Ipoglicemia - Come arginare il problema

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1 Ipoglicemia - Come arginare il problema Giulio Marchesini Malattie del Metabolismo e Dietetica Clinica, Università di Bologna

2 Disclosures Giulio Marchesini Advisory Board: Sanofi, Roche Honoraria: Sanofi, Merck Sharp & Dome, Novartis Clinical Studies: Boehringer Ingelheim, Sanofi, Lilly, Novo Nordisk, GILEAD, GENFIT, Jannsen

3 Hypoglycemia and emergency use Farmer, Diabet Med 2012 The estimated total cost of the emergency call, initial ambulance attendance and treatment at scene was around ; if transport to hospital was necessary, the additional ambulance transport costs were plus emergency department costs of ; and the cost of primary care follow-up was estimated as a further The average cost per emergency call was 263. By extrapolation, we estimate that, in the whole of England, the annual cost of treatment for hypoglycemia by the ambulance service (excluding those aged < 1 year), which does not include the costs of hospital admission, is in the order of 13.6m.

4 Annual National Hospitalizations (N = 99,628) Proportion of ED Visits Resulting in Hospitalization No % (95%CI) % Most commonly implicated medications Warfarin 33, ( ) 46.2 Insulins 3, ( ) 40.6 Oral antiplatelet agents 13, ( ) 41.5 Oral hypoglycemic agents 10, ( ) 51.8 Opioid analgesics 4, ( ) 32.4 Antibiotics 4, ( ) 18.3 Digoxin 3, ( ) 80.5 Antineoplastic agents 3, ( ) 51.5 Antiadrenergic agents 2, ( ) 35.7 Renin angiotensin inhibitors 2, ( ) 32.6 Sedative or hypnotic agents 2, ( ) 35.2 Anticonvulsants 1, ( ) 40.0 Diuretics 1, ( ) 42.4 Budnitz, NEJM 2011

5 Length of stay and inpatient mortality of patients with diabetes who had an episode of hypoglycaemia in a non critical care setting at University Hospital Birmingham, UK 148 admissions (2.3%) with severe hypoglycaemia (</= 2.2 mmol/l), 500 admissions (7.8%) with mild to moderate hypoglycaemia ( mmol/l) and 5726 admissions with no recorded hypoglycaemic episode (> 3.9 mmol/l). Conclusion: Hypoglycaemia is associated with increased length of stay and inpatient mortality. Whilst causative evidence is lacking, our data are consistent with the need to avoid hypoglycaemia in our current and continued approach for optimal glycaemic control in people with diabetes admitted to hospital. Nirantharakumar, Diabet Med 2012

6 ADA/EASD position statement: DPP-4 inhibitors as 2nd or 3rd line treatment Inzucchi SE, et al. Diabetes Care 2012;35:

7 Number of participants with severe hypoglycemia (ACCORD Study) Miller, BMJ 2010 A role for new drugs (incretins, gliptins, glifozins)?

8 Zoungas, N Engl J Med 2010 Hypos & cardiovascular outcomes ADVANCE study

9 Zoungas, N Engl J Med 2010 Hypos & cardiovascular outcomes ADVANCE study

10 New therapeutic targets The patient in the lead

11 Tailored therapy Inzucchi. Diabetologia Ismail-Beigi. Ann Intern Med 2011

12 Diabetes Care, 2014 Tailored therapy

13 Start low e go slow

14 Gaede, NEJM 2003 STENO-2: percentuale di pazienti a target

15 Giorgino, Ann NY Acad Sci 2013 CVD prevention in DM

16 Giorgino, Ann NY Acad Sci 2013 CVD prevention in DM

17 Hypoglycemia and 5-yr mortality McCoy, Diabetes Care 2012 Data 1020 DM from a diabetes clinic Type 2 diabetes: n = 797 After 5 years, patients who reported severe hypoglycemia had 3.4-fold higher mortality (95% CI ; P = 0.005) compared with those who reported mild/no hypoglycemia. CONCLUSIONS Self-report of severe hypoglycemia is associated with 3.4-fold increased risk of death. Patient-reported outcomes, including patient-reported hypoglycemia, may therefore augment risk stratification and disease management of patients with diabetes. CCI: Charlson Comorbidity Index

18 Lipska, JAMA Intern Med 2014

19 Lipska, JAMA Intern Med 2014

20 Malnutrition, psychiatric diseases, dementia & functional disability are frequently associated with hypoglycemia and poor outcome Lipska, JAMA Intern Med 2014

21 Emergency Hospitalization for Adverse Drug Events in Older Americans (65 years of age or older) National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance 40 % 20 33,3 Insulin and oral hypoglycemic agents are implicated in about 25% of emergency hospitalizations for adverse drug events 0 13,9 13,3 Warfarin Insulin Antiplatelet agents 10,7 Oral hypoglycemic agents Proportion of emergency department visits resulting in hospitalization Budnitz, N Engl J Med 2011

22 Lombardo, PloS ONE 2013

23 Lombardo, PloS ONE 2013

24 Hospital admission rates for acute diabetic complications in Italy, Acute Diabetic Complications Hypoglycemic coma N Rate /100,000 Residents Rate / 1000 Diabetics N Rate /100,000 Residents Rate / 1000 Diabetics , ( ) 1, ( ) , ( ) 1, ( ) , ( ) 1, ( ) , ( ) 1, ( ) , ( ) 1, ( ) , ( ) 1, ( ) , ( ) 1, ( ) , ( ) 1, ( ) , ( ) 1, ( ) , ( ) 1, ( ) Lombardo, PloS ONE 2013

