Les NOUVEAUX ANTIDIABÉTIQUES ORAUX

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1 48 e CONGRÈS de l A.M.U.B. Les NOUVEAUX ANTIDIABÉTIQUES ORAUX Dr. Françoise FÉRY Service d Endocrinologie Hôpital ERASME Session ACTUALITÉS DIAGNOSTIQUES et THÉRAPEUTIQUES Modérateurs : Drs D DE TAVERNIER M MAHIEU T PEPERSACK Samedi 6 septembre 2014

2 Conflits d intérêt en rapport avec la présentation Honoraires de conférence Participation à des «Advisory Boards» Etudes cliniques sponsorisées en cours Consultance Voyages-Congrès NÉANT

3 The rate of introduction of new classes of antidiabetic drugs has accelerated during the past 20 years Kahn SE et al. The Lancet 383: , 2014 Classes of glucose-lowering drugs Animal insulin Metformin Sulfonylureas Insulin analogues α-glucosidase inhibitors Human insulin Glinides Thiazolidinediones SGLT2 inhibitors Bromocriptine Colesevelam DPP4 inhibitors Inhaled insulin Pramlintide GLP-1 receptor agonists Year

4 Agonistes du GLP-1 R Inhibiteurs DPP-4 Inhibiteurs des α-glucosidases Inhibiteurs des co-transporteurs SGLT2 Pioglitazone

5 Healthy(eating( (Weight(control( (Increased(physical(activity Efficacy'( "HbA 1c ) Hypoglycemia Weight Major'side'effect(s) Costs METFORMIN low neutral/loss GI/lactic8acidosis low METFORMIN) + SGLT2 INHIBITOR Efficacy'( "HbA 1c ) Hypoglycemia Weight Major'side'effect(s) Costs SULFONYLUREA moderate gain hypoglycemia low THIAZOLIDINE+, DIONE low, gain œdema,,hf,,fx DPP#4%INHIBITOR intermediate% low% neutral% rare% % GLP$1&RECEPTOR& AGONIST low loss GI INSULIN& (usually& basal) est gain hypoglycemia variable METFORMIN) + SULFONYLUREA+ + or TZD DPP#4% i THIAZOLIDINE+, DIONE, + SU or DPP#4% i DPP#4%INHIBITOR% + % or % SU TZD GLP$1&RECEPTOR& AGONIST& + SU or TZD INSULIN& (usually& basal)& + TZD or DPP#4% i or GLP$1& RA& or GLP$1& RA& or % INSULIN& or INSULIN& or GLP$1& RA& or INSULIN& or INSULIN& % INSULIN&(multiple&daily&doses)

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7 Glycémie (mg/dl) Insuline (µu/ml) From Nauck MA et al. Diabetologia 29:46-52, 1986

8 Glycémie (mg/dl) Insuline (µu/ml) From Nauck MA et al. Diabetologia 29:46-52, 1986

9 Actions of GLP-1 on selected tissues Kidney Natriuresis Heart & Blood Vessels Contractility & heart rate Ischemia induced damage endothelium dpt vasodilatation GLP-1 Pancreas Insulin secretion Glucagon secretion (both glucose-dependent) Brain Satiety - Food intake Neuroprotection Stomach Gastric emptiyng

10 La DPP-4 est une peptidase exprimée dans un grand nombre de tissus qui, dans le plasma, clive sélectivement l extrémité N-terminale des peptides possédant une proline ou une alanine en 2 ème position Demi vie plasmatique du GLP-1 ~ 2 min Nécessité d administration en perfusion sc continue

11 Sitagliptine (Januvia ) Vildagliptine (Galvus ) Saxagliptine (Onglyza ) Linagliptine (Trajenta ) Alogliptine (Vipidia ) Anagliptine Teneligliptine Gemigliptine Dutogliptine...

12 Healthy(eating( (Weight(control( (Increased(physical(activity Efficacy'( "HbA 1c ) Hypoglycemia Weight Major'side'effect(s) Costs METFORMIN low neutral/loss GI/lactic8acidosis low METFORMIN) + Efficacy'( "HbA 1c ) Hypoglycemia Weight Major'side'effect(s) Costs SULFONYLUREA moderate gain hypoglycemia low THIAZOLIDINE+, DIONE low, gain œdema,,hf,,fx DPP#4%INHIBITOR intermediate% low% neutral% rare% % GLP$1&RECEPTOR& AGONIST low loss GI INSULIN& (usually& basal) est gain hypoglycemia variable

13 Adjusted mean HbA 1c in the completers cohort Adjusted mean HbA 1c (%) Changes in weight (kg) p < Changes in HbA 1c (%) p < 0.05 Treatment dura+on (weeks)

14 Monotherapy: DPP- 4 inhibitors vs mekormin Weighted mean difference in change in HbA 1c (%) 0.20 (0.08 to 0.32) Combined with mekormin: DPP- 4 inhib vs sulfonylurea 0.07 (0.03 to 0.11)

