemizzante. Devono essere impiegati di preferenza farmaci con basso rischio di ipoglicemia e ininfluenti (o con effetto favorevole) sul peso (Grado C; MLE 3). Hanno queste caratteristiche gli agonisti del recettore GLP-1, gli inibitori del SGLT-2 e gli inibitori della DPP-4. Possibili alternative sono i TZD e le insuline basali. In circostanze particolari possono essere impiegati per il controllo della glicemia colesevelam, bromocriptina e inibitori delle alfa-glucosidasi, farmaci con modesta efficacia ipoglicemizzante ma basso rischio di effetti indesiderati (Grado C; MLE 3). Sulfaniluree e glinidi sono opzioni meno favorevoli a causa del rischio di ipoglicemia (Grado B; MLE 2).
Nei pazienti con A1c iniziale > 9% (75 mmol/mol) e che presentino sintomi di iperglicemia, è raccomandata la terapia insulinica, da sola o in combinazione con metformina o altri ipoglicemizzanti orali (Grado A; MLE 1). La pramlintide e gli agonisti del recettore del GLP-1 possono essere impiegati ai pasti insieme all’insulina per ridurre l’iperglicemia post-prandiale, il peso e l’A1c (Grado B; MLE 2). Anche gli agonisti a lunga durata d’azione del recettore del GLP-1 influenzano favorevolmente la glicemia a digiuno.

Integrazione 2016: non usare metformina se eGFR < 45 mL/min e monitorare sempre i livelli di vitamina B12. È opportuna cautela nell’uso di:

  • GLP-1 agonisti nei pazienti con anamnesi di pancreatite o gastroparesi diabetica;
  • inibitori DPP-IV in quelli con storia di pancreatite;
  • inibitori della glucosidasi nei pazienti con insufficienza renale.

È controindicato l’impiego di GLP-1 agonisti nei pazienti con anamnesi personale o familiare di carcinoma midollare della tiroide o MEN-2.

R 18. Nel DM2 l’impiego dell’insulina deve essere considerato quando gli ipoglicemizzanti orali non consentono di raggiungere gli obiettivi glicemici e nei pazienti non ancora trattati che presentino iperglicemia sintomatica (Grado A; MLE 1). Nella maggioranza di questi casi la scelta iniziale deve cadere sulla terapia con insuline a lunga durata d’azione (Grado C; MLE 3). Come insuline basali, gli analoghi dell’insulina glargine e detemir devono essere preferiti alle insuline ad azione intermedia NPH per il minor rischio di indurre ipoglicemia (Grado C; MLE 3).
Quando è necessario il controllo dell’iperglicemia post-prandiale, devono essere utilizzate le insuline ad azione rapida (analoghi lispro, aspart e glulisina o insuline per via inalatoria). Queste insuline iniziano e cessano la loro azione più rapidamente delle regolari e si associano a minor rischio di ipoglicemia (Grado B; MLE 2).

Tabella 11
Tappe raccomandate per l’aggiunta di insulina alla terapia ipoglicemizzante (4 [LE 4; NE])
Valori glicemici Dose totale giornaliera Attenzioni
1° tappa: iniziare insulina basale (a lunga durata d’azione)
A1C < 8% (64 mmol/mol) 0.1-0.2 U/kg Valutare la sospensione della SU
Preferire analoghi basali a NPH
A1C > 8% (64 mmol/mol) 0.2-0.3 U/kg
2° tappa: titolare l’insulina ogni 2-3 giorni per raggiungere gli obiettivi glicemici a
Regime fisso Aumentare di 2 U/die  
Regime personalizzabile FBG > 180 mg/dL (10 mmol/L) Aggiungere 4 U  
FBG 140-180 mg/dL (7.8-10 mmol/mol) Aggiungere 2 U  
FBG 110-139 mg/dL (6.1-7.7 mmol/l) Aggiungere 1 U  
3° tappa: monitoraggio dell’ipoglicemia
Glicemia < 70 mg/dL (3.88 mmol/L) Ridurre del 10-20%  
Glicemia < 40 mg/dL (2.22 mmol/L) Ridurre del 20-40%  

Abbreviazioni: A1C = emoglobina A1C; FBG = glicemia a digiuno; NPH = neutra protamina Hagedorn; SU = sulfaniluree.

a Nella maggior parte dei pazienti con DM2 che assumono insulina, gli obiettivi sono A1C < 7% (53 mmol/mol) e glicemia a digiuno e pre-prandiale < 110 mg/dL (6.1 mmol/L) senza ipoglicemia. Gli obiettivi individuali di A1C e glicemia a digiuno possono essere aggiustati sulla base di età, durata del diabete, presenza di comorbilità, complicanze del diabete, rischio ipoglicemico.

 Le formulazioni pre-miscelate di insulina (con un rapporto fisso fra la componente a breve e a lunga durata d’azione) devono essere limitate ai soli pazienti in cui è problematica l’aderenza ai regimi intensivi di terapia insulinica. Queste preparazioni, infatti, riducono la flessibilità posologica e accentuano il rischio di ipoglicemia in confronto agli schemi con sola insulina basale oppure basal-bolus (Grado B; MLE 2). Al contrario, i regimi basal-bolus di terapia insulinica sono flessibili e sono raccomandati per il trattamento insulinico intensivo (Grado B; MLE 3).

R 19. Allorché gli obiettivi terapeutici non sono raggiunti o non sono mantenuti, l’intensificazione della terapia farmacologica deve essere effettuata in associazione al monitoraggio glicemico e all’aggiustamento della posologia terapeutica condotto a intervalli appropriati (per esempio trimestrali) (Grado C; MLE 3). L’algoritmo AACE 2015 delinea le scelte del trattamento da condurre o modificare sulla base dei livelli di A1c (4 [LE 4; NE]).

Tabella 12
Tappe raccomandate per l’intensificazione della terapia insulinica quando è necessario un controllo ai pasti (4 [LE 4; NE])
Opzione terapeutica Dose di insulina Attenzioni
1° tappa: aggiungere terapia ai pasti
Agonisti del recettore GLP-1, inibitori SGLT2 o inibitori DPP-4 - Se non si raggiungono gli obiettivi glicemici, aggiungere insulina ai pasti
insulina ai pasti TDD = 0.3-0.5 U/kg (50% basale; 50% ai pasti) Preferire analogo basale + analogo rapido ai pasti rispetto a NPH + insulina pronta o premiscelata
2° tappa: titolare l’insulina ogni 2-3 giorni per raggiungere gli obiettivi glicemici a
Regime fisso   Aumentare TDD di 2 U/die  
Regime personalizzabile FBG > 180 mg/dL (10 mmol/L) Aumentare TDD di 4 U  
FBG 140-180 mg/dL (7.8-10 mmol/mol) Aumentare TDD di 2 U  
FBG 110-139 mg/dL (6.1-7.7 mmol/l) Aumentare TDD di 1 U  
2-h PPG o successiva glicemia pre-prandiale >180 mg/dL (10 mmol/L) Aumentare del 10% la dose per il pasto successivo  
insulina premiscelata Glicemia a digiuno/ pre-prandiale > 180 mg/dL (10 mmol/L) Aumentare del 10% TDD  
3° tappa: monitoraggio dell’ipoglicemia
Ipoglicemia a digiuno Ridurre la dose di insulina basale  
Ipoglicemia notturna Ridurre la dose di insulina basale o ridurre la dose di insulina rapida assunta a cena o con lo spuntino serale  
Ipoglicemia inter-prandiale Ridurre la dose di insulina rapida assunta prima del pasto precedente  

Abbreviazioni: DPP-4 = dipeptidil-peptidasi 4; FBG = glicemia a digiuno; GLP-1 = agonisti del recettore glucagon-like peptide 1; NPH = neutra protamina Hagedorn; PPG = glicemia post-prandiale; SGLT2 = co-trasportatore 2 sodio-glucosio; TDD = dose totale quotidiana.

a Nella maggior parte dei pazienti con DM2 che assumono insulina, gli obiettivi sono A1C < 7% (53 mmol/mol) e glicemia a digiuno e pre-prandiale < 110 mg/dL (6.1 mmol/L) senza ipoglicemia. Gli obiettivi individuali di A1C e glicemia a digiuno possono essere aggiustati sulla base di età, durata del diabete, presenza di comorbilità, complicanze del diabete, rischio ipoglicemico.

 

Q 4. Raccomandazioni AACE-Chapter Italia

R 14. Anche se la terapia medica nutrizionale, come quella preventiva, nelle nostre realtà rimane di difficile implementazione per carenza di risorse, ha un ruolo fondamentale e non può essere demandata ad altri. La limitata efficacia della TMN nel ridurre peso corporeo, HbA1c ed LDL può essere aumentata attraverso frequenti contatti con gli operatori sanitari (Franz MJ, et al. Lifestyle weight-loss intervention outcomes in overweight and obese adults with type 2 diabetes: a systematic review and meta-analysis of randomized clinical trials. J Acad Nutr Diet 2015, 115: 1447-63).

R 16. Alcuni dei farmaci citati non sono disponibili in Italia (colesevelam, bromocriptina QR e pramlintide). Lo studio TECOS (Green JB, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2015, 373: 232-42) ha smentito il rischio di ricovero per scompenso cardiaco nell’utilizzo di sitagliptin. Lo studio EMPAREG (Zinman B, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015, 373: 2117-28) può far salire gli SGLT-2 inibitori in prima linea.

R 17. L’indicazione a iniziare la terapia farmacologica secondo l’algoritmo AACE (anche nella versione 2016) in rapporto al compenso metabolico del paziente (HbA1c) è del tutto condivisibile sul piano evidence-based. L’ente regolatorio AIFA condiziona attualmente in maniera significativa la rimborsabilità di alcune classi di farmaci. Queste restrizioni riguardano sia l’utilizzo di alcuni farmaci in monoterapia, sia l’utilizzo in combinazione. Ad esempio in Italia:

  • è possibile iniziare la terapia con DPP-4 inibitori in monoterapia solo in caso di insufficienza renale (con posologia variabile secondo molecola ed eGFR);
  • è possibile iniziare la terapia con inibitori SGLT-2 in monoterapia solo in caso di intolleranza a metformina;
  • GLP-1 agonisti e inibitori DDP-4 sono rimborsabili solo ai pazienti con HbA1c compresa fra 7.5% e 8.5% (9% in alcune condizioni specifiche);
  • non è rimborsabile l’associazione fra terapia insulinica multi-iniettiva e GLP-1 agonisti.

La tabella illustra per ogni molecola i contesti di appropriatezza in relazione alle schede tecniche e alla rimborsabilità.

 

Le indicazioni sono quelle contenute nei rispettivi RCP (ultima consultazione su https://farmaci.agenziafarmaco.gov.it/bancadatifarmaci/ in data 14/02/16). RCP dell’Exenatide e del Dapaglifozin non presenti nella banca dati del Ministero; si è fatto ricorso agli RCP forniti da AstraZeneca.
In relazione alle indicazioni in associazione doppia o tripla, qualora le rispettive RCP fossero in contraddizione, si è tenuto conto del RCP più recente.
Per quanto riguarda la rimborsabilità di gliptine e incretino–mimetici si fa riferimento all’aggiornamento AIFA 2015.
Le note in nero indicano le indicazioni secondo RCP, coincidenti con la rimborsabilità, ad eccezione di quanto previsto dalle note in rosso, che indicano limitazioni alla rimborsabilità, aggiuntive rispetto alle indicazioni previste dal RCP.
Un riquadro azzurro indica la rimborsabilità, in coerenza con il Piano terapeutico, per le indicazioni descritte dalle note, sempre subordinata ai valori di HbA1c, che debbono essere:

  • compresi tra 7.5 e 8.5% al primo Piano Terapeutico;
  • ≤ 8.5% (o ≤ 9% nei pazienti fragili) nei Piani Terapeutici successivi al primo.

Un riquadro blu indica la rimborsabilità, in coerenza con il Piano terapeutico, per le indicazioni descritte dalle note, non subordinata ai valori di HbA1c.

Note:

  • + = indicata secondo RCP
  • No = non indicata secondo RCP
  • (a)= associazione non esplicitata nelle «indicazioni», ma comunque contemplata nell’RCP
  • (b)= in associazione doppia soltanto se metformina controindicata/non tollerata o in associazione triplice a metformina
  • (c)= soltanto se metformina controindicata/non tollerata
  • (d)= anche in tripla associazione con metformina
  • (e)= in tripla associazione con metformina
  • (f)= anche in associazione con metformina e/o pioglitazone
  • (g)= nel RCP si fa esplicito riferimento alla glimepiride e non ad altre sulfoniluree
  • (h)= nel RCP si fa esplicito riferimento a degludec e detemir, ma non ad altre insuline
  • (i)= anche in tripla associazione con metformina o sulfoniluree
  • (j)= nel RCP si fa esplicito riferimento all’associazione con altri ipoglicemizzanti orali non meglio specificati
  • (k)= anche in tripla o quadrupla associazione con metformina e/o sulfoniluree
  • (l)= rimborsabilità soltanto se Cl. Creat. < 50 mL/min (sec. Cockroft-Gault)
  • (m)= rimborsabile soltanto se metformina controindicata/non tollerata
  • (n)= rimborsabile soltanto se in associazione tripla con metformina

 

R 18. L’insulina nasale non è disponibile in Italia, mentre è ora disponibile degludec e a breve sarà commercializzata glargine U-300, entrambe con riduzione del rischio di ipoglicemia (Ratner RE, et al. Hypoglycaemia risk with insulin degludec compared with insulin glargine in type 2 and type 1 diabetes: a pre-planned meta-analysis of phase 3 trials. Diabetes Obes Metab 2013, 15: 175-84. Ritzel R, et al. Patient-level meta-analysis of the EDITION 1, 2 and 3 studies: glycaemic control and hypoglycaemia with new insulin glargine 300 U/ml versus glargine 100 U/ml in people with type 2 diabetes. Diabetes Obes Metab 2015, 17: 859-67).


 

Q 5. Come gestire la glicemia nel diabete mellito tipo 1?

R 20. Il DM1 deve essere trattato con terapia insulinica (Grado A; MLE 1) utilizzando, nell’assoluta maggioranza dei casi, gli analoghi dell’insulina (Grado A; MLE 1).
Nel DM1 devono essere di regola adottati regimi terapeutici che tendono a riprodurre la fisiologica secrezione insulinica, somministrando l’insulina necessaria sia alle esigenze basali che a quelle dei pasti (Grado A; MLE 1). Sono utilizzabili i seguenti approcci terapeutici:

  • iniezioni giornaliere multiple di insulina (MDI), somministrando 1 o 2 iniezioni sottocutanee al giorno di insulina basale, per controllare la glicemia durante la notte e fra i pasti, e iniezioni di insulina ad azione rapida (o, se disponibile, insulina inalatoria) prima di ciascun pasto, in modo da controllare la glicemia post-prandiale (Grado A; MLE 1);
  • infusione sottocutanea continua di insulina (CSII) per ottenere una somministrazione più fisiologica, in modo da migliorare il controllo glicemico e ridurre il rischio di ipoglicemia (Grado A; MLE 1).

 

Q 5. Raccomandazioni AACE-Chapter Italia

R 20. L’insulina inalatoria non è in commercio in Italia.
È opportuno aggiungere che la riduzione più precoce possibile dell’HbA1c modifica la storia naturale del DM1, con un effetto duraturo (memoria metabolica) sulla riduzione delle complicanze micro- e macro-vascolari (Nathan DM; DCCT/EDIC Research Group. The diabetes control and complications trial/epidemiology of diabetes interventions and complications study at 30 years: overview. Diabetes Care 2014, 37: 9-16).


 

Q 6. Come gestire l’ipoglicemia?

R 21. L’ipoglicemia può essere definita come un valore di glicemia < 70 mg/dL (3.9 mmol/L), associato o meno a sintomi come ansia, palpitazioni, tremori, sudorazione, senso di fame, parestesie, modifiche del comportamento, disfunzione cognitiva, convulsioni e coma. lpoglicemia severa è quella che richiede l’assistenza da parte di un’altra persona per la somministrazione di carboidrati, glucagone o di altre misure correttive.
L’ipoglicemia deve essere trattata, quando possibile, con la somministrazione orale di glucosio a pronto assorbimento. Se il paziente non è in grado di deglutire o non è vigile e collaborante, il personale sanitario deve somministrare un’infusione di glucosio endovena o, se in ambiente non ospedaliero, un familiare addestrato deve iniettare una fiala di glucagone per via sc o im (Grado A; MLE 1). La dose abituale di glucagone è 1 mg (1 U) nell’adulto, da dimezzare (0.5 mg) nei bambini sotto i 20 kg. Appena il paziente torna a essere vigile e in grado di deglutire correttamente, deve rapidamente ricevere un apporto di carboidrati a rapido assorbimento (es. succo di frutta), seguito da uno spuntino o da un pasto che contenga sia carboidrati complessi che proteine (o lipidi), come cracker con formaggio o un sandwich di pane e burro (Grado C; MLE 3).
I pazienti con ipoglicemia severa e alterazione dello stato mentale e quelli con ipoglicemia che persiste anche dopo l’intervento terapeutico iniziale devono essere ricoverati (Grado A; MLE 1).
Nei pazienti con ipoglicemia silente e assenza di un’adeguata risposta del sistema nervoso autonomo, assicurare alcune settimane senza episodi di ipoglicemia può ridurre il rischio e prevenire la recidiva di una nuova ipoglicemia severa.
In caso di ipoglicemia severa in pazienti con DM2 in trattamento combinato con inibitori dell’alfa-glucosidasi e secretagoghi o insulina, è necessario somministrare per os glucosio o cibi con lattosio (latte e derivati), perché l’assorbimento di disaccaridi e carboidrati complessi può risultare compromesso (Grado C; MLE 3).

 

Q 6. Raccomandazioni AACE-Chapter Italia

R 21. L’ipoglicemia deve essere trattata, quando possibile, con la somministrazione orale di glucosio a pronto assorbimento (con la regola del 15: 15 g per via orale con controlli ogni 15 minuti).
Nei pazienti in terapia intensiva multi-iniettiva e/o con micro-infusore il controllo delle glicemie dovrebbe essere eseguito sistematicamente:

  • prima dei pasti e degli spuntini;
  • occasionalmente dopo i pasti principali;
  • prima di andare a letto;
  • prima di un esercizio fisico;
  • prima di guidare;
  • sempre nel sospetto di ipoglicemia;
  • dopo la correzione delle ipoglicemie.

In accordo con le raccomandazioni degli Standard Italiani e dell’ADA, per prevenire le ipoglicemie l’auto-controllo quotidiano è indispensabile per i pazienti con DM1 e per quelli con DM2 insulino-trattati. Si raccomanda che l’intensità dei controlli si adatti alle diverse tipologie di pazienti:

  • < 18 anni, o in gravidanza, o in trattamento con micro-infusore: 6-8/die;
  • in trattamento insulinico basal-bolus: 4-5/die;
  • in trattamento insulinico non intensivo o combinato: 2-4/die;
  • trattati con secretagoghi orali: da 6/settimana a 2/die (se rischio elevato);
  • GDM in trattamento dietetico: 2/die;

La frequenza dell’auto-controllo deve essere adattata agli eventi intercorrenti e intensificata in presenza di situazioni cliniche quali patologie intercorrenti, ipoglicemie inavvertite, ipoglicemie notturne, variazioni della terapia ipoglicemizzante.
La mancata percezione dell’ipoglicemia nel DM1 può essere prevenuta con l’educazione terapeutica strutturata mirata alla prevenzione delle ipoglicemie e con l’utilizzo del CGM (Yeoh E, et al. Interventions that restore awareness of hypoglycemia in adults with type 1 diabetes: a systematic review and meta-analysis. Diabetes Care 2015, 38: 1592-609).


 

Q 7. Come gestire l’ipertensione arteriosa nei diabetici?

R 22. L’obiettivo pressorio nei pazienti con DM o prediabete deve essere di regola 130/80 mm Hg, ma deve essere personalizzato in rapporto alle caratteristiche dei singoli soggetti (tab 7) (Grado B; MLE 2).
Un obiettivo più aggressivo, come 120/80 mm Hg, deve essere limitato alla minoranza dei pazienti che non appaiono esposti a rischio di eventi avversi o di effetti collaterali dovuti ai farmaci ipotensivi (Grado C; MLE 3).
Nei pazienti fragili devono essere presi in considerazione obiettivi pressori più moderati, soprattutto in presenza di complicanze del diabete, comorbilità o effetti indesiderati della terapia (Grado D; MLE 4).

R 23. Nei soggetti diabetici con ipertensione arteriosa, le modifiche dello stile di vita devono comprendere la riduzione dell’apporto di sale con la dieta (vedi Dietary Approach to stop Hypertension, DASH), l’inizio di un’attività fisica appropriata alle condizioni del paziente e, se necessario, il consulto con un dietista diplomato o con un educatore certificato per il diabete (CDE) (Grado A; MLE 1).
In caso di mancata risposta alle modifiche dello stile di vita, per raggiungere gli obiettivi terapeutici bisogna utilizzare il trattamento farmacologico (Grado A; MLE 1). Gli agenti anti-ipertensivi devono essere selezionati sia sulla base della loro efficacia sia della loro utilità nel prevenire o rallentare la progressione dell’impegno micro-vascolare retinico e renale. Devono essere preferiti gli inibitori dell’enzima di conversione dell’angiotensina (ACE) o i bloccanti del recettore dell’angiotensina II (ARB) (Grado C; MLE 3).
Quando risulti necessario per raggiungere gli obiettivi terapeutici appropriati, può essere utilizzata una terapia di combinazione che, oltre ai farmaci attivi sul RAS, comprenda anche calcio-antagonisti, diuretici, bloccanti alfa- e ß-adrenergici o ß -bloccanti selettivi di nuova generazione (Grado A; MLE 1).

Tabella 13
Ordine di priorità suggerito per l’inizio della terapia anti-ipertensiva
Terapia Riferimenti bibliografici (livello di evidenza e disegno dello studio)
Basata su prove di evidenza
Bloccanti RAAS (ACE-inibitori o ARB) (198 [LE 1; RCT]; 199 [LE 1; RCT])
Diuretici tiazidici (194 [LE 4; revisione NE])
β-bloccanti (199 [LE 1; RCT])
Terapia personalizzata
Calcio-antagonisti (214 [LE 1; RCT, analisi post-hoc])
Anti-aldosteronici
Inibitori diretti della renina
α1-bloccanti selettivi
α2-agonisti centrali
Vasodilatatori diretti
(202 [LE 4; CPG NE])
Abbreviazioni: ACE = enzima di conversione dell’angiotensina; ARB = bloccanti del recettore dell’angiotensina II; RAAS = sistema renina-angiotensina-aldosterone.

 

Q 7. Raccomandazioni AACE-Chapter Italia

R 22. La pressione deve essere misurata ad ogni visita.
Valori > 130/80 mmHg devono essere confermati nell'arco di un mese.
Si concorda con gli obiettivi pressori proposti da AACE, anche se si ricorda che negli SI 2014 viene raccomandato come obiettivo pressorio un valore < 140/80 mmHg.
Nessun cenno viene fatto alla diabetica gravida con ipertensione, in cui gli SI indicano un target < 150/90 mmHg (< 140/90 in presenza di danno d’organo).

R 23. Il tentativo con il solo cambiamento dello stile di vita deve durare al massimo 3 mesi.
I pazienti devono essere rivalutati ogni 4-8 settimane durante la definizione del trattamento efficace per il raggiungimento del target terapeutico e poi ogni 3 mesi se in trattamento anti-ipertensivo stabile.
L’utilizzo dei GLP-1 agonisti o degli SGLT-2 inibitori può aggiungere un significativo beneficio sia sulla pressione sistolica che diastolica (riduzione rispettivamente di 4–6 mmHg e di 2–4 mmHg) (Visboll T, et al. Effects of glucagon-like peptide-1 receptor agonists on weight loss: systematic review and meta-analyses of randomised controlled trials. BMJ 2012, 344, d7771. Liakos A, et al. Efficacy and safety of empagliflozin for type 2 diabetes: a systematic review and meta-analysis. Diabetes Obes Metab 2014, 16: 984-93), consentendo così di non aumentare la posologia degli anti-ipertensivi nei pazienti non a target
.
Nei diabetici sartani e tiazidici sono associati a ridotto rischio di mortalità e di eventi correlati a scompenso cardiaco; i tiazidici a ridotto rischio di scompenso cardiaco; i calcio-antagonisti a ridotto rischio di ictus
(Emdin CA, et al. Blood pressure lowering in type 2 diabetes: a systematic review and meta-analysis. JAMA 2015, 313: 603-15).
È opportuno sottolineare che i sartani in Italia hanno limitazioni alla rimborsabilità e, quindi, finiscono per non poter essere una prima scelta.


 

Q 8. Come gestire la dislipidemia nei diabetici?

R 24. Tutti i pazienti con DM devono essere indagati per la presenza di dislipidemia (Grado B; MLE 2).
In presenza di dislipidemia, la terapia deve comprendere modificazioni dello stile di vita e, ove necessario, il consulto con un dietista diplomato e/o un CDE (Grado B; MLE 2).

R 25. Nei pazienti con alterazioni della glicemia le complicanze macro-vascolari possono essere già presenti prima della diagnosi di DM. Pertanto, nei pazienti con pre-diabete l’assetto lipidico deve essere gestito con modalità analoghe a quelle dei pazienti con DM (Grado D; MLE 4).

R 26. Nei soggetti con pre-diabete o DM che non presentano malattia CV aterosclerotica (ASCVD) o fattori di rischio CV maggiori (cioè quelli con rischio CV moderato), la terapia deve essere mirata a raggiungere un livello < 100 mg/dL (2.6 mmol/L) di colesterolo legato a lipoproteine a bassa densità (LDL-C) o un valore di non-HDL-C < 130 mg/dL (3.4 mmol/L) (Grado B; MLE 2).
Nei pazienti ad alto rischio CV, caratterizzati dall’associazione di DM con la diagnosi di ASCVD o con la presenza di almeno un fattore di rischio maggiore per ASCVD (ipertensione arteriosa, anamnesi familiare di malattia CV, bassi livelli di HDL-C o fumo di sigaretta), contemporaneamente alle modifiche dello stile di vita si deve iniziare la somministrazione di una statina, qualunque sia il valore di LDL-C (Grado A; MLE 1). In questi pazienti ad alto rischio CV l’obiettivo terapeutico è rappresentato da valori di LDL-C < 70 mg/dL (1.8 mmol/L) o di non-HDL-C < 100 mg/dL (2.6 mmol/L) (tab 7) (Grado B; MLE 2).
Se la concentrazione di trigliceridi è > 200 mg/dL (2.3 mmol/L), è appropriato utilizzare i livelli di non-HDL-C per la stima del rischio ASCVD (Grado C; MLE 3).
Nei pazienti diabetici con ASCVD o almeno un fattore di rischio maggiore, possono essere considerati come obiettivi terapeutici secondari la concentrazione di apolipoproteina B (apo B) < 80 mg/dL e quella di particelle lipoproteiche a bassa densità (LDL-P) < 1000 nmol/L. Nei pazienti senza ASCVD né fattori di rischio aggiuntivi, sono accettabili valori di apo B < 90 mg/dL e di LDL-P < 1200 nmol/L (Grado D; MLE 4).

R 27. Se il cambiamento dello stile di vita non è sufficiente a raggiungere gli obiettivi ottimali dell’assetto lipidico, deve essere impiegata una terapia farmacologica (Grado A; MLE 1). Le statine, in assenza di controindicazioni al loro uso, rappresentano il farmaco di scelta.
Il dosaggio delle statine deve essere titolato per raggiungere i livelli di LDL-C e non-HDL-C precedentemente indicati (tabella 7), a meno questo non sia possibile per effetti collaterali o intolleranza (Grado A; MLE 1). Se tali obiettivi non vengono raggiunti con la sola statina, deve essere presa in considerazione la combinazione con un sequestrante degli acidi biliari, con un inibitore dell’assorbimento del colesterolo o con la niacina. Questi ultimi farmaci possono essere impiegati da soli in caso di intolleranza o di eventi avversi indotti dalle statine (Grado C; MLE 3).
Nei pazienti con livelli appropriati di LDL-C ma che presentino trigliceridemia > 200 mg/dL (2.3 mmol/L) e bassi valori di HDL-C (< 35 mg/dL, 0.9 mmol/L), possono essere impiegati fibrati, niacina o dosi elevate di acidi grassi omega-3 per raggiungere gli obiettivi del non-HDL-C (tabella 7) (Grado B; MLE 2).
Nei pazienti con livelli di trigliceridi > 500 mg/dL (5.6 mmol/L), possono essere impiegati gli acidi grassi omega-3 ad alta dose, i fibrati e la niacina (Grado C; MLE 3).

Integrazioni 2016: il rischio CV viene stratificato (con gli stessi cut-off) in alto e molto alto (invece che moderato e alto). Vengono inseriti gli inibitori PSCK9 (1 o 2 iniezioni mensili) dopo fallimento delle statine in prevenzione primaria o secondaria (pregresso evento maggiore ASCVD) con significativa riduzione degli eventi CV e per ridurre i livelli di LDL nelle forme familiari (in combinazione con statina).

 

Q 8. Raccomandazioni AACE-Chapter Italia

R 27. Ad integrazione, si ricorda che in Italia la niacina è stata ritirata dal commercio e la possibilità prescrittiva delle statine si differenzia dalla rimborsabilità delle stesse (nota 13), anche tra Regione e Regione.
Le statine sono controindicate in gravidanza.
L’unico inibitore dell’assorbimento del colesterolo disponibile è ezetimibe.
Nella nostra pratica clinica per le condizioni precliniche va considerato il rischio CV del singolo soggetto valutato con le carte europee del rischio SCORE: se il paziente con prediabete ha un rischio CV > 2-3%, il trattamento prevede la rimborsabilità della statina.
In caso di idiosincrasia o di effetti collaterali seri con statina, è necessario somministrare ezetimibe. Questo farmaco, in associazione con statina a lungo termine, ha indotto una significativa riduzione del rischio di eventi CV.
L’utilizzo delle statine può provocare un aumento del rischio di diabete (OR = 1.45, Danaei G, et al. Statins and risk of diabetes: an analysis of electronic medical records to evaluate possible bias due to differential survival. Diabetes Care 2013, 36: 1236-40), con effetti diversi in relazione a tipo e dose della statina (Navarese EP, et al. Meta-analysis of impact of different types and doses of statins on new-onset diabetes mellitus. Am J Cardiol 2013, 111: 1123-30) e un aumento clinicamente molto modesto di HbA1c nei soggetti diabetici (+ 0.12%) (Erqou S, et al. Statins and glycaemic control in individuals with diabetes: a systematic review and meta-analysis. Diabetologia 2014, 57: 2444-52). Ovviamente, la riduzione del rischio CV è notevolmente superiore a questi potenziali svantaggi.


 

Q 9. Come gestire la nefropatia nei diabetici?

R 28. Lo studio della funzione renale deve essere effettuato con la determinazione del filtrato glomerulare stimato (eGFR) e dell’albuminuria (AER), in modo da identificare precocemente, stadiare e monitorare la progressione della nefropatia diabetica (Grado C; MLE 3). L’indagine deve essere eseguita:

  • nei pazienti con DM1 diagnosticato prima dell’età di 30 anni ogni anno a partire da 5 anni dopo la diagnosi;
  • nei pazienti con DM2 e in quelli con DM1 diagnosticato dopo i 30 anni, al momento della diagnosi e, successivamente, ogni anno.

Ai pazienti con nefropatia deve essere offerto un counseling riguardante il controllo ottimale della glicemia, della dislipidemia e della pressione arteriosa e la cessazione del fumo (Grado B; MLE 2). Inoltre, in questi pazienti deve essere condotto un monitoraggio sistematico di albuminuria, filtrazione glomerulare, elettroliti e lipidi plasmatici (Grado B; MLE 2).
Con il declinare della funzione renale devono essere valutate le condizioni ad essa potenzialmente associate: anemia, alterazioni minerali e scheletriche (Grado D; MLE 4). È raccomandato eseguire un consulto nefrologico con largo anticipo rispetto all’insorgenza di insufficienza renale terminale (Grado D; MLE 4).

Tabella 14
Relazioni fra categorie di albuminuria e proteinuria (263 [LE 4; NE])
a,b
  Categorie
Valutazione Da normale a lievemente aumentata (A1) Moderatamente aumentata (A2) Severamente aumentata (A3)
AER (mg/24 h) < 30 30-300 > 300
PER (mg/24 h) < 150 150-500 > 500
ACR (mg/mmol)
(mg/g)
< 3
< 30
3-30
30-300
> 30
> 300
PCR (mg/mmol)
(mg/g)
< 15
< 150
15-50
150-500
> 50
> 500
Strisce reattive per proteine Da negativo a tracce Da tracce a + > +
Abbreviazioni: ACR = rapporto albumina-creatinina; AER = tasso di escrezione albumina; PCR = rapporto proteine-creatinina; PER = tasso di escrezione proteine.
a Ristampato con autorizzazione di Macmillan Editori Ltd: Kidney International Supplement 2013;3(1):1-150, copyright 2013.
b Albuminuria e proteinuria possono essere misurate utilizzando il tasso di escrezione in raccolte urinarie temporizzate, il rapporto delle concentrazioni con la concentrazione di creatinina in campioni urinari estemporanei e utilizzando strisce reattive in campioni urinari estemporanei. Le correlazioni fra i metodi di misura all’interno di una categoria non sono esatte. Per esempio, le correlazioni fra AER e ACR e fra PER e PCR si basano sul presupposto che il tasso di escrezione medio di creatinina sia di circa 1.0 g/die (10 mmol/die). Le conversioni sono arrotondate per praticità (la conversione esatta da mg/g di creatinina a mg/mmol di creatinina si fa moltiplicando per 0.113.) Il tasso di escrezione di creatinina dipende da età, sesso, etnia e dieta; perciò le correlazioni fra queste categorie sono solo un’approssimazione. ACR è considerato normale se < 10 mg/g (< 1 mg/mmol), normale-alto se 10-30 mg/g (1-3 mg/mmol), nel range nefrosico se > 2.200 mg/g (> 220 mg/mmol). La relazione fra i risultati con strisce reattive e altri metodi di dosaggio dipende dalla concentrazione delle urine.

 

R 29. Nei pazienti con DM e nefropatia cronica (CKD) di categoria G2, G3a e G3b, e nei G4 con dimostrata lenta progressione (cfr fig 2 per le definizioni), è raccomandato il blocco del sistema renina-angiotensina-aldosterone (RAAS) (Grado A; MLE 1).
I livelli sierici di potassio devono essere strettamente monitorati (Grado A; MLE 1) e l’impiego dei farmaci RAAS è controindicato in gravidanza. ACE-inibitori e ARB non devono essere usati in combinazione a causa dell’aumentato rischio di effetti collaterali, in particolare di iperpotassiemia severa (Grado B; MLE 2).

Figura 2
Guida alla frequenza di monitoraggio (numero di volte/anno) in relazione a GFR e categoria di albuminuria Categorie per albuminuria persistente
Descrizione e range
A1 A2 A3
Da normale a lievemente aumentata Moderatamente aumentata Molto aumentata
< 30 mg/g
< 3 mg/mM
30 - 300 mg/g
3-30 mg/mM
> 300 mg/g
> 300 mg/mM
Categorie GFR (mL/min/1.73 m2)
Descrizione e range
G1 Normale o aumentata > 90 1 se CKD 1 2
G2 Lievemente diminuita 60-89 1 se CKD 1 2
G3a Da lievemente a moderatamente diminuita 45-59 1 2 3
G3b Da moderatamente a severamente diminuita 30-44 2 3 3
G4 Severamente diminuita 15-29 3 3 4+
G5 Insufficienza renale terminale < 15 4+ 4+ 4+

Figura 2. Griglia che illustra il rischio di progressione di GFR e albuminuria con l’intensità dei colori. Il numero in ogni casella suggerisce la frequenza del monitoraggio (numero di volte/anno). Il verde indica malattia stabile con dosaggi annuali se presente IRC; il giallo indica prudenza e richiede ≥ 1 dosaggi/anno; l’arancio richiede 2 dosaggi/anno; il rosso richiede 3 dosaggi/anno, e il rosso-mattone può richiedere uno stretto monitoraggio (≥ 4 dosaggi/anno, almeno ogni 1-3 mesi). Questi parametri generali si basano sull’opinione di esperti ed è necessario prendere in considerazione le comorbilità e lo stato di malattia, nonché la probabilità di variazione dello schema terapeutico individuale.
IRC = insufficienza renale cronica; GFR = velocità di filtrazione glomerulare.
Frequenza delle raccomandazioni dal gruppo di lavoro KDIGO CKD (263 [LE 4; NE]; 266 [LE 4; NE]). Modificata e ristampata con autorizzazione di Macmillan Editori Ltd: Kidney International 2011;80(1):17-28, copyright 2011.