25 Geller, JAMA Intern Med 2014

26 NICE-Sugar study Intensive treatment & outcome Finfer. N Engl J Med 2009

27 Hypos and survival in critically ill pts NICE-SUGAR study In critically ill patients, intensive glucose control leads to moderate and severe hypoglycemia, both of which are associated with an increased risk of death NICE-Sugar Study Investigators, N Engl J Med 2011

28 Episodes accompanied by cardiac symptoms (%) Hypoglycaemia in T2DM: A possible link to increased CV risk/events Possible mechanisms 1,2 Hypoglycaemia as link to tissue ischaemia 3 Haemodynamic changes: Activation of autonomic nervous system fold increased secretion of adrenaline and noradrenaline * * ECG changes: Longer QT interval Hypokalaemia 10 5 Haemorheological changes: Platelet activation Increased viscosity *P <0.01 vs episodes during hyperglycaemia and normoglycaemia 1 Desouza CV et al. Diabetes Care 2010;33: Robert TC et al. Diabetes 2003;52: Desouza C et al. Diabetes Care 03; 26: Study of 72-h continuous glucose monitoring and simultaneous cardiac Holter monitoring in patients with T2DM treated with insulin and history of frequent hypoglycaemia and coronary artery disease (n=19) 54 episodes of hypoglycaemia reported (BGL <70 mg/dl) 59 episodes of hyperglycaemia reported (BGL >200 mg/dl)

29 Hsu, Diabetes Care 2013

30 Risk for severe hypoglycaemia (incidence rate ratio) Declining renal function increases risk of severe hypoglycaemia + CKD + Diabetes CKD + Diabetes + CKD Diabetes CKD Diabetes Around 74% of sulphonylurea-induced severe hypoglycaemic events (loss of consciousness) occur in patients with reduced renal function 1. Moen MF, et al. Clin J Am Soc Nephrol Jun;4(6):

31 RIFLESSIONI: trial di prevenzione CV Tutti i grandi trial di prevenzione CV degli ultimi 5-6 anni CON QUALSIASI PROTOCOLLO hanno fallito (ACCORD, ADVANCE, VADT, ORIGIN, NICE-SUGAR) Nella maggior parte dei casi si documenta un effetto negativo dell ipoglicemia (pazienti fragili), che aumenta il rischio CV Il rischio non era evidente negli studi più vecchi, con target meno ambiziosi (Effetto LEGACY) Mortalità CV nei trial scesa da 3% a <1%: statine, antipertensivi, rivascolarizzazione.. Come giungere ad un controllo ottimale senza ipoglicemia? Quali effetti questo potrebbe avere sul rischio CV? Quali regole?

32 Vantaggi/svantaggi degli inibitori del DPP-4 VANTAGGI Ben tollerati Basso rischio di ipolicemie Efficacia simile ai vecchi antidiabetici orali (dati AIFA: HbA1c - 0.9%) Effetto neutro sul peso Associabili ad altre terapie (anche insulina) Utilizzabili anche in IRC Maggiore efficacia su glicemia post-prandiale SVANTAGGI Alto costo Scarsi dati su uso prolungato

33 Vantaggi/svantaggi delle incretine VANTAGGI Riduzione peso (dati AIFA: 3.5 kg) Buona efficacia (dati AIFA: HbA1c 1.1%) Basso rischio di ipoglicemia Associabili ad altri farmaci (anche insulina) Maggiore efficacia su iperglicemia post-prandiale Potenziali effetti protettivi sulla beta-cellula SVANTAGGI Somministrazione iniettiva Alto costo Scarsi dati su uso prolungato Effetti avversi (nausea, vomito, diarrea)

34 Composite endpoints DPP-4i & GLP-1a

35 Composite endpoints DPP-4i & GLP-1a

36 Vantaggi/svantaggi degli SGLT2-inibitori VANTAGGI Riduzione peso (3-5 kg) Buona efficacia (HbA1c 1.1%) Basso rischio di ipoglicemia Associabili ad altri farmaci (anche insulina) Maggiore efficacia su iperglicemia post-prandiale SVANTAGGI Scarsi dati su uso prolungato Effetti avversi (infezioni vie urinarie) Costo (?)

37 Phase III pooled efficacy data - Empaglifozin Placebo corrected values

38 Cefalù, ADA Chicago 2013 Canaglifozin Effects on body weight

39 Canaglifozin Episodes of hypoglycemia Cefalù, ADA Chicago 2013

40 Prevalenza e costi del DM farmaco-trattato: periodo Prevalenza (15 anni): +70%

41 Al 31 Dicembre 2013 Documento regionale incretine Aggiunta di 2 farmaco a metformina

42 Al 31 Dicembre 2013 Documento regionale incretine Aggiunta di 2 farmaco a metformina

43 Aprile-Settembre 2013 Documento regionale incretine Cross da SULF a INCR

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45 Il paziente al centro Personalised Medicine E molto più importante sapere che tipo di persona ha una malattia piuttosto che quale malattia abbia una certa persona Ippocrate, 400 a.c.