15 Monotherapy: DPP- 4 inhibitors vs mekormin Weighted mean difference in change in body weight (kg) kg (0.9 to 2.1) Combined with mekormin: DPP- 4 inhib vs sulfonylurea kg (- 1.5 to - 2.3)

16 Ambulatory Treatment of Type 2 Diabetes in the U.S Turner LW et al. Diabetes Care 37: , 2014 % National trends in the ambulatory treatment of type 2 diabetes Source: NDTI, Metformin Sulfonylureas Glitazones DPP-4 inhibitors GLP-1 R agonists

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18 HbA 1c evolution over time 4351 recently diagnosed type 2 diabetic patients Monotherapy 3053 recently diagnosed type 2 diabetic patients Intensive vs conventional therapy HbA 1c (%) Years Years

19 Glycemic durability with DPP-4 inhibitors in type 2 diabetes A systematic review and meta-analysis of long-term randomised controlled trials Esposito K et al. BMJ Open 2014;4:e doi: /bmjopen randomised controlled trials (including participants) published between 2008 and 2013 Duration of studies : 76 to 108 weeks HbA 1c (%) This analysis suggests that the effect of DPP-4 inhibitors on HbA 1c decreases during the 2 nd year of treatment Year

20 Cardiovascular safety of sulfonylureas: a meta-analysis of randomized clinical trials Monami M et al. Diab Obes & Metab 15: , 2013 Mantel-Haenszel odds ratio with 95% confidence interval [MH-OR (95%, CI)] for major cardiovascular events The results of this meta-analysis need to be interpreted with caution, (limitations in trial quality, under-reporting of cardiovascular events & mortality, different types of comparators,...) MH-OR (95%, CI) First author (year) MH-OR LL (95%CI) UL (95%CI) p Overall Favours sulfonylureas Favours comparators

21 All Danish residents >20 years, initiating single-agent ISs or metformin between 1997 and 2006 were followed for up to 9 yrs (median 3.3 yrs). A total of subjects were included, of whom had previous MI

22 Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus (SAVOR-TIMI 53) Scirica BM et al. N Engl J Med 369: , 2013 Alogliptin after Acute Coronary Syndrome in Patients with Type 2 Diabetes (EXAMINE) White WB et al. N Engl J Med 369: , patients with type 2 diabetes who had a history of, or were at risk for, cardiovascular events randomly assigned to receive saxagliptin or placebo. Median follow-up: 2.1 years patients with type 2 diabetes and either an acute myocardial infarction or unstable angina randomly assigned to receive alogliptin or placebo. Median follow-up: 18 months Primary End Point (composite of cardiovascular death, nonfatal myocardial infarc+on, or nonfatal ischemic stroke) Pa+ent with End Point (%) Hazard ra+o : 1.00 (95%CI, ) p<0.001 for noninferiority Placebo Saxaglip+n Cumula+ve Incidence of Primary End- Point Events (%) Hazard ra+o : 0.96 p<0.001 for noninferiority Placebo Aloglip+n Days Months

23 Cardiovascular Outcome Study of Linagliptin versus Glimepiride in Patients with Type 2 Diabetes (CAROLINA) 6000 type 2 diabetic patients allocated to receive Linagliptin or Glimepiride aged 40 to 85 years HbA 1c : % with pre-existing cardiovascular disease or specified diabetes end-organ damage or age >70 years or two or more specified cardiovascular risk factor Primary Outcome Measures : time to first occurence of any of the following adjudicated components of the primary composite endpoint: CV death, non-fatal MI (excluding silent MI), non-fatal stroke and hospitalisation for unstable angina Estimated completion date: September 2018

24 Head-to-head comparison of DPP-4 inhibitors and sulfonylureas A meta-analysis from randomized clinical trials Zhang Y et al. Diabetes Metab Res Rev 30: , 2014 Il ne fait pas de doute que le risque d hypoglycémies est plus élevé sous sulfonylurée que sous inhibiteurs de la DPP-4 mais... OR for hypoglycemia DPP-4 inhibitors Sulfonylureas Odds Ratio Odds Ratio Study Events Total Events Total Weight 95%CI 95%CI Total (95%CI) % 0.13 [ ] p< Favours DPP-4 inhibitors Favours Sulfonylureas

25 A meta-analysis of the hypoglycemic risk in randomized controlled trials with sulphonylureas in patients with type 2 diabetes Monami M et al. Diabetes Obes Metab 16: , September 2014 Odds ratio for hypoglycemia with sulfonylureas in comparison with other classes of hypoglycemic agents or placebo Severe hypoglycemia Yearly Comparators OR p n trials patient/yr n events incidence DPP4 i i SGLT2 i Glinides Metformin 3.51 GLP1-R a Glitazones Placebo 1.89 Insulin Any hypoglycemia SGLT2 i DPP4 i i 6.76 α gluc i GLP1-R Glitazones Placebo 3.34 Metformin 2.74 Insulin Glinides

26 Glycosylated Hemoglobin (%) Most recently measured HbA 1c (%)