R 30. Nei pazienti con DM e CKD in stadio G2-G4, è raccomandata la perdita di peso (se indicata) in associazione a regolare esercizio fisico (Grado D; MLE 4).

 

Q 9. Raccomandazioni AACE-Chapter Italia

R 29. In casi selezionati ACE-inibitori e sartani possono essere usati in combinazione, con monitoraggio accurato di potassiemia e funzione renale (Palmer, et al. Comparative efficacy and safety of blood pressure-lowering agents in adults with diabetes and kidney disease: a network meta-analysis. Lancet 2015, 385: 2047-56).

R 30. Attenzione alla dieta ipoproteica nei soggetti con IRC conclamata che hanno una progressione della malattia renale.
Per la perdita di peso nei pazienti G2 e G3a obesi o in sovrappeso si possono usare SGLT-2 inibitori o GLP-1 analoghi
.


 

Q 10. Come gestire la retinopatia nei diabetici?

R 31. I pazienti con DT2 devono essere esaminati al momento della diagnosi da un oculista con esperienza specifica per l’esame del fundus oculi in midriasi (Grado C; MLE 3). Il follow-up oculistico deve avere cadenza annuale, ma, in caso di negatività, il controllo può essere effettuato ogni due anni (Grado B; MLE 2).
Nei pazienti con DM1 l’esame oculistico deve essere effettuato entro 5 anni dalla diagnosi di DM (Grado C; MLE 3).
Le gestanti diabetiche devono effettuare controlli oculistici più frequenti, sia durante la gravidanza sia nel primo anno post-partum (Grado B; MLE 2).
In caso di retinopatia proliferante o in progressione e nei casi trattati con VEGF, Il follow-up deve essere condotto a intervalli minori di un anno (Grado C; MLE 3).
Per rallentare la progressione della retinopatia, deve essere assicurato il controllo ottimale di glicemia, pressione arteriosa e assetto lipidico (Grado A; MLE 1).

 

Q 10. Raccomandazioni AACE-Chapter Italia

R 31. Ad integrazione di quanto indicato da AACE, aggiungiamo alcuni punti.
Nel DM2 se l’esame è negativo, deve essere ripetuto ogni 2 anni; inoltre è possibile l’esame del fondo oculare con il retinografo senza midriasi.
È
necessario informare la gravida diabetica circa la possibilità di progressione della RD.
Gli standard italiani forniscono indicazioni più dettagliate sull’intensità e le modalità del follow-up in relazione alle diverse situazioni cliniche. Il paziente dovrà essere rivisto:

  • in assenza di disturbi in sede di screening:
    • dopo 24 mesi in assenza di lesioni;
    • dopo 12 mesi se presenti microaneurismi;
    • dopo 6-12 mesi se presenti emorragie isolate e/o microaneurismi e/o essudati duri isolati lontani dalla macula, oppure noduli cotonosi non associati ad altri segni di retinopatia non proliferante grave;
  • in ambiente specialistico:
    • entro 3-6 mesi se presenti essudati duri;
    • in urgenza se presenti riduzione dell’acuità visiva non correggibile, emorragie e/o essudati duri peri-maculari, neo-vasi della papilla ottica e/o della retina, emorragie pre-retiniche, neo-vasi di grandi dimensioni o associati a emorragie pre-retiniche, tessuto fibro-vascolare retino-vitreale o papillo-vitreale, distacco di retina, rubeosi dell’iride.

La foto-coagulazione laser pan-retinica è efficace nel ridurre la progressione della RD e l’incidenza di emorragia del vitreo (Evans JR, et al. Laser photocoagulation for proliferative diabetic retinopathy. Cochrane Database Syst Rev 2014, 11: CD011234) e i farmaci anti-VEGF sono efficaci nell’edema maculare (Virgili G, et al. Anti-vascular endothelial growth factor for diabetic macular oedema. Cochrane Database Syst Rev 2014, 10: CD007419) ma non nella RD proliferante (Martinez-Zapata MJ, et al. Anti-vascular endothelial growth factor for proliferative diabetic retinopathy. Cochrane Database Syst Rev 2014, 11: CD008721).


 

Q 11. Come diagnosticare e gestire la neuropatia diabetica?

R 32. La neuropatia diabetica è una condizione ben diagnosticabile sul piano clinico, ma è sempre necessaria la diagnosi differenziale rispetto ad altre alterazioni neurologiche.
I pazienti con DT1 devono effettuare un esame neurologico completo 5 anni dopo la diagnosi di DM e, successivamente, a intervalli annuali (Grado B; MLE 2).
I pazienti con DT2 devono effettuare un esame neurologico completo alla diagnosi di DM e, successivamente, a intervalli annuali (Grado B; MLE 2).
L’esame del piede deve comprendere una sua ispezione completa: struttura, deformità, integrità e temperatura della cute, presenza di ulcere, irrorazione, polsi arteriosi ed esiti di amputazioni minori (Grado B; MLE 2) (per una trattazione più completa fare riferimento all’ADA Foot Care Task Force Report (6), condiviso da AACE).
L’obiettività neurologica deve valutare la sensibilità epicritica mediante filamenti da 1 e 10 g, la sensibilità vibratoria mediante diapason da 128 MHz, i riflessi osteo-tendinei e la sensibilità tattile, puntoria e termica (mediante le sensazioni di caldo e freddo) (Grado B; MLE 2).
La neuropatia iperalgica può non associarsi a segni obiettivi e la diagnosi clinica in alcuni casi necessita di conferma con la biopsia cutanea o altre misure surrogate di sofferenza delle piccole fibre nervose (SFN) (Grado D; MLE 4).
La presenza di neuropatia autonomica cardio-vascolare deve essere indagata nel DM2 al momento della diagnosi e nel DM1 5 anni dopo la diagnosi. Successivamente deve essere controllata a intervalli annuali (Grado D; MLE 4). I test diagnostici devono includere la variabilità della frequenza cardiaca durante la manovra di Valsalva e l’inspirazione profonda e le modificazioni della pressione arteriosa nel passaggio dal clino all’ortostatismo (Grado D; MLE 4).

R 33. Per la prevenzione della neuropatia è raccomandato un attento controllo della glicemia, personalizzato secondo obiettivi adeguati al singolo paziente (Grado A; MLE 1). Nessun provvedimento terapeutico si è dimostrato in grado di far recedere il danno neuropatico una volta instaurato, ma tutti gli interventi che riducono lo stress ossidativo e migliorano il controllo glicemico, la dislipidemia e l’ipertensione hanno un effetto potenzialmente favorevole sulla sua progressione.

R 34. Per la gestione della neuropatia diabetica dolorosa considerare l’uso di anti-depressivi triciclici, anti-epilettici e inibitori della ricaptazione della serotonina e della noradrenalina (Grado A; MLE 1).

R 35. Il danno neuropatico a carico delle grandi fibre deve essere gestito con esercizi fisici per migliorare la forza muscolare, l’andatura e l’equilibrio. È necessario gestire il dolore in modo adeguato (Grado B; MLE 2):

  • utilizzando ortesi per la prevenzione e il trattamento delle deformità del piede;
  • allungando il tendine di Achille nel piede equino secondario a retrazione del tendine;
  • gestendo le ulcere cutanee che non tendono alla riparazione con chirurgia o ingessatura.

R 36. La SFN deve essere gestita con:

  • la protezione del piede mediante calze pulite e imbottite;
  • l’uso di scarpe idonee (se necessario dotate di mezzi di supporto);
  • l’ispezione regolare del piede e delle calzature;
  • la prevenzione dei danni termici e l’uso di creme emollienti.

Per il controllo del dolore, fare riferimento ai farmaci di cui alla R 34 (Grado B; MLE 2).

 

 Figura 3. Algoritmo per il trattamento del dolore neuropatico dopo esclusione di eziologia non diabetica e stabilizzazione del controllo glicemico (314 [LE 4; revisione NE]; 357 [LE 4; NE])
Ristampato da Journal of Clinical Endocrinology and Metabolism, Vol. 95, A. Vinik, "The approach to the management of the patient with neuropathic pain," pp. 4802-4816. Copyright 2010, con autorizzazione di Elsevier.

 

Tabella 15
Aspetti clinici, diagnosi e trattamento della neuropatia autonomica diabetica (310 [EL 3; CSS])
Sintomi Esami Trattamenti
Cardiaci
Tachicardia a riposo, intolleranza allo sforzo HRV, scintigrafia MUGA Tallio, scintigrafia MIBG Esercizi progressivi sotto controllo, ACE-inibitori, β-bloccanti
Bradicardia da sforzo, intolleranza allo sforzo HRV, scintigrafia MUGA Tallio, scintigrafia MIBG, dosaggio dopamina e scintigrafia con dopamina Esercizi progressivi sotto controllo, dopamino-agonisti
Ipotensione ortostatica, capogiri, debolezza, spossatezza, sincope HRV, pressione arteriosa in clino e ortostatismo, catecolamine Presidii meccanici, clonidina, midodrina, octreotide, eritropoietina
Gastrointestinali
Gastroparesi, controllo glicemico “ballerino" Studio dello svuotamento gastrico, pasto baritato Pasti piccoli e frequenti e farmaci procinetici (metoclopramide, domperidone; eritromicina; lubiprostone; linaclotide; analgesici gastrici orali; combinazione di atropina, iosciamina, fenobarbital e scopolamina; Maalox; xilocaina viscosa)
Dolore addominale, sazietà precoce, nausea, vomito, gonfiore, eruttazioni Endoscopia, manometria, elettrogastrogramma Antibiotici, anti-emetici, agenti che aumentano la massa, anti-depressivi triciclici, tossina botulinica a livello pilorico, pace-maker gastrico
Stipsi Endoscopia Dieta ad alto contenuto di fibre, agenti che aumentano la massa, lassativi osmotici, agenti lubrificanti
Diarrea (spesso notturna alternata a stipsi) Nessuno Fibre alimentari solubili, restrizione di glutine lattosio, farmaci anti-colinergici, colestiramina, antibiotici, somatostatina, supplementi enzimatici pancreatici
Disfunzione sessuale
Disfunzione erettile H&P, HRV, indice pressorio pene-braccio, tumescenza peniena notturna Terapia sessuologica, counseling psicologico, inibitori PDE5, iniezioni di PG-E1, dispositivi o protesi
Secchezza vaginale Nessuno Lubrificanti vaginali
Disfunzione vescicale
Pollachiuria, minzione imperiosa, nicturia, ritenzione urinaria, incontinenza Cistometrografia, ecografia post-minzionale Betanecolo, cateterismo intermittente
Disfunzione sudo-motoria
Anidrosi, intolleranza al caldo, secchezza cutanea, iperidrosi Riflesso assonale sudo-motorio quantitativo, test del sudore, sudorimetria, flusso ematico cutaneo Emollienti e lubrificanti cutanei, scopolamina, glicopirrolato, tossina botulinica, vasodilatatori, supplementi di arginina
Disfunzione pupillo-motoria e viscerale
Vista annebbiata, deficit di adattamento alla luce ambientale, pupilla di Argyll-Robertson Pupillometria, HRV Attenzione alla guida notturna
Compromissione della sensibilità viscerale: infarto miocardico silente, ipoglicemia non avvertita Esame obiettivo, anamnesi Riconoscimento di presentazione insolita di infarto miocardico, controllo dei fattori di rischio, controllo delle glicemie
Abbreviazioni: ACE = ACE-inibitori; H&P = anamnesi ed esame obiettivo; HRV = variabilità della frequenza cardiaca; MIBG = metaiodo-benzil-guanidina; MUGA = angio-scintigrafia multiunit.

 

Q 11. Raccomandazioni AACE-Chapter Italia

Alla luce della relazione con morbilità e mortalità CV (Montorsi P, et al. Association between erectile dysfunction and coronary artery disease: Matching the right target with the right test in the right patient. Eur Urol 2006, 50, 721–31), bisogna ricercare il deficit erettile (già alla diagnosi nel DM2) e rivalutarlo successivamente una volta l'anno.
La valutazione deve essere eseguita con la somministrazione di questionari validati (quale l’IIEF 5), il dosaggio del testosterone, e l’ecocolor-doppler arterioso penieno.
La condizione di ipogonadismo funzionale può peggiorare ulteriormente il compenso metabolico (Giagulli VA, et al. Adding liraglutide to lifestyle changes, metformin and testosterone therapy boosts erectile function in diabetic obese men with overt hypogonadism. Andrology 2015, 3: 1094-103).

R 32. Ad integrazione si ricorda che esiste una correlazione tra entità della neuropatia e morbilità e mortalità (Brownrigg JR, et al. Peripheral neuropathy and the risk of cardiovascular events in type 2 diabetes mellitus. Heart 2014, 100: 1837-43).
È fortemente raccomandabile l’approccio educazionale per prevenire le ulcere diabetiche (Dorresteijn JA, et al. Patient education for preventing diabetic foot ulceration. Cochrane Database Syst Rev 2014, 12: CD001488).
Per la diagnostica della neuropatia autonomica CV sono necessari sempre 3 test: ipotensione, respiro profondo con Valsalva e clino-ortostatismo.

R 36. Alcuni esami diagnostici e terapie riportati in tab. 15 non sono disponibili In Italia e/o rimborsabili a carico del SSN.


 

Q 12. Come gestire la malattia cardiovascolare nei diabetici?

R 37. Poiché la CVD è la prima causa di morte nei pazienti con DM, la gestione integrata del DM deve comprendere fin dall’inizio l’intervento sui fattori di rischio CV (Grado B; MLE 2). Gli obiettivi per la riduzione del rischio CV sono sintetizzati nella tabella 7.

R 38. Per la prevenzione secondaria è raccomandato l’uso di aspirina a basso dosaggio (75–162 mg/die) (Grado A; MLE 1), anche se singoli pazienti possono trarre beneficio dall’impiego di dosi più elevate (Grado B; MLE 2).
Per la prevenzione primaria l’impiego dell’aspirina deve essere limitato ai soli pazienti a rischio CV elevato (rischio a 10 anni > 10%) (Grado D; MLE 4).

R 39. La valutazione (TC) delle calcificazioni coronariche o la tradizionale diagnostica per immagini coronarica possono essere utili per decidere se il paziente è un candidato all’intensificazione del controllo glicemico, lipidico e/o pressorio (Grado B; MLE 2). Non è stato chiaramente dimostrato che lo screening della coronaropatia silente con vari test da sforzo possa migliorare gli esiti cardiaci e quindi questi test non sono raccomandati come screening (Grado A; MLE 1).

 

Q 12. Raccomandazioni AACE-Chapter Italia

R 37. È opportuno ricordare il rischio di eventi acuti precipitati da ipoglicemia, da cui l’importanza di prevenire le ipoglicemie soprattutto nei pazienti con malattia CV (Sanon VP, et al. Hypoglycemia from a cardiologist's perspective. Clin Cardiol 2014, 37: 499-504).

R 38. L’ADA suggerisce di prendere in considerazione l’aspirina anche in prevenzione primaria nei diabetici > 50 anni con almeno un altro fattore di rischio cardiovascolare (ADA. 8. Cardiovascular Disease and Risk Management. Diabetes Care 2016, 39: S60-S71).

R 39. Riteniamo non realistico indicare la TC coronarica come screening di prima linea dell’ischemia silente. Nei pazienti con ragionevole aspettativa e qualità di vita, con elevata probabilità di malattia coronarica e comunque candidabili a rivascolarizzazione, suggeriamo screening mediante ECG da sforzo o equivalenti. Importante anche il monitoraggio annuale con ECG (alla ricerca di anomalie della ripolarizzazione, sovra-slivellamenti, extra-sistolia sopra-ventricolare, ecc) e bi-triennale con ecocardiografia (per ricercare segni precoci di cardiopatia metabolica, quali disfunzione diastolica, alterazioni della funzione ventricolare, discinesie, ecc) che possono preludere a un evento ischemico acuto (ADA. Cardiovascular disease and risk management. Diabetes Care 2016, 39: S60-S71).


 

Q 13. Come gestire l’obesità nei diabetici?

R 40. La presenza di obesità deve essere accertata mediante l’uso dell’indice di massa corporea (BMI) (Grado B; MLE 2): i soggetti con BMI ≥ 30 kg/m2 sono classificati come obesi, mentre quelli con BMI compreso fra 25 e 30 kg/m2 sono classificati come sovrappeso. Cut-off più bassi sono appropriati per i soggetti di etnia indiana o sudorientale.
Nei soggetti con BMI compreso fra 25 e 35 kg/m2 deve essere misurata la circonferenza della vita (Grado D; MLE 4): i pazienti di sesso maschile con circonferenza vita > 102 cm e quelli di sesso femminile con circonferenza > 88 cm sono a rischio più elevato di malattie metaboliche.
Per determinare la severità dell’obesità e condurne una stadiazione completa, oltre alle misure antropometriche, devono essere indagate la presenza di complicanze dell’obesità, comprese le altre componenti della sindrome metabolica, la sindrome delle apnee notturne e l’artrosi (Grado D; MLE 4).

R 41. Elementi fondamentali nella gestione dell’obesità sono le modificazioni dello stile di vita, che devono comprendere cambiamenti del comportamento, dieta ipocalorica e attività fisica regolare (azioni prescritte in modo personalizzato) (Grado A; MLE 1).
Quando le modificazioni dello stile di vita non ottengono un decremento ponderale adeguato, deve essere preso in considerazione il ricorso alla terapia farmacologica (Grado A; MLE 1). Il trattamento farmacologico può essere iniziato contemporaneamente alle modificazioni dello stile di vita nei soggetti con BMI compreso fra 27.0 e 29.9 kg/m2 che presentino almeno una complicanza dell’obesità come DM2 (Grado D; MLE 4) e nei soggetti con BMI > 30 kg/m2 anche in assenza di complicanze (Grado D; MLE 4).
Nei pazienti con BMI ≥ 35 kg/m2 che presentino complicanze di rilievo dell’obesità compreso DM2, deve essere preso in considerazione il ricorso alla chirurgia bariatrica (Grado B; MLE 2).
I pazienti con DM2 che vengono sottoposti a procedure che inducono malassorbimento (come il by-pass gastrico Roux-en-Y o la diversione bilio-pancreatica con switch duodenale) devono seguire un attento follow-up post-operatorio, a causa del rischio di ipoglicemia e di deficit di micro-nutrienti (Grado D; MLE 4).

Integrazione 2016: Fino al 2015, l’FDA ha approvato 8 farmaci da utilizzare nei pazienti con sovrappeso o obesità in aggiunta alle modificazioni dello stile di vita. Dietil-proprione, fendimetrazina e fentermina sono approvati per l’uso a breve termine (alcune settimane), mentre orlistat, fentermina/topiramato a rilascio prolungato (ER), lorcaserina, naltrexone/bupropione e liraglutide 3 mg possono essere impiegati a lungo termine. Negli studi clinici, i 5 farmaci approvati per l’utilizzo a lungo termine hanno ottenuto un significativo calo ponderale dopo un anno di trattamento (il calo netto rispetto al placebo va dal 2.9% con orlistat al 9.7% con fentermina/topiramato ER). Questi farmaci migliorano i valori pressori e lipidici, prevengono la progressione a DM e migliorano il controllo glicemico e lipidico nei pazienti con DM2. La chirurgia bariatrica deve essere presa in considerazione solo dopo fallimento delle terapie comportamentali e farmacologiche.

 

Q 13. Raccomandazioni AACE-Chapter Italia

R 41. A integrazione, si ricorda che gli anziani con BMI 29-30 kg/m2 sembrano a minor rischio di sviluppare eventi CV e avere una sopravvivenza più lunga (Veronese N, et al. Inverse relationship between body mass index and mortality in older nursing home residents: a meta-analysis of 19,538 elderly subjects. Obes Rev 2015, 16: 1001-15). La dieta in questi pazienti determina sarcopenia e, se necessaria, va sempre prescritta in aggiunta all’attività fisica. In tutti gli altri casi la riduzione del peso è una strategia essenziale per la cura del paziente obeso con malattia diabetica.
È opportuno sottolineare la necessità che la scelta dell’anti-diabetico tenga in considerazione il suo possibile effetto sul peso (favorevole per GLP-1 analoghi e SGLT-2 inibitori).
Dei farmaci anti-obesità citati, in Italia sono disponibili solo orlistat e liraglutide 3 mg, a carico del paziente.
Nel soggetto diabetico con obesità di II o III stadio sec. WHO, dopo fallimento delle altre misure, va presa in considerazione anche la chirurgia bariatrica con interventi di media complessità (sleeve gastrectomy). Le metanalisi più recenti dimostrano con elevato livello di evidenza che la chirurgia bariatrica è più efficace degli interventi farmacologici nella remissione a breve termine del DM2, anche nei soggetti con BMI < 35 kg/m2 (Müller-Stich B, et al. Surgical versus medical treatment of type 2 diabetes mellitus in nonseverely obese patients: a systematic review and meta-analysis. Ann Surg 2015, 261: 421-9). Inoltre il by-pass gastrico Roux-en-Y è più efficace della sleeve-gastrectomy nel ridurre il rischio CV (Wang MC, et al. Laparoscopic Roux-en-Y gastric bypass versus sleeve gastrectomy for obese patients with type 2 diabetes: a meta-analysis of randomized controlled trials. Am Surg 2015, 81: 164-9. Douglas IJ, et al. Bariatric surgery in the United Kingdom: a cohort study of weight loss and clinical outcomes in routine clinical care. PLOS Med 2015, 12: e1001925).


 

Q 14. Qual è il ruolo della medicina del sonno nella cura dei diabetici?

R 42. Gli adulti con DM2, soprattutto I soggetti di sesso maschile con età superiore a 50 anni, devono essere indagati per la presenza di apnee ostruttive del sonno (OSA), una condizione comune in questa popolazione (Grado D; MLE 4). Questa condizione deve essere sospettata sulla base di una storia di sonnolenza diurna e di russamento, soprattutto se un familiare conferma fasi di apnea. La valutazione da parte di uno specialista del sonno deve essere considerata nel sospetto di OSA o di sindrome delle gambe senza riposo e quando i pazienti sono intolleranti agli apparecchi a pressione positiva continua (CPAP) (Grado A; MLE 1). La OSA deve, infatti, essere trattata mediante CPAP o analoghi sistemi di erogazione dell’ossigeno (Grado A; MLE 1). La perdita di peso in questi casi è prioritaria, perché associata a un significativo miglioramento dell’OSA.

 

Q 14. Raccomandazioni AACE-Chapter Italia

R 42. Suggeriamo di indagare questa possibilità in pazienti in franco sovrappeso o obesi (Rajan P and Greenberg H. Obstructive sleep apnea as a risk factor for type 2 diabetes mellitus. Nat Sci Sleep 2015, 7: 113-25).


 

Q 15. Come trattare il diabete in ospedale?

R 43. L’Insulina consente il rapido controllo dell’iperglicemia e deve pertanto essere utilizzata nella maggior parte dei degenti con iperglicemia (Grado A; MLE 1). Nelle unità di terapia intensiva (ICU), i pazienti critici con iperglicemia persistente dovrebbero essere trattati con l’infusione endovenosa di insulina (Grado A; MLE 1). Nei pazienti non critici la gestione della glicemia deve essere effettuata secondo schemi di somministrazione sottocutanea, che comprendano una quota basale e somministrazioni per gli apporti nutrizionali e le eventuali correzioni glicemiche (Grado A; MLE 1). La somministrazione deve essere sincronizzata con i pasti, la nutrizione enterale o quella parenterale (Grado A; MLE 1). La somministrazione di insulina “al bisogno” deve essere fortemente scoraggiata (Grado A; MLE 1). Devono essere preferiti l’insulina regolare per la somministrazione endovenosa e gli analoghi dell’insulina per la somministrazione sottocutanea (Grado D; MLE 4).

R 44. In tutti i pazienti ospedalizzati, indipendentemente da una precedente diagnosi di DM, deve essere misurata la glicemia (Grado C; MLE 3). I pazienti con DM già noto devono eseguire anche la determinazione della A1C, se non effettuata nel corso dei 3 mesi precedenti (Grado D; MLE 4). La A1C deve inoltre essere dosata nei pazienti ospedalizzati senza DM noto che presentino iperglicemia (Grado D; MLE 4).
In tutti i pazienti con DM noto e nei non diabetici sottoposti a terapie a rischio di provocare iperglicemia, come i corticosteroidi e la nutrizione enterale o parenterale, deve essere intrapreso il monitoraggio del glucosio con determinazione al letto del paziente (POC) (Grado D; MLE 4). I pazienti con iperglicemia persistente richiedono un protratto monitoraggio POC con trattamento analogo a quelli con storia nota di DM.

R 45. Deve essere formulato uno schema terapeutico individualizzato per la prevenzione e il trattamento dell’ipoglicemia e nella cartella clinica devono essere documentati gli eventuali episodi ipoglicemici e le loro modalità di gestione (Grado C; MLE 3).

R 46. Al momento della dimissione dall’Ospedale, deve essere documentata la prescrizione di adeguati piani di trattamento e follow-up, sia per i pazienti con DM già noto che per quelli che presentino per la prima volta iperglicemia o elevati livelli di A1C (Grado D; MLE 4). La gestione domiciliare del DM deve iniziare immediatamente dopo la dimissione e a questo scopo devono essere fornite al paziente delle chiare istruzioni che lo guidino (Grado D; MLE 4).

 

Q 15. Raccomandazioni AACE-Chapter Italia

R 43. La glicemia nel paziente ospedalizzato che non si alimenta o in area critica deve oscillare tra 140 e 180 mg/dL; nel paziente che si alimenta deve essere < 140 mg/dL a digiuno e < 180 mg/dL dopo i pasti. Tali valori non devono essere forzati, soprattutto se il paziente è critico ed è ricoverato in ambiente di terapia intensiva (Malmberk K, et al. Intense metabolic control by means of insulin in patients with diabetes mellitus and acute myocardial infarction (DIGAMI 2): effects on mortality and morbidity. Eur Heart J 2005, 26: 650-61. Fullerton B, et al. Intensive glucose control versus conventional glucose control for type 1 diabetes mellitus. Cochrane Database Syst Rev 2014, 2: CD009122).

R 45. Ogni reparto ospedaliero deve avere un protocollo interno per la gestione dell’ipoglicemia. La sicurezza è l’aspetto prioritario, per cui se questa non può essere assicurata, si potrà utilizzare uno schema basal-bolus anche nei pazienti critici.


 

Q 16. Come stabilire un piano di cura integrato per il diabete nel bambino e nell’adolescente?

R 47. I principi del trattamento farmacologico di qualsiasi forma di DM in età pediatrica non dovrebbero, allo stato attuale, differire da quelli dell’adulto (Grado D; MLE 4). Fanno eccezione i bambini al di sotto dei 4 anni di età, nei quali il bolo di insulina al momento del pasto può essere somministrato dopo, invece che prima, l’assunzione del cibo, a causa della variabilità e scarsa prevedibilità dell’apporto di calorie e carboidrati in questa età.
Nei bambini e negli adolescenti con DM1, devono essere preferiti i regimi insulinici MDI o l’impiego della CSII (Grado C; MLE 3). Le iniezioni multiple, tuttavia, possono costituire un problema in alcuni contesti scolastici.
Durante la pubertà possono rendersi necessari un più elevato rapporto insulina/carboidrati e dosi più elevate di insulina basale (Grado C; MLE 3) e il fabbisogno insulinico può accrescersi del 20-50% durante il periodo mestruale nelle adolescenti (Grado C; MLE 3).
Nei bambini e negli adolescenti con DM2, devono essere dapprima impiegate le modificazioni della dieta e dello stile di vita (Grado A; MLE 1). L’aggiunta di metformina e/o insulina dovrebbe essere effettuata solo quando gli obiettivi glicemici non sono raggiungibili con l’intervento sullo stile di vita (Grado B; MLE 2).
L’International Society of Pediatric and Adolescent Diabetes ha pubblicato nel 2009 un’estensiva revisione delle linee guida per la gestione dei bambini con DM, disponibile sul loro sito Internet (13).

R 48. Gli adolescenti con DM1 devono essere trattati in stretta collaborazione con il paziente e i suoi familiari. La ADA, il Juvenile Diabetes Research Foundation (JDRF) e il National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK) offrono le risorse per aiutare nella fase di transizione (14-16).

 

Q 16. Raccomandazioni AACE-Chapter Italia

R 47. Ricordiamo che in Italia la metformina è prescrivibile solo dopo i 10 anni di età.


 

Q 17. Come trattare il diabete in gravidanza?

R 49. Nelle donne con GDM, la glicemia deve essere trattata con i seguenti obiettivi terapeutici (Grado C; MLE 3):

  • glicemia pre-prandiale ≤ 95 mg/dL (5.3 mmol/L),
  • glicemia 1 ora dopo il pasto ≤ 140 mg/dL (7.8 mmol/L), oppure
  • glicemia 2 ore dopo il pasto ≤ 120 mg/dL (6.7 mmol/L).

R 50. Tutte le donne con DM in atto (DM1, DM2 o pregresso GDM) devono avere accesso alle cure prima del concepimento, in modo da assicurare un apporto nutrizionale adeguato e il controllo metabolico al momento del concepimento, durante la gravidanza e nel post-partum (Grado B; MLE 2). Per il trattamento dell’iperglicemia post-prandiale in corso di gravidanza devono essere utilizzati di preferenza gli analoghi rapidi dell’insulina (Grado D; MLE 4), anche se può essere impiegata l’insulina regolare in caso di indisponibilità degli analoghi.
Il fabbisogno basale di insulina può essere soddisfatto mediante l’uso di CSII (con insulina ad azione rapida) o con l’impiego sottocutaneo di insulina ad azione protratta (ad esempio, NPH o detemir, classificate dalla U.S. Food and Drug Administration [FDA] come categoria B per la gravidanza) (Grado A; MLE 1).
Benché l’insulina sia il trattamento di scelta del DM in gravidanza, la metformina e la glibenclamide si sarebbero dimostrate alternative efficaci e prive di effetti collaterali in alcune donne con DM2 (Grado C; MLE 3).

 

Q 17. Raccomandazioni AACE-Chapter Italia

R 50. Poiché non si hanno evidenze conclusive per l’utilizzo degli anti-diabetici orali nelle diabetiche durante la gravidanza, l’uso di metformina o glibenclamide è assolutamente off-label, da riservare solo a studi sperimentali.
L’utilizzo dei tre analoghi rapidi (lispro, glulisine, aspart) è sicuro, ma nella scheda tecnica italiana solo l’aspart ha l’indicazione in gravidanza.
Come basale suggeriamo di evitare NPH e detemir (rischio di ipoglicemie) e preferire glargine.


 

Q 18. Come e quando impiegare il monitoraggio glicemico?

R 51. La A1C deve essere determinata almeno 2 volte l’anno in tutti i pazienti con DM e non meno di 4 volte l’anno nei pazienti non a target (Grado D; MLE 4).

R 52. Il SMBG deve essere effettuato in tutti i pazienti in terapia insulinica, con un minimo di due determinazioni giornaliere e – idealmente - prima di ogni iniezione di insulina (Grado B; MLE 2). Una verifica più frequente del SMBG - dopo i pasti e a metà della notte – è richiesta nei pazienti insulino-trattati con episodi ipoglicemici frequenti, con livelli di A1C non a target, o in quelli con sintomi ipoglicemici (Grado C; MLE 3). Anche i pazienti che non richiedono la terapia insulinica traggono vantaggio dal SMBG, soprattutto per il feed-back fornito sugli effetti del loro intervento farmacologico e sullo stile di vita. La frequenza dei controlli deve essere personalizzata.

R 53. Il monitoraggio glicemico continuo (CGM) deve essere considerato nei pazienti con DM1 e DM2 in terapia insulinica basal-bolus, per migliorare i livelli di A1C e ridurre le ipoglicemie (Grado B; MLE 2). Alcune segnalazioni suggeriscono un possibile beneficio del CGM anche in pazienti non sottoposti a terapia insulinica (Grado D; BEL 4).

 

Q 18. Raccomandazioni AACE-Chapter Italia

R 52. La pratica clinica suggerisce che l'SMBG è utile anche nei pazienti non in terapia insulinica, nonostante i limiti nella rimborsabilità delle strisce reattive per glucometro ne scoraggino l'impiego.

R 53. Esistono fortissime evidenze a favore del CGM nel DM1, sia con MDI in basal-bolus che con CSII, (Lagendam M, et al. Continuous glucose monitoring systems for type 1 diabetes mellitus. Cochrane Database Syst Rev 2012, 1: CD008101. Poolsup N, et al. Systematic review and meta-analysis of the effectiveness of continuous glucose monitoring (CGM) on glucose control in diabetes. Diabetol Metab Syndr 2013, 5: 39).


 

Q 19. Come e quando impiegare i micro-infusori insulinici?

R 54. Potenziali candidati all’uso del CSII sono i pazienti con DM1 e quelli con DM2 insulino-dipendenti (Grado A; MLE 1).
L’impiego del CSII deve essere limitato a pazienti motivati e in grado di effettuare l’autogestione del DM, con particolare riferimento agli aggiustamenti della terapia insulinica. Per la sicurezza del paziente, i medici prescrittori devono avere esperienza di terapia con CSII e coloro che utilizzano la CSII devono aver ricevuto un’educazione esauriente e devono essere rivalutati periodicamente.
Nei pazienti a rischio di ipoglicemia deve essere considerato l’uso della CSII integrata con sensore, dotata di una soglia glicemica prefissata per la cessazione dell’infusione (Grado A; MLE 1).

Tabella 16
Meta-analisi degli studi su CSII pubblicati dal 2003
Riferimenti bibliografici (livello di evidenza e disegno dello studio) Obiettivi della meta-analisi Numero/tipo di studi inclusi nella meta-analisi Risultati clinici
(586 [LE 1; MRCT]) Indagine sull’impatto metabolico e psico-sociale in bambini, adolescenti e adulti della terapia con CSII rispetto ad altre modalità di trattamento (p.e., MDI, terapia convenzionale) (n = 1547) Sui 2483 studi identificati, 61 corrispondevano ai criteri iniziali; la revisione finale è stata eseguita su 52 studi (37 accoppiati, 4 randomizzati crossover e 11 in parallelo) pubblicati fra 1979 e 2001 Rispetto a MDI, la terapia con CSII era associata a miglioramento significativo del controllo glicemico (diminuzione di A1C e glicemie medie).
L’analisi delle complicanze di CSII prima del 1993 ha mostrato la diminuzione del rischio di eventi ipoglicemici con il micro-infusore insulinico, ma un rischio potenzialmente aumentato di cheto-acidosi diabetica.

Note:

  • non sono state incluse nell’analisi per mancanza di dati le variazioni del fabbisogno insulinico e del peso corporeo;
  • CSII non sembra associata ad aumentato rischio di deterioramento psico-sociale, sebbene fosse difficile valutare gli effetti sulle prospettive dei pazienti e sul funzionamento psico-sociale per incongruenze del disegno e della metodologia dello studio.
(587 [LE 1; MRCT]) Confronto degli effetti di CSII rispetto a MDI su controllo glicemico, rischio ipoglicemico, fabbisogno insulinico e eventi avversi in adulti con DM1 (n = 908), bambini con DM1 (n = 74) e pazienti con DM2 (n = 234) A partire da 673 studi identificati, la revisione finale è stata eseguita su 22 RCT (17 in DM1, 2 in DM2, 3 pediatrici) pubblicati fino al marzo 2007 Maggior riduzione di A1C e minor fabbisogno insulinico con CSII rispetto a MDI in adulti e adolescenti con DM1; rischio ipoglicemico equivalente negli adulti (dati non disponibili negli adolescenti); nei pazienti con DM2 non è stato rilevato nessun dato conclusivo a favore di CSII.
(588 [LE 1; MRCT]) Confronto degli effetti di CSII rispetto a MDI su controllo glicemico e ipoglicemia in adulti e bambini con DM1 (n = 669) o DM2 (n = 239) A partire da 107 studi identificati, la revisione finale è stata eseguita su 15 RCT pubblicati tra il 2002 e il marzo 2008 Nei pazienti con DM1, A1C era lievemente ridotta con CSII rispetto a MDI; gli effetti di CSII sull’ipoglicemia non sono chiari.
Nei pazienti con DM2, gli esiti di CSII e MDI sono stati simili.
Note: non chiara per mancanza di dati l’efficacia di CSII nei pazienti con ipoglicemia non avvertita o grave recidivante.
(589 [LE 1; MRCT]) Valutazione degli effetti su controllo glicemico e incidenza di ipoglicemia grave di CSII (studi di 36 mesi) e MDI (oltre 10 episodi di ipoglicemia grave per 100 pazienti-anno) in pazienti con DM1 (n = 1414) A partire da 61 studi identificati, la revisione finale è stata eseguita su 22 RCT e studi prima/dopo pubblicati tra il 1996 e il 2006 Rischio di ipoglicemia grave diminuito con CSII rispetto a MDI; riduzione maggiore osservata nei pazienti con DM di più lunga durata e in quelli con il maggior tasso basale di ipoglicemia grave in corso di terapia con MDI.
A1C era inferiore con CSII rispetto a MDI, con miglioramento maggiore nei pazienti con i maggiori livelli iniziali di A1C durante MDI
(172 [LE 1; MRCT]) Confronto di controllo glicemico e incidenza di ipoglicemia con CSII (insulina analogo rapido, n = 444) rispetto a MDI (n = 439) in pazienti con DM2 trattati per almeno 12 settimane A partire da 177 studi identificati, la revisione finale è stata eseguita su 11 RCT pubblicati tra il 2000 e il 2008 A1C era significativamente inferiore con CSII rispetto a MDI; la riduzione di A1C era evidente solo negli studi in cui l’età media dei pazienti era > 10 anni.
Il tasso di ipoglicemia grave era sovrapponibile tra CSII e MDI.
Abbreviazioni: A1C = emoglobina A1C; CSII = infusione sottocutanea continua di insulina; LE = livello di evidenza; MDI = iniezioni giornaliere multiple; MRCT = meta-analisi di studi controllati randomizzati; RCT = studio controllato randomizzato; DM1 = diabete mellito tipo 1; DM2 = diabete mellito tipo 2.

 

Tabella 17
RCT di confronto fra CSI e MDI nei pazienti con DM2
Fonte

Numero randomizzato Disegno Follow-up A1C (%) (DS)a
Basale CSII MDI P
(595 [LE 3; CCS]) 15 Osservazionale 30 settimane 7.9 (1.9) 5.0 (0.9) ND < 0.001
 (594 [LE 3; CCS]) 10  Osservazionale  3 notti successive  FPG: 209 (52.3) mg/dL  FPG: 99.1 (28.8) mg/dL  ND   < 0.0001
(593 [LE 1; RCT, piccola numerosità campionaria, non in cieco]) 17 Crossover 2 periodi di 12 settimane 9 (1.6) 7.7 (0.8) 8.6 (1.6) < 0.03
(592 [LE 1; RCT, non in cieco]) 107 Parallelo 1 anno CSII: 8.4 (1.1)
MDI: 8.1 (1.2)
6.6 (0.8) 6.4 (0.8) 0.19
(591 [LE 1; RCT, piccola numerosità campionaria, non in cieco]) 40 Crossover 2 periodi di 18 settimane CSII-MDI: 10.1 (1.6)
MDI-CSII 10.2 (1.4)
−0.8 (1.5)b +0.4 (1.3)b 0.007
(590 [LE 1; RCT, non in cieco]) 132 Parallelo 24 settimane CSII: 8.2 (1.4)
MDI: 8.0 (1.1)
7.6 (1.2) 7.5 (1.2) NS
(597 [LE 1; RCT, piccola numerosità campionaria, non in cieco]) 20 RCT 4 mesi CSII: 13.2c
MDI: 12.8
9.2 (HbA1) 10.6 (HbA1) < 0.05
(596 [LE 1; RCT, non in cieco]) 331 RCT 6 mesi 9 1.1 (1.2) 0.4 (1.1) < 0.0001

Abbreviazioni: A1C = emoglobina A1C; CSII = infusione sottocutanea continua di insulina; DS = deviazione standard; FPG = glicemia a digiuno; MDI = iniezioni giornaliere multiple; ND = non disponibile; NS = non significativo; RCT = studio controllato randomizzato; DM2 = diabete mellito tipo 2.

a Variazioni del controllo glicemico espresse come A1C a meno di specificazione diversa.

b I valori di A1C per CSII e MDI sono presentati da Wainstein et al come effetto diretto del trattamento nella coorte dei completati.

c Riportato nello studio come mediana mmol idrossimetilfurfural (HMF) per mole di emoglobina (Hb) e convertito a percentuale mediana di HbA1 sulla base della seguente formula, determinata per confronto con un metodo cromatografico su colonna nel range da 4 a 13%: HbA1 (%) = 0.21 (A1C in mmol HMF/mol Hb) - 0.35 (597 [LE 1; RCT, piccola numerosità campionaria, non in cieco]).

 

Tabella 18
Dati riassuntivi sulle analisi costo-efficacia di confronto fra terapia insulinica con micro-infusore e con iniezioni multiple giornaliere in adulti e bambini con DM1
Fonte Obiettivo dello studio, prospettiva, origine dei dati Guadagno in QALY Costo per QALY (ICER) Ulteriori risultati rilevanti
(599 [LE 3; SS]) Stimare costo-efficacia a lungo termine (60 anni) di CSII in confronto a MDI in adulti e bambini con DM1.
Prospettiva assicurativa statunitense.
Modello computerizzato di simulazione (CORE Diabetes Model).
CSII rispetto a MDI = 0.262

CSII: $ 16.992
MDI: $ 27.195

Il miglior controllo glicemico con CSII ha portato a ridotta incidenza di complicanze diabetiche, compresi PDR, ESRD, PVD.
L’NNT per PDR era 9 (cioè è sufficiente trattare solo 9 pazienti con CSII per evitare un caso di PDR).

(598 [LE 3; SS])

Stimare costo-efficacia a lungo termine (60 anni) di CSII in confronto a MDI in adulti con DM1.
Prospettiva amministrativa canadese.
Modello computerizzato di simulazione (CORE Diabetes Model).

CSII rispetto a MDI = 0.655

CSII: Can$ 27.265
MDI: Can$ 23.797

 
(600 [LE 3; SS])

Resoconto della valutazione della clinica e del rapporto costo-efficacia utilizzando CSII per trattare il DM (DM1 e in gravidanza).
NICE, Regno Unito.
Revisione sistematica e valutazione economica (su 74 studi)

NA NA

CSII ha un rapporto costo-efficacia favorevole nel DM1 sia nei bambini che negli adulti.
Non c’è evidenza che CSII sia meglio di MDI in gravidanza.

(602 [LE 3; SS])

Fare una previsione a lungo termine (60 anni) di risultati clinici ed economici di CSII in confronto a MDI in pazienti con DM1.
Regno Unito; prospettiva amministrativa del sistema sanitario nazionale.
Modello computerizzato di simulazione (CORE Diabetes Model).

CSII rispetto a MDI = 0.76

CSII: £ 80.511
MDI: £ 61.10
(varianza = £ 25.648/QALY guadagnati con CSII)

Il miglior controllo glicemico con CSII rispetto a MDI ha portato a ridotta incidenza di complicanze diabetiche.
Nei pazienti con DM1, CSII rappresenta un buon acquisto sulla base degli attuali standard britannici.

(603 [LE 1; RCT, analisi post-hoc])

Stimare costo-efficacia a lungo termine di SAPT in confronto a MDI nel DM1.

SAPT rispetto a MDI = 0.376

Costo nell’arco della vita:
SAPT: $ 253.493
MDI: $ 167.170
ICER = (c1-c2)/q1 – q2 = $ 229.582

 

Nonostante i maggiori benefici clinici di SAPT in confronto a MDI, allo stadio attuale di sviluppo SAPT non sembra essere economicamente allettante negli USA per gli adulti con DM1.
È possibile che ulteriori sviluppi con riduzione del costo dei materiali mono-uso possano cambiare questa valutazione.

 (604 [LE 3; SS])  

Fare una previsione a lungo termine di risultati clinici ed economici di CSII in confronto a MDI in pazienti danesi con DM1.
Meta-analisi del trattamento con CSII da oltre 50 studi.

 CSII associato a migliore aspettativa di vita aggiustata per la qualità rispetto a MDI (QALY non calcolato) I costi nell’arco della vita erano maggiori con CSII rispetto a MDI, con ICER in termini di costi per QALY all’interno del range considerato un buon investimento   

CSII ha portato a miglioramento dei risultati clinici a lungo termine per il miglior controllo glicemico rispetto a MDI.
L’impatto economico di CSII rispetto a MDI rappresenta probabilmente un buon investimento rispetto al costo.

Abbreviazioni: CORE = Centro per la ricerca sui risultati; CSII = infusione sottocutanea continua di insulina; LE = livello di evidenza; ESRD = nefropatia terminale; ICER = costo-efficacia incrementale; MDI = iniezioni giornaliere multiple; NA = not applicabile; NHS = Sistema sanitario nazionale (Regno Unito); NICE = Istituto Nazionale per la salute e l’eccellenza clinica; NNT = numero che è necessario trattare; PDR = retinopatia diabetica proliferativa; PVD = vasculopatia periferica disease; QALY = anni di vita aggiustati per la qualità; SAPT = terapia con infusore integrato con sensore; DM1 = diabete mellito tipo 1; DM2 = diabete mellito tipo 2

 

Q 19. Raccomandazioni AACE-Chapter Italia

R 54. Al momento, anche per un problema di risorse, l’utilizzo in Italia è usualmente limitato al DM1 (sia adulti che bambini) con indicazioni precise (documento di consenso AMD-SID-SIEDP):

  1. controllo glicemico inadeguato, malgrado terapia insulinica intensiva multi-iniettiva (HbA1c >8.5%), anche nei bambini di età inferiore a 12 anni;
  2. ipoglicemie inavvertite o notturne o severe;
  3. estrema sensibilità insulinica (terapia insulinica < 20 UI/die o < 0.4 U/kg);
  4. programmazione della gravidanza o gravidanza in atto;
  5. necessità di flessibilità per lo stile di vita (lavoro a turni, frequenti viaggi, attività fisica non prevedibile);
  6. gastroparesi;
  7. trapianto renale;
  8. frequenza elevata di ospedalizzazioni o di visite ambulatoriali urgenti per episodi di scompenso acuto;
  9. difficoltà ad accettare le iniezioni multiple (soprattutto in pediatria).

La scelta del paziente richiede un’attenta valutazione, non solo delle caratteristiche cliniche del paziente, ma anche della capacità dello stesso a partecipare attivamente all’educazione all’utilizzo di questo strumento. Il paziente e un suo vicino (familiare, amico, partner, ecc) devono anche partecipare ai corsi di educazione che hanno lo scopo di insegnare la conta dei carboidrati, come intervenire in caso di stop di erogazione dell’insulina, come intervenire in caso di ipoglicemia e accettare continui corsi di rivalutazione effettuati dall’equipe diabetologica.
Il team diabetologico del centro prescrittore deve avere adeguata expertise (e risorse) per poter assicurare l’assistenza più completa.


 

Q 20. Quali sono gli elementi essenziali per l’educazione e l’approccio di team alla cura del DM?

R 55. La gestione dei pazienti con DM viene effettuata in modo ottimale da un team multidisciplinare strutturato (Grado D; MLE 4). Il team deve comprendere medico di medicina generale, endocrinologo, infermiere con competenza specialistica, dietista, fisioterapista e psicologo.
Gli aspetti educazionali, sociali e logistici della gestione clinica e le modificazioni della terapia associate con l’età e lo sviluppo accrescono la complessità delle cure nei bambini con DM.

R 56. Le persone con DM devono ricevere un’esaustiva educazione all’auto-gestione (DSME) sia al momento della diagnosi sia nel tempo, secondo le necessità (Grado D; MLE 4). La DSME migliora i risultati clinici e la qualità della vita nei soggetti con DM, fornendo le conoscenze e la competenza necessarie alla auto-gestione.
La gestione terapeutica dello stile di vita deve essere valutata e discussa con tutti i pazienti con DM o Prediabete, sia al momento della diagnosi che nel corso della vita successiva (Grado D; MLE 4).
Ne sono parte la MNT (caratterizzata nei soggetti sovrappeso e obesi dalla modifica e riduzione dell’introito di calorie e di grassi, per ottenere un’adeguata perdita di peso), un’attività fisica prescritta in modo appropriato alle condizioni del paziente, l’astensione dal fumo e un’adeguata quantità e qualità del sonno. Ulteriori elementi dei programmi DSME comprendono i principi e le opzioni del trattamento glicemico, le modalità di monitoraggio del glucosio, gli aggiustamenti della posologia insulinica, le complicanze acute del DM, la prevenzione, riconoscimento e trattamento dell’ipoglicemia.

 

Q 20. Raccomandazioni AACE-Chapter Italia

R 55. Le caratteristiche e i componenti del team diabetologico per l’educazione terapeutica strutturata in Italia sono diversi.


 

Q 21. Quali vaccinazioni dovrebbero essere fatte nei diabetici?

R 57. AACE sostiene le raccomandazioni dei Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP), che suggeriscono che tutti I pazienti con DM siano vaccinati per l’influenza e le infezioni pneumococciche.
Nei pazienti con DM di età > 6 mesi dovrebbe essere praticata ogni anno la vaccinazione anti-influenzale (Grado C; MLE 3), mentre dopo i due anni di vita deve essere effettuata la vaccinazione con il polisaccaride pneumococcico (Grado C; MLE 3).
Negli adulti di età compresa fra 19 e 64 anni deve essere somministrata una dose singola di vaccino polisaccaridico pneumococcico 23-valente (PPSV23) (Grado C; MLE 3), mentre nei soggetti di età > 65 anni il vaccino pneumococcico coniugato 13-valente dovrebbe essere somministrato in successione con il PPSV23 (Grado C; MLE 3).
La rivaccinazione è indicata anche nei diabetici con sindrome nefrosica, nefropatia cronica e altre condizioni di compromissione immunitaria, come nei soggetti sottoposti a trapianto d’organo.

R 58. Negli adulti di età compresa fra 20 e 59 anni, subito dopo aver posto la diagnosi di DM deve essere effettuata la vaccinazione per l’epatite B (Grado C; MLE 3). Negli adulti con età ≥ 60 anni deve essere considerata l’opportunità della vaccinazione sulla base del rischio di infezione da HBV e della probabilità di una risposta immunitaria adeguata (Grado C; MLE 3).

R 59. Tutti I bambini e gli adolescenti con DM dovrebbero ricevere le vaccinazioni di routine secondo il programma normale (Grado C; MLE 3).

R 60. Anche se la vaccinazione per tetano-difterite-pertosse (Tdap) è tipicamente inclusa nelle vaccinazioni di routine dell’infanzia, tutti gli adulti con DM dovrebbero ricevere un richiamo ogni 10 anni (Grado D; MLE 4).

R 61. I pazienti con DM possono necessitare di ulteriori vaccinazioni per proteggersi nei confronti di altre malattie infettive. Sulla base delle esigenze del singolo paziente può essere considerata l’opportunità di effettuare le seguenti vaccinazioni: morbillo, parotite, rosolia, varicella e poliomielite. Inoltre, i pazienti che viaggiano all’estero possono effettuare la vaccinazione per le specifiche malattie endemiche (Grado D; MLE 4).

 

Q 21. Raccomandazioni AACE-Chapter Italia

In Italia esiste il piano nazionale vaccinazioni, che prevede la vaccinazione obbligatoria durante i primi mesi di vita per Pneumococco, HBV e Hemophylus influenzae B; inoltre, vengono effettuate entro il 18° anno di età la vaccinazione per il Meningococco C e nelle donne per il virus HPV 6.

R 57. La vaccinazione anti-influenzale viene effettuata in Italia ai pazienti particolarmente fragili quali i diabetici. Nei diabetici è stato dimostrato che riduce le ospedalizzazioni e soltanto negli ultra65enni la mortalità, ma la qualità dell’evidenza è molto bassa (Remschmidt C, et al. Vaccines for the prevention of seasonal influenza in patients with diabetes: systematic review and meta-analysis. BMC Med 2015, 13: 53).


 

Q 22. Come trattare la depressione nel contesto del diabete?

R 62. In tutti gli adulti con DM dovrebbe essere effettuata una valutazione di screening per la depressione, perché questa condizione, se non riconosciuta e trattata, può avere serie implicazioni nei pazienti diabetici (Grado A; MLE 1).

R 63. I pazienti affetti da depressione dovrebbero essere presi in carico dagli specialisti in psicologia che fanno parte del team per la cura del DM (Grado D; MLE 4).

 

Q 22. Raccomandazioni AACE-Chapter Italia

R 62. Anche se esiste una relazione tra s. depressiva, farmaci anti-depressivi e malattia diabetica, e la depressione nel diabetico ne aumenta il rischio CV, sembra eccessivo sostenere che tutti i diabetici debbano essere sottoposti a screening per depressione.
La presenza di depressione nel maschio con diabete conclamato richiede anche un’accurata ricerca di una possibile condizione di deficit di testosterone, che, se presente, va trattato con terapia sostitutiva, sia per migliorare il compenso metabolico che per superare meglio la depressione stessa (Fiore V, et al. The association between diabetes and depression: a very disabling condition. Endocrine 2015, 48,14-24).
D’altra parte alcuni anti-depressivi (olanzapina, clozapina e i farmaci di quella classe) sono diabetogeni, fanno aumentare il peso, il comportamento iperfagico e inducono un peggioramento del compenso glico-metabolico in chi è già diabetico (Hennings JM, Schaaf L, Fulda S. Glucose metabolism and antidepressant medication. Curr Pharm Des 2012, 18: 5900–19).


 

Q 23. Qual è l’associazione fra diabete e cancro?

R 64. Sulla base dell’accresciuto rischio di sviluppare alcuni tipi di carcinoma, documentato nei soggetti con obesità o DM2, il team diabetologico deve informare i pazienti di questo potenziale problema e incoraggiare uno stile di vita più salutare (Grado D; MLE 4). Devono essere fortemente raccomandati la riduzione del peso, l’esercizio regolare e una dieta più sana (Grado C; MLE 3). Inoltre, questi pazienti devono essere sottoposti con maggiore frequenza e attenzione rispetto alla popolazione generale allo screening delle neoplasie associate con i disordini metabolici (Grado B; MLE 2).

R 65. Al momento non è stata stabilita una correlazione certa fra l’uso di alcuni farmaci ipoglicemizzanti e l’aumento del rischio di neoplasie o di mortalità legata al cancro. Il team diabetologico dovrebbe essere attento alle possibili associazioni e raccomandare interventi terapeutici basati sul profilo di rischio individuale del paziente (Grado D; MLE 4).

R 66. Nei pazienti oncologici il clinico deve escludere l’impiego di farmaci considerati potenzialmente inopportuni per quella specifica neoplasia, anche in assenza di prove certe. (Grado D; MLE 4).

 

Q 23. Raccomandazioni AACE-Chapter Italia

R 64-66. L’avvio delle chemioterapie anti-neoplastiche è sempre sfavorevole sul compenso glico-metabolico e ciò richiede una stretta concertazione con l’oncologo.
Il diabete correla con aumentato rischio di cancro del pancreas (Wang M, et al. Cancer risk among patients with type 2 diabetes mellitus: a population-based prospective study in China. Sci Rep 2015, 5: 11503), mentre la metformina riduce l’incidenza di cancro, soprattutto del polmone (Yu H, et al. Effect of metformin on cancer risk and treatment outcome of prostate cancer: a meta-analysis of epidemiological observational studies. PLOS One 2014, 9: e116327. Zhang ZY, et al. Reduced risk of lung cancer with metformin therapy in diabetic patients: a systematic review and meta-analysis. Am J Epidemiol 2014, 180: 11-4.) e aumenta la sopravvivenza nel cancro, soprattutto della mammella, colo-rettale, ovarico, endometriale (Zhang ZJ, et al. The prognostic value of metformin for cancer patients with concurrent diabetes: a systematic review and meta-analysis. Diabetes Obes Metabol 2014, 16: 707-10).


 

Q 24. Quali sono le attività lavorative con necessità specifiche per la gestione del diabete?

R 67. I conducenti di veicoli commerciali sono ad alto rischio di sviluppare DM2. Le persone affette da DM che sono impegnate in specifiche occupazioni, come i conducenti, i piloti, gli anestesisti e coloro che effettuano immersioni, richiedono specifiche attenzioni gestionali, focalizzate in primo luogo su trattamenti che riducano il rischio di ipoglicemia (Grado C; MLE 3).

 

Q 24. Raccomandazioni AACE-Chapter Italia

R 67. È da sottolineare l'importanza del numero dei controlli glicemici per le categorie lavorative a rischio (con la relativa prescrivibilità delle strisce reattive).


 

4. APPENDICE: BASI di EVIDENZA

In this update, there are 671 citations of which 226 (34%) are EL 1 (strong), 121 (18%) are EL 2 (intermediate), 117 (17%) are EL 3 (weak), and 205 (31%) are EL 4 (no clinical evidence). The majority of recommendations are EL 1 or 2: 347/671 (52%), which is slightly increased from 180/375 (48%) in the 2011 AACE CPG (1 [EL 4; NE]). The evidence base presented here provides relevant information for the recommendations in the Executive Summary.

 

Q 1. Come indagare e diagnosticare il Diabete Mellito?

Q 1.1. Diagnosi di DM

DM refers to a group of metabolic disorders that result in hyperglycemia, regardless of the underlying etiology. DM is diagnosed by using any of 3 established criteria for elevated blood glucose concentrations (Table 6) (17 [EL 4; consensus NE]).
An International Expert Committee has recommended that an A1C level ≥6.5% also be used as a criterion for diagnosis of DM (18 [EL 4; consensus NE]). Subsequent analyses of the fidelity of DM diagnosis using A1C versus FPG or 2-hour OGTT (Table 6) have brought this practice into question (19 [EL 3; SS]). Moreover, A1C is known to be affected by nonglycemic factors such as changes in red blood cell maturity and survival and impaired renal function, and it may be unreliable as a measure of glycemic burden in some patients from certain ethnic groups, including those of African American and Latino heritage (20 [EL 3; SS]; 21 [EL 4; review NE]; 22 [EL 3; SS]). On the basis of these limitations, A1C measurement cannot be recommended as a primary method for diagnosingDM. The diagnosis of DM is best confirmed by 1 of the 3 established direct measures of plasma glucose, with A1C as a secondary criterion (Table 6). In the absence of unequivocal hyperglycemia, the same type of test should be repeated on a different day to confirm the diagnosis of DM because of glucose level variability (23 [EL 4; review NE]). In view of physiological changes in pregnancy that could affect glycated hemoglobin levels, A1C should not be used for GDM screening or diagnosis (24 [EL 3; CCS]).

 

Q 1.2. Classificazione del DM

DM is classified into T1D, T2D, GDM, monogenic DM, and other less common conditions such as chronic pancreatitis, pancreatic resection, or rare insulin resistance and mitochondrial syndromes. T1D accounts for <10% of all DM cases and occurs more commonly in children and young adults but can occur at any age. It is also more common in persons of European ancestry and is caused by absolute insulin deficiency that usually results from an immune-mediated destruction of the pancreatic β cells. In a minority of patients with T1D, evidence for autoimmunity is lacking, and the etiology of islet destruction is unclear. Severe insulinopenia in T1D predisposes patients to diabetic ketoacidosis (DKA). However, DKA can also occur in patients with T2D (25 [El 4; NE]; 26 [EL 3; SS]).
T2D accounts for >90% of all cases of DM; it remains undiagnosed for years in many affected persons because they are asymptomatic. Consequently, up to 25% of patients with T2D have already developed at least 1 microvascular complication by the time of diagnosis (27 [EL 1; RCT]). Insulin resistance and concurrent relative insulin deficiency and glucagon dysregulation underlie T2D pathophysiology (28 [EL 4; NE]; 29 [EL 2; PCS]). Cross sectional surveys indicate a higher prevalence of diagnosed DM in African Americans, Hispanic Americans, and other persons of non-European origin compared with European Americans (30 [EL 3; SS]).


 

Q 2. Come gestire il Prediabete?

Prediabetes is a condition defined by an increased risk of developing DM and CVD. Prediabetes can be identified by the presence of IGT (OGTT result of 140 to 199 mg/dL 2 hours after ingesting 75 g of glucose), IFG (FPG value of 100 to 125 mg/dL), or A1C value of 5.5 to 6.4% (Table 6). The metabolic syndrome, based on National Cholesterol Education Program IV Adult Treatment Panel III (NCEP ATP III) criteria, may be considered a prediabetes equivalent. Polycystic ovary syndrome (PCOS) is also a prediabetes condition (31 [EL 4; consensus NE]). Risk factors suggesting a need for screening are listed in Table 5 (31 [EL 4; consensus NE]).
Prevention of T2D depends upon systematic lifestyle modifications including caloric intake reduction (e.g., 500 kcal deficit per day) and regular exercise (30 minutes aerobic work at least 5 days per week) to lose >7% body weight (4 [EL 4; NE]). Lifestyle management alone may be adequate for low-risk states and can reduce DM incidence by as much as 58% (4 [EL 4; NE]). The weight-loss agents orlistat (120 mg 3 times daily) (32 [EL 1; RCT]) and phentermine/topiramate extended release (up to 15/92 mg once daily) (33 [EL 1; RCT]) prevented or delayed new cases of DM in 48 to 79% of patients with prediabetes taking these medications for 2 to 4 years in the respective studies. Weight-loss surgery may normalize glycemia in patients with prediabetes, prevent the appearance of overt T2D, and reduce its progression. In the Swedish Obese Subjects Study, bariatric surgery reduced the incidence of DM by 75% over 10 years (P<.001) (34 [EL 2; PCS]).
For patients in whom lifestyle modification after 3 to 6 months has failed to produce necessary improvement, pharmacologic intervention may be appropriate. In fact many, if not the majority, of patients will benefit from starting medications concomitantly with lifestyle intervention, just as in other metabolic diseases. No antihyperglycemic medications are approved by the FDA solely for the management of prediabetes and/or the prevention of T2D. Metformin (35 [EL 1; RCT]) and acarbose (36 [EL 1; RCT]; 37 [EL 1; RCT]; 38 [EL 4; opinion NE]) might be appropriate for certain patients. TZDs reduced the risk of DM progression by 60 to 72% (39 [EL 1; RCT]; 40 [EL 1; RCT]); however, because of their potential for long-term adverse effects, their usage in this population is controversial. More extensive discussion can be found in the American College of Endocrinology consensus on the management of prediabetes (31 [EL 4; consensus NE]). Metformin is an antihyperglycemic drug that is not approved for obesity; however, the Diabetes Prevention Program (DPP) demonstrated that it reduces the risk of developing DM in persons with IGT (35 [EL 1; RCT]; 41 [EL 1; RCT, follow-up study]). In 3 studies, orlistat reduced conversion to DM (32 [EL 1; RCT]; 42 [EL 1; RCT]; 43 [EL 1; MRCT]). One of these studies reported a reduction from 10.9 to 5.2% (P = .041) in the conversion rate to DM (42 [EL 1; RCT]). Orlistat therapy is also associated with decreases in A1C; in 1 study, A1C decreased by 1.1% and 0.2% in the orlistat and control groups, respectively. Orlistat therapy also resulted in a mean weight loss of 5% (44 [EL 2; MNRCT]).
Phentermine/topiramate extended release reduced the annualized incidence rates of T2D by 70.5 and 78.7% among patients receiving the 7.5/46 mg and 15/92 mg doses, respectively, over 2 years (P<.05 versus placebo). These reductions were related to the degree of weight loss (10.9% and 12.1% in the low- and high-dose groups, respectively, versus 2.5% in the placebo group; P<.0001) and were accompanied by significant improvements in cardiometabolic parameters (33 [EL 1; RCT]).
High-dose liraglutide (3 mg) reduced weight by a mean of 9 kg, and 84% of patients with prediabetes at baseline had normal glucose values after 1 year; after 2 years, up to 62% of patients taking liraglutide 2.4 or 3 mg (pooled analysis) maintained normal glucose levels (45 [EL 1; RCT]; 46 [EL 1; RCT]). This is likely the result of both the substantial weight loss and the incretin effect of this agent on blood glucose control (45 [EL 1; RCT]; 46 [EL 1; RCT]). A large-scale study specifically examining the effect of liraglutide on the incidence of T2D is underway.


 

Q 3. Quali sono gli obiettivi glicemici del trattamento del DM?

Q 3.1. Obiettivi glicemici negli adulti ambulatoriali non in gravidanza

There is no dispute that elevated glucose levels are associated with micro- and macrovascular complications of DM. Similarly, it has been accepted that strategies aimed at lowering glucose concentrations can lead to lower rates of microvascular and perhaps macroangiopathic complications (47 [EL 1; RCT]; 48 [EL 3; SS]; 49 [EL 1; RCT, posttrial monitoring]; 50 [EL 3; SS]; 51 [EL 1; RCT]; 52 [EL 1; RCT, posthoc analysis]). What have remained under debate are the specific targets for glucose control in patients with DM.
Healthy persons do not exhibit preprandial plasma glucose concentrations >99 mg/dL or >120 mg/dL 2 hours after meals. Indeed, there was a progressively increased risk of T2D in males with FPG levels >87 mg/dL in 1 study (53 [EL 3; SS]) and >94 mg/dL in another study based on long-term follow-up (54 [EL 3; SS]). Similarly, standardized DCCT (Diabetes Control and Complications Trial)- aligned A1C levels remained <6.0% in healthy individuals. Epidemiologic evidence shows a continuous relationship between A1C and CVD and all-cause mortality, with the lowest rates at A1C levels <5% (55 [EL 2; PCS]).
Logically, one should aim for “normal” A1C levels when treating patients with DM. However, it is unknown whether treating patients with DM—some with pre-existing diabetic complications—using complicated regimens to force glucose concentrations into the normal range actually prevents or delays those complications. In the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial, intensive therapy targeting an A1C <6% significantly reduced the risks and progressions of retinopathy, nephropathy, and neuropathy compared with a standard approach targeting an A1C of 7 to 8% (52 [EL 1; RCT, posthoc analysis]; 56 [EL 1; RCT]). Significant reductions in the risk or progression of nephropathy were seen in the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation) study, which targeted an A1C <6.5% in the intensive therapy group versus standard approaches (57 [EL 1; RCT]). In ACCORD, mortality increased with increasing A1C among intensively treated patients, with the excess mortality only affecting patients whose A1C remained >7% (58 [EL 1; RCT]). Meanwhile, a U-shaped mortality curve was observed in the standard therapy group, with increasing death rates at both low (<7%) and high (>8%) A1C levels (58 [EL 1; RCT]). Similar U-shaped curves were found in a 7-year observational study of patients with T1D (59 [EL 2; PCS]) and a 22-year observational study of >20,000 patients with T2D (60 [EL 2; RCCS]). A corollary of this issue is the safety of those therapies in view of the demonstrated increase of frequency of severe hypoglycemia during attempts at intensive glycemic control (57 [EL 1; RCT]; 61 [EL 1; RCT]; 62 [EL 1; RCT]; 63 [EL 1; RCT]). As discussed in “Q6. How is hypoglycemia managed?,” much of the mortality in ACCORD may have been related to hypoglycemia, and the hazard ratio (HR) for hypoglycemia-associated deaths was actually higher in the standard treatment than the intensive therapy groups (64 [EL 3; SS]).
No RCTs have yet established optimal glycemic targets. Professional organizations have relied on results from existing intervention trials achieving improved A1C levels and epidemiologic analyses of various studies to arrive at consensus statements or expert opinions regarding targets. Thus, some (4 [EL 4; NE]) have recommended a general target A1C level ≤6.5%, while others have recommended a general target of <7% (65 [EL 4; NE]; 66 [EL 4; CPG NE]). In all cases, the potential risks of intensive glycemic control may outweigh its benefits, especially in patients with frequent severe hypoglycemia, hypoglycemia unawareness, or a very long duration of DM, particularly in the presence of established and advanced atherosclerosis, advanced age, and terminal illness.
In patients with DM, an A1C level >7% is associated with increased risk of micro- and macrovascular complications (50 [EL 3; SS]; 51 [EL 1; RCT]; 67 [EL 1; RCT]; 68 [EL 1; RCT]). Strategies aimed at lowering glycemic levels (as evidenced by A1C lowering) have decreased microvascular complications and, in some cases, macrovascular complications (48 [EL 3; SS]; 49 [EL 1; RCT, posttrial monitoring]; 50 [EL 3; SS]; 51 [EL 1; RCT]; 52 [EL 1; RCT, posthoc analysis]; 69 [EL 1; RCT]). As discussed in “Q4. How are glycemic targets achieved?” as well as in the 2015 AACE Algorithm for Diabetes Management (4 [EL 4; NE]), some newer therapies carry a lower risk of hypoglycemia, which may enable more patients to safely achieve individualized target A1C levels. To achieve the target A1C levels, fasting and preprandial glucose levels should be <110 mg/dL. The evidence in support of a PPG target is predominantly based on cross-sectional and prospective epidemiologic studies with few RCTs (4 [EL 4; NE]; 70 [EL 2; PCS]).


 

Q 4. Come raggiungere gli obiettivi glicemici nel diabete mellito tipo 2?

Q 4.1. Come modificare lo stile di vita

The components of therapeutic lifestyle changes include healthful eating, regular physical activity, sufficient sleep, avoidance of tobacco products, limited alcohol consumption, and stress reduction.
Nutritional medicine in DM comprehensive care consists of 3 components: counseling about general healthful eating, MNT, and specialized nutrition support. The last category applies to those patients receiving enteral or parenteral nutrition in which medications provided for glycemic control must be synchronized with carbohydrate delivery; however, this topic is beyond the scope of this CPG. The components of healthful eating for patients with DM are described in Table 8 (4 [EL 4; NE]; 71 [EL 3; SS]; 72 [EL 4; position NE]; 73 [EL 4; position NE]; 74 [EL 4; review NE]; 75 [EL 3; SS]; 76 [EL 1; RCT]; 77 [EL 4; review NE]; 78 [EL 4; review NE]; 79 [EL 4; review NE]; 80 [EL 4; NE review]; 81 [EL 4; review NE]; 82 [EL 4; review NE]; 83 [EL 2; MNRCT]; 84 [EL 4; CPG NE]; 85 [EL 2; PCS, data may not be generalizable to patients with diabetes already]; 86 [EL 3; SS]; 87 [EL 4; review NE]; 88 [EL 4; NE review]; 89 [EL 4; review NE]). The physician or a registered dietitian should discuss these recommendations in plain language with patients at the initial visit after DM diagnosis and then periodically during follow-up office visits (4 [EL 4; NE]). Comments should be broad and nontechnical, about foods suitable for the general population (including those without DM) that promote health versus foods that may promote disease or disease complications. Discussions between patients and healthcare professionals should include information on specific foods and meal planning, grocery shopping, and dining-out strategies.
MNT addresses the metabolic needs of patients with DM and involves a more detailed discussion, usually in terms of calories, grams, and other metrics. The goal is to intensify efforts of healthy eating behaviors aimed at optimizing glycemic control and reducing the risks of DM complications. These recommendations should also be discussed and implemented by the physician or a registered dietitian for all patients with DM.
All patients should be advised how to achieve and maintain a healthful weight. For overweight individuals with a BMI of 25 to 29.9 kg/m2, this corresponds to achieving a normal range BMI of 18.5 to 24.9 kg/m2. For obese individuals with a BMI >30 kg/m2, the initial recommended target is a weight loss of at least 5 to 10% of body weight. Several randomized clinical trials lasting 1 year (90 [EL 1; RCT, single blinded]; 91 [EL 1; RCT, not blinded, adherence not controlled for]) or 2 years (92 [EL 1; RCT, not blinded]; 93 [EL 1; RCT]) have compared diets and report successful weight loss regardless of macronutrient content (e.g., low fat, low carbohydrate, etc.). In a randomized comparison of the Atkins, Ornish, Weight Watchers, and Zone diets, weight change did not differ between diets (about 5 kg), and adherence to the diet was the single most important criterion of successful weight loss (90 [EL 1; RCT, single blinded]). The key to adopting the principles given in Tables 7 and 8 is to personalize the recommendations on the basis of a patient’s specific medical conditions, lifestyle, and behaviors. Patients unable to accomplish this should be referred to a registered dietitian or weight-loss program with a proven success rate. In areas underserved by registered dietitians, physicians should take on more responsibility during patient encounters for nutritional counseling and reinforcing healthful eating patterns.
A review and position paper on MNT for both T1D and T2D was recently published (94 [EL 4; NE]). Key recommendations address the need for consistency in day-to-day carbohydrate intake, adjusting insulin doses to match carbohydrate intake (e.g., use of carbohydrate counting), limitation of sucrose-containing or high-glycemic index foods, adequate protein intake, “heart-healthy” diets, weight management, regular physical activity, and increased glucose monitoring. Data from the Look AHEAD (Action for Health in Diabetes) and DPP studies provide additional evidence that lowering caloric intake is the main driver for weight loss. The Look AHEAD trial is the longest RCT to evaluate intensive lifestyle change on weight loss in patients with T2D (95 [EL 1; RCT, not blinded]). The maximal weight loss in patients with T2D in Look AHEAD was greater than among patients with prediabetes in the DPP. The magnitude of weight loss after 1 year in Look AHEAD was related to the frequency of using meal replacements, amount of physical activity performed, and attendance at behavioral sessions (96 [EL 1; RCT]). For a discussion of the Look AHEAD results, see section 4.Q13.4.
There is good evidence that regular physical activity improves glucose control in persons with T2D (97 [EL 1; RCT, small sample size]; 98 [EL 2; NRCT]; 99 [EL 2; NRCT]; 100 [EL 2; NRCT]). Because physical activity is usually combined with caloric restriction and weight loss, as in combined lifestyle intervention programs, distinguishing the effects of increased physical activity alone from those of calorie restriction and weight loss is often difficult. However, studies on exercise alone show improved glucose control (101 [EL 1; RCT]; 102 [EL 4; commentary NE]; 103 [EL 1; RCT]). Regular physical exercise—both aerobic exercise and strength training—is important to improve a variety of CVD risk factors, decrease the risk of falls and fractures, and improve functional capacity and sense of well-being (102 [EL 4; commentary NE]). Physical activity is also a main component in weight loss and maintenance programs. Activity of at least 150 minutes per week of moderate-intensity exercise such as brisk walking (e.g., a 15- to 20-minute mile) or its equivalent (e.g., yoga, walking during golf, water aerobics, physical play with children, etc.), is now well accepted and part of the nationally recommended guideline for physical activity. For persons with T2D, recommendations include flexibility and strength training exercises in addition to aerobic exercise (101 [EL 1; RCT]). The Look AHEAD study had a goal of ≥175 minute/week of moderately intense activity in addition to a focus on increased lifestyle daily activity. The 1-year results revealed a significant association between minutes of physical activity and weight loss, indicating that those who were more active lost more weight (96 [EL 1; RCT]). The benefits and risks of increasing physical activity and the practical aspects of implementing a physical training program in people with T2D are discussed in detail in a position paper (104 [EL 4; consensus NE]). The key points are that patients must be evaluated initially for contraindications and/or limitations to increased physical activity; an exercise prescription should be developed for each patient according to both goals and limitations; and additional physical activity should be started slowly and built up gradually.
People with T1D generally experience the same benefits of regular physical exercise as T2D patients. However, patients requiring insulin therapy must also learn about the acute and chronic effects of exercise on glucose regulation and how to adjust insulin dosages and food intake to maintain glucose control before, during, and after exercise to avoid significant hypoglycemia or hyperglycemia (105 [EL 4; NE]). The final component of therapeutic lifestyle change is the use of behavior modification strategies in support of healthy eating and regular activity. However, several studies have shown that attempts to include lifestyle change counseling as part of routine primary care fail to help patients achieve or sustain weight loss. In addition, the initial success of a structured lifestyle program may fade without continued support (106 [EL 1; RCT, not blinded]), suggesting that ongoing behavioral strategies in addition to education on healthy eating and physical activity should be included in lifestyle intervention programs. Look AHEAD’s long-term behavior modification program included regular individual and periodic group contact modeled on the DPP. The results demonstrated that extended behavioral support within an intensive lifestyle intervention program helps facilitate meaningful weight loss for up to 8 years (95 [EL 1; RCT, not blinded]). The behavioral strategy “toolbox” in both the DPP and Look AHEAD studies suggested an array of options including motivational interviewing, goal setting to improve adherence, refresher courses, campaigns, and incentives such as prizes.

 

Q 4.2. Terapia farmacologica ipoglicemizzante per T2D

The goal of glycemic treatment in subjects with T2D is to achieve clinical and biochemical targets with as few adverse consequences as possible. This straightforward statement has important implications for the choice of specific antihyperglycemic agents in T2D, which should be guided by the patient’s medical needs and treatment goals, as well as the agent’s glucose-reducing potency, tolerability and side-effect profile, ease of administration and convenience, cost effectiveness, and extraglycemic effects. All currently available oral glucose-lowering agents are more or less similar in their glucose-lowering potency (107 [EL 1; MRCT]; 108 [EL 3; CSS]). As monotherapy, most oral antihyperglycemic agents reduce A1C by 0.5 to 2.0%. Larger decrements are seen in patients with more marked A1C elevations, likely explaining the apparent greater efficacy of older agents versus newer ones (4 [EL 4; NE]). However, the various classes of glucose-lowering agents differ widely in other respects (Table 9).
Complete descriptions of available antihyperglycemic agents, their mechanisms of action, and rationale for use in different clinical situations can be found in the 2015 AACE Comprehensive Diabetes Management Algorithm Consensus Statement (4 [EL 4; NE]) as well the 2012 Joint ADA/European Association for the Study of Diabetes (EASD) Algorithm Consensus Statement (109 [EL 4; NE]). In addition to lowering glucose, the priority in DM management is to minimize the risks of hypoglycemia and weight gain. The AACE preferentially recommends agents that do not increase these risks (Table 10).
Metformin carries a low risk of hypoglycemia, is weight neutral, produces durable antihyperglycemic effects, and has robust cardiovascular safety; however, it should not be used in patients with advanced renal impairment (69 [EL 1; RCT]; 110 [EL 1; RCT]; 111 [EL 4; NE]; 112 [EL 2; RCCS]). It is equally efficacious across all weight categories (normal, overweight, and obese) in T2D (113 [EL 1; MRCT]). Metformin may have anorectic effects, is sometimes associated with weight loss, may cause gastrointestinal (GI) adverse effects (e.g., dyspepsia, loose stools, or diarrhea), and may be associated with the development of vitamin B12 deficiency over time (114 [EL 1; RCT]). Metformin should be continued as background therapy and used in combination with other agents, including insulin, in patients who do not reach their glycemic target on monotherapy. When metformin is contraindicated or not tolerated, acceptable alternatives include GLP-1 receptor agonists, SGLT2 inhibitors, DPP-4 inhibitors, and α-glucosidase inhibitors. TZDs, sulfonylureas, and glinides may also be used, although caution should be exercised owing to the potential for weight gain, hypoglycemia, or other risks.
Sulfonylureas and glinides increase insulin secretion in a glucose level-independent fashion. Ideal candidates for treatment with sulfonylureas are patients with T2D whose duration of DM is <5 years and who do not have end-organ complications (e.g., CKD), and are willing to follow a healthy diet and exercise plan and perform SMBG to reduce the likelihood of hypoglycemia. For unknown reasons, not all patients with T2D respond to sulfonylureas (primary failure), and antihyperglycemic effectiveness declines after several years of treatment in many patients (secondary failure) (115 [EL 1; RCT]). The main side effect of the sulfonylureas is hypoglycemia, which can be more prolonged than that produced by insulin, particularly when longer-acting formulations are used in the elderly (116 [EL 4; NE]). Renal insufficiency also increases the risk of sulfonylurea-associated hypoglycemia.
TZDs have been shown to improve insulin sensitivity and to preserve or improve β-cell secretory function in patients with T2D. In addition to their glycemic effects, these agents also improve a wide range of cardiovascular risk markers (117 [EL 1; RCT]; 118 [EL 1; MRCT]) and may help prevent central nervous system insulin resistance related cognitive dysfunction (119 [EL 2; PCS]). Clinical studies and meta-analyses of RCTs reported that treatment with pioglitazone results in a statistically significant reduction in the composite outcome of nonfatal acute myocardial infarction, stroke, and all-cause mortality (120 [EL 1; MRCT]). TZDs are also useful in patients with nonalcoholic steatohepatitis (121 [EL 4; review NE]); however, they lead to weight gain comparable to that with sulfonylurea and insulin therapy (122 [EL 2; MNRCT]). TZDs may also cause fluid retention (particularly in patients with cardiac or renal disease), which may contribute to TZD-associated weight gain and peripheral edema. Because of this, TZDs are contraindicated in patients with New York Heart Association class 3 and 4 congestive heart failure. TZDs can also reduce bone mineralization and are associated with nonosteoporotic bone fractures (123 [EL 1; RCT, posthoc analysis]; 124 [EL 2; PCS]). The TZD rosiglitazone has been withdrawn from use in Europe and was severely restricted in the United States because of concerns over a possible increase in CVD risk (125 [EL 4; review NE]). The FDA recently lifted this restriction (126 [EL 4; NE]). According to the FDA, pioglitazone, but not rosiglitazone, may be associated with increased rates of bladder cancer, although there is not enough evidence to support a clear association (127 [EL 4; NE]). A recent cumulative exposure analysis involving data from 1.01 million persons from multiple countries over 5.9 million person-years found no association between exposure to pioglitazone and bladder cancer (128 [EL 3; SS]).
The GLP-1 receptor agonists and DPP-4 inhibitors increase insulin secretion in a glycemic level-dependent manner. In addition to glucose lowering, the GLP-1 receptor agonists may slow gastric emptying, promote early satiety, and reduce food intake, which may result in weight loss. Currently approved GLP-1 receptor agonists include albiglutide, dulaglutide, exenatide, and liraglutide, which are administered by injection on a twice daily, daily, or weekly basis. These agents are most useful as add-on therapies for patients with inadequately controlled DM during oral monotherapy (129 [EL 1; RCT]; 130 [EL 1; RCT follow-up study]; 131 [EL 1; RCT]; 132 [EL 1; RCT]; 133 [EL 1; RCT]; 134 [EL 4; animal study NE]; 135 [EL 1; RCT]; 136 [EL 1; RCT]; 137 [EL 1; RCT]). Several clinical trials have compared the effects of adding a GLP-1 receptor agonist (exenatide twice daily or liraglutide) to insulin (glargine insulin or mixed insulin) in patients with inadequately controlled T2D on oral agents (138 [EL 1; RCT]; 139 [EL 1; RCT]; 140 [EL 1; MRCT]). All of the studies show equivalent or slightly better A1C lowering by GLP-1 receptor agonists with the advantages of a 2- to 3-kg weight loss and little or no additional hypoglycemia.
The main adverse effects with GLP-1 receptor agonists are nausea, vomiting, and diarrhea (141 [EL 1; MNCT]), which usually diminish over time. Approximately 5 to 10% of patients cannot tolerate these drugs due to GI effects. In rodents, GLP-1 receptor agonists may increase the frequency of benign and malignant C-cell neoplasms; however, in humans, neither acute pancreatitis nor medullary thyroid carcinoma has been convincingly shown to be caused by incretin-based therapies (142 [EL 4; NE]). Nevertheless, GLP-1 receptor agonists should be used cautiously in patients with a history of pancreatitis and discontinued if acute pancreatitis develops during use. All GLP-1 receptor agonists except twice-daily exenatide are contraindicated in patients with a personal or family history of medullary thyroid carcinoma and in patients with multiple endocrine neoplasia syndrome type 2. The FDA has stated that patients taking a GLP-1 receptor agonist do not need to be monitored for medullary thyroid carcinoma (e.g., with calcitonin levels).
DPP-4 inhibitors do not cause weight gain; they can be administered in patients with CKD at full dosage when not cleared by the kidneys (linagliptin) or with appropriate dose adjustment for agents that are renally cleared (sitagliptin, saxagliptin, alogliptin); they lack significant GI adverse effects (143 [EL 4; opinion NE]); and they have been associated with reduction in cardiovascular events in analyses of registration trials (144 [EL 1; MRCT]), although neither benefit nor harm was seen in cardiovascular outcome studies conducted in subjects with advanced CVD in placebo-controlled, randomized studies with alogliptin or saxagliptin (145 [EL 1; RCT]; 146 [EL 1; RCT]). The trial comparing saxagliptin with placebo showed an increased likelihood of hospitalization for congestive heart failure and an increase in hypoglycemia (146 [EL 1; RCT]); this should lead to caution in the use of this agent in persons with a history of heart failure who also have existing CVD. With regard to hypoglycemia, it should be noted that approximately 40% of the patients receiving saxagliptin in the trial also received a sulfonylurea, a combination that increases the likelihood of hypoglycemia. The main adverse effects noted with DPP-4 inhibitors are a small increase in upper respiratory tract viral infections (rates of nasopharyngitis were 6.4% with a DPP-4 inhibitor versus 6.1% with comparators; risk ratio, 1.2; 95% confidence interval [CI] 1.0 to 1.4) and a rare hypersensitivity reaction (141 [EL 1; MNCT]).
The SGLT2 inhibitors are the newest oral agents approved for the treatment of T2D. The glucosuric effect of these agents leads to weight loss in most patients. Most patients also experience decreases in systolic blood pressure. Elderly patients on loop diuretics need to be monitored for postural hypotension. Because they exert their glycemic effects in the kidney, these agents have limited efficacy in patients with CKD. Also, by increasing glycosuria, SGLT2 inhibitors may increase the risk of urinary infection and fungal genital tract infection. Small increases in LDL-C levels (4 to 8 mg/dL) occurred with canagliflozin, dapagliflozin, and empagliflozin in pivotal trials. Dehydration due to increased diuresis could lead to hypotension and adverse cardiovascular effects, although no cardiac safety signals have been reported (147 [EL 4; NE]). Bone fracture has been described in postmarketing safety reporting. As with all new agents, aggressive postmarketing surveillance for SGLT2 inhibitor adverse effects is ongoing.
Colesevelam, α-glucosidase inhibitors, and bromocriptine primarily affect PPG levels and are worth consideration in selected patients. Colesevelam carries a low risk of hypoglycemia and also reduces LDL-C, for which it was originally developed. Its main adverse effect is constipation, but it is not systemically absorbed and therefore is not likely to have systemic adverse effects (148 [EL 4; NE]).
α-Glucosidase inhibitors also have a low risk for hypoglycemia, although patients may not tolerate the GI side effects (e.g., bloating, flatulence, diarrhea). Clinical trials have shown some cardiovascular benefit in patients with IGT or DM (36 [EL 1; RCT]; 37 [EL 1; RCT]).
The dopamine receptor agonist bromocriptine does not cause hypoglycemia. It can cause nausea and orthostasis and should not be used in patients taking antipsychotic drugs. Bromocriptine may be associated with reduced cardiovascular event rates (149 [EL 1; RCT]).
Because many patients do not achieve adequate glycemic control with monotherapy, combining antihyperglycemic agents is often appropriate (4 [EL 4; NE]). Metformin is quite effective when administered in combination with the other agents, as long as one avoids its use in patients with CKD (creatinine ≥1.4 mg/dL in females or ≥1.5 mg/dL in males) (4 [EL 4; NE]) or GI intolerance. Sulfonylureas, in contrast, are problematic when used in combinations because they can cause hypoglycemia and may reduce, eliminate, or minimize the weight-loss benefit of drugs such as metformin, GLP-1 receptor agonists, and SGLT2 inhibitors (122 [EL 2; MNRCT]).

 

Q 4.2.1. Uso dell’insulina nel T2D

Insulin is usually initiated in T2D when combination therapy with other agents fails to maintain the glycemic goal, or when a patient, whether drug naïve or on a treatment regimen, presents with an A1C level >9.0% and symptomatic hyperglycemia (4 [EL 4; NE]). The traditional postponement of insulin therapy after prolonged failure of lifestyle and oral agents to achieve glycemic control has been revised in the last decade to incorporate primarily basal insulin therapy much sooner, often in combination with oral agents or GLP-1 receptor agonists (4 [EL 4; NE]; 109 [EL 4; NE]).
Insulin therapy may be initiated as a basal, basal-bolus, prandial, or premixed regimen, although for most patients, starting with a basal insulin analog added to the existing antihyperglycemic regimen is preferred (Table 11) (4 [EL 4; NE]). The combination of insulin with any antihyperglycemic agent raises the potential for hypoglycemia. Patients should be closely monitored, and those on sulfonylureas or glinides may require dosage reductions or discontinuation of the oral agent. TZDs can be associated with weight gain, edema, and increased risk of congestive heart failure in combination with insulin. Basal insulin analogs are preferred over NPH insulin because of a reduced risk of hypoglycemia (150 [EL 1; RCT]; 151 [EL 1; MRCT]; 152 [EL 1; MRCT]; 153 [EL 1; RCT]). The insulin regimen to be prescribed and the exact treatment goals should be discussed with the patient.
Insulin-treated patients should be instructed in SMBG. Most insulin-treated patients with T2D should conduct SMBG ≥2 times daily, but the frequency and timing should be dictated by the particular needs and goals of the patient, as well as hypoglycemia risk (see Q18. When and how should glucose monitoring be used?).
Premixed insulins are popular with patients, but they provide less dosing flexibility and have been associated with a higher frequency of hypoglycemia compared to basal and basal-bolus regimens (154 [EL 1; RCT]; 155 [EL 3; SS]; 156 [EL 1; RCT]). Nevertheless, there are some patients for whom a simpler regimen is a reasonable compromise.
When mealtime glucose control is needed or when glycemic goals are not met on a basal insulin regimen plus oral agents or a GLP-1 receptor agonist, insulin therapy intensification to a basal-bolus regimen (using a rapid-acting insulin analog or inhaled insulin) should be considered (Table 12).
Use of the amylin analog pramlintide in conjunction with bolus insulin improves both glycemia and weight in patients with T2D (157 [EL 1; RCT, small sample size]; 158 [EL 1; RCT, not blinded]). The incretins (GLP-1 receptor agonists and DDP-4 inhibitors) have properties similar to those of pramlintide and also increase endogenous insulin secretion. The combination of basal insulin and incretin therapy decreases basal glucose and PPG and may minimize weight gain and the risk of hypoglycemia compared with basal-bolus insulin regimens. Pharmacokinetic and pharmacodynamic studies of combination GLP-1 receptor agonists and basal insulin analogs have shown an additive effect on blood glucose decreases (138 [EL 1; RCT]; 159 [EL 1; RCT]; 160 [EL 4; NE]; 161 [EL 1; RCT]; 162 [EL 1; RCT, not blinded, not placebo controlled]). The combined use of DPP-4 inhibitors or SGLT2 inhibitors with insulin is also effective in improving glycemic control with a relatively low risk of hypoglycemia (163 [EL 1; RCT]; 164 [EL 1; RCT]).
Hypoglycemia and weight gain are the most common adverse effects of insulin therapy (4 [EL 4; NE]; 165 [EL 4; NE]). Rates and the clinical impact of hypoglycemia are frequently underestimated (166 [EL 4; NE]), but about 7 to 15% of insulin-treated patients with T2D experience at least 1 episode of hypoglycemia per year (167 [EL 1; RCT, not blinded]), and 1 to 2% have severe hypoglycemia (165 [EL 4; NE]; 166 [EL 4; NE]). The frequency of hypoglycemia increases with intensive insulin targets, use of sulfonylureas, decreased caloric intake, delayed meals, exercise, alcohol consumption, CKD, T2D duration, and cognitive impairment (166 [EL 4; NE]). Large randomized trials conducted in subjects with established T2D have revealed that subjects with a history of 1 or more severe hypoglycemic events had an approximately two- to fourfold higher rate of mortality for reasons that remain unknown (64 [EL 3; SS]; 168 [EL 1; RCT]). It has been proposed that hypoglycemia may be a marker for persons at higher risk of death rather than being its proximate cause (166 [EL 4; NE]); nevertheless, avoidance of hypoglycemia by appropriately reducing insulin dosages seems prudent.
Patients receiving insulin gain about 1 to 3 kg more weight than they do with other treatment agents. Patients with proliferative retinopathy and an A1C >10% are at highest risk of worsening retinopathy (169 [EL 4; NE]).
More detail on insulin therapy initiation, titration, and intensification for T2D can be found in the 2015 AACE Comprehensive Diabetes Management Algorithm (4 [EL 4; NE]).


 

Q 5. Come gestire la glicemia nel diabete mellito tipo 1?

Insulin therapy is necessary for life in all patients with T1D (EL 1; “all-or-nothing”). Physiologic insulin regimens, using both basal and prandial insulin, provided by either MDI or CSII, have not been formally tested in RCTs against nonphysiologic insulin regimens (once or twice daily insulin). Rather, physiologic insulin regimens have been formally studied as 1 component of a comprehensive treatment strategy for patients with T1D.
Numerous RCTs have compared basal insulin analogs with NPH insulin in addition to rapid-acting analogs with regular human insulin. With insulin analogs, no additional improvements in A1C have been shown, but there is a consistent reduction of moderate and severe hypoglycemia (170 [EL 4; review NE]). In comparisons of MDI and CSII for T1D, there have been small but consistent improvements in A1C, as well as substantial reductions in severe hypoglycemia (171 [EL 1; MRCT]; 172 [EL 1; MRCT]).

 

Q 5.1. Principi fondamentali di terapia insulinica nel T1D

The starting dose of insulin is usually based on weight, with doses ranging from 0.4 to 0.5 units/kg/day of total insulin with higher amounts required for patients who are obese (increasingly common in T1D) or have a sedentary lifestyle, as well as during puberty.
In general, basal insulin requirements are usually 40 to 50% of the total daily insulin doses. No data support the superiority of 2 injections of a basal insulin analog over 1injection of basal insulin analog in patients with T1D.
The dose of prandial insulin is usually determined by estimating the carbohydrate content of the meal. Insulin to-carbohydrate (I:C) ratios usually range from 1:20 for the very insulin sensitive to 1:5 for the insulin-resistant patient. Similarly, correction dose insulin for premeal or between meal hyperglycemia is based on the insulin sensitivity factor (ISF), which is based on the overall insulin sensitivity of the patient, loosely estimated by the individual’s total daily insulin dose. Although various formulas have been used to estimate the appropriate ISF, this parameter should only be viewed as an estimation due to numerous factors that can alter blood glucose. The most commonly used formula is:
1,800/total daily dose of insulin = Number of mg/dL of glucose that will be reduced by 1 unit of insulin
The other key factor that needs to be appreciated is insulin action time. For most subcutaneous injections, this ranges from 4 to 6 hours. There are no data to quantify an individual patient’s insulin action time and in fact it can change from day to day.
With the knowledge of the I:C ratio, ISF, and insulin action time, patients on MDI or CSII can calculate the appropriate correction dose insulin. This is significantly simpler with CSII, as most pumps include bolus calculators to perform the calculations by pressing a few buttons. For those using MDI, there are a variety of smart phone apps available, in addition to several blood glucose meters that can assist patients with these calculations. Most patients using MDI, however, will need to estimate the “insulin on board” from the last injection of prandial insulin based on standard curves that can be provided to them (170 [EL 4; review NE]).

 

Q 5.2. Farmaci complementari per il T1D

The amylin analog pramlintide, the only other medication approved for the treatment of T1D, is administered with prandial insulin. A1C reductions are consistently modest, and mild weight loss is common. Nausea is a common adverse effect. There is a potential risk of severe hypoglycemiaif patients do not appropriately reduce the prandial insulin dosage (173 [EL 1; RCT]; 174 [EL 1; RCT]; 175 [EL 1; RCT]; 176 [EL 1; MRCT]). Tachyphylaxis is often seen after several years of therapy.
While there is growing interest and anecdotal reports of successful use of both GLP-1 receptor agonists and SGLT2 inhibitors in T1D, to date appropriate trials have not been published, and formal recommendations cannot be provided. In addition, recommendations for the use of metformin in T1D cannot be made due to lack of indication and concerns of lactic acidosis in a population predisposed to ketoacidosis. Nevertheless, the use of metformin in T1D has been of great interest, and new data should be available in the future (177 [EL 1; MRCT]).


 

Q 6. Come gestire l’ipoglicemia?

Q 6.1. Definizione

The classical definition of hypoglycemia in patients with DM is a low blood glucose level accompanied by symptoms of hypoglycemia (e.g., palpitations, hunger; see section 4.Q6.2) that are relieved by the ingestion of glucose (i.e., the Whipple triad) (178 [EL 4; review NE]). However, hypoglycemia may be asymptomatic, and any blood glucose <70 mg/dL is generally considered hypoglycemia (179 [EL 4; NE]). In addition, hypoglycemia symptoms can occur in the normal glucose range in a patient with very high glucose levels that drop quickly. SMBG can be helpful but is not necessarily diagnostic because of glucose meter inaccuracy.
Severe hypoglycemia is defined as any low blood glucose event that requires assistance from another person to administer carbohydrates or glucagon or take other corrective action (179 [EL 4; NE]).

 

Q 6.2. Sintomi

Hypoglycemia manifests as neurogenic and/or neuroglycopenic symptoms that range in severity from mild to life threatening and include anxiety, palpitations, tremor, sweating, hunger, paresthesias, behavioral changes, cognitive dysfunction, seizures, and coma. Certain hypoglycemia-related responses (psychomotor function) are altered in the elderly compared with younger patients. Although severe hypoglycemia generally results in recognizable symptoms, mild-to-moderate hypoglycemia may remain asymptomatic and unreported in patients with T2D or with hypoglycemia unawareness (179 [EL 4; NE]).

 

Q 6.3. Eziologia

In patients with DM, iatrogenic hypoglycemia stems from an imbalance among insulinogenic therapy, food intake, physical activity, organ function (gluconeogenesis), and counterregulation with glucagon and/or epinephrine (hypoglycemia-associated autonomic failure). Hyperinsulinemia, increased alcohol intake, starvation, and organ failure may be aggravating factors (166 [EL 4; NE]; 180 [EL 4; NE]). Noniatrogenic hypoglycemia (i.e., insulinoma) is beyond the scope of these guidelines.

 

Q 6.4. Rischi

The primary cause of hypoglycemia is intensification of therapy to achieve a lower A1C target, as demonstrated by intensive therapy trials. Over 3.5 years in the ACCORD study, severe hypoglycemia occurred at an annualized rate of 3.1% of patients in the intensive therapy group (mean endpoint A1C 6.4%; target <6.0%) versus 1.0% per year in the standard therapy group (mean endpoint A1C 7.5%) (62 [EL 1; RCT]). During the ADVANCE study, in which the goal A1C of 6.5% was met in the intensive group, 0.7% of intensively treated patients experienced severe hypoglycemia on an annual basis compared with 0.4% of patients per year in the standard care group (57 [EL 1; RCT]). Finally, in the UKPDS (United Kingdom Prospective Diabetes Study), wherein intensive treatment led to a mean endpoint A1C of 7.0%, hypoglycemia occurred in 1.8% of insulin-treated patients per year in the intensive group versus 0.7% of conventionally treated patients per year (69 [EL 1; RCT]). The risk of hypoglycemia is greater in older patients and those with longer DM duration, kidney failure, or lesser insulin reserve. Dementia is another important risk factor for hypoglycemia, and recurrent hypoglycemia appears to increase the risk of dementia (181 [EL 3; SS]; 182 [EL 2; RCCS]; 183 [EL 2; PCS]). The failure to recognize symptoms of hypoglycemia can increase the risk of subsequent hypoglycemia by causing autonomic failure, leading to a cycle of recurrent hypoglycemia and hypoglycemia unawareness (180 [EL 4; NE]).

 

Q 6.5. Complicanze

Recent studies have suggested an association of hypoglycemia with adverse cardiovascular events. In ADVANCE, severe hypoglycemia was associated with significant risk increases for cardiovascular events including death (168 [EL 1; RCT]). In ACCORD, hypoglycemia was considered a suspect behind the increased mortality observed in the intensive-treatment arm. However, glucose levels at time of death were unknown, and the hypothesis remains unproven (58 [EL 1; RCT]; 64 [EL 3; SS]). Moreover, the HR for hypoglycemia-related mortality was even higher in the standard therapy arm of that study (adjusted HR in intensive treatment arm: 1.41, 95% CI, 1.03 to 1.93; in standard therapy arm: 2.30, 95% CI, 1.46 to 3.65) (64 [EL 3; SS]). A recent meta-analysis of prospective and retrospective clinical trials demonstrated that severe hypoglycemia doubled the risk of cardiovascular events (184 [EL 2; MNRCT]), while an observational trial showed that, over a period of 5 years, mortality was 3.4 times higher among patients who reported severe hypoglycemia at baseline (185 [EL 2; PCS]). The proposed mechanism for these effects posits that hypoglycemia reduces baroreceptor sensitivity and increases sympathoadrenal system activity, which can trigger a fatal ventriculararrhythmia in the setting of reduced baroreflex sensitivity (186 [EL 4; NE]).
Other short- and long-term consequences of severe hypoglycemia include neurologic conditions ranging from temporary cognitive impairment to dementia as well as major vascular events such as stroke, myocardial infarction, acute cardiac failure, ventricular arrhythmias, and sudden death (166 [EL 4; NE]; 180 [EL 4; NE]; 187 [EL 4; NE]). The complications of hypoglycemia are also associated with short-term disability and higher healthcare costs (188 [EL 4; NE]).

 

Q 6.6. Gestione

Hypoglycemia is the primary limiting factor in the treatment of both T1D and T2D. It remains a significant barrier in terms of treatment adherence and achievement of glycemic goals (166 [EL 4; NE]).
Long-term management of hypoglycemia depends on appropriate adjustment of therapy to prevent hypoglycemia or reduce its frequency and severity in patients prone to hypoglycemia (e.g., the elderly and patients with T1D). In T2D, hypoglycemia typically occurs in association with use of exogenous insulin, sulfonylureas (especially glyburide) (189 [EL 1; MRCT]), and glinides; symptoms may be mild, moderate, or severe. The risk of hypoglycemia may be further increased by the addition of other antihyperglycemic agents to sulfonylureas or insulin. Therefore, in adults with T2D, treatment strategies should emphasize classes of pharmaceutical agents that are not associated with severe hypoglycemia, many of which are available (Table 9). Also, the role of hypoglycemia must be considered in determining ideal A1C goals for each patient. These issues are reviewed in the AACE algorithm for T2D (4 [EL 4; NE]).
SMBG is an important tactic to help patients document hypoglycemia, although it is essential that the glucose meter meet accuracy standards. CGM may be useful in patients with recurrent asymptomatic hypoglycemia (hypoglycemia unawareness) (179 [EL 4; NE]).
Patients who have marked swings in glucose levels are particularly susceptible to hypoglycemia unawareness. This condition can be reversed by a period of therapy that dampens glycemic excursions and hypoglycemia avoidance (190 [EL 2; NRCT]; 191 [EL 3; SCR]).


 

Q 7. Come gestire l’ipertensione nei diabetici?

The majority of persons with T2D either have uncontrolled hypertension or are on treatment for elevated blood pressure (192 [EL 3; SS]). Hypertension is not only more prevalent in persons with T2D than in the general population, it also predicts progression to DM. Once diagnosed with hypertension, an individual is 2.5 times more likely to be diagnosed with DM within the next 5 years (193 [EL 2; PCS]; 194 [EL 4; review NE]). The combination of hypertension and DM magnifies the risk of DM-related complications. The UKPDS demonstrated that hypertension treatment decreased both micro- and macrovascular complications of DM (195 [EL 1; RCT]). This study showed that each 10 mm Hg decrease in systolic blood pressure (achieved with either an ACE inhibitor [captopril] or an β-adrenergic blocker [atenolol]) was associated with a 15% reduction in rates of DM-related mortality, an 11% reduction in myocardial infarction, and a 13% reduction in the microvascular complications of retinopathy or nephropathy (196 [EL 2; PCS]).
Subsequent trials that have included large numbers of persons with DM, including the HOT (Hypertension Optimal Treatment) trial (197 [EL 1; RCT]), the HOPE (Heart Outcomes Prevention Evaluation) study (198 [EL 1; RCT]), the LIFE (Losartan Intervention for Endpoint Reduction in Hypertension) study (199 [EL 1; RCT]), and ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) (200 [EL 1; RCT]), have demonstrated that blood pressure control improves cardiovascular outcomes when aggressive blood pressure targets are achieved. Numerous other studies have also demonstrated decreased nephropathy and retinopathy progression. Based on these data, the Seventh Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7), AACE, and ADA previously recommended that blood pressure in DM be controlled to <130/80 mm Hg (201 [EL 4; NE]; 202 [EL 4; CPG NE]; 203 [EL 4; NE]; 204 [EL 4; NE]).
However, the target for blood pressure lowering remains somewhat controversial as clinical trial data to support the level of 130/80 mm Hg are sparse. Epidemiologic data suggest no evidence of a threshold for adverse outcomes, with a normal blood pressure level <115/75 mm Hg (205 [EL 4; review NE]). Clinical trial data show that intensifying therapy with blood pressure-lowering medications slows the progression of nephropathy and retinopathy (195 [EL 1; RCT]; 196 [EL 2; PCS]; 206 [EL 1; RCT, questionnaires and other variables may have confounded]). Neither the ACCORD blood pressure trial nor subanalyses of other large blood pressure trials have shown that targeting a systolic blood pressure <120 mm Hg (compared with <140 mm Hg) has any impact on the standard composite outcome of fatal and nonfatal major cardiovascular events in persons with DM, although stroke was significantly reduced (HR 0.59; 95% CI, 0.39 to 0.89; P = .01) (207 [EL 1; RCT]). Thus, data from prospective RCTs do not support a positive effect of blood pressure targets below 130/80 mm Hg on cardiovascular outcomes. Consequently, various recently published guidelines from different societies have generally recommended a blood pressure target for persons with DM of <140/80 to 90 mm Hg, with an option to individualize to the lower target of <130/80 mm Hg (8 [EL 4; NE]; 208 [EL 4; NE]; 209 [EL 4; NE]; 210 [EL 4; NE]; 211 [EL 4; NE]; 212 [EL 4; NE]).
Once the diagnosis of hypertension is established, the data are clear that blood pressure lowering prevents both micro- and macrovascular complications associated with DM. Analysis of the UKPDS data suggests that blood pressure lowering should be the first priority in managing a patient presenting with newly diagnosed hypertension and DM. While glucose and lipid management remain important, blood pressure lowering will have the greatest and most immediate impact on morbidity and mortality (195 [EL 1; RCT]; 206 [EL 1; RCT, questionnaires and other variables may have confounded]).
Accurate measurement of blood pressure remains fundamental to the diagnosis and effective management of hypertension (8 [EL 4; NE]). The equipment, which can be aneroid, mercury, or electronic, should be inspected and validated on a regular maintenance schedule. Initial training and regularly scheduled retraining in the standardized technique provides consistency in measurements. The patient must be properly prepared and positioned; blood pressure should be measured after being seated quietly for at least 5 minutes in a chair (rather than on an exam table), with feet on the floor and arm supported at heart level. Caffeine, exercise, and smoking should be avoided for at least 30 minutes prior to measurement. Measurement of blood pressure in the standing position is indicated periodically, especially in those at risk for postural hypotension. An appropriately sized cuff (cuff bladder encircling at least 80% of the arm) should be used to ensure accuracy. At least 2, and preferably 3, measurements should be made and the average recorded.
While 24-hour ambulatory blood pressure monitoring (ABPM) is not included as part of the diagnostic criteria for hypertension, it has become an important tool for guiding patient management. Patients whose 24-hour ABPM mean blood pressure exceeds 135/85 mm Hg are nearly twice as likely to have a cardiovascular event as those with values that remain <135/85 mm Hg, irrespective of the level of the office blood pressure (213 [EL 4; review NE]). Routine use of ABPM, at least annually, should be considered for the evaluation of white coat hypertension, masked hypertension, and nighttime nondipping status, all of which are associated with increased long-term morbidity and mortality.
Blood pressure targets are based upon the combination of data from clinical trials and epidemiology studies and should be individualized for patients with consideration of their anticipated lifespan and risk factors for heart disease and stroke (e.g., presence of metabolic syndrome, smoking, and evidence of end organ damage). In the presence of multiple risk factors, consideration can be given to an intensive goal of <120/80 mm Hg, provided it can be attained safely, with a less intense goal of <130/80 mm Hg in patients with complicated comorbidities and/or medication side effects. Frequent reassessment is needed to ensure that the blood pressure goal is maintained without unacceptable adverse effects. If side effects develop, consideration should be given to reducing dosage and/or changing the class of medication. If such changes do not alleviate symptoms, consideration should be given to relaxing the target to the higher level of <140/80 to 90 mm Hg, which will still provide cardiovascular protection.
The selection of medications can be guided by disease and ethnic-specific considerations. Clinical trials with diuretics, ACE inhibitors, ARBs, β-adrenergic blockers, and calcium antagonists have a demonstrated benefit in the treatment of hypertension in both T1D and T2D (Table 13) (8 [EL 4; NE]; 197 [EL 1; RCT]; 198 [EL 1; RCT]; 199 [EL 1; RCT]; 214 [EL 1; RCT, posthoc analysis]). Whether any class is superior to another is no longer considered when choosing therapy because most patients with DM will need at least 2 to 4 drugs to achieve target blood pressure. The choice of pharmacologic agents is guided by additional considerations such as the presence of albuminuria, CVD, heart failure, or postmyocardial infarction status; possible metabolic side effects; number of pills per day; and cost. Early in the disease process, the primary concerns will be slowing of nephropathy and retinopathy while minimizing impact on triglycerides (Table 13). As heart disease develops, consideration of cardiovascular benefits factor into the choice of agents for blood pressure lowering; given that diastolic heart disease develops early in T2D, the use of ARBs could be considered earlier, before the diagnosis of systolic heart failure. However, the combination of multiple RAAS blockers (i.e., ACE inhibitor, ARB, and/or renin inhibitor) should generally be avoided (215 [EL 1; RCT]; 216 [EL 4; NE]).
The UKPDS study group performed a 10-year post trialmonitoring observational study that demonstrated a loss of benefit within 2 years if tight blood pressure control was not maintained (206 [EL 1; RCT, questionnaires and other variables may have confounded]). These data reinforce the imperative to initiate blood pressure-lowering therapy with continued reinforcement to maintain compliance with therapy. The introduction of fixed-dose combination tablets combining 2 or 3 agents in 1 pill has facilitated patient compliance and adherence with multidrug regimens and should be encouraged as part of initial therapy. The use of multiple fixed-dose combination tablets can provide a 4-drug regimen with just 2 tablets, thus allowing a patient to reach their blood pressure goal while optimizing compliance with therapy. ABPM should be utilized to guide blood pressure management because it allows assessment of the patient’s blood pressure variability, thus facilitating medication adjustments to develop an appropriate individualized treatment regimen and avoid overtreatment.


 

Q 8. Come gestire la dislipidemia nei diabetici?

Q 8.1. Obiettivi lipemici

Treatment targets for dyslipidemia in DM are based on the presence of ASCVD risk factors including hypertension, a family history of ASCVD, low HDL-C, and smoking, as well as serum levels of LDL-C, other lipids, lipoproteins, or lipoprotein components (Table 7). T2D carries a high lifetime risk for developing ASCVD, so risk should be stratified as moderate (patients <40 years of age, no major risk factors) or high (≥1 major risk factors). A potential third category of very high risk (patients with T2D and established ASCVD) could also be considered. Risk stratification in this manner can guide management strategies. In patients at high or very high risk for ASCVD, the goals for LDL-C, non-HDL-C, and ApoB should be <70 mg/dL, <100 mg/dL, and <80 mg/dL, respectively. In patients at moderate risk, the respective goals should be <100 mg/dL, <130 mg/dL, and <90 mg/dL (4 [EL 4; NE]; 7 [EL 4; CPG NE]; 217 [EL 3; SS]). Other targets include a triglyceride concentration <150 mg/dL in all patients, and LDL-P <1,200 nmol/L in patients at moderate risk and <1,000 nmol/L in those at high risk (4 [EL 4; NE]; 7 [EL4; CPG NE]).

 

Q 8.2. Gestione della dislipidemia

A thorough review of the management of dyslipidemia can be found in the 2012 AACE Guidelines for Management of Dyslipidemia and Prevention of Atherosclerosis (218 [EL 4; NE]), and updated targets are discussed in the 2015 AACE Comprehensive Diabetes Management Consensus Statement (4 [EL 4; NE]). In prediabetes and DM, multiple disturbances in lipoprotein metabolism result from the combined effects of insulin deficiency, insulin resistance, and hyperglycemia. T2D dyslipidemia is characterized by increased levels of triglyceride-rich lipoproteins (very low-density lipoprotein, intermediate-density lipoprotein, and remnant particles), low levels of HDL-C, and increased levels of small, dense LDL-P (219 [EL 4; review NE]). Hypertriglyceridemia is thus indirectly linked with changes in HDL-C and LDL-C composition that are conducive to accelerated atherogenesis (220 [EL 4; review NE]). Patients who have T1D with persistent proteinuria are at particularly increased risk of premature atherosclerosis (221 [EL 4; NE]). However, the rising prevalence of overweight and obesity may contribute to increased rates of the lipid and lipoprotein pattern related to insulin resistance among prediabetic individuals and those with T2D (222 [EL 1; RCT]).

 

Q 8.3. Screening e follow-up della dislipidemia (7 [EL 4; CPG NE])

  • Screen all adult patients with yearly fasting lipid profile: total cholesterol, triglycerides, HDL-C, and LDL-C.
  • If not at goal, lipid profiling should be repeated more frequently after initiation of treatment. ApoB determination may also be useful to confirm goal attainment but is not recommended for routine screening (4 [EL 4; NE]; 218 [EL 4; NE]).
  • LDL-C and calculated non-HDL-C (total cholesterol – HDL-C) are the primary targets of therapy, with respective goals set according to risk levels (Table 7). If LDL-C is at goal but non-HDL-C is above goal, consider additional LDL-C or triglyceride-lowering therapies (preferably first with maximally tolerated statin therapy). Once both LDL-C and non-HDL-C targets have been achieved, consider evaluation of secondary targets, either ApoB or LDL-P, and treat accordingly (218 [EL 4; NE]) (4 [EL 4; NE]).
  • Additional biomarkers, including high sensitivity C-reactive protein (hs-CRP), lipoprotein(a), and lipoprotein-associated phospholipase A2 (LpPLA2), are independent risk factors shown to increase ASCVD risk. Measuring these biomarkers may enhance understanding of an individual patient’s risk for consideration of more aggressive therapy (218 [EL 4; NE]).

 

Q 8.4. Raccomandazioni terapeutiche per la dislipidemia

All patients should receive information about physical activity recommendations, a meal plan designed to improve glucose and lipids, and cardiovascular risk reduction strategies. Consultation with a CDE is desirable (7 [EL 4; CPG NE]; 223 [EL 1; RCT]).
CARDS (Collaborative Atorvastatin Diabetes Study), an RCT involving patients with T2D plus hypertension, smoking, retinopathy, and/or microalbuminuria, demonstrated the benefits of statin therapy for primary prevention of CVD in patients with DM (224 [EL 1; RCT]). To date, no RCT dedicated solely to patients with DM has examined CVD secondary prevention. However, several trials with large DM subpopulations, including the GREACE (Greek Atorvastatin and Coronary-Heart-Disease Evaluation), TNT (Treating to New Targets), and PROVE-IT (Pravastatin or Atorvastatin Evaluation and Infection Therapy) trials, have shown significant reductions in mortality and CVD events (225 [EL 1; RCT]; 226 [EL 1; RCT]; 227 [EL 1; RCT, retrospective study]). Therefore, in high-risk patients with DM who have had a prior ASCVD event or those who have DM plus at least 1 additional major ASCVD risk factor (hypertension, family history of ASCVD, low HDL-C, or smoking), a statin should be started along with therapeutic lifestyle changes regardless of baseline LDL-C level (7 [EL 4; CPG NE]; 228 [EL 1; MRCT]; 229 [EL 1; MRCT]). Lipids should be rechecked within 12 weeks. If the LDL-C or non-HDL-C concentration remains >70 mg/dL or >100 mg/dL, respectively, the statin dosage should be titrated with the goal of lowering LDL-C to <70 mg/dL and non-HDL-C to <100 mg/dL (Table 7). If these targets cannot be achieved with maximally tolerated statin therapy, the goal should be to reduce LDL-C by >50%; more potent statins can reduce LDL-C up to 60% (7 [EL 4; CPG NE]; 218 [EL 4; NE]). Measurement of ApoB may be useful in some cases to confirm an ApoB goal of <80 mg/dL (or LDL-P <1,000 nmol/L), even if LDL-C is ≤70 mg/dL (218 [EL 4; NE]). The combination of a statin with another lipid-lowering agent may be required to achieve these targets.
The moderate risk category describes persons with DM without known ASCVD or any of the other major cardiovascular risk factors (hypertension, family history, low HDL-C, smoking). In such patients, treatment should begin with therapeutic lifestyle changes for an initial 6- to 8-week trial. Goals for the primary targets—LDL-C and non-HDL-C—are <100 mg/dL and <130 mg/dL, respectively (212 [EL 4; NE]; 223 [EL 1; RCT]; 224 [EL 1; RCT]; 230 [EL 1; RCT]). The secondary targets ApoB (<90 mg/dL) or LDL-P (<1,200 nmol/L) may also be considered. When goals of therapy are not achievable, for whatever reason, a 30 to 50% reduction in LDL-C is desirable. For patients older than 40 years without diagnosed ASCVD but who have ≥1 additional major ASCVD risk factor, statin therapy may be considered even if the LDL-C concentration is <100 mg/dL (212 [EL 4; NE]; 223 [EL 1; RCT]; 224 [EL 1; RCT]; 230 [EL 1; RCT]). In patients younger than 40 years, initiation of statin therapy for primary prevention of CVD in both males and females needs to be individualized, based on other risk factors and comorbidities. The use of various 10-year or life-time risk calculators is an option to decide the intensity of treatment, but currently available risk calculators lack sufficient accuracy and are limited by discrepancies between predicted and observed event rates (231 [EL 4; NE]; 232 [EL 4; NE]). In patients with statin intolerance or unacceptable adverse events, a bile acid sequestrant (233 [EL 1; RCT]), niacin (234 [EL 1; RCT]; 235 [EL 4; review NE]; 236 [EL 1; RCT]), or cholesterol absorption inhibitor (237 [EL 1; RCT]; 238 [EL 1; RCT]) should be considered alone or in combination. No study has yet been designed to investigate the cardiovascular outcomes benefit of adding bile acid sequestrants, niacin, or cholesterol absorption inhibitors to statins in patients whose atherogenic markers (LDL-C, non-HDL-C, ApoB, and LDL-P) are not already at target levels.
In patients with end-stage renal disease (ESRD) or advanced heart failure, or in those on hemodialysis, no clear evidence supports an ASCVD benefit from LDLC-lowering therapy (239 [EL 4; NE]; 240 [EL 4; NE]). Patients with eGFR <60 mL/min/1.73 m2 who are not dialysis-dependent are at high risk for ASCVD events and should be managed using the LDL-C, non-HDL-C, and ApoB goals defined here. Such patients should be monitored closely to determine whether statin dose adjustment is necessary depending on comorbidities, drug interactions, and renal status (239 [EL 4; NE]; 240 [EL 4; NE]).
In patients with LDL-C at goal but a fasting triglyceride concentration ≥150 mg/dL or low HDL-C (≤35 mg/dL), the following actions should be implemented:

  • Optimize glycemic control and emphasize weight loss (if indicated) (7 [EL 4; CPG NE]; 223 [EL 1; RCT])
  • Modify, if possible, any medications that may contribute to hypertriglyceridemia
  • In patients with fasting triglyceride concentrations of 200 to 499 mg/dL, titrate statin therapy to maximum tolerated dose to achieve goals for LDL-C and non-HDL-C as well as the secondary target (ApoB or LDL-P) (7 [EL 4; CPG NE]; 217 [EL 3; SS]; 241 [EL 2; PCS]); non statin therapies in combination with statins are often required in these settings
  • In the setting of persistently elevated fasting triglycerides (>200 mg/dL) against the background of maximally tolerated LDL-C-lowering therapies, triglyceride-reducing therapies such as a fibrate, high-dose omega-3 fatty acid, or niacin may be utilized to further reduce non-HDL-C (218 [EL 4; NE]; 242 [EL 4; consensus]; 243 [EL 4; review NE]; 244 [EL 3; SS]; 245 [EL 1; RCT]; 246 [EL 3; SS])
  • If the fasting triglyceride concentration is ≥500 mg/dL (i.e., severe hypertriglyceridemia), begin treatment with a very low-fat diet and reduced intake of simple carbohydrates and initiate a fibrate, high-dose omega-3-fatty acid, and/or niacin. All 3 of these triglyceride-lowering therapies may be required in combination in patients with severe hypertriglyceridemia (247 [EL 4; review NE]). No RCT has yet been designed to investigate the additive benefit of reducing severe hypertriglyceridemia to prevent pancreatitis. Observational data and retrospective analyses, however, do support triglyceride-lowering therapy for prophylaxis against or treatment of acute pancreatitis (248 [EL 4; NE]; 249 [EL 3; SS]). Rule out other secondary causes and reassess lipid status when the triglyceride concentration is <500 mg/dL (235 [EL 4; review NE]; 250 [EL 4; NE]). Additional statin therapy and possibly other agents are usually required to achieve the primary LDL-C and non-HDL-C goals (235 [EL 4; review NE]), as well as secondary goals for ApoB or LDL-P, for the purpose of cardiovascular event prevention (248 [EL 4; NE]; 249 [EL 3; SS]). No RCT has yet been designed to investigate the benefit of reducing severe (triglycerides >500 mg/dL) or moderate (>200 mg/dL) hypertriglyceridemia to prevent CVD.

Modification of triglycerides with the proliferator activated receptor-α agonist fenofibrate failed to reduce ASCVD events in 2 separate trials in patients with T2D: FIELD (Fenofibrate Intervention and Event Lowering in Diabetes) (251 [EL 1; RCT]) and ACCORD-Lipid (245 [EL 1; RCT]). The mean baseline triglyceride levels were 153 mg/dL in FIELD (251 [EL 1; RCT]) and 162 mg/dL in ACCORD-Lipid (245 [EL 1; RCT]). Posthoc and prespecified subgroup analyses and meta-analyses of 5 major fibrate trials—HHS (Helsinki Heart Study), VA-HIT (Veterans Affairs HDL Intervention trial), BIP (Bezafibrate Infarction Project), FIELD, and ACCORD-Lipid—have shown a cardiovascular benefit in patients with moderate dyslipidemia (triglycerides >200 mg/dL and HDL-C <40 mg/dL, either isolated or together) but not in patients without dyslipidemia (218 [EL 4; NE]; 252 [EL 4; NE]; 253 [EL 1; MRCT]; 254 [EL 1; MRCT]; 255 [EL 4; NE]).
Two separate RCTs tested the HDL-C-raising hypothesis in patients with coronary artery disease optimally treated with statins with or without ezetimibe. In AIMHIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes), the atherogenic markers LDLC, non-HDL-C, and ApoB were 74, 108, and 81 mg/dL, respectively, prior to randomization (256 [EL 1; RCT]). Before randomization in HPS2-THRIVE (Heart Protection Study 2—Treatment of HDL to Reduce the Incidence of Vascular Events), LDL-C, non-HDL-C, and ApoB were 63, 84, and 68 mg/dL, respectively, and triglyceride and HDL-C levels were 120 mg/dL and 44 mg/dL, respectively (257 [EL 1; RCT]). In each of these trials, the addition of niacin resulted in small improvements in lipids, but these changes were not accompanied by any significant reduction in ASCVD events (256 [EL 1; RCT]; 257 [EL 1; RCT]). Thus niacin cannot be recommended as adjunctive therapy if LDL-C, non-HDL-C, and ApoB goals are already met. However, in other settings, where the goals of these atherogenic markers have not been met, niacin remains a viable treatment option.

 

Q 8.5. Gestione dei lipidi nel prediabete

The principles and goals of lipid management in prediabetes are the same as those for DM described previously (Table 7). No randomized intervention trials dedicated to patients with prediabetes use ASCVD events as outcome measures. Diet, exercise, and weight loss or maintenance should be emphasized for all prediabetes patients.
Moderate-potency or high-potency statins, possibly combined with cholesterol absorption inhibitors or bile acid sequestrants, are effective for achieving LDL-C, non-HDL-C, and ApoB or LDL-P goals in prediabetes (7 [EL 4; CPG NE]). Low HDL-C is also common in prediabetes. Low HDL-C and high triglycerides are both associated with increased levels of LDL-P. Niacin is effective in raising HDL-C, but it also increases insulin resistance and may accelerate the appearance of overt DM. Fibrates may be considered, but the use of gemfibrozil is discouraged owing to its interaction with statin clearance and the risk for severe rhabdomyolysis.
Meta-analyses of statin RCTs indicate that statin use is associated with significant increases in the risk of progression to T2D among patients with prediabetes: a 9% increase with moderate statin dosing and 12% increase with intensive statin dosing (258 [EL 1; MRCT]; 259 [EL 1; MRCT]). Patients with prediabetes should be warned of the potential added risk of conversion to DM with statin use. The net comparison of benefit versus risk is >4 ASCVD events prevented for 1 conversion from prediabetes to DM (260 [EL 4; NE]). A thorough risk-benefit analysis, taking into account the patient’s individual risk of converting to DM versus prevention of ASCVD, should be discussed with the patient.


 

Q 9. Come gestire la nefropatia nei diabetici?

Diabetic nephropathy accounts for 40 to 50% of all cases of ESRD in the U.S. and occurs in about 40% of patients with DM, increasing with age (261 [EL 3; SS]). Diabetic nephropathy is represented histologically by the presence of basement membrane thickening, mesangial expansion, podocyte loss, and nodular or diffuse glomerulosclerosis (262 [EL 4; NE]). The pathologic changes, which modestly correlate with the degree of kidney injury as measured by blood and urine tests, are typically present before functional tests are positive (262 [EL 4; NE]). Consequently, prevention of microvascular complications such as nephropathy should be started upon diagnosis of DM and be intensified in those with evidence of kidney damage. Guidelines for the diagnosis and management of CKD in patients with DM have recently been updated by the Kidney Disease: Improving Global Outcomes (KDIGO) working group (263 [EL 4; NE]) and the Kidney Disease Outcomes Quality Initiative (KDOQI) Committee (264 [EL 4; NE]). The AACE concurs with both guidelines in general.
The KDIGO guidelines recommend phasing out the term microalbuminuria and replacing it with the term albuminuria. Testing for the presence of albuminuria can be done using a spot urine sample or a timed collection. AER levels >30 mg/g creatinine or 30 mg/day indicate kidney damage and are also a marker of cardiovascular risk (263 [EL 4; NE]; 264 [EL 4; NE]). Urinary albumin may be seen in the setting of urinary tract or systemic infection, after exercise, or in the presence of hematuria, so confirmation is necessary to establish the diagnosis of diabetic nephropathy. An AER of >300 mg/g creatinine or >300 mg/day indicates greater damage and greater risk for progression of renal insufficiency, anemia, CVD, and infections. Sudden onset or rapidly increasing AER should prompt additional tests to rule out other kidney diseases. Table 14 lists correlations between AER, urine dipstick, and tests of total protein excretion.
GFR should be estimated from a creatinine-based calculation such as the Modification in Renal Disease (MDRD) or Chronic Kidney Disease Epidemiology (CKDEPI) equations. The CKD-EPI equation is more accurate for calculation of eGFR above 60 mL/min/1.73 m2, and this equation is currently preferred (263 [EL 4; NE]). However, most laboratories report a calculated eGFR using the MDRD when eGFR is <60 mL/min/1.73 m2. Figure 2 depicts the new classification system for CKD in patients with DM that incorporates both eGFR and albuminuria in the risk assessment. Note that in Figure 2, stage 3 CKD has been divided into 2 categories, G3a for eGFR 45 to 60 mL/min/1.73 m2 and G3b for eGFR 30 to 45 mL/min/1.73 m2. The terminology used to describe CKD provides a composite picture by integrating the cause, eGFR, and AER. For example, a patient with DM, an eGFR of 40 mL/min/1.73 m2, and an AER of 250 mg/g creatinine would be categorized as “diabetes/G3b/A2.” The “heat grid” shown in Figure 2 indicates the new terminology, the level of risk for cardiovascular events and progression of kidney disease by color intensity, and the recommended frequency for monitoring renal parameters (263 [EL 4; NE]; 265 [EL 2; MNRST]; 266 [EL 4; NE]). Progression of CKD is classified as rapid if the decline in eGFR is ≥5 mL/min per 1.73 m2 per year or if the patient has a dramatic increase in AER.
Prevention of the development of diabetic nephropathy includes optimal control of plasma glucose (A1C goal <6.5% unless limited by hypoglycemia), blood pressure control with RAAS inhibition as first-line therapy, treatment of hyperlipidemia, and smoking cessation (264 [EL 4; NE]). Intensive glucose control (A1C levels <7% in T2D and <7.5% in T1D) in several early intervention studies reduced the risk of incident albuminuria (A2) and progression of AER to proteinuria (47 [EL 1; RCT]; 51 [EL 1; RCT]; 57 [EL 1; RCT]; 68 [EL 1; RCT]; 69 [EL 1; RCT]). Intensive glucose control has not been shown to diminish the progression of diabetic nephropathy or cardiovascular mortality in patients with advanced CKD, but these patients have an increased risk of hypoglycemia, so glycemic targets and therapies may need to be modified as diabetic nephropathy progresses.
The KDIGO guidelines recommend that patients without albuminuria be treated to a blood pressure <140/90 mm Hg, but <130/80 mm Hg in the presence of albuminuria (267 [EL 4; NE]). Although care must be taken to avoid orthostasis and drug side effects, AACE recommends individualized blood pressure targets, with a goal of about 130/80 mm Hg for most patients (see Q7. How is hypertension managed in patients with diabetes?).
Smoking cessation and lipid lowering are also important interventions for prevention of cardiorenal complications of DM, which are increased at every level of CKD (265 [EL 2; MNRST]). Therapy with statins reduces the relative risk of major vascular events in patients with DM by 17% for every 39 mg/dL decrease in LDL-C (228 [EL1; MRCT]). Patients with DM and CKD up to stage 4, including posttransplant patients, benefit from lipid lowering with statins. However, the beneficial effect of statins is lost in patients who require dialysis (228 [EL 1; MRCT]; 268 [EL 1; RCT]; 269 [EL 1; MRCT]; 270 [EL 1; RCT]; 271 [EL 1; MRCT]).
Slowing the progression of kidney dysfunction is critical for patient survival and quality of life. Therapies shown to positively affect AER and declining eGFR include ACE inhibitors and ARBs. Consequently, T1D and T2D patients with albuminuria should be treated with an ACE inhibitor or ARB at the highest tolerated dose (198 [EL 1; RCT]; 272 [EL 1; RCT]). Data are lacking on the effectiveness of ACE inhibitor and ARBs in patients with DM and reduced eGFR who do not have albuminuria. However, AACE recommends RAAS blockade in all patients with DM who have CKD categories G2, G3a, G3b, and if slow progression is demonstrated, category G4. The RAAS-blocking drugs may potentiate hyperkalemia and may cause harm when used with nonsteroidal anti-inflammatory drugs (NSAIDs) or in patients with renovascular hypertension or dehydration. They are not safe for use in pregnancy. Combination therapy with an ACE inhibitor and ARB or with a renin inhibitor added to 1 of the other RAAS-blockading agents does not prolong survival or prevent progression of CKD (216 [EL 4; NE]; 273 [EL 1; RCT]; 274 [EL 1; RCT]). In patients with advanced CKD (G3b and higher), combination therapy increases the risk of hyperkalemia and acute kidney injury and is therefore not recommended (216 [EL 4; NE]; 274 [EL 1; RCT]; 275 [EL 4; review NE]). Data on the use of aldosterone antagonists with ACE inhibitors or ARB classes is limited, but the same cautions apply.
If the GFR continues to decline despite excellent glycemic and blood pressure control, protein restriction may be of some benefit. KDIGO recommends limiting protein intake to 0.8 g/kg per day (approximately 10% of daily calories) in patients with progressive diabetic nephropathy or eGFR <30 mL/min/1.73 m2. Additional dietary restrictions may be required to control potassium and phosphorus levels. Salt intake should be limited to 2 g per day in all patients with DM who require antihypertensive medications. Obesity is a risk factor for hypertension and incident CKD, so weight loss along with exercise is recommended for patients with DM without evidence of kidney disease as well as patients with category G2 to G4 CKD. Unintended weight loss is associated with poorer outcomes in dialysis patients.
Patients with CKD are at risk for drug toxicity and acute kidney injury. Antihyperglycemic therapies should be modified to reduce excessive drug exposure and hypoglycemia (276 [EL 3; CSS]). Many other drugs should be avoided or used with caution in patients with CKD. Patients should be informed of their CKD diagnosis and should avoid dehydration and imaging that requires gadolinium, high phosphate-containing bowel preparations, or high doses of iodinated contrast dyes.
Patients with diabetic nephropathy should undergo annual or more frequent assessment of electrolytes to assess potassium and acid-base status; blood counts to assess anemia status; and calcium, phosphorus, vitamin D, and parathyroid hormone (PTH) measurements to assess mineral metabolism (263 [EL 4; NE]). Hyperkalemia is managed by dietary restriction and adjustment of antihypertensive medications. For those with a bicarbonate level <22 mEq/L, the addition of oral sodium bicarbonate is recommended to correct the acidosis. Anemia, defined as hemoglobin (Hb) <13 g/dL in males and <12 g/dL in females, should be further investigated with iron, transferring saturation (TSAT), ferritin, vitamin B12, and folate levels (277 [EL 4; NE]). Deficiencies should be replaced, and a TSAT target of ≥30% achieved, regardless of ferritin level (277 [EL 4; NE]). Iron given intravenously may produce better results than oral replacement. AACE recommends adequate calcium intake and achievement of 25(OH)D3 levels of >30 ng/dL in all patients. Supplementing vitamin D2 or D3 may reduce PTH without causing harm (277 [EL 4; NE]; 278 [EL 3; SS]). Active vitamin D preparations may be necessary to keep the PTH level from increasing as kidney function declines. Hyperphosphatemia should be corrected into the normal range with dietary modification and judicious use of phosphate binders.
Referral to a nephrologist is appropriate when the presentation is atypical, progression of albuminuria or decline in eGFR is rapid, or when secondary manifestations of CKD require expert advice. Referral of patients with stage 4 CKD to a nephrologist allows time for sufficient planning to accommodate individual patient needs (279 [EL 4; opinion NE]). Renal transplantation is the preferred replacement therapy for patients with DM and ESRD because long-term outcomes are superior to those achieved with dialysis. For patients with T1D, the possibility of combined kidney-pancreas transplantation allows for considerably better outcomes (280 [EL 2; PCS]).


 

Q 10. Come gestire la retinopatia nei diabetici?

Diabetic retinopathy is the leading cause of blindness in adults. The lesions of diabetic retinopathy include background or nonproliferative retinopathy, macular edema, preproliferative retinopathy, and proliferative retinopathy. Approximately 50% of patients with T1D develop background retinopathy after 7 years, and most have some form of retinopathy after 20 years (281 [EL 4; review NE]). Diabetic retinopathy is present in 25 to 45% of patients with T2D, and between 2 and 8% of patients with T2D have proliferative retinopathy and/or macular edema (282 [EL 3; SS]). Diabetic retinopathy is present in approximately 20, 40, and 70% of patients with T2D after <10, 10 to 20, and >20 years of the disease, respectively, with prevalence rates of proliferative retinopathy and/or macular edema around 2, 10, and 25% at the respective durations (283 [EL 2; MNRCT]). Higher levels of glucose and blood pressure, as well as the presence of nerve and renal diabetic complications, are associated with greater likelihood of developing retinopathy (284 [EL 3; SS]).
The goal is to detect clinically significant retinopathy before vision is threatened. Funduscopy performed by internists or endocrinologists is often suboptimal; therefore, referral to an experienced ophthalmologist for an annual dilated eye examination is recommended (285 [EL 2; MNRCT]). The complete ophthalmologic examination can also detect other common conditions such as cataracts, glaucoma, and macular degeneration. The use of nonmydriatic fundus cameras equipped with digital transmission technology enables large-scale, POC screening for retinopathy (286 [EL 3; SS]). Patients with abnormal retinal photographs are then triaged to full examination by an ophthalmologist. This 2-step approach can be an efficient strategy for retinopathy screening at the population level, particularly in remote areas (287 [EL 3; SS]). However, the system is still under development and does not replace the current recommendation for an annual dilated eye examination by an ophthalmologist from the time of diagnosis because of the lag between onset and diagnosis of T2D (288 [EL 3; CSS]). Given the relatively low prevalence of proliferative retinopathy and/or macular edema in T2D during the first decade after diagnosis, however, the suggestion is now being made that T2D patients who have had a negative ophthalmologic examination may safely have the screening interval increased to 2 years (289 [EL 4; NE]; 290 [EL 2; RCCS]). As retinopathy develops over a period of 5 or more years from initial hyperglycemia, screening should be initiated within 5 years of diagnosis in patients with T1D (291 [EL 3; SS]). Pregnancy is a risk factor for progression of retinopathy, and ophthalmologic examinations should be performed repeatedly during pregnancy and for 1 year postpartum (292 [EL 2; PCS, longitudinal follow-up study]). Patients with active lesions may be followed up more frequently, while those who have had repeatedly normal eye findings can be seen less frequently.
Optimization of glucose and blood pressure are proven strategies for primary prevention of diabetic retinopathy (68 [EL 1; RCT]; 195 [EL 1; RCT]; 196 [EL 2; PCS]; 293 [EL 2; PCS]). Good control of glycemia and blood pressure are also effective in slowing the progression of pre-existing background retinopathy.
There is, in addition, evidence that certain pharmacologic treatment approaches may have specific benefit in diabetic retinopathy, including ACE inhibitors, ARBs (294 [EL 1; RCT]; 295 [EL 1; RCT]), and fibrate lipid-lowering agents (56 [EL 1; RCT]; 296 [EL 1; RCT, substudy]; 297 [EL 2; RCCS]). Research into other novel pharmacologic agents with potential benefits may lead to additional medical treatments (298 [EL 1; RCT, small sample size]).
Panretinal scatter laser photocoagulation is the treatment of choice for high-risk proliferative retinopathy (299 [EL 4; review NE]). For macular edema, the combination of focal laser photocoagulation with intravitreal antivascular endothelial growth factor modalities appears to offer optimal benefit (300 [EL 1; MRCT]). Vitrectomy is reserved for patients with persistent vitreous hemorrhage or significant vitreous scarring and debris (299 [EL 4; review NE]).


 

Q 11. Come diagnosticare e gestire la neuropatia diabetica?

Diabetic neuropathy affects about half of all patients with DM, contributing to substantial morbidity and mortality and resulting in a huge economic burden for DM care (301 [EL 4; NE]; 302 [EL 3; SS]). It is the most common form of neuropathy in developed countries and is responsible for 50 to 75% of nontraumatic amputations (302 [EL 3; SS]; 303 [EL 4; NE]). It is a major cause of falls in older patients that lead to lacerations, fractures, and traumatic brain injuries (304 [EL 4; NE]). Diabetic neuropathy is a set of clinical syndromes that affect distinct regions of the nervous system, singly or in combination. It may be silent and go undetected while exercising its ravages, or it may present with clinical symptoms and signs that, although nonspecific and insidious with slow progression, also mimic those seen in many other diseases. Diabetic neuropathy is, therefore, diagnosed by exclusion. Unfortunately neither endocrinologists nor nonendocrinologists have been trained to recognize the condition, and even when diabetic neuropathy is symptomatic, less than one-third of physicians recognize the cause or discuss this with their patients (305 [EL 1; RCT]).
Diabetic neuropathy encompasses multiple different disorders involving proximal, distal, somatic, and autonomic nerves. It may be acute and self-limiting or a chronic, indolent condition. It may be focal such as a mononeuritis involving single nerves or entrapment neuropathies (e.g., carpal tunnel syndrome, ulnar entrapment, and peroneal entrapment, among others). Proximal lumbosacral, thoracic, and cervical radiculoplexus neuropathies involving the proximal limb girdle are, for the most part, inflammatory demyelinating conditions requiring immunotherapy and, if caught early, are reversible (306 [EL 4; NE]; 307 [EL 4; review NE]; 308 [EL 4; position NE]; 309 [EL 4; NE]). The distal neuropathies are characteristically symmetric, glove and stocking distribution, length dependent sensorimotor polyneuropathies that develop on a background of long-standing chronic hyperglycemia superimposed upon CVD risk factors (310 [EL 3; CSS]; 311 [EL 2; PCS]; 312 [EL 2; PCS]). They may be acute or chronic. The acute variety usually occurs within 8 weeks of initiating intensification of glycemic control with insulin or oral agents that results in a too-rapid lowering of blood glucose by >30% or A1C by >2% (313 [EL 2; PCS]; 314 [EL 4; review NE]). There may also be atypical variants of diabetic neuropathy such as SFNs, which present predominantly with pain and autonomic features (306 [EL 4; NE]; 315 [EL 2; CSS]). Risk factors include metabolic syndrome (316 [EL 3; CSS]), IFG, and IGT (317 [EL 2; PCS]; 318 [EL 3; retrospective chart review SS]). The scope of diabetic neuropathy is reviewed elsewhere (304 [EL 4; NE]; 319 [EL 4; review NE]; 320 [EL 4; NE]; 321 [EL 4; NE]; 322 [EL 4; NE]; 323 [EL 4; NE]; 324 [EL 4; NE]; 325 [EL 1; MRCT]; 326 [EL 4; NE]).
Prevalence rates of neuropathy in DM are between 5 and 100%, depending on diagnostic criteria used (327 [EL 3; CSS]; 328 [EL 3; CSS]). Because of the lack of agreement on the definition and diagnostic assessment of neuropathy, several consensus conferences were convened to overcome the current problems. The most recent of these has redefined the minimal criteria for the diagnosis of typical distal symmetric polyneuropathy (DSPN) (305 [EL 1; RCT]):

  1. Possible DSPN. The presence of symptoms or signs of DSPN, which may include the following:
  • Symptoms: decreased sensation, positive neuropathic sensory symptoms (e.g., “asleep numbness,” prickling or stabbing, burning, or aching pain) predominantly in the toes, feet, or legs
  • Signs: symmetric decrease of distal sensation or unequivocally decreased or absent ankle reflexes
  1. Probable DSPN. The presence of a combination of symptoms and signs of neuropathy including any 2 or more of the following: neuropathic symptoms, decreased distal sensation, or unequivocally decreased or absent ankle reflexes
  2. Confirmed DSPN. The presence of an abnormality of nerve conduction plus a symptom or symptoms, or a sign or signs, of neuropathy. If nerve conduction is normal, a validated measure of SFN (with class 1 evidence) may be used. To assess for the severity of DSPN, several approaches have been recommended (329 [EL 4; NE]).
  3. Subclinical DSPN. Abnormal nerve conduction or a validated measure of SFN (with class 1 evidence) without signs or symptoms of neuropathy. Definitions 1, 2, or 3 can be used for clinical practice, and definitions 3 or 4 can be used for research studies.
  4. SFN should be graded as follows (330 [EL 4; NE]):
  5. Possible: the presence of length-dependent symptoms and/or clinical signs of small-fiber damage
  6. Probable: the presence of length-dependent symptoms, clinical signs of smallfiber damage, and normal sural nerve conduction
  7. Definite: the presence of length-dependent symptoms, clinical signs of smallfiber damage, normal sural nerve conduction, and altered intraepidermal nerve-fiber density at the ankle and/or abnormal thermal thresholds at the foot

Several reviews discuss useful approaches to the treatment of the common forms of diabetic neuropathy, as well as algorithms for pain management, diagnosis, and treatment of the manifestations of autonomic neuropathy (331 [EL 4; review NE]; 332 [EL 4; review NE]). Treatment guidelines published by the American Academy of Neurology, Toronto Expert Panel, and European Federation of Neurological Societies suggest that pregabalin, gabapentin, venlafaxine, duloxetine, tricyclic antidepressants, and opioids are the drugs with the best evidence to support their use for painful neuropathy (329 [EL 4; NE]; 333 [EL 4; NE CPG]; 334 [EL 1; NE CPG]). However, no treatments have been approved for the prevention or reversal of diabetic neuropathy. Even tight glycemic control at best limits the progression of neuropathy in patients with T1D, as shown in the DCCT and EDIC (Epidemiology of Diabetes Interventions and Complications) studies, and does not affect neuropathy in patients with T2D, as seen in the ACCORD, UKPDS, and ADVANCE studies (335 [EL 4; NE]).
Large-fiber neuropathies may involve sensory and/or motor nerves, and most affected patients present with a glove and stocking distribution of sensory loss (336 [EL 4; review NE]). Once large-fiber diabetic neuropathy has been diagnosed, therapy should be initiated to reduce symptoms and prevent further progression. It is vitally important to institute measures to prevent foot ulcers that lead to amputations. In general these are daily inspection, protective socks, appropriate footwear, and avoidance of injury. Cardinal interventions to prevent falls and fractures are to improve strength and balance in patients with large-fiber neuropathy (337 [EL 2; PCS]; 338 [EL 1; RCT]; 339 [EL 1; RCT]). Patients with DM who have large-fiber neuropathies are uncoordinated and ataxic and are 17 times more likely to fall than their counterparts without neuropathy (340 [EL 2; RCCS]). Low-impact activities that emphasize muscular strength and coordination and challenge the vestibular system such as a Bosu ball; use of rubber bands to strengthen lower limb muscles; and Pilates, yoga, and Tai Chi to strengthen the body core, may also be particularly helpful (341 [EL 2; PCS, small sample size]; 342 [EL 2; PCS, small sample size]).
Small-nerve fiber dysfunction usually occurs early and is often present without objective signs or electrophysiologic evidence of nerve damage (343 [EL 3; SS]).
Skin punch biopsy, a minimally invasive procedure, allows morphometric quantification of intraepidermal nerve fibers. The European Federation of the Neurological Societies and the Peripheral Nerve Society endorse intraepidermal nerve fiber quantification to confirm the clinical diagnosis of SFN with a strong (Level A) recommendation (344 [EL 4; consensus NE]). Intraepidermal nerve fiber density inversely correlates with both cold and heat detection thresholds (345 [EL 3; CSS]). Intraepidermal nerve fiber density is significantly reduced in symptomatic patients with normal findings from nerve conduction studies and those with metabolic syndrome, IGT, and IFG, suggesting early damage to small nerve fibers (346 [EL 3; CSS]; 347 [EL 3; CSS]). Intraepidermal nerve fiber density is also reduced in painful neuropathy compared with that observed in painless neuropathy (348 [EL 3; SS]). Diet and exercise intervention in IGT leads to increased intraepidermal nerve fiber density (349 [EL 2; PCS]). These data suggest that intraepidermal nerve fiber loss is an early feature of the metabolic syndrome, prediabetes, and established DM, and the loss progresses with increasing neuropathic severity. There may be nerve regeneration with treatment.
Noninvasive tests of small nerve fiber function have recently been recognized. Corneal confocal microscopy may be used to detect small nerve fiber loss in the cornea. This technique correlates with neuropathy severity and can be used to monitor responses to transplantation and other procedures (347 [EL 3; CSS]). Contact heat-evoked potentials use nociceptive heat as a stimulus, and the response is recorded through electroencephalographic readings. This technique can be used to detect SFN in the absence of other indices (350 [EL 2; NRCT]). Sudomotor function assesses the sweat response by analyzing sweat production or sweat chloride concentrations and detects early neurophysiologic abnormalities in peripheral autonomic function (351 [EL 2; PCS]).
Strategies for management of SFN include simple measures that can protect the foot deficient in functional C fibers from developing ulceration, and therefore, from gangrene and amputation. Wearing padded socks can promote ulcer healing and/or reduce the likelihood of ulcer development (352 [EL 2; PCS]). Patients should inspect the plantar surface of their feet with a mirror on a daily basis and test bathwater with a part of the body that is not insensate before submerging a numb foot. Patients should also be cautioned against falling asleep in front of the fireplace with their insensate feet close to the fire. Emollient creams can moisturize dry skin and prevent cracking and infection.
A definition of peripheral neuropathic pain in DM, adapted from one recently proposed by the International Association for the Study of Pain (308 [EL 4; position NE]), is “pain arising as a direct consequence of abnormalities in the peripheral somatosensory system in people with diabetes.” It has been estimated that between 3 and 25% of persons with DM might experience neuropathic pain (353 [EL 4; review NE]). In practice, the diagnosis of neuropathic pain in DM is a clinical one, relying on the patients’ description of pain: the symptoms are distal, symmetric, and associated with nocturnal exacerbations, and they are commonly described as prickling, deep aching, sharp, electric-shock like, and burning with hyperalgesia (354 [EL 4; review]). There is frequently allodynia on examination (353 [EL 4; review NE]; 354 [EL 4; review]). Symptoms are usually associated with clinical signs of peripheral neuropathy, although occasionally in acute neuropathic pain, symptoms may occur in the absence of signs. A number of simple numeric rating scales can be used to assess the frequency and severity of painful symptoms (353 [EL 4; review NE]), and other causes of neuropathic pain must be excluded. Outcome measures to assess response to therapy should include patient-reported improvements in the measures and numeric rating scales (355 [EL 4; review NE]), including the Neuropathic Pain Symptoms Inventory, the Brief Pain Inventory, and the Neuropathic Pain Questionnaire. Quality of life improvement should also be assessed, preferably using a validated neuropathy specific scale such as NeuroQol or the Norfolk Quality of Life Scale (356 [EL 3; SS]).
Physicians must be able to differentiate painful diabetic neuropathy from other unrelated or coexisting conditions. The most common of these are claudication, Morton’s neuroma, Charcot neuroarthropathy, fasciitis, osteoarthritis, and radiculopathy. The algorithm provided (Fig. 3) distinguishes between the different conditions that can produce pain and provides recommendations for their management (314 [EL 4; review NE]; 357 [EL 4; NE]). The FDA has approved only the serotonin and norepinephrine reuptake inhibitor duloxetine, the anticonvulsant pregabalin, and the opioid tapentadol for neuropathic pain, but level 1 evidence also exists to support the use of tricyclic antidepressants (e.g., amitriptyline) and the anticonvulsant gabapentin (358 [EL 1; MRCT]; 359 [EL 1; MRCT]). Recent studies have shown improvement of pain with an α2δ1 calcium antagonist (360 [EL 1; RCT, posthoc analysis]) and tapentadol, a weak opioid agonist with norepinephrine reuptake inhibition, which thereby combines 2 pain relief mechanisms (361 [EL 1; RCT]). Topical treatment using a 5% lidocaine plaster applied to the most painful area (362 [EL 1; RCT]) is effective in some studies.
Recent studies have highlighted metformin-associated B12 deficiency, which can lead to neuropathy-like symptoms.
These symptoms can be reversed by supplementation with methylcobalamin, the biologically active form of vitamin B12 (363 [EL 1; RCT]; 364 [EL 4; NE]; 365 [EL 3; CSS]; 366 [EL 4; NE]). New thresholds for B12 levels have now been established (364 [EL 4; NE]; 365 [EL 3; CSS]).
Cardiovascular autonomic neuropathy is significantly associated with overall mortality (367 [EL 4; review NE]; 368 [EL 2; MNRCT]) and in some studies, but not all, with morbidity including silent myocardial ischemia, coronary artery disease, stroke, diabetic neuropathy progression, and perioperative morbidity. Some pathogenetic mechanisms may link cardiovascular autonomic neuropathy to cardiovascular dysfunction and diabetic complications (367 [EL 4; review NE]). Cardiovascular autonomic neuropathy assessment may be used for cardiovascular risk stratification in patients with and without established CVD, as a marker for patients requiring more intensive monitoring during the perioperative period and other physiological stresses, and as an indicator for more or less intensive pharmacotherapeutic and lifestyle management of comorbid conditions. Cardiovascular autonomic neuropathy may be useful for prediction of cardiovascular risk, and a combination of cardiovascular autonomic neuropathy (369 [EL 3; SS]) and symptoms of peripheral neuropathy increase the odds ratio to 4.55 for CVD and mortality (314 [EL 4; review NE]). Indeed, this is the strongest predictor of CVD risk, far greater than blood pressure, lipoprotein profile, and even adenosine scans (370 [EL 4; NE]). The reported prevalence of diabetic autonomic neuropathy varies widely (7.7 to 90%) depending on the cohort studied and the methods used for diagnosis (371 [EL 4; review NE]; 372 [EL 4; review NE]). All the manifestations of autonomic nerve dysfunction, along with suggested testing, the symptom complex, and possible therapies, are listed in Table 15 (310 [EL 3; CSS]). A more complete discussion can be found in recent reviews (369 [EL 3; SS]; 373 [EL 4; NE]).
Cardiovascular reflex tests are the criterion standard in clinical autonomic testing (374 [EL 4; position NE]). The most widely used tests assessing cardiac parasympathetic function are based on the time-domain heart rate response to deep breathing, a Valsalva maneuver, and postural change. Valsalva maneuvers must not be performed in patients with proliferative retinopathy. Cardiovascular sympathetic function is assessed by measuring the blood pressure response to orthostatic change and a Valsalva maneuver. The combination of cardiovascular autonomic tests with sudomotor function tests may allow a more accurate diagnosis of diabetic autonomic neuropathy (375 [EL 4; NE]). Frequency domain measurements of the total spectral power, the standard deviation of normal R-R intervals, and the root means squared of the standard deviation of R-R intervals have recently been shown to be the most sensitive indicator of autonomic imbalance. These changes also precede the rise in circulating levels of inflammatory cytokines such as interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α), as well as a fall in the high molecular weight adiponectin/leptin ratios in newly diagnosed DM (376 [EL 2; PCS]; 377 [EL 4; NE]).
Patients with DM and features of cardiac autonomic dysfunction such as unexplained tachycardia, bradycardia, orthostatic hypotension, and poor exercise tolerance or those with other symptoms of autonomic dysfunction should be evaluated for the presence of cardiovascular autonomic neuropathy. Screening for cardiovascular autonomic neuropathy should be performed at diagnosis of T2D and 5 years after the diagnosis of T1D.
Retrospective and prospective studies have suggested a relationship between hyperglycemia and the development and severity of diabetic neuropathy, as well as significant effects of intensive insulin treatment on prevention of neuropathy (378 [EL 4; review NE]). Treating oxidative stress may improve peripheral and autonomic neuropathy in adults with T2D (379 [EL 1; RCT]; 380 [EL 1; RCT]; 381 [EL 1; RCT]; 382 [EL 1; RCT]). A systematic review of α-lipoic acid in the treatment of diabetic neuropathic pain found that this drug may help relieve pain and improve neuropathy, possibly through its potent antioxidant properties to reduce glutathione concentrations (383 [EL 4; NE]). The SYDNEY (Symptomatic Diabetic Neuropathy), ALADIN (Alpha-Lipoic Acid in Diabetic Neuropathy), and SYDNEY 2 trials showed benefit in painful neuropathy, and the NATHAN (Neurological Assessment of Thioctic Acid in Diabetic Neuropathy) 1 trial showed improvement in neuropathy scores and delayed progression (384 [EL 1; RCT]; 385 [EL 1; RCT]).
TZDs, which reduce hyperglycemia through reductions in insulin resistance, may also reduce chronic inflammation and potentially affect pathways leading to peripheral neuropathy (386 [EL 4; review NE]; 387 [EL 1; RCT]; 388 [EL 3; SS]). Fibrates and statins may protect against peripheral nerve function decline in adults with T2D (389 [EL 2; PCS]; 390 [EL 2; PCS]). Older adults taking statins show a greater benefit than younger adults because of their higher attributable risk of CVD (391 [EL 4; review NE]). A modest association between statin use and peripheral neuropathy was found in a review of the 1999-2004 National Health and Nutrition Examination Survey (NHANES) data, but the authors cautioned not to overinterpret the findings, which may be explained by many uncontrolled, confounding factors, so no causal inference can be made (392 [EL 3; SS]).
Small studies in patients with DM have shown that aerobic exercise improved quantitative test results for peripheral nerve function and cardiac autonomic neuropathy (393 [EL 2; PCS]). Among participants and/or those with peripheral neuropathy and DM, balance training is effective in improving balance outcomes and probably reduces risk of falls (394 [EL 3; SS]; 395 [EL 2; NRCT cieco singolo]).


 

Q 12. Come gestire la malattia CV nei diabetici?

CVD is increased two- to threefold in patients with DM. The best data have come from studies that ascertained cardiovascular mortality as a function of FPG, 2-hour PPG, or A1C in nondiabetic and diabetic populations (55 [EL 2; PCS]; 396 [EL 2; RCCS]; 397 [EL 3; SS]; 398 [EL 2; PCS]). In a meta-analysis involving 447,064 patients, the rate of fatal coronary heart disease in patients with DM was reported to be 5.4% versus 1.6% in nondiabetic subjects. Diabetic females had a significantly higher relative fatal cardiovascular risk than males (3.50 versus 2.06) (399 [EL 2; MNRCT]). The original 7-year East-West Study in a Finnish population showed that the incidence of myocardial infarction in patients with DM and no preceding myocardial infarction at baseline was equivalent to that of persons without DM who had had a previous myocardial infarction at baseline. The incidence of myocardial infarction in the diabetic population was almost sixfold greater than the incidence in nondiabetic persons with no previous myocardial infarction at baseline (400 [EL 3; SS]). A subsequent 18-year follow-up of the same cohort confirmed that the patients with DM without evidence of any ischemic heart disease at baseline had as great or a greater risk for CVD-related death and total CVD as persons without DM who had had previous ischemic heart disease at baseline (401 [EL 3; SS]). A nationwide study of 3.3 million residents in Denmark with a 5-year follow-up showed similar results (402 [EL 3; SS]).
It is difficult to quantitatively define the factors responsible for DM being a CVD risk factor because insulin resistance, hypertension, lipid abnormalities, endothelial dysfunction, inflammation, and procoagulant factors are all present in patients with T1D and T2D, as well as in those with less severe forms of hyperglycemia. Early epidemiologic studies indicated that the age-adjusted cardiovascular event rate for patients with DM was twofold greater than that of the nondiabetic individual at each identical level of systolic blood pressure from 105 to 195 mm Hg (403 [EL 4; review NE]). The 12-year follow-up of MRFIT (Multiple Risk Factor Intervention Trial) showed that at every level of total cholesterol, the rate of CVD related death was threefold higher for patients with DM versus the rate in patients without DM (404 [EL 2; PCS]). Patients with DM not only have an increase in risk factors for CVD, but the risk factors cause more disease in a hyperglycemic environment. Autonomic neuropathy is a risk factor for CVD and a strong predictor for CVD events (369 [EL 3; SS]; 405 [EL 1; RCT]).
Comprehensive risk reduction programs have decreased the incidence of acute myocardial infarction in patients with DM by 67.8% from 1990 to 2010 (406 [EL 3; SS]). The recent American College of Cardiology (ACC)/American Heart Association (AHA) Task Force on Practice Guidelines recommends the use of a newly developed risk prediction algorithm based on atherosclerotic events to determine the 10-year risk of patients developing a cardiovascular event (407 [EL 4; NE]). However, Ridker and Cook presented analyses from several large studies suggesting that the new risk prediction algorithm significantly overpredicts event rates (232 [EL 4; NE]). The AACE recommends starting a statin in patients with DM and at least 1 major additional ASCVD risk factor regardless of LDL-C level if they are >40 years of age; primary prevention strategies for younger patients should be individualized (see Q8. How is dyslipidemia managed in patients with diabetes?).

 

Q 12.1. Controllo glicemico

Hyperglycemia increases CVD both by its direct effects and indirectly via effects on other cardiovascular risk factors. Abnormal glucose regulation is common in patients referred to a cardiologist for coronary artery disease and is associated with poor outcomes (408 [EL 3; SS]; 409 [EL 2; PCS]; 410 [EL 3; SS]). Intensive glycemic control reduces micro- and macrovascular complications in patients with DM. The 2 large clinical trials of glycemic control in patients with DM of only a few years’ duration (DCCT and UKPDS) both showed marked decreases in microvascular complications with intensive glycemic control versus standard glucose control: DCCT, 60 to 70% (68 [EL 1; RCT]); UKPDS, 25% reduction (50 [EL 3; SS]). While neither showed a decrease in myocardial infarction during the trial, both showed reductions in macrovascular events in the intensively treated cohort in long-term extension studies (49 [EL 1; RCT, posttrial monitoring]; 411 [EL1; RCT]).
The beneficial effects of intensive glycemic control in reducing vascular complications appear to be inversely related to the extent of vascular disease at the time it is initiated. The ACCORD (62 [EL 1; RCT]), ADVANCE (57 [EL 1; RCT]), and VADT (Veterans Affairs Diabetes Trial) (61 [EL 1; RCT]) trials investigated the effect of intensive glycemic control versus standard glycemic control on the development of new cardiovascular events in patients with mean durations of diagnosed T2D of 8.5 to 11 years either with baseline previous cardiovascular events (35 to 45% of patients) or high cardiovascular risk. The duration of the trials was 3.5 to 7.0 years. All 3 trials failed to show a significant benefit of intensive glycemic control in reducing new cardiovascular events.
Subanalyses of the ACCORD study indicated that patients without a previous cardiovascular event or those who entered the study with an A1C level ≤8% had a significant benefit from intensive glycemic control (62 [EL 1; RCT]). A subanalysis from the VADT trial indicated that patients who entered the trial with a duration of DM <15 years had a decrease in cardiovascular events with intensive glycemic control (412 [EL 2; PCS]).
A randomized controlled substudy in the VADT trial investigated the utility of measuring coronary artery calcification in predicting subsequent clinical cardiovascular events (413 [EL 1; RCT, posthoc analysis with other methodological limitations]). At the end of the 6-year study, the extent of baseline coronary artery calcification was found to correlate very well with the development of clinical cardiovascular events. Patients who entered the study with high coronary artery calcification scores (>100) had no reduction in clinical cardiovascular events with intensive glycemic control, while those who entered with low scores (<100) had a 90% reduction in clinical events with the intensive glycemic control regimen.
Glycemic control can have a long-term effect on the rate and severity of future vascular complications (49 [EL 1; RCT, posttrial monitoring]; 411 [EL 1; RCT]). In contrast, there is no such legacy effect of blood pressure control on cardiovascular risk (206 [EL 1; RCT, questionnaires and other variables may have confounded]).

 

Q 12.2. Terapia anti-aggregante

The use of aspirin for primary prevention has become controversial owing to recent data showing little to no benefit in certain patient populations (9 [EL 1; MRCT but small sample sizes and event rates]). In patients with proven CVD, aspirin (75 to 162 mg daily) is generally indicated (9 [EL 1; MRCT but small sample sizes and event rates]). Adjuvant therapies such as adenosine diphosphate receptor antagonists may also be helpful, especially if peripheral vascular disease is present.
Data from the many clinical trials and observational studies on the use of low-dosage aspirin in the primary prevention of CVD in patients with DM continue to be controversial (405 [EL 1; RCT]). Several recent meta-analyses show no statistically significant benefit on either total cardiovascular outcomes or individual events such as death, myocardial infarction, or stroke (10 [EL 1; MRCT]). An observational study in patients with T2D reported that low dosage aspirin was associated with a paradoxical increase in CVD risk in primary prevention, and the risk of GI bleeding was rather high (414 [EL 1; RCT]). Observational studies such as The Fremantle Diabetes Study reported beneficial reductions in all-cause and CVD-related mortality with regular low-dosage aspirin use, particularly in males older than 65 years (12 [EL 2; PCS]). These conflicting findings may reflect the results of studies showing that patients with DM have an increased resistance to the effects of aspirin (415 [EL 1; MRCT]). This aspirin resistance has been linked in part to an effect of hyperglycemia (416 [EL 2; PCS]). Most studies (11 [EL 1; MRCT]; 12 [EL 2; PCS]; 415 [EL 1; MRCT]), but not all (416 [EL 2; PCS]), support the use of low-dosage aspirin in the secondary prevention of CVD in patients with DM. Once-daily low-dose aspirin may be associated with incomplete inhibition of cyclooxygenase 1 (COX-1) activity and thromboxane A2 (TXA2)-dependent platelet function in patients with DM (417 [EL 2; PCS]). Some data support the use of twice-daily low-dose aspirin in patients with DM and CVD (418 [EL 1; RCT]).

 

Q 12.3. Coronaropatia silente

Although screening for asymptomatic coronary artery disease in patients with T2D does not improve cardiac outcomes, the measurement of coronary artery calcification may be useful in assessing whether some patients with long-standing DM are reasonable candidates for intensification of glycemic control and or lipid lowering. The impression in the past was that diagnosing asymptomatic CVD in patients with DM would result in improved care and better long-term clinical outcomes; however, findings from well-conducted clinical trials have not supported this idea (405 [EL 1; RCT]).
The use of coronary calcification scores might help to identify those patients who will receive the most benefit from intensive glycemic control (413 [EL 1; RCT, posthoc analysis with other methodological limitations]). A large prospective study is necessary to validate such an approach. Meanwhile, in those patients with long-standing DM, coronary artery calcification scores could separate those who already have extensive disease from those with significantly less severe disease.


 

Q 13. Come gestire l’obesità nei diabetici?

The natural history of obesity reflects a small positive energy balance over a prolonged period of time, which produces excess fat storage and adipose tissue mass. BMI (weight in kilograms divided by height in meters squared) is used to differentiate normal weight (18.5 to 24.9 kg/m2); overweight (25 to 29.9 kg/m2); and obesity classes I (30 to 34.9 kg/m2), II (35 to 39.9 kg/m2), and III (≥40 kg/m2) (419 [EL 4; NE]). Clinical correlation is required since BMI may not reflect adipose tissue mass in muscular athletes, sarcopenic obesity, paraplegia, frailty, and other conditions. Also, lower BMI criteria for obesity have been recommended for some ethnicities (e.g., ≥23 kg/m2 is considered overweight in southeast Asians) (420 [EL 4; NE]).
While insulin resistance can exist independent of obesity, excess weight gain, particularly with accumulation of fat in ectopic compartments such as visceral adipose tissue, can exacerbate insulin resistance and increase risk for the development of metabolic syndrome, nonalcoholic fatty liver disease (NAFLD), hypertension, prediabetes, and T2D. Whether individuals are insulin sensitive or resistant, increased adiposity can also lead to biomechanical complications of obesity including osteoarthritis, OSA, gastroesophageal reflux disease (GERD), urinary stress incontinence, and disability. Thus, primary prevention is needed to prevent obesity, and secondary treatment and prevention is required to stabilize or decrease body weight and prevent the emergence of complications in patients who are overweight or obese without complications. When excess adiposity adversely impacts health by causing obesity-related complications, more aggressive interventions are needed to induce and sustain weight loss and treat the complications (421 [EL 4; NE]).

 

Q 13.1. Modificazioni dello stile di vita per il calo ponderale

Lifestyle change is a cornerstone for weight management in the patient with or without DM, and includes 3 components: caloric restriction, increased energy expenditure through increased physical activity, and behavior changes related to lifestyle. All diets are superior to no diet, and differences between individual diets with different macronutrient composition are minimal (93 [EL 1; RCT]; 422 [EL 1; MRCT]). Therefore, healthy meal plans such as the Mediterranean, low carbohydrate, low fat (with an emphasis on high-water content, low-energy-dense foods), low glycemic index, DASH Diet (which emphasizes fruits, vegetables, and low-fat dairy products), and vegetarian diets have been advocated to take into account personal and cultural preferences that accommodate nutrition guidelines (423 [EL 4; NE]). Caloric reduction is critical for weight loss regardless of the meal plan. For longer-term compliance, a moderate calorie deficit of ~500 kcal below energy expenditure is commonly advocated, although many patients are successfully initiated on very low calorie diets (~800 kcal/day) including the use of meal replacements (bars and shakes) that add structure to the diet (96 [EL 1; RCT]).
Increased physical activity is important for maintaining weight loss. For cardiometabolic conditioning, a recommendation consistent with guidelines proposed by the ADA, AHA, and American College of Sports Medicine (ACSM) would include 30 minutes of moderate intensity exercise 5 days per week for a total of 150 minutes/week, or 20 to 25 minutes of intense exercise 3 days per week for a total of 60 to 75 minutes/week combined with resistance training involving each major muscle group 2 to 3 days per week (104 [EL 4; consensus NE]; 424 [EL 4; NE]). However, it is important to individualize the prescription for physical activity. Reduction in sedentary behavior can be helpful.
The third component of lifestyle focuses on behavior modification (423 [EL 4; NE]). The components of a lifestyle program include education and behavior modification including self-monitoring of food intake and physical activity, learning to cope with negative thoughts by means other than eating, portion control, and consuming meals at regular times and in places where one can focus on the act of eating. A mental health professional is commonly needed to address issues such as disordered eating and depression, which, if not treated proactively, can jeopardize the effectiveness of lifestyle therapy.

 

Q 13.2. Terapia farmacologica dell’obesità

The first step in evaluating medications for the overweight patient is to determine whether the patient is taking drugs that produce weight gain, including some antihyperglycemic agents (Table 9), antidepressants, and antiseizure medications (425 [EL 4; NE]; 426 [EL 4; NE]; 427 [EL 1; RCT]). If such agents are identified and there are acceptable weight-neutral or weight loss-inducing alternatives, the healthcare professional should consider changing the medication (425 [EL 4; NE]).
Several drugs are approved by the FDA for weight reduction in patients with and without DM (426 [EL 4; NE]; 428 [EL 4; NE]). These include several sympathomimetic amines (phentermine, benzphetamine, and phendimetrazine), which are approved for short-term use (≤12 weeks). Five medicines are approved for long-term use and, therefore, are more useful in the treatment of obesity as a chronic if not lifelong disease. These include orlistat (32 [EL 1; RCT]; 429 [EL 1; MRCT]), lorcaserin (430 [EL 1; RCT]; 431 [EL 1; RCT]; 432 [EL 1; RCT]), phentermine/topiramate extended release (33 [EL 1; RCT]; 433 [EL 1; RCT]; 434 [EL 1; RCT]; 435 [EL 1; RCT]; 436 [EL 1; RCT]), naltrexone/bupropion extended release (437 [EL 1; RCT]; 438 [EL 1; RCT]; 439 [EL 1; RCT]; 440 [EL 1; RCT]), and a high-dose formulation of liraglutide (45 [EL1; RCT]; 46 [EL 1; RCT]; 441 [EL 1; RCT]).
All weight-loss medications are approved for patients with BMI 27 to 29.9 kg/m2 with at least 1 obesity-related complication and BMI ≥30 kg/m2 regardless of complications. These drugs vary with respect to efficacy as defined by weight loss in RCTs and differ regarding adverse effect profile, cautions, and warnings. In addition, lorcaserin and phentermine/topiramate extended release are classified by the U.S. Drug Enforcement Administration as having the potential for abuse and are schedule IV controlled substances (442 [EL 4; NE]). However, these differences enable individualized treatment. On any treatment program there are patients who do very well and for whom the medication should be continued; for others, the treatment may be ineffective, and the patient may lose little weight or even gain weight. The FDA has advised drug discontinuation if <5% of body weight is lost after 12 weeks on the maximal dose of the medication. At that point, an alternative weight-loss medication may be prescribed.
All weight-loss medications serve as an adjunct to lifestyle modification therapy. Except for orlistat, these medications act to decrease appetite and enhance compliance with a reduced-calorie meal plan. Therefore, maximal benefit is achieved in conjunction with lifestyle therapy, and all clinical trials demonstrated greater weight loss when the medication was added to lifestyle modification than that achieved with lifestyle modification plus placebo. The patient should be familiarized with the drugs and their potential side effects and should receive effective lifestyle support for weight loss during pharmacologic therapy (443 [EL 1; MRCT]; 444 [EL 1; MRCT]).

 

Q 13.3. Chirurgia bariatrica

Bariatric surgery is an effective approach for attaining significant and durable weight loss in severely obese patients with and without DM. Because metabolic as well as weight-related comorbidities are often improved or resolved through weight loss due in part to neuroendocrine mechanisms, the term metabolic surgery is often used instead of bariatric surgery. In general, metabolic operations alter the GI tract by reducing stomach capacity (gastric restrictive operations); rerouting nutrient flow, leading to some degree of malabsorption (bypass procedures); or combining both concepts. Metabolic procedures have evolved since the jejunoileal bypass was abandoned in the 1970s. Commonly performed procedures along with frequency of use include Roux-en-Y gastric bypass (RYGB, 49%), sleeve gastrectomy (SG, 30%), adjustable gastric banding (AGB, 19%), and biliopancreatic diversion (BPD, 2%). A meta-analysis of 136 mostly short-term studies in more than 22,000 patients showed an overall loss of 61.2% of excess body weight, with effects differing by procedure. In those with gastric banding, the loss of excess body weight was 47.5%. It was 61.6% after gastric bypass and 68.2% with gastroplasty. The highest success rate of 70.1% reduction in excess body weight was seen with BPD (445 [EL 2; MNRCT]). In patients with severe obesity and T2D, bariatric surgery has been shown to provide significantly improved outcomes at 12 months for weight loss, number of DM medications used, and glycemic control (e.g., A1C and fasting glucose levels) compared to patients receiving intensive lifestyle therapy (446 [EL 1; RCT, not blinded]; 447 [EL 1; RCT, not blinded]).
These procedures carry a mortality risk (which is low when performed in centers of excellence), as well as morbidity due to surgical and nutritional complications. The patients require life-long medical follow-up and must adhere to ongoing lifestyle modification for optimal outcomes. However, the development of laparoscopic approaches to all these metabolic operations in the mid 1990s has significantly reduced perioperative morbidity and mortality.
The indications for weight-loss surgery have evolved since the seminal National Institutes of Health (NIH) guidelines from 1991 (448 [EL 4; NE]). In the 2011 guidelines for bariatric surgery specifically in patients with T2D, the International Diabetes Federation (IDF) recommended considering surgery for individuals with T2D who are obese (BMI >30 kg/m2) and had not achieved the IDF treatment targets with an optimal medical regimen, especially if other cardiovascular risk factors were present (449 [EL 4; NE]). In 2013, joint clinical practice guidelines from the AACE, Obesity Society (TOS), and American Society for Metabolic & Bariatric Surgery (ASMBS) recommended consideration of surgical weight loss for all patients with BMI >40 kg/m2 (unless surgery would pose significant risk) and for patients with BMI >35 kg/m2 who have at least 1 major obesity-related comorbidity (450 [EL 4; NE]).

 

Q 13.4. Effetti del calo ponderale nel T2D

Weight loss has long been known to enhance insulin sensitivity and improve glycemia in patients with T2D (451 [EL 4; NE]). It is highly effective whether achieved through lifestyle modification (452 [EL 1; RCT]; 453 [EL 2; PCS]; 454 [EL 1; MRCT]; 455 [EL 1; RCT]), pharmacotherapy (431 [EL 1; RCT]; 436 [EL 1; RCT]; 438 [EL 1; RCT]; 456 [EL 1; RCT]), or bariatric surgery (34 [EL 2; PCS]; 446 [EL 1; RCT, not blinded]; 447 [EL 1; RCT, not blinded]; 457 [EL 2; PCS]). These studies have consistently shown that weight loss lowers A1C while decreasing the need for conventional DM medications and producing significant decreases in blood pressure and improvements in lipids and lipoproteins.
The long-term benefits of weight reduction in T2D were underscored by the Look AHEAD study, which randomized patients with T2D to either intensive lifestyle intervention consisting of a moderate calorie reduction diet, regular exercise, and behavioral interventions or the standard DM support and education program (452 [EL 1; RCT]; 458 [EL 1; RCT]). Mean weight loss from baseline was greater in the intensive subgroup (~9% after 1 year and 4.7% after 4 years) than in the standard subgroup (1.1% weight loss at 4 years) and was associated with more marked reductions in A1C. In fact, progressive declines in FPG, A1C, systolic and diastolic blood pressure, and triglycerides, together with progressive increments in HDLC, were observed as the amount of weight loss increased from 5 to >15%. The Look AHEAD study was terminated early because the subgroups did not differ in terms of a complex cardiovascular outcome measure (459 [EL 1; RCT]).
Until 2012, the only obesity medication approved for chronic use in the U.S. was orlistat, which has been shown to be effective in T2D (456 [EL 1; RCT]; 460 [EL 1; RCT]; 461 [EL 1; RCT]). The weight loss produced by orlistat led to A1C reductions of 0.75% units after 1 year of therapy (baseline value 8.9%) in patients with T2D who were overweight or obese; sulfonylurea dosages also decreased in 1 study (461 [EL 1; RCT]). The other long-term weight-loss medications approved by the FDA have also been shown to be safe and effective in treating patients with T2D who are overweight or obese. In the 52-week study of lorcaserin 10 mg twice daily plus lifestyle modification in patients with T2D (BLOOM-DM [Behavioral Modification and Lorcaserin for Obesity and Overweight Management in Diabetes Mellitus] trial) A1C decreased by 0.9% (baseline 8.1%, P<.001 versus placebo), together with a 4.5% weight loss and reduced need for antihyperglycemic medications (431 [EL 1; RCT]). Phentermine/topiramate extended release significantly reduced A1C values below that observed in patients randomized to lifestyle plus placebo in a cohort of patients with mild-to-moderate, shorterduration T2D and also in patients with severe, long-standing T2D on multiple medications (433 [EL 1; RCT]; 435 [EL 1; RCT]; 436 [EL 1; RCT]). In both cohorts, patients randomized to phentermine/topiramate extended release experienced a decreased need for antihyperglycemic medications and improvements in cardiovascular risk factors. Naltrexone/bupropion extended release (COR [Contrave Obesity Research]–Diabetes study) produced greater weight loss (5.0% versus 1.8% from baseline), A1C reduction (0.6% versus 0.1% units), and improvements in triglycerides and HDL-C compared with lifestyle alone (438 [EL 1; RCT]). The high dose (3 mg) formulation of liraglutide significantly reduced weight in persons without diabetes who were obese (45 [EL 1; RCT]; 46 [EL 1; RCT]; 441 [EL 1; RCT]), while lower dosages of this agent have significantly reduced both weight and A1C in glucose-control studies involving patients with T2D (4 [EL 4; NE]).
Bariatric surgery procedures in patients with T2D have produced marked reductions in both A1C and DM medications and can result in DM remission (normal A1C values without antihyperglycemic agents) in some patients. In the Swedish Obese Subjects Study, bariatric surgery produced DM remission rates of 72% and 30% after 2 and 15 years, respectively, and was associated with a reduction in microvascular DM complications (457 [EL 2; PCS]; 462 [EL 2; PCS]). In addition, follow-up over 20 years demonstrated that both cardiovascular disease events and mortality were reduced in patients treated by surgery (457 [EL 2; PCS]). In the STAMPEDE (Surgical Therapy and Medications Potentially Eradicate Diabetes Efficiently) trial, glycemic control in subjects with T2D following bariatric surgery was improved compared with that in medically treated patients (447 [EL 1; RCT, not blinded]). These data should be interpreted cautiously because glycemic control in the medically treated patients will vary depending on the intensity of therapy. In addition, there was no weight-loss arm using intensive lifestyle/behavior therapy plus weight-loss medications. Thus, the data support bariatric surgery as an effective therapeutic approach in T2D patients with BMI ≥35 with uncontrolled DM and obesity refractory to lifestyle and pharmacotherapy.


 

Q 14. Qual è il ruolo della medicina del sonno nella cura dei diabetici?

Daytime drowsiness is the most obvious symptom of a sleep disorder and has been shown to be associated with an increased risk of accidents, increased errors in judgment, and diminished performance (463 [EL 3; SS]). Sleep deprivation also increases major risk factors for heart disease as it aggravates insulin resistance, hypertension, hyperglycemia, dyslipidemia, and inflammatory cytokines. Restless leg syndrome is increasingly being recognized as a medical cause of sleep disturbance, and medication can be quite successful in relieving it (464 [EL 3; CSS]). When OSA or restless leg syndrome is suspected, the usual course is to refer to a sleep specialist who may choose to do an overnight study in a sleep laboratory, although most sleep disturbances can be diagnosed with overnight oximetry testing at home after a careful history and physical (465 [EL 4; NE]; 466 [EL 1; RCT, not blinded]). OSA is especially common in adults with DM, occurring in approximately 2 of 3 males with DM older than 65 years (467 [EL 4; review NE]).
OSA is the most common type of sleep apnea and is caused by physical obstruction of the airway during sleep. OSA refers to numerous episodes during sleep where the individual stops breathing and is then awakened by the need for oxygen. Usually the individual is unaware of the awakenings, which may happen hundreds of times per night and are accompanied by very loud snoring and grunts and snorts when breathing resumes. OSA is more common in males, the elderly, and individuals with obesity (468 [EL 3; CSS]; 469 [EL 3; CSS]). Treatment of OSA in patients with DM can lower FPG, PPG, and A1C levels as much as or more than oral agents (470 [EL 3; CSS]; 471 [EL 3; SS]). Successful OSA treatment may lead to improvements in cardiovascular outcomes (472 [EL 2; PCS]; 473 [EL 1; RCT, single-blind]; 474 [EL 1; RCT, single-blind]), although data have not shown a consistent benefit in terms of metabolic control (470 [EL 3; CSS]; 471 [EL 3; SS]; 475 [EL 1; RCT, small sample size]; 476 [EL 1; RCT, small sample size]; 477 [EL 2; PCS]). Patients with newly diagnosed OSA should persevere through the initial, often frustrating phase of CPAP when finding the right equipment can be a challenge. When CPAP is successful, it can dramatically improve quality of life (478 [EL 2; CPS]). Because of recent improvements in the technology, this treatment should be re-evaluated for patients in whom CPAP failed in the past. For certain subgroups with OSA, surgery to widen the airway or devices that reposition the jaw may be appropriate.


 

Q 15. Come trattare il diabete in ospedale?

DM represents the seventh leading cause of death (479 [EL 3; SS]) and is the second-leading comorbid condition among hospital discharges in the United States (480 [EL 3; SS]). The association between inpatient hyperglycemia and increased risk for complications and mortality is well established (481 [EL 3: SS]; 482 [EL 2; PCS]). Hyperglycemia is associated with prolonged hospital stay, increased incidence of infections, greater disability after hospital discharge, and death (483 [EL 2; RCCS]; 484 [EL 2; PCS]).
Substantial evidence indicates that correction of hyperglycemia with insulin administration reduces hospital complications and mortality in the critically ill, as well as in general medicine and surgery patients (485 [EL 1; RCT]; 486 [EL 2; MNRCT]). Several RCTs including the real-world NICE-SUGAR (Normoglycemia in Intensive Care Evaluation and Survival Using Glucose Algorithm Regulation) study (487 [EL 1, RCT]; 488 [EL 1; RCT, protocol violations]; 489 [EL 1 RCT, not blinded]) and meta-analyses (486 [EL 2; MNRCT]; 490 [EL 1, MRCT]; 491 [EL 1, MRCT]) have reported higher rates of severe hypoglycemia and increased morbidity and mortality with intensive insulin therapy (glycemic targets of 80 to 110 mg/dL) compared to more relaxed glycemic targets. The AACE/ADA consensus statement on inpatient glycemic control outlines the argument in favor of more relaxed glycemic targets in the ICU, as high as 140 to 180 mg/dL (5 [EL 4; consensus NE]). Although strong evidence is lacking, somewhat lower glucose targets may be appropriate in selected patients, such as surgical populations in units that have shown low rates of hypoglycemia. However, glucose targets <110 mg/dL are not recommended. In addition, minimizing glycemic variability, independent of glucose levels, could result in lower rates of complications and cardiovascular mortality in critically ill patients (492 [EL 2; PCS]; 493 [EL 3: SS]; 494 [EL 2; RCCS]), and in reduced hospital stays and mortality in non-ICU settings (495 [EL 2; RCCS]).

 

Q 15.1. Trattamento dell’iperglicemia nel paziente ricoverato

Patients with DM have a threefold greater chance of hospitalization compared to those without DM (496 [EL 3; SS]; 497 [EL 3; SS]), and it is estimated that 20% of all adults discharged have DM, with 30% requiring 2 or more hospitalizations in any given year (496 [EL 3; SS]). It is well established that hyperglycemia in patients with or without a prior diagnosis of DM increases both mortality and disease-specific morbidity in hospitalized patients (5 [EL 4; consensus NE]; 481 [EL 3: SS]; 483 [EL 2; RCCS]; 498 [EL 2; PCS]), and that goal-directed insulin therapy can improve outcomes (485 [EL 1; RCT]; 499 [EL 1, RCT]; 500 [EL 2; PCS]). This topic has been extensively reviewed in the AACE/ADA Consensus Statement on Inpatient Hyperglycemia (5 [EL 4; consensus NE]), 2014 ADA Standards of Medical Care in DM (212 [EL 4; NE]), and 2012 Endocrine Society Clinical Practice Guideline for the Management of Hyperglycemia in Hospitalized Patients in the Noncritical Care Setting (501 [EL 4; NE]).
The management of hyperglycemia in the hospital setting presents multiple challenges including variable nutritional status and altered levels of consciousness, as well as resource limitations for monitoring glycemia during these changes. Given the paramount importance of patient safety, reasonable glucose targets in the hospital setting should be set at modestly higher levels than targets for outpatients with DM. For most critically ill patients in the ICU, a glucose concentration range of 140 to 180 mg/dL is recommended, provided these targets can be safely achieved. For patients in non-ICU settings, a premeal glucose target of <140 mg/dL and a random blood glucose of <180 mg/dL is recommended; however, glycemic targets should be modified according to clinical status. For patients who are able to achieve and maintain glycemic control without hypoglycemia, a lower target range may be reasonable. For patients with terminal illness and/or with limited life expectancy or at high risk for hypoglycemia, a higher target range (<180 mg/dL) may be reasonable.
Insulin therapy is the preferred method of glycemic control in most hospitalized patients. In ICUs, intravenous infusion of insulin is the preferred route of administration. In the critical care setting, a variety of continuous insulin infusion protocols have been shown to be effective in achieving glycemic control with a low rate of hypoglycemic events and also to improve hospital outcomes (499 [EL 1, RCT]; 500 [EL 2; PCS]; 502 [EL 3; SS]; 503 [EL 3; SS]). Recently, computer-based algorithms aiming to direct nursing staff adjustment of insulin infusion rate have become commercially available (504 [EL 3; SS]; 505 [EL 3; SS]). No major clinical outcome differences have been reported in the frequency of hypoglycemic events, length of ICU or hospital stay, or mortality among different intravenous insulin algorithms. Thus, most insulin algorithms appear to be appropriate alternatives for managing hyperglycemia in critically ill patients, and the choice depends on physicians’ preferences and cost considerations.
Most patients with T2D and all patients with T1D in the ICU receiving intravenous insulin infusion will require transition to a subcutaneous regimen (5 [EL 4; consensus NE]). Patients suitable for this transition ideally have a stable infusion rate and blood glucose levels in the target range. Several studies recommend starting at a daily insulin dose ~80% of the intravenous insulin used in the preceding 12 to 24 hours and splitting it into basal and bolus insulin (5 [EL 4; consensus NE]). Nondiabetic patients with stress or newly diagnosed hyperglycemia who have required an insulin rate ≤1 to 2 units/hour at the time of transition may not require a scheduled subcutaneous insulin regimen (506 [EL 4; NE]). Many of these patients can be treated with correction insulin to determine if they will require scheduled subcutaneous insulin.
Outside of the critical care setting, scheduled subcutaneous insulin regimens with a combination of basal, nutritional, and correctional components is recommended. Prolonged use of sliding scale insulin as the sole method of glucose control is strongly discouraged. RCTs have shown that treatment with a basal prandial regimen using insulin analogs is preferred to sliding scale regular insulin alone. This approach results in improved glycemic control and lower rates of hospital complications in general medical and surgical patients with T2D (485 [EL 1; RCT]; 507 [EL 1; RCT]; 508 [EL 1; RCT]). Patients with T1D should be treated with basal-prandial insulin regimens to avoid severe hyperglycemia and DKA. In insulin-naïve patients with T2D, a starting total daily insulin dose between 0.3 and 0.5 units/kg/day has been shown to be effective and safe in general medicine and surgery patients. Patients with T2D receiving insulin therapy before admission are at risk for severe hyperglycemia in the hospital if insulin therapy is discontinued. Assessment of the need for modification of the home insulin regimen is important as requirements vary according to clinical stressors and altered caloric intake (5 [EL 4; consensus NE]; 509 [EL 4; NE]). Lower starting total daily insulin doses of 0.20 to 0.25 units/kg are recommended in patients with impaired kidney function (510 [EL 1; RCT, not blinded, small sample size]; 511 [EL 2; RCCS]), in the elderly, and in those with poor caloric intake (511 [EL 2; RCCS]; 512 [EL 3; SS]). In addition, for those receiving insulin prior to admission, reducing the total daily insulin dose by 20 to 25% is recommended to avoid hypoglycemia in hospitalized patients with poor caloric intake (512 [EL 3; SS]).
Each of the major classes of noninsulin antihyperglycemic agents has substantial limitations for inpatient use, so they are generally not recommended (5 [EL 4; consensus NE]; 501 [EL 4; NE]). These agents provide limited flexibility or opportunity for rapid titration in a setting where acute changes in patient status often demand such action. A recent randomized pilot study reported that the use of the DPP-4 inhibitor sitagliptin plus correction doses with rapid-acting insulin resulted in similar daily glucose control compared to patients treated with basal-bolus insulin or basal insulin plus sitagliptin (513 [EL 1; RCT, not blinded]). Patients with an admission glucose >180 mg/dL treated with DPP-4 inhibitors, however, had worse glucose control compared with patients treated with basal-bolus insulin therapy. Despite the shortcomings of oral antihyperglycemic therapy in the hospital setting, transition to oral agents 1 or 2 days before discharge is often necessary for patients whose glycemia was well controlled on oral agents before admission.

 

Q 15.2. Monitoraggio glicemico in ospedale

Bedside capillary POC testing is the preferred method for guiding ongoing glycemic management of hospitalized patients (5 [EL 4; consensus NE]; 501 [EL 4; NE]). POC testing is usually performed 4 times a day: before meals and at bedtime for patients who are eating. For nil per os patients or those receiving continuous enteral nutrition, POC testing is recommended every 4 to 6 hours. More frequent glucose monitoring is indicated in patients treated with continuous intravenous insulin infusion or after a medication change that could alter glycemic control, such as corticosteroid use, abrupt discontinuation of enteral or parenteral nutrition, or frequent episodes of hypoglycemia.

 

Q 15.3. Terapia medica nutrizionale

MNT is an essential component of inpatient glycemic management in patients with DM and hyperglycemia. The goals of inpatient MNT for patients with DM are to help optimize glycemic control, provide adequate calories to meet metabolic demands, address individual needs based on personal food preferences, and provide a discharge plan for follow-up care. Most hospitalized patients require 25 to 35 calories/kg/day; critically ill patients require between 15 and 25 calories/kg/day (514 [EL 4; NE]; 515 [EL 4; NE]). This translates to a diet containing approximately 1,800 to 2,000 calories/day or ~200 g carbohydrate per day divided between meals. Care must be taken not to overfeed hospitalized patients because this can exacerbate hyperglycemia. No single meal planning system is ideal for hospitalized patients; however, hospitals should provide a consistent carbohydrate DM meal-planning system (514 [EL 4; NE]). The carbohydrate components of breakfast, lunch, dinner, and snacks may vary, but the day-to-day carbohydrate content of specific meals and snacks should be kept constant. Patients requiring clear or full liquid diets should receive ~200 g carbohydrate per day in equally divided amounts at meal and snack times. Patients on liquid diets, in particular during the perioperative period, do not meet these nutritional needs. Increasing evidence indicates that food intake should be initiated as quickly as possible with progression from clear liquids to full liquids to solid foods as rapidly as tolerated in surgical patients (516 [EL 4; NE]). Early enteral feeding is safe and well tolerated and is associated with reduced wound morbidity, improved wound healing, fewer septic complications, diminished weight loss, and improved protein kinetics (516 [EL 4; NE]).

 

Q 15.4. Ipoglicemia ed esiti del ricovero

Several meta-analyses of RCTs have reported a 6- or 7.7-fold risk ratio for occurrence of hypoglycemia with intensive insulin therapy versus conventional glycemic control in critically ill patients (490 [EL 1, MRCT]; 517 [EL 1; MRCT]), with some studies showing a risk ratio >10 (490 [EL 1, MRCT]). Inpatient hypoglycemia has been associated with higher rates of hospital complications, longer hospital stays, higher healthcare resource utilization, and increased hospital mortality, creating a J-shaped relationship between glucose levels and death rates (518 [EL 3; CSS]; 519 [EL 3; SS]). A glucose <50 mg/dL has been found to be associated with 22.2% mortality compared to 2.3% in patients without hypoglycemia (520 [EL 2; PCS]). Hypoglycemia is associated with adverse cardiovascular outcomes, such as prolonged QT intervals, ischemic electrocardiogram changes, angina, arrhythmias, and death (521 [EL 2; PCS]).
Despite these epidemiologic associations between hypoglycemia and poor clinical outcomes, data demonstrating that insulin-induced hypoglycemia is the direct cause of harm in hospitalized patients are sparse. It is the severity of hypoglycemia, not the insulin therapy, that is associated with an increased risk of mortality in the critically ill (519 [EL 3; SS]). Hypoglycemia resulting from severe systemic illness (spontaneous hypoglycemia), rather than insulin induced hypoglycemia, is associated with increased risk of inpatient mortality and complications (522 [EL 3; SS]; 523 [EL 2; RCCS]; 524 [EL 2; PCS]).

 

Q 15.5. Raccomandazioni dopo la dimissione ospedaliera

Patients with stress, or hospital-related, hyperglycemia, defined as any blood glucose concentration >140 mg/dL without evidence of previous DM, should undergo hemoglobin A1C testing during the hospital stay (501 [EL 4; NE]). Measurement of A1C provides the opportunity to differentiate patients with stress hyperglycemia from those with DM who were previously undiagnosed, as well as to identify patients with known DM who would benefit from intensification of their glycemic management. In the presence of hyperglycemia, an A1C >6.5% suggests the diagnosis of DM. Because about half of patients admitted with stress-related hyperglycemia have confirmed DM at 1 year (525 [EL 2; PCS]), they should be closely monitored after discharge.
Few studies have focused on the optimal management of hyperglycemia after hospital discharge. Although insulin is used for most patients with DM in the hospital, many patients do not require insulin after discharge. Clinical guidelines (5 [EL 4; consensus NE]; 501 [EL 4; NE]) recommend tailoring the discharge treatment regimen for patients with DM based on the admission A1C value. Patients with acceptable DM control could be discharged on their prehospitalization treatment regimen (oral agents and/or insulin therapy) if there are no contraindications. Patients with preadmission suboptimal control should have intensification of therapy at discharge, either by additional or increased dosage of oral agents, addition of basal insulin, or a more complex insulin regimen as warranted by their admission glucose control (526 [EL 2; PCS]).


 

Q 16. Come stabilire un piano di cura integrato per il DM nel bambino e nell’adolescente?

Advances in molecular and genetic science have uncovered multiple causes of DM in the neonatal period through the first year of life. It is beyond the scope of this paper to elucidate each genetic cause of neonatal DM. Clinically, these vary from permanent neonatal DM to transient forms, which remit only to recur later in childhood (transient neonatal DM). Although all forms of neonatal DM result from compromised insulin secretion, there is variation in presentation ranging from early and acute onset of DKA to mild, asymptomatic hyperglycemia resulting from heterozygous glucokinase mutations. Important advances have been made in understanding the molecular mechanisms of those forms produced by mutations in the KCNJ1 gene encoding the potassium channel protein Kir6.2 in β cells (527 [EL 3; SS]) and in the ABCC8 gene encoding the sulfonylurea receptor protein SUR1 (528 [EL 3; SS]). Other causes have also been defined, including mutations in the insulin gene (529 [EL 3; SS]). Recognizing these disorders and distinguishing them from T1D is important. Most cases result from new mutations, but they are heritable, and several forms respond to sulfonylureas, negating the need for insulin therapy and improving glycemic control (530 [EL 2; PCS]). Excellent reviews on this topic are available (531 [EL 4; review NE]; 532 [EL 4; guidelines NE]).
Monogenic DM, initially called MODY (533 [EL 4; review NE]) because of its description as “maturity-onset diabetes” occurring in young adults, is currently being described with greater frequency in children and adolescents, as well as in adults. These genetic forms of DM result from compromised insulin secretion, in 1 case by mutations in the gene encoding the enzyme glucokinase (GK), and in the other cases by mutations in genes encoding transcription factors important for pancreas formation and later for insulin secretion (534 [EL 3; SS]). They are uncommon, and most cases in surveyed populations are the result of mutations in GK or in the gene encoding hepatic nuclear factor 1a (HNF1A) (535 [EL 3; SS]). Diagnosing these cases is important for many reasons. Although new mutations do occur, these conditions are usually inherited as autosomal dominant traits. Diagnosis in 1 family member frequently leads to discovery of pedigrees in which many family members are being inappropriately treated as having T1D or T2D (536 [EL 4; review NE]), or GDM (537 [EL 3; SS]). Making the correct diagnosis is important for genetic counseling and instituting proper therapy. Many affected patients respond to insulin secretagogues, do not require insulin or insulin sensitizers, or require no therapy (in the case of glucokinase deficiency).
Cystic fibrosis-related diabetes (CFRD) is a combination of insulin resistance plus insulin deficiency disorder. Oral agents such as TZDs or DPP-4 inhibitors can usually control glucose levels in these patients for several years, but the insulin deficiency will eventually require insulin therapy, which may involve intensive regimens such as basal-bolus insulin or even insulin pumps. The main goal is prevention of glucosuria, weight loss, and asthenia rather than tight glucose control. Steroid use in patients with CFRD may radically affect glucose levels. The patient, family, and endocrinologist should remain in close communication so insulin dosages can be adjusted as needed.
T1D is the most common form of DM occurring in children and adolescents, and its incidence is increasing in most populations throughout the world. The same types of insulin and administration regimens used in older patients are also used in children. Most physicians treating DM in children use MDI regimens, and when appropriate, CSII (538 [EL 3; SS]). Some use morning NPH insulin when it is difficult for the child to receive or administer a midday injection. CSII is also being used more often in infants and toddlers who eat frequently; the use of pumps can help parents improve the care of very young patients (539 [EL 2; PCS]). In adolescents, the main problems with glycemic control often involve social and behavioral complications (540 [EL 3; SS]). The increased insulin resistance associated with puberty, especially when coupled with obesity, sometimes requires large insulin doses and high insulin-to carbohydrate ratios.
Although T2D has been reported in preschool children, one must be cautious making this diagnosis in preadolescent children, taking care to exclude T1D by assessing immune markers and monogenic DM through a careful family history and genetic testing. Guidelines for differentiating T1D from T2D in children have been published (532 [EL 4; guidelines NE]), but several reports have demonstrated that these are imperfect and that phenotypic overlap between these disorders in children is common. T2D remains a diagnosis of exclusion in adolescents. Lifestyle modification (healthy diet and increased physical activity) is always the first treatment choice, but the effectiveness in children has not been extensively studied. Treatment of T2D in children does not differ appreciably from its treatment in adults. Metformin has been studied (541 [EL 1; RCT]) and remains the only oral medication formally indicated by the FDA for use in children with T2D, although rosiglitazone and glimepiride report pediatric studies in their labels. Insulin is effective and used widely alone or in combination with metformin.
The TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth) trial demonstrated that current therapy for children or adolescents with T2D is inadequate; monotherapy with metformin was associated with durable glycemic control in only half of children and adolescents with T2D, and its effectiveness lasted <18 months (542 [EL 1; RCT]). Multiple ongoing trials are examining the use of newer medications in adolescents with T2D, including DPP-4 inhibitors, GLP-1 receptor agonists, and SGLT2 inhibitors. These agents may improve glucose levels without weight gain (or with weight loss) and/or hypoglycemia. However, although these classes are approved for adults, none are currently FDA approved for people younger than 18 years of age. Nevertheless, many pediatric endocrinologists use these agents in combination in younger patients to avoid the use of insulin and TZDs due to risks of weight gain and hypoglycemia.
SMBG frequency in pediatric patients with T1D has been shown to be predictive of A1C levels and complications (543 [EL 3; SS]). However, CGM benefits pediatric patients only when used on a virtually daily basis. When CGM was used ≥6 days per week, decreases in both A1C and the frequency and severity of hypoglycemia have been reported (544 [EL 2; PCS]; 545 [EL 1; MRCT]).
Incorporation of an exercise and nutrition plan are critical for managing either T1D or T2D in children and adolescents. Ideally, a nutritionist should consult with the entire family. The care of children and adolescents with DM involves not only parents and the healthcare team, but also grandparents, older siblings, teachers, coaches, and any other adults in regular contact with the child. It is important for these caregivers to maintain regular contact with each other and the healthcare team. Texting and emailing of glucose values can be helpful.
The management approach to treating the adolescent with T1D is like playing jazz: it requires improvisation and persistence. The healthcare professional should discuss the following with adolescents who have DM: drug and alcohol avoidance and abuse prevention, cigarette smoking prevention and cessation, sexual activity, pregnancy prevention and consequences, and automobile responsibilities and hypoglycemia prevention and management while driving. Transitioning to DM care for adults requires a well thought out plan with patients and their families. The ADA, JDRF, and NIDDK offer resources to help with transition planning (14 [EL 4; NE]; 15 [EL 4; NE]; 16 [EL 4; NE]).
An extensive review of CPGs for the care of DM in children from the International Society of Pediatric and Adolescent Diabetes was published in 2009 and is available on their website (13 [EL 4; CPG NE]).


 

Q 17. Come trattare il diabete in gravidanza?

Abnormal glucose tolerance develops at higher rates and at younger ages among offspring of females with DM. Maternal DM is one of the strongest risk factors for the development of T2D among Pima Indian children (546 [EL 2; PCS]; 547 [EL 3; CCS]; 548 [EL 3; SS]). By the time these offspring reach childbearing age, they are very likely to be obese and have DM, thereby perpetuating a vicious cycle (548 [EL 3; SS]). That this is not simply a genetic predisposition is inferred from the finding of lower rates of DM in offspring of females who were born before their mothers developed DM (549 [EL 3; SS]); this is true among sibling pairs whose birth dates straddle the onset of their mother’s DM (546 [EL 2; PCS]). Thus, all females with DM in the childbearing years should have preconception care and guidance to target an A1C level of <6.5% (212 [EL 4; NE]; 550 [EL 2; PCS]). Frequent POC A1C monitoring allows the clinician to assess the most recent average glucose by comparing the current A1C POC test with the previous week’s POC A1C. The rate of change and direction of the change reflects the trend of recent glucose levels. Although the steady state is not achieved until 6 to 8 weeks later, a rising A1C reflects recent hyperglycemia and allows the clinician an opportunity to discuss the observation and work with the patient for solutions.
The HAPO (Hyperglycemia and Adverse Pregnancy Outcomes) study confirmed findings in the Pima Indians (546 [EL 2; PCS]) that, even among offspring of females without GDM as it is currently defined (551 [EL 2; PCS]; 552 [EL 4; consensus NE]; 553 [EL 4; review NE]; 554 [EL 3; PCS]; 555 [EL 3; SS]), there is a linear association between maternal glucose concentration during pregnancy and newborn weight, rates of large-for-gestational-age, and cesarean delivery. DM during pregnancy and even maternal obesity itself (552 [EL 4; consensus NE]) set the stage for a vicious cycle with offspring of mothers with DM during pregnancy being more likely to become obese and to develop DM at younger ages (554 [EL 3; PCS]). Maternal DM and obesity, although major risk factors for the metabolic health of the offspring, are not the only factors at play in the early stages of childhood that can have lasting adverse effects on offspring. Both low and high birth weight are associated with higher rates of DM (555 [EL 3; SS]). Abnormal birth weight directly affects the offspring and leads to higher rates of GDM eventually in the offspring, thereby compounding the vicious cycle. Early diagnosis and treatment of DM, careful preconception care and guidance for females with DM or at risk for GDM, and meticulous control of glucose abnormalities throughout pregnancy are currently our best hope to break this cycle (556 [EL 4; review NE]). Thus, subjects with DM risk factors (Table 5) should be screened at the first prenatal visit for undiagnosed T2D using standard criteria (Table 6), and all pregnant subjects without a prior diagnosis of DM should be screened for GDM with a 2-hour OGTT using a 75-g glucose load at 24 to 28 weeks’ gestation. Glucose criteria diagnostic for GDM are an FPG >92 mg/dL, 1-hour post-glucose challenge value ≥180 mg/dL, or 2-hour value ≥153 mg/dL (557 [EL 4; CPG]).
In T1D, optimal care may necessitate CGM and CSII. The rapid-acting insulin analogs for pump therapy that have been studied in pregnancy include lispro and aspart (558 [EL 2; NRCT]; 559 [EL 3; retrospective study SS]; 560 [EL 3; retrospective study SS]; 561 [EL 1; RCT]). The data that detemir is safe in pregnancy are convincing, and this agent is now considered pregnancy category B (562 [EL 3; SCR]; 563 [EL 3; retrospective study SS]; 564 [EL 1; RCT, not blinded]; 565 [EL 1; RCT, not blinded]). Glargine is widely used; however, there are still no conclusive reports on its safety, and it remains pregnancy category C. Although insulin is the preferred treatment approach, metformin and glyburide have been shown to be effective alternatives without adverse effects in some females. Metformin crosses the placenta and is classified as category B for pregnancy; sulfonylureas do not cross the placenta. Regardless, the optimal therapy for subjects with GDM or T2D who are not able to maintain normoglycemia with a proper meal plan is insulin (212 [EL 4; NE]).


 

Q 18. Come e quando impiegare il monitoraggio glicemico?

Current glucose monitoring strategies can be classified into 2 categories: patient self-monitoring, which would allow patients to change behavior (diet and/or exercise) or medication dose (most often insulin), and long-term assessment, which allows both the patient and the clinician to evaluate overall glucose control and risk for complications over weeks or months. Although some form of glucose self-monitoring has long been available, current forms of self-monitoring include SMBG and CGM, while long-term assessment is most often by A1C.
A1C is defined as the stable adduct of glucose at the N-terminal amino group of the β chain of hemoglobin. Glycated hemoglobin is quantified most commonly with methods that distinguish it from nonglycated hemoglobin on the basis of either charge (cation-exchange chromatography, electrophoresis, isoelectric focusing) or structural characteristics (affinity chromatography, immunoassays). A1C and mean glucose are directly related over the lifespan of the red blood cell (100 to 120 days), but 50% of A1C is determined by glycemia during the 1 month preceding measurement. Currently, 99% of laboratories in the United States use a standardized and certified assay traced to the DCCT. More recently, using CGM, each level of A1C was measured as “estimated average glucose.” There are numerous patient populations in which A1C may not reflect average glucose. These reasons can include changes in erythrocyte survival time (e.g., hemolysis, splenomegaly, or use of epoetin alfa), alterations in the hemoglobin molecule (hemoglobinopathies), iron status, or recent blood transfusion (23 [EL 4; review NE]). Renal failure also results in a different A1C level than would be seen in those with normal kidney function (566 [EL 2; PCS]).
Current glucose meters perform rapid tests with small blood volumes and are easily operated by laypersons with DM in the outpatient setting. They are equipped with a variety of features, ranging from storing results of glucose tests performed to simple pattern analysis to Bluetooth connectivity to smartphones. The ISO (Institutional Organization for Standardization) specifies requirements for in vitro glucose monitoring systems that measure capillary blood glucose, for specific design verification procedures, and for the validation of self-measurement performance by laypersons with DM. The 2013 ISO 15197 standard for glucose meter accuracy is stricter than the 2003 version. The new standard requires that 95% of values fall within 15% for glucose levels >100 mg/dL and within ±15% for glucoses <100 mg/dL. The 2003 version allowed ±20% difference for glucose >75 mg/dL. Each of the meter chemistries has its own set of potential interfering substances; however, newer technology is helping to reduce these.
In T1D, SMBG has not been studied on its own, but rather as one component of a comprehensive treatment strategy (68 [EL 1; RCT]). SMBG frequency (in a retrospective analysis) has been shown to be predictive of A1C levels (543 [EL 3; SS]; 567 [EL 3; SS]; 568 [EL 2; RCCS]; 569 [EL 3; CSS]).
Patient adherence to monitoring and treatment is the greatest predictor of glycemic control. When used appropriately, CGM can lead to decreased A1C and reduced hypoglycemic exposure (570 [EL 1; RCT]; 571 [EL 1; RCT]). CGM currently uses interstitial fluid glucose as an alternative to plasma glucose. Both currently approved systems use glucose oxidase embedded on the sensor. With current technology, there is usually a lag time of up to 7 minutes between the plasma and interstitial glucose and the receiver display. Despite improvements, accuracy of the current generation of CGM devices is not yet deemed sufficient by the FDA to approve them to replace standard glucose meters for insulin-dosing decisions. Additional research is needed before recommendations can be made regarding CGM use in patients with T2D.


 

Q 19. Come e quando impiegare i micro-infusori insulinici?

Insulin pumps have been used for more than 30 years (572 [EL 4; review NE]). By definition, they provide constant, continuous infusion of short-acting insulin driven by mechanical force and delivered via a soft cannula under the skin. In the United States, it is estimated that 20 to 30% of patients with T1D and <1% of insulin-treated patients with T2D use CSII (573 [EL 3; SS]). The FDA estimates that the number of U.S. patients with T1D using CSII was ~375,000 in 2007, up from approximately 130,000 in 2002 (574 [EL 4; review NE]).
Recent advances in insulin pumps include dose calculators (“wizards”), which are standard on all current models; the ability to program different basal insulin rates to match activities; color touch screens; universal serial bus (USB)-rechargeable batteries; prefilled insulin cartridges; and disposability. In addition, pumps now offer multiple infusion set types, various catheter tubing lengths, and tubeless pumps with an integrated infusion set and reservoir. Clinical trials are underway to validate methods that accelerate insulin action, including the addition of hyaluronidaseto the tubing, heating of the injection site, intradermal insulin injection, and new formulations of rapid acting insulin (575 [EL 4; NE]; 576 [EL 4; NE]; 577 [EL 4; NE]; 578 [EL 2; PCS]). CGM sensor-augmented pumps with a “threshold suspend” function represent the first step toward an automatic or semiautomatic closed-loop insulin delivery device. Such pumps suspend insulin delivery for 2 hours (or until the suspension is manually overridden) when the CGM sensor glucose level declines below a specified threshold (579 [EL 3; CCS]; 580 [EL 1; RCT, not blinded]).
Prompted by these advances in pump technology, the AACE recently updated its Consensus Statement on CSII (581 [EL 4; NE]), which includes a thorough review of the state of the art. Numerous other position statements and guidelines are available from the ADA (582 [EL 4; review NE]); the American Association of Diabetes Educators (583 [EL 4; CPG NE]); the American Academy of Pediatrics (584 [EL 4; position NE]); and the European Society for Paediatric Endocrinology, the Lawson Wilkins Pediatric Endocrine Society, and the International Society for Pediatric and Adolescent Diabetes, which published a joint consensus statement regarding the use of insulin pumps in children (585 [EL 4; consensus NE]).
Table 16 presents a summary of important clinical research findings on CSII efficacy and safety in patients with T1D, including the results of key meta-analyses covering clinical research on insulin pump therapy published after 2003 (172 [EL 1; MRCT]; 586 [EL 1; MRCT]; 587 [EL 1; MRCT]; 588 [EL 1; MRCT]; 589 [EL 1; MRCT]). Table 17 summarizes evidence from RCTs of CSII in T2D (590 [EL 1; RCT, not blinded]; 591 [EL 1; RCT, not blinded, small sample size]; 592 [EL 1; RCT, not blinded]; 593 [EL 1; RCT, small sample size, not blinded]; 594 [EL 3; CCS]; 595 [EL 3; CCS]; 596 [EL 1; RCT, not blinded]; 597 [EL 1; RCT, small sample size, not blinded]).
Based on this evidence and other currently available data, CSII appears to be justified for basal-bolus insulin therapy in appropriately selected patients with T1D who have inadequate control with MDI. The ideal CSII candidate is a patient with T1D or absolutely insulin-deficient T2D (as confirmed with C-peptide measurement) who currently takes insulin multiple times per day, assesses blood glucose levels multiple times daily, is motivated to achieve tighter glycemic control, and is willing and intellectually and physically able to undergo the rigors of insulin pump therapy initiation and maintenance. Eligible patients should be capable of frequent SMBG (at least initially) and/or CGM device use. Furthermore, candidates must be able to master carbohydrate counting, insulin correction, and adjustment formulas and be prepared to troubleshoot problems related to pump operation and plasma glucose levels. Lastly, patients should be emotionally mature, with a stable life situation, and be willing to maintain frequent contact with members of their healthcare team, in particular their pump-supervising physician and CDE.
Concerns have been raised about the costs incurred by CSII. However, recent evidence indicates that CSII is a cost-effective treatment option, both in general and compared with MDI for children and adults with T1D. Table 18 summarizes the key assumptions and findings of recent representative cost-effectiveness analyses comparing CSII with MDI in specific patient populations (598 [EL 3; SS]; 599 [EL 3; SS]; 600 [EL 3; SS]; 601 [EL 3; retrospective review SS]; 602 [EL 3; SS]; 603 [EL 1; RCT, posthoc analysis]; 604 [EL 3; SS]).


 

Q 20. Quali sono le cose essenziali per l’educazione e l’approccio di team alla cura del diabete?

A team must be involved in DM care. Working with different healthcare professionals allows the patient to learn in-depth information about a variety of topics related to their stated, and usually unstated, health concerns. It also ensures that the patient’s needs are cared for and addressed. Use of other healthcare professionals’ skills and specialties ensures the patient has the best care and understanding of their condition. Often, problems may be apparent to one healthcare professional but go unnoticed by another. For example, recognizing a patient’s illiteracy or vision problems in a group class may be difficult, but these problems may be obvious during a one-on-one encounter.
Diabetes Healthsense from the National Diabetes Education Program, a joint venture of the NIH and CDC, is an important resource for all diabetes care teams (605 [EL 4; NE]). This website offers over 150 resources developed by behavior change experts to help patients better adhere to clinician recommendations about diabetes management.

 

Q 20.1. Educatori certificati per il diabete

A CDE is generally a nurse or registered dietitian but could be another healthcare professional. CDEs teach in a variety of inpatient and outpatient settings. They cover all topics related to DM management from insulin administration to foot care. They often have more time than physicians to devote to each patient, which allows them to focus on specific needs. Often patients report they receive more practical knowledge from their CDE than they do from their physician. Having a CDE credential indicates the passing of the certification examination and special ability in this area.

 

Q 20.2. Dietisti diplomati

A healthful diet is necessary for everyone to maintain good health. However, persons with DM especially need to follow their prescribed meal plan and physical activity program as an integral part of their therapy. Registered dietitians can develop a healthful eating plan and can also provide related DM education. They can document problems such as disordered meal patterns, timing of meals, eating disorders, lack of money for food, or other physiologic and psychosocial problems. These issues may not be identified during physician office visits.

 

Q 20.3. Infermieri e personale paramedico

Registered nurses, as well as licensed practical nurses (LPNs) and medical assistants (MAs), can provide an assessment before the physician sees the patient, which allows for a better focus on any identified problems. Teaching medication administration is another important area that can be delegated to a nurse or MA. Physician time can be saved when the nurse fields phone calls related to medication administration, assessment of medication tolerability, and other DM-related management issues.

 

Q 20.4. Praticanti infermieri e ausiliari medici

A patient may see these nonphysician clinicians in conjunction with the physician. These healthcare professionals can set up treatment plans and set goals that other team members will implement in the patient’s care, allowing the physician to focus on specific treatment issues. These clinicians may also be able to assume some treatment decisions, thus freeing the physician to concentrate on other healthcare issues.

 

Q 20.5. Medici di medicina generale

Each patient should have a primary care physician who addresses other aspects of care beyond DM alone. Typically, specialists have longer wait times for appointments, so that patients might not be seen on a timely basis for medical issues that need more immediate evaluation. Other specialists such as a cardiologist, nephrologist, ophthalmologist, psychologist, and podiatrist might be warranted as part of the DM healthcare team. It is important for patients to see the appropriate specialist as part of their care.


 

Q 21. Quali vaccinationi dovrebbero essere fatte nei diabetici?

Bacterial and viral infections cause significant morbidity and mortality in patients with DM (606 [EL 4; NE]). A recent Canadian cohort study of adults with DM <65 years of age showed that DM increased the risk of influenza associated hospitalizations by 6% (risk ratio 1.06, 95% CI 1.02 to 1.10; absolute risk difference 6 per 1,000 adults per year) even though the rates of influenza and pneumonia were similar between diabetic and nondiabetic populations (P = .11) (607 [EL 3; SS]). Both community-acquired and nosocomial infections with pneumococcal bacteria may also be higher among patients with DM, who may also be at greater risk of death from these diseases (608 [EL 3; CSS]; 609 [EL 2; PCS]; 610 [EL 2; PCS]). However, vaccines can safely and effectively reduce serious complications from influenza. A case-control study demonstrated that vaccines reduced DM-related hospital admissions by as much as 79% during flu epidemics (611 [EL 2; RCCS]). In addition, no evidence suggests that people with DM have inadequate serologic or clinical responses to these vaccinations. The CDC ACIP recommends a yearly influenza vaccine for all individuals with DM, although live attenuated influenza vaccine should be used with caution because its safety in patients with DM has not been established. Inactivated influenza vaccine may be considered for patients with DM (612 [EL 4; NE]). The CDC ACIP also recommends single administration of the 23-valent pneumococcal vaccine (PPSV23) for adults with diabetes aged 19 to 64 years (613 [EL 4; NE]). Furthermore, the 13-valent pneumococcal conjugate vaccine (PCV13) should be administered in series with the PPSV23 to all adults ≥65 years (614 [EL 4; NE]).

Q 21.1. Vaccino per l’epatite B

Over the past 2 decades, the CDC has received 29 case reports of hepatitis B virus (HBV) infection in hospitals and long-term care facilities; of these, 25 were in patients with DM who were receiving blood glucose monitoring from healthcare personnel who were providing care for more than 1 patient. HBV remains stable and highly transmissible for long periods of time on surfaces such as lancing devices, blood glucose meters, and insulin pens. The reservoirs of these devices can retain sufficient blood to transmit the virus and thus should never be shared between patients (615 [EL 4; NE]).
Other CDC analyses suggest that acute HBV infections occur in approximately twice as many adults with DM as those without when persons with HBV-related risk behaviors are excluded. Acute infections are also more likely to progress to chronic hepatitis B. Seroprevalence of antibody to the HBV core antigen, which suggests past or current infection, is 60% higher among adults with DM than those without. DM may also increase HBV-associated mortality (615 [EL 4; NE]).
As a result of these findings, the CDC ACIP now recommends that all adults with DM aged 19 to 59 years be vaccinated against HBV as soon as possible after DM diagnosis, and HBV vaccination should be considered for individuals age ≥60 years after assessment of risk and the likelihood of an adequate immune response. The differential age recommendations are based on economic models that yielded age-stratified calculations. The incremental cost per quality-adjusted life-year (QALY) saved was $75,100 for adults up to 59 years, but costs per QALY saved increased substantially with greater age after this point because of other causes of mortality, as well as declining immune responses to the vaccine in older adults (615 [EL 4; NE]).


 

Q 22. Come trattare la depressione nel contesto del diabete?

Routine screening for depression in adults with DM is recommended. Untreated comorbid depression can have serious clinical implications for patients with DM because depression contributes to poor self-care, less treatment related adherence, and poor glycemic control (616 [EL 1; meta-analysis]). In addition, depression may be a risk factor for developing DM (617 [EL 2; MNRCT]). Depression and DM also are associated with a significantly increased all-cause and CVD-related mortality rate (618 [EL 2; PCS]). Chronic use of antidepressant medication is associated with a modestly increased relative risk of T2D (619 [EL 3; SS]). This may reflect the association of DM with depression rather than suggest an adverse effect of these agents (620 [EL 2; PCS]). The impact of the newer agents for treating depression is yet to be established, especially if they contribute to weight gain (621 [EL 2; NRCT]).
Collaboration with mental health professionals skilled in treating patients with DM can improve glycemic control and psychological well-being (622 [EL 1; RCT, single blinded]). Patients with depression or DM-related distress should be referred to mental health professionals who are integrated into the DM care team (212 [EL 4; NE]).


 

Q 23. Qual è l’associazione fra diabete e cancro?

Epidemiologic evidence suggests increased risks of cancer and cancer mortality in patients with obesity and DM (623 [EL 3; SS]; 624 [EL 2; PCS]; 625 [EL 2; PCS]). Whether antihyperglycemic therapy increases cancer risk remains unknown due to limited and conflicting data, although the latest analyses do not support increased cancer risk for any given treatment. Readers should consult the AACE/ACE Consensus Statement on Diabetes and Cancer for a complete discussion (626 [EL 4; NE]).
Increased BMI (>25 kg/m2) is associated with an increased risk of a wide variety of cancers. The strongest associations appear to be for endometrial, gall bladder, esophageal (adenocarcinoma), renal, thyroid, ovarian, breast, and colorectal cancer, with weaker but still statistically significant associations for leukemia, malignant and multiple melanoma, pancreatic cancer, and non-Hodgkin lymphoma (627 [EL 2; MNRCT]; 628 [EL 2; MNRCT]; 629 [EL 2; MNRCT]; 630 [EL 2; MNRCT]; 631 [EL 2; MNRCT]). Increased BMI may, however, be protective for lung, esophageal (squamous) (628 [EL 2; MNRCT]), and prostate cancer (632 [EL 3; SS]) in males, although more aggressive prostate cancers seem to be more common in males who are overweight or obese (633 [EL 4; NE]). In females, increased BMI may be protective for premenopausal breast and lung cancer (628 [EL 2; MNRCT]). As noted in the 2013 AACE/ACE Consensus Statement on Diabetes and Cancer, a higher BMI is also closely associated with increased levels of endogenous insulin, insulin-like growth factors, inflammatory cytokines, and other factors that can have downstream procancer growth effects (626 [EL 4; NE]). These and other potential mechanisms have been recently reviewed (634 [EL 4; NE]).
DM also significantly increases the risk of various common cancers, including endometrial, breast, hepatic, bladder, pancreatic, and colorectal cancers. As with increased BMI, the risk of prostate cancer appears to be decreased among males with DM (635 [EL 2; MNRCT]; 636 [EL 2; MNRCT]; 637 [EL 2; MNRCT]; 638 [EL 2; MNRCT]; 639 [EL 2; MNRCT]; 640 [EL 2; MNRCT]).
In addition to the other obesity-related mechanisms noted above, hyperinsulinemia appears strongly connected to the development of cancer in patients with DM. Animal models suggest that increased activation of insulin and insulin growth factor 1 (IGF-1) receptor leads to increased tumor volume (641 [EL 4; NE]; 642 [EL 4; NE]; 643 [EL 4; NE]). Whether hyperglycemia contributes to cancer development is less clear. Energy for tumor cell growth and proliferation comes from glucose but also from amino acids such as glutamine (644 [EL 4; NE]). In fact, cancer cells can thrive using nonglycemic energy sources due to genetic mutations in tumor cells, as well changes to intracellular signaling stimulated by activation of growth factor receptors (644 [EL 4; NE]; 645 [EL 4; NE]; 646 [EL 4; NE]).
The evidence for the effects of specific antihyperglycemic agents on cancer risk is limited and confounded by factors such as the indications for specific drugs, effects on other cancer risk factors such as body weight and hyperinsulinemia, and the complex progressive nature of hyperglycemia and pharmacotherapy in T2D. Metformin may have a neutral effect or modestly decrease cancer incidence and mortality, particularly colorectal, hepatocellular, and lung cancer (647 [EL 2; PCS]; 648 [EL 2; MNRCT]; 649 [EL 1; MRCT]; 650 [EL 2; MNRCT]). The effect of metformin on cancer outcomes is currently being explored in prospective trials. Pioglitazone may be associated with a very small, nonsignificant risk of bladder cancer, although recent evidence from a large population study suggests there is no significant association (127 [EL 4; NE]; 128 [EL 3; SS]). TZD therapy in general is not associated with other cancers.
The risk of cancer with incretin therapies has garnered much attention since the publication of a meta-analysis finding an increased incidence of pancreatic disease in individuals taking these medications (651 [EL 3; SS]). However, a thorough review of available data conducted by the FDA and the European Medicines Agency (EMA) has not uncovered evidence to support a causal association (652 [EL 4; NE]). In particular, results from a pooled analysis of sitagliptin data (653 [EL 1; MRCT]), as well as from the SAVOR (Saxagliptin Assessment of Vascular Outcomes Recorded) (146 [EL 1; RCT]) and EXAMINE (Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care) trials (145 [EL 1; RCT]) did not show any increased incidence of pancreatic disease among patients taking these agents. Results from 2 retrospective cohort studies indicate no risk of pancreatitis with exenatide (654 [EL 3; SS]; 655 [EL 3; SS]), while 1 study reported an increased risk for past users but not for recentor current users (656 [EL 2; PCS]). An increase in thyroid carcinoma occurred in preclinical trials of liraglutide; in liraglutide clinical trials, 1.3 cases of thyroid cancer per 1,000 patient-years occurred in patients taking liraglutide versus 1.0 cases per 1,000 patient-years in those receiving placebo (657 [EL 4; NE]).
Contrary to preliminary evidence suggesting that exogenous insulin may be associated with an increased cancer risk, recent studies have not substantiated this risk, including the large-scale ORIGIN (Outcome Reduction with an Initial Glargine Intervention) trial, which involved >6,000 patients receiving glargine over a median trial duration of 6 years. In ORIGIN, use of insulin glargine was not associated with an increased risk of any cancer (HR, 1.0; 95% CI, 0.88 to 1.13) or cancer death (HR, 0.94; 95% CI, 0.77 to 1.15) (658 [EL 1; RCT]).
Among the SGLT2 inhibitors, more cases of bladder cancer occurred among dapagliflozin-treated than control treated patients in clinical trials, and the product labeling indicates that this agent should not be used in patients with active bladder cancer and should be used with caution in patients with a history of bladder cancer (659 [EL 4; NE]). An increased incidence of bladder cancer was not observed in clinical trials with canagliflozin (660 [EL 4; NE]).


 

Q 24. Quali sono le attività lavorative con necessità specifiche per la gestione del diabete?

The licensing and certification of various occupations, including commercial drivers and pilots, anesthesiologists, and commercial or recreational divers, is restricted for persons with insulin-treated DM because of the potential risk hypoglycemia may pose to the patient and others.

 

Q 24.1. Rischio di incidenti

An area of great concern has been whether DM might lead operators of commercial vehicles (e.g., bus, truck, taxi, ferry, or airplane) to lose control and have an accident, putting themselves or others at risk of injury. Eye disease associated with DM, including the various forms of retinopathy and cataract, is of course a potential cause of impaired driving ability, and there is general consensus that ascertainment of the visual acuity of commercial motor vehicle drivers or airline pilots is a reasonable measure for measuring such risk. Similarly, coronary artery disease, CVD, musculoskeletal conditions, and diabetic neuropathy might in various ways impair safe driving or piloting ability. The U.S. Federal Motor Carrier Safety Administration and Federal Aviation Administration both require medical certification for operating commercial motor vehicles (used in interstate commerce) and airplanes; these are based on a medical examination including vision, audiometric, and cardiac assessments, as well as standard history and physical examination. Both organizations cite the use of insulin for glycemic control as a criterion for disqualification. Although an insulin-waiver program exists for drivers, this is a complex undertaking, leading many to refuse the treatment even if medically needed. It should be noted that individual states might have separate regulations governing commercial drivers’ licenses (661 [EL 4; NE]). For commercial pilots, insulin treatment is an absolute disqualification (662 [EL 4; NE]).

 

Q 24.2. Ipoglicemia e trattamenti ipoglicemizzanti

Hypoglycemia may impair judgment and motor ability, which could increase the likelihood of an accident during operation of a motor vehicle or airplane. The Federal Motor Carrier Safety Administration Evidence Report on Diabetes and Commercial Motor Vehicle Driver Safety addressed a set of key questions relevant to this topic (663 [EL 4; NE]):

  1. Are individuals with DM at increased risk for a motor vehicle crash compared with individuals who do not have DM?
  2. Is hypoglycemia an important risk factor for a motor vehicle crash among individuals with DM?
  3. What risk factors are associated with an increased incidence of severe hypoglycemia, and what is the incidence of severe hypoglycemia with different treatments and treatment modalities (e.g., use of insulin and injectable noninsulin drugs such as GLP-1 receptor agonists)?
  4. How effective is hypoglycemia awareness training in preventing the consequences of hypoglycemia?

The authors of the report performed a set of meta-analyses of existing publications to address these 4 questions. They showed evidence that, taken as a whole, individuals with DM do not have a significantly increased risk of motor vehicle accidents compared with drivers without DM. However, a separate analysis of studies conducted within the U.S. showed a 25% increase in risk of accidents, while studies conducted outside the U.S. showed no increased risk. This was particularly true when non-U.S. and U.S. cohorts of insulin-treated persons were compared. The analysis of the 2 available U.S. studies showed a 2.75-fold greater risk of motor vehicle accident when insulin-treated persons were compared with individuals without DM (P =.001), while studies from outside the U.S. demonstrated no significant difference in accident risk. In contrast, a metaanalysis restricted to U.S. studies of persons with DM not using pharmacologic treatment or using oral antihyperglycemic agents did not show a significant increase in risk of accidents. In the individual studies included in the analysis, sulfonylurea use did not significantly increase the risk of accident (664 [EL 2; RCCS]; 665 [EL 2; RCCS]; 666 [EL 2; RCCS]).
The applicability of these studies to the current population of persons with DM in the U.S. is limited because recommended treatment goals and approaches have changed dramatically since the follow-up periods of most of the cited studies. First, the studies of insulin users involved mostly patients with T1D, but the use of a basal insulin analog as the sole administered insulin for T2D is associated with considerably lower hypoglycemia rates than older insulin preparations or the use of basal-bolus treatment (667 [EL 1; RCT, not blinded]). Second, sulfonylurea treatment is associated with a greater likelihood of hypoglycemia than all other noninsulin antihyperglycemic agents (metformin, TZDs, α-glucosidase inhibitors, DPP-4 inhibitors, and GLP-1 receptor agonists) and carries a nearly a twofold greater likelihood of hypoglycemia than basal insulin (668 [EL 1; MRCT]). Unfortunately, reliable large population studies of motor vehicle accidents involving patients with T2D treated with current approaches are not available (studies of oral antihyperglycemic agents included in the meta-analysis examined data from the late 1980s to early 1990s). Finally, and perhaps most importantly, the role of SMBG in preventing episodes of hypoglycemia was not well addressed in the available studies.

 

Q 24.3. Autisti professionisti e stile di vita

Over the past 2 decades, the prevalence of obesity among commercial motor vehicle operators has risen even faster than in the general population. Commercial drivers may be away from home for long periods of time with infrequent stops, usually driving for long periods. At times they have limited control over their work environment, and little time for exercise. Meals tend be irregular, and dining choices are often limited. A population-based survey of 1,265 U.S. long-haul truck drivers, 76% of whom were physically inactive, showed that 69% were obese compared to 31% in the age-matched U.S. adult working population, and 51% versus 19% were smokers (669 [EL 3; SS]). Obesity, hypertension, and DM in turn increase the risk of OSA among drivers (670 [EL 2; RCCS]), which is not only a risk factor for accidents but also may contribute to worsening of glycemia and other cardiovascular risk factors. Although the details differ, commercial car drivers represent another large group with similar health concerns (671 [EL 3; SS]).
Because commercial vehicle operators (particularly drivers) exhibit a variety of lifestyle issues that put them at high risks of DM and associated comorbidities, this group would particularly benefit from improved healthcare access with a focus on measures to reduce obesity.


 

 RINGRAZIAMENTI

Ringraziamo Amanda M. Justice per il suo contributo determinante nella scrittura di questa linea guida.

Membri del Gruppo di Lavoro AACE per lo Sviluppo di un Piano Integrato di Trattamento per il Diabete e/o autori: Yehuda Handelsman, MD, FACP, FACE, FNLA*; Zachary T. Bloomgarden, MD, MACE*; George Grunberger, MD, FACP, FACE*; Guillermo Umpierrez, MD, FACP, FACE*; Robert S. Zimmerman, MD, FACE*; Timothy S. Bailey, MD, FACP, FACE, ECNU; Lawrence Blonde, MD, FACP, FACE; George A. Bray, MD, MACP, MACE; A. Jay Cohen, MD, FACE, FAAP; Samuel Dagogo-Jack, MD, DM, FRCP, FACE; Jaime A. Davidson, MD, FACP, MACE; Daniel Einhorn, MD, FACP, FACE; Om P. Ganda, MD, FACE; Alan J. Garber, MD, PhD, FACE; W. Timothy Garvey, MD; Robert R. Henry, MD; Irl B. Hirsch, MD; Edward S. Horton, MD, FACP, FACE; Daniel L. Hurley, MD, FACE; Paul S. Jellinger, MD, MACE; Lois Jovanovič, MD, MACE; Harold E. Lebovitz, MD, FACE; Derek LeRoith, MD, PhD, FACE; Philip Levy, MD, MACE; Janet B. McGill, MD, MA, FACE; Jeffrey I. Mechanick, MD, FACP, FACE, FACN, ECNU; Jorge H. Mestman, MD; Etie S. Moghissi, MD, FACP, FACE; Eric A. Orzeck, MD, FACP, FACE; Rachel Pessah-Pollack, MD, FACE; Paul D. Rosenblit, MD, PhD, FACE, FNLA; Aaron I. Vinik, MD, PhD, FCP, MACP, FACE; Kathleen Wyne, MD, PhD, FNLA, FACE; Farhad Zangeneh, MD, FACP, FACE.

Revisori: Alan J. Garber, MD, PhD, FACE; Lawrence Blonde MD, FACP, FACE; Jeffrey I. Mechanick, MD, FACP, FACE, FACN, ECNU.

*Copresidenti

 

CONFLITTI DI INTERESSE

Copresidenti

Yehuda Handelsman: compensi come oratore e consulente e sostegno alla ricerca da Boehringer Ingelheim GmbH, GlaxoSmithKline plc e Novo Nordisk A/S; compensi come consulente e sostegno alla ricerca da Amgen Inc, Gilead, Merck & Co Inc e Sanofi-Aventis U.S. LLC; sostegno alla ricerca da Intarcia Therapeutics Inc, Lexicon Pharmaceuticals Inc e Takeda Pharmaceutical Company Limited; compensi come consulente da Halozyme Inc; compensi come oratore e consulente da Amarin Corporation, Amylin Pharmaceuticals LLC, Janssen Pharmaceuticals Inc e Vivus Inc.

Zachary Bloomgarden: compensi come oratore da Merck & Co Inc e Santarus Inc; compensi come consulente da Bristol-Myers Squibb Company/AstraZeneca e Boehringer Ingelheim GmbH; compensi come oratore e consulente da Johnson & Johnson Services Inc e Novo Nordisk A/S; azionista di Abbott Laboratories, Covidien, F. Hoffman-La Roche Ltd, Hospira Inc, Pfizer Inc, St. Jude Medical, Inc e Zoetis; azionista e compensi come consulente da Novartis AG.

George Grunberger: compensi come oratore e consulente e sostegno alla ricerca per il suo ruolo di investigatore da Bristol-Myers Squibb Company, Eli Lilly and Company e Novo Nordisk A/S; compensi come oratore da Amarin Corporation, Janssen Pharmaceuticals Inc, Merck & Co Inc, Sanofi-Aventis U.S. LLC, Santarus Inc, Takeda Pharmaceutical Company Limited e Valeritas Inc.

Guillermo Umpierrez: compensi come consulente e sostegno alla ricerca da Boehringer Ingelheim GmbH, Merck & Co Inc, Novo Nordisk A/S, Sanofi-Aventis U.S. LLC e Regeneron.

Robert S. Zimmerman: compensi come oratore da Janssen Pharmaceuticals Inc, Johnson & Johnson Services Inc, Merck & Co Inc e Santarus Inc; sostegno alla ricerca da Novo Nordisk A/S.

 

Autori e/o membri delgruppo di lavoro

Timothy Bailey: compensi come oratore e consulente e sostegno alla ricerca da Novo Nordisk A/S; compensi come consulente e sostegno alla ricerca da Bayer AG BD, Medtronic Inc e Sanofi-Aventis U.S. LLC; sostegno alla ricerca da Abbott Laboratories, ACON Laboratories Inc, Alere, Animas Corporation, Cebix Incorporated, Bristol-Myers Squibb Company, Dexcom Inc, Eli Lilly and Company, GlaxoSmithKline plc, Halozyme Inc, Insulet Corporation, LifeScan Inc, MannKind Corporation, Merck & Co Inc, Orexigen Therapeutics Inc e Tandem Diabetes Care.

Lawrence Blonde: compensi come oratore e consulente e sostegno alla ricerca a Ochsner Medical Center per il suo ruolo di investigatore da Novo Nordisk A/S e Sanofi-Aventis U.S. LLC; sostegno alla ricerca a Ochsner Medical Center per il suo ruolo di investigatore da Eli Lilly and Company; compensi come oratore da Amylin Pharmaceuticals, LLC; compensi come oratore e consulente da AstraZeneca, Bristol-Myers Squibb Company, Janssen Pharmaceuticals Inc e Merck & Co, Inc; compensi come consulente da Eisai Inc, GlaxoSmithKline plc e Quest Diagnostics Incorporated.

George Bray: compensi come oratore da Herbalife International of America Inc e come consulente da Medifast Inc.

Alan J. Cohen: compensi come oratore da AstraZeneca, Sanofi-Aventis U.S. LLC e Takeda Pharmaceutical Company Limited; compensi come oratore e sostegno alla ricerca da Boehringer Ingelheim GmbH/Eli Lilly and Company, Merck & Co Inc e Novo Nordisk A/S.

Samuel Dagogo-Jack: compensi per il suo ruolo come consulente legale esperto di diabete da Sidley Austin LLP e Adams and Reese LLP; compensi come consulente da Janssen Pharmaceuticals Inc, Merck & Co Inc e Santarus Inc; compensi come consulente e sostegno alla ricerca per il suo ruolo di investigatore principale da Novo Nordisk A/S; sostegno alla ricerca per il suo ruolo di investigatore principale da AstraZeneca e Boehringer Ingelheim GmbH.

Jaime Davidson: compensi come consulente da Aspire Bariatrics e GlaxoSmithKline plc; compensi come membro del comitato consultivo da Amgen Inc e Eli Lilly and Company; compensi come oratore e membro del comitato consultivo da AstraZeneca/Bristol-Myers Squibb Company, Novo Nordisk A/S e Janssen Pharmaceuticals Inc.

Daniel Einhorn: compensi come consulente da Bristol-Myers Squibb Company/AstraZeneca; compensi come consulente e sostegno alla ricerca da Eli Lilly and Company e Novo Nordisk A/S; compensi come consulente e partecipazioni azionarie da Freedom Meditech Inc, GlySens Incorporated e Halozyme Inc; compensi come oratore e consulente e sostegno alla ricerca da Janssen Pharmaceuticals Inc; sostegno alla ricerca da AstraZeneca, MannKind Corporation, Sanofi Aventis U.S. LLC e Takeda Pharmaceutical Company Limited.

Om Ganda: compensi come membro del comitato consultivo da Amgen Inc. e Sanofi-Aventis U.S. LLC e sostegno alla ricerca da Amarin Corporation.

Alan J. Garber: compensi come membro del comitato consultivo, oratore e consulente da Janssen Pharmaceuticals Inc., Merck & Co. Inc., Novo Nordisk A/S e Vivus Inc; compensi come oratore e consulente da Salix Pharmaceuticals Inc./Santarus Inc; compensi come membro del comitato consultivo e consulente da Bayer AG; compensi come membro del comitato consultivo da Halozyme Therapeutics Inc e GlaxoSmithKline plc; compensi come oratore da Eisai Inc; compensi come consulente da Lexicon Pharmaceuticals Inc e Viking Therapeutics.

W. Timothy Garvey: sostegno alla ricerca da Amylin Pharmaceuticals Inc, Merck & Co Inc, Sanofi-Aventis U.S. LLC e Weight Watchers International Inc; sostegno alla ricerca e compensi come membro del comitato consultivo da Eisai Inc; compensi come membro del comitato consultivo da Alkermes plc, AstraZeneca, Bristol-Myers Squibb Company, Daiichi Sankyo Company Limited, Janssen Pharmaceuticals Inc, LipoScience Inc, Novo Nordisk A/S, Takeda Pharmaceutical Company Limited e Vivus Inc.

Robert R. Henry: sostegno alla ricerca da Hitachi Ltd. e Sanofi-Aventis U.S. LLC; compensi come consulente e membro del comitato consultivo da Alere, ClinMet, Eisai Inc e Isis Pharmaceuticals Inc; compensi come oratore da Amgen Inc, Daiichi Sankyo Company Limited, Elcelyx Therapeutics Inc, Merck & Co. Inc e Vivus Inc; compensi come oratore, consulente e membro del comitato consultivo da Boehringer Ingelheim GmbH, F. Hoffman-La Roche Ltd/Genentech Inc, Gilead, Intarcia Therapeutics Inc, Johnson & Johnson Services Inc/Janssen Pharmaceuticals Inc e Novo Nordisk A/S; compensi come oratore, consulente e membro del comitato consultivo e sostegno alla ricerca da Eli Lilly and Company.

Irl B. Hirsch: sostegno alla ricerca per il suo ruolo di investigatore principale da Halozyme Inc e Sanofi-Aventis U.S. LLC; compensi come consulente da Abbott Laboratories BD e F. Hoffman-La Roche Ltd.

Edward Horton: compensi come membro del comitato consultivo da Amarin Corporation, Amylin Pharmaceuticals LLC, GI Dynamics, Gilead, Janssen Pharmaceuticals Inc, Merck & Co Inc, Sanofi-Aventis U.S. LLC, Takeda Pharmaceutical Company Limited e Theracos Inc.

Daniel L. Hurley riferisce di non avere nessun relazione finanziaria o nessun interesse commerciale.

Paul S. Jellinger: compensi come oratore da Amarin Corporation, Boehringer Ingelheim GmbH, Bristol-Myers Squibb Company/AstraZeneca, Janssen Pharmaceuticals Inc e Novo Nordisk A/S.

Lois Jovanovič riferisce di non avere nessun relazione finanziaria o nessun interesse commerciale.

Harold E. Lebovitz: compensi come membro del comitato consultivo da Biocon, Intarcia Therapeutics Inc, MetaCure e Poxel SA; compensi come consulente da AstraZeneca, Janssen Pharmaceuticals Inc e Sanofi-Aventis U.S. LLC; dividendi azionari da AbbVie Inc e Merck & Co Inc.

Derek LeRoith: compensi come consulente da Bristol-Myers Squibb Company/AstraZeneca, Janssen Pharmaceuticals Inc, Merck & Co Inc, Novo Nordisk A/S e Sanofi-Aventis U.S. LLC.

Philip Levy: compensi come oratore da Boehringer Ingelheim GmbH, Daiichi Sankyo Company Limited, Janssen Pharmaceuticals Inc e Novo Nordisk A/S.

Janet B. McGill: compensi come oratore e consulente da Janssen Pharmaceuticals Inc e Merck & Co Inc; compensi come consulente e sostegno alla ricerca a Washington University School of Medicine da MannKind Corporation, Novo Nordisk A/S e Sanofi-Aventis U.S. LLC; compensi come consulente da Abbott Laboratories, AstraZeneca, Boehringer Ingelheim GmbH, Eli Lilly and Company e McNEIL-PPC Inc; sostegno alla ricerca a Washington University School of Medicine da Andromeda Biotech Ltd, Intarcia Therapeutics Inc, Novartis AG e Takeda Pharmaceutical Company Limited.

Jeffrey I. Mechanick: compensi per letture e sviluppo di programma da Abbott Nutrition.

Jorge H. Mestman riferisce di non avere nessun relazione finanziaria o nessun interesse commerciale.

Etie S. Moghissi: compensi come oratore da Boehringer Ingelheim GmbH, Janssen Pharmaceuticals Inc, Takeda Pharmaceutical Company Limited; compensi come oratore e consulente da Novo Nordisk A/S; compensi come consulente da Amylin Pharmaceuticals LLC, AstraZeneca e Sanofi-Aventis U.S. LLC.

Eric Orzeck riferisce di non avere nessun relazione finanziaria o nessun interesse commerciale.

Rachel Pessah-Pollack riferisce di non avere nessun relazione finanziaria o nessun interesse commerciale.

Paul D. Rosenblit: compensi come oratore e membro del comitato consultivo da Amarin Corporation; compensi come oratore da Boehringer Ingelheim GmbH, Bristol-Myers Squibb Company e Janssen Pharmaceuticals Inc; compensi come membro del comitato consultivo e sostegno alla ricerca per il suo ruolo di investigatore principale da Dexcom Inc; sostegno alla ricerca per il suo ruolo di investigatore principale da Amgen Inc, Daiichi Sankyo Company Limited, Eli Lilly and Company, GlaxoSmithKline plc, MannKind Corporation, Novartis AG, Orexigen Therapeutics Inc, Pfizer Inc e Sanofi-Aventis U.S. LLC; compensi come oratore e sostegno alla ricerca per il suo ruolo di investigatore principale da AstraZeneca, Eisai Inc., Merck & Co Inc, Novo Nordisk A/S e Takeda Pharmaceutical Company Limited.

Aaron I. Vinik: compensi come consulente da Isis Pharmaceuticals Inc, Merck & Co Inc e Pamlab Inc; compensi come consulente e sostegno alla ricerca per il suo ruolo di investigatore principale da Pfizer Inc; sostegno alla ricerca per il suo ruolo di investigatore principale da Impeto Medical, Intarcia Therapeutics Inc, Tercica Inc e ViroMed Laboratories Inc.

Kathleen Wyne: compensi come oratore da AbbVie Inc, Novo Nordisk A/S e Salix Pharmaceuticals Inc.

Farhad Zangeneh: compensi come oratore e consulente da Abbott Laboratories, AbbVie Inc, Amarin Corporation, AstraZeneca, Auxilium, Boehringer Ingelheim GmbH, Bristol-Myers Squibb Company, Daiichi Sankyo Company Limited, Eisai Inc, Eli Lilly and Company, Forest Laboratories Inc, GlaxoSmithKline plc, Janssen Pharmaceuticals Inc, Novo Nordisk A/S, Salix Pharmaceuticals Inc, Takeda Pharmaceutical Company Limited e Vivus Inc.

 

Medical Writer

Sign.na Amanda M. Justice: compensi per scrittura/consulenza editoriale da Asahi-Kasei Corporation e Sanofi-Aventis U.S. LLC.


 

BIBLIOGRAFIA

Nota: per ogni citazione bibliografica viene indicato il livello di evidenza (LE) (con un punteggio da 1 a 4) e il tipo di disegno dello studio. Per un’identificazione più facile, i migliori livelli di evidenza (LE 1 e LE 2) sono evidenziati in rosso.

  1. Handelsman Y, Mechanick JI, Blonde L, et al. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for developing a diabetes mellitus comprehensive care plan. Endocr Pract. 2011;17 Suppl 2:1-53. [LE 4; NE]
  2. Mechanick JI, Camacho PM, Cobin RH, et al. American Association of Clinical Endocrinologists Protocol for Standardized Production of Clinical Practice Guidelines--2010 update. Endocr Pract. 2010;16:270-83. [LE 4; CPG NE; Fig. 1; Tab. 1-4]
  3. Mechanick JI, Camacho PM, Garber AJ, et al. American Association of Clinical Endocrinologists and American College of Endocrinology Protocol for Standardized Production of Clinical Practice Guidelines, Algorithms, and Checklists - 2014 Update and the AACeG4G Program. Endocr Pract. 2014;20:692-702. [LE 4; CPG NE; Tab. 1-4]
  4. Garber AJ, Abrahamson MJ, Barzilay JI, et al. American association of clinical endocrinologists/ American college of endocrinology’ comprehensive diabetes management algorithm 2015. Endocr Pract. 2015; 21:438-447. [LE 4; NE]
  5. Moghissi ES, Korytkowski MT, DiNardo M, et al. American Association of Clinical Endocrinologists and American Diabetes Association consensus statement on inpatient glycemic control. Endocr Pract. 2009;15:353-369. [LE 4; consensus NE]
  6. Boulton AJ, Armstrong DG, Albert SF, et al. Comprehensive foot examination and risk assessment: a report of the task force of the foot care interest group of the American Diabetes Association, with endorsement by the American Association of Clinical Endocrinologists. Diabetes Care. 2008;31:1679-1685. [LE 4; NE]
  7. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110:227-239. [LE 4; CPG NE]
  8. James PA, Oparil S, Carter BL, et al. 2014 evidence based guideline for the management of high blood pressure in adults: Report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;311:507-520. [LE 4; NE]
  9. Younis N, Williams S, Ammori B, Soran H. Role of aspirin in the primary prevention of cardiovascular disease in diabetes mellitus: a meta-analysis. Expert Opin Pharmacother. 2010;11:1459-1466. [LE 1; MRCT ma bassa numerosità campionaria e tasso di eventi]
  10. Antithrombotic Trialists’ (ATT) Collaboration, Baigent C, Blackwell L, et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet. 2009;373:1849-1860. [LE 1; MRCT]
  11. Zhang C, Sun A, Zhang P, et al. Aspirin for primary prevention of cardiovascular events in patients with diabetes: A meta-analysis. Diabetes Res Clin Pract. 2010;87:211- 218. [LE 1; MRCT]
  12. Ong G, Davis TM, Davis WA. Aspirin is associated with reduced cardiovascular and all-cause mortality in type 2 diabetes in a primary prevention setting: the Fremantle Diabetes study. Diabetes Care. 2010;33:317-321. [LE 2; PCS]
  13. Hanas R, Donaghue KC, Klingensmith G, Swift PG. ISPAD clinical practice consensus guidelines 2009 compendium. Pediatr Diabetes. 2009;10 Suppl 12:1-2. [LE 4; CPG NE]
  14. National Diabetes Education Program. Transitions From Pediatric to Adult Health Care. Bethesda, MD: National Institute of Diabetes and Digestive and Kidney Diseases. Available at: http://ndep.nih.gov/transitions/. [LE 4; NE]
  15. Peters A, Laffel L; American Diabetes Association Transitions Working Group. Diabetes care for emerging adults: recommendations for transition from pediatric to adult diabetes care systems: a position statement of the American Diabetes Association, with representation by the American College of Osteopathic Family Physicians, the American Academy of Pediatrics, the American Association of Clinical Endocrinologists, the American Osteopathic Association, the Centers for Disease Control and Prevention, Children with Diabetes, The Endocrine Society, the International Society for Pediatric and Adolescent Diabetes, Juvenile Diabetes Research Foundation International, the National Diabetes Education Program, and the Pediatric Endocrine Society (formerly Lawson Wilkins Pediatric Endocrine Society). Diabetes Care. 2011;34:2477-85. [LE 4; NE]
  16. Juvenile Diabetes Research Foundation. Life Stages. New York, NY: JDRF. Available at: http://jdrf.org/lifewith-t1d/#life-stages. [LE 4; NE]
  17. American Association of Clinical Endocrinologists/American College of Endocrinology. American Association of Clinical Endocrinologists/American College of Endocrinology statement on the use of hemoglobin A1c for the diagnosis of diabetes. Endocr Pract. 2010;16:155-156. [LE 4; consensus NE]
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  655. Dore DD, Seeger JD, Arnold Chan K. Use of a claimsbased active drug safety surveillance system to assess the risk of acute pancreatitis with exenatide or sitagliptin compared to metformin or glyburide. Curr Med Res Opin. 2009;25:1019-1027. [LE 3; SS]
  656. Dore DD, Bloomgren GL, Wenten M, et al. A cohort study of acute pancreatitis in relation to exenatide use. Diabetes Obes Metab. 2011;13:559-566. [LE 2; PCS]
  657. Victoza (liraglutide rDNA origin) injection prescribing information. Princeton, NJ: Novo Nordisk, Inc; 2013. [LE 4; NE]
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  659. Farxiga (dapagliflozin) prescribing information. Princeton, NJ: Bristol-Myers Squibb Company; 2014. [LE 4; NE]
  660. Invokana (canagliflozin) prescribing information. Titusville, NJ: Janssen Pharmaceuticals, Inc; 2013. [LE 4; NE]
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