Les nouveaux anti-diabétiques oraux: comment faire le bon choix?

Transcription

1 3 ème Journée Liégeoise de Diabétologie Samedi 15 novembre 2014 Les nouveaux anti-diabétiques oraux: comment faire le bon choix? Pr Nicolas PAQUOT Département de Médecine Interne Service de Diabétologie, Nutrition et Maladies métaboliques

2 Prévalence du diabète de type 2 en Belgique: + 33% en 6 ans Sweden 7.3% 460,000 Belgium % (315,000) % ( ) Netherlands 3.7% 432,000 France 6.2% 2.7 million Spain 9.9% 3.0 million Germany 10.2% 6.3 million Italy 6.6% 2.9 million ME 422HQ09PM065(6) - NS : Prevalence data, : Thalès data 2009 Sources: American Diabetes Association, 2008, Centers for Disease Control, 2008, Adapted from IDF E-Atlas. Available at Accessed 9 March 2007.

3 Source: National Health and Nutrition Examination Survey.

4 Source: National Health Interview Survey.

5 Prévention des complications

6 La place des biguanides dans le traitement du diabète sucré. Journées de Diabétologie de l Hôtel-Dieu 1974, pages Le traitement du diabète de type 2 Régime et exercice physique ECHEC Sujets obèses + BIGUANIDE (METFORMINE) Sujets de poids normal + INSULINO-SÉCRÉTEUR (SULFAMIDÉ) ÉCHEC ÉCHEC + INSULINO-SÉCRÉTEUR (SULFAMIDÉ) + BIGUANIDE ÉCHEC ÉCHEC + INSULINE Luyckx A, Daubresse JC, Carpentier JL & Lefèbvre P.

7 Le premier choix = Metformine (sauf contre-indications) En comparaison avec le traitement conventionnel (patients obèses, UKDPS) 32% réduction du risque des complications diabétiques p= % réduction du risque des décès liés au diabète p= % réduction de la mortalité toutes causes p= % réduction du risque des infarctus du myocarde p=0.01 UKPDS 34. Lancet 1998; 352:

8 En deuxième ligne? Nombreuses combinaisons possibles

9 En deuxième ligne? Nombreuses combinaisons possibles?

10 Sulfamides et gliptines actuellement commercialisés en Belgique A. Scheen, Rev Med Liège 2014;69:

11 Comment faire son choix? Preuves scientifiques (EBM) Mécanisme d action Efficacité Tolérance et sécurité Coût Aspects individuels

12 Sulfamidés: mécanisme d action Glucose GLUT 2 Na + K + Na + K + KIR - K + Sulfonylureas Pancreatic ß cell Insulin granules K + - Ca 2+ Ca 2+ V m Canaux potassiques également dans le cœur! Ca 2+ Voltage-gated Ca 2+ channel Sécrétion d insuline indépendamment de la glycémie!

13 Sulfamidés Quelques questions non (ou imparfaitement) résolues Epuisement de la cellule B (UKPDS, ADOPT) Sécurité cardio-vasculaire (UGDP, méta-analyses mais UKPDS, ADVANCE, ADOPT rassurants) Risque hypoglycémique (sujets à risque)

14 DPP-4 Inhibitors: An Incretin-Based Glucose-Dependent Mechanism for Improving Glycemic Control GI tract Ingestion of food Inactive GLP-1 Release of active incretins GLP-1 and GIP a DPP-4 enzyme Inactive GIP Pancreas Glucose-dependent Insulin from beta cells (GLP-1 and GIP) Beta cells Alpha cells Glucose-dependent Glucagon from alpha cells (GLP-1) Peripheral glucose uptake Hepatic glucose production Blood glucose in fasting and postprandial states

15 DPP-4 Inhibitors: An Incretin-Based Glucose-Dependent Mechanism for Improving Glycemic Control GI tract DPP-4 inhibitor Ingestion of food Inactive GLP-1 Release of active incretins GLP-1 and GIP a X DPP-4 enzyme Inactive GIP Pancreas Glucose-dependent Insulin from beta cells (GLP-1 and GIP) Beta cells Alpha cells Glucose-dependent Glucagon from alpha cells (GLP-1) Peripheral glucose uptake Hepatic glucose production Blood glucose in fasting and postprandial states

16 DPP-4 Inhibitors: An Incretin-Based Glucose-Dependent Mechanism for Improving Glycemic Control GI tract DPP-4 inhibitor Ingestion of food Inactive GLP-1 Release of active incretins GLP-1 and GIP a X GLP-1 analogues DPP-4 enzyme Inactive GIP Pancreas Glucose-dependent Insulin from beta cells (GLP-1 and GIP) Beta cells Alpha cells Glucose-dependent Glucagon from alpha cells (GLP-1) Peripheral glucose uptake Hepatic glucose production Blood glucose in fasting and postprandial states

17 HbA 1c avec sitagliptine ou Glipizide ajouté à la metformine: Efficacité comparable 8.2 HbA 1c, % ±SE Sulfonylurea a + metformin (n=411) Sitagliptin b + metformin (n=382) Weeks Nauck MA et al., 2007

18 Comparaison Sitagliptine + Metformine vs Glipizide + Metformine Poids corporel Hypoglycémies Body weight (kg ± SE) Glipizide + metformin Sitagliptin + metformin Incidence (%) % P< % Weeks 0 Week 52 Glipizide + metformin Sitagliptin + metformin Nauck MA et al., 2007

19 Gliptines et affections pancréatiques 19 Pancreatic Safety of Incretin-Based Drugs FDA and EMA Assessment N Engl J Med 2014;379: Both agencies agree that assertions concerning a causal association between incretin-based drugs and pancreatitis or pancreatic cancer, as expressed recently in the scientific literature and in the media, are inconsistent with the current data.

20 Etudes à visée cardiovasculaire actuellement en cours avec les gliptines (inhibiteurs de la DPP-4) 20 Etudes en cours Sitagliptin Start: Dec 2008 TECOS Projected completion: Dec 2014 N=14,000 Trial Evaluating Cardiovascular Outcomes With Sitagliptin Primary Outcome: Time to first confirmed occurrence of CV event, a composite defined as CV-related death, nonfatal MI, nonfatal stroke, or unstable angina requiring hospitalization Alogliptin Start: Sept 2009 EXAMINE Projected completion: May 2015 N=5,400 Saxagliptin Start: May 2010 SAVOR Projected completion: June 2014 N=16,500 Examination of Cardiovascular Outcomes: Alogliptin vs Standard of Care in Patients With Type 2 Diabetes Mellitus and Acute Coronary Syndrome Primary Outcome: Time from randomization to the occurrence of the primary major adverse cardiac events, a composite of CV death, nonfatal MI, and nonfatal stroke Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus Trial Primary Outcome: The primary efficacy outcome variable of the study is defined as the composite end point of CV death, nonfatal MI, or nonfatal ischemic stroke Linagliptin CAROLINA Start: Oct 2010 Projected completion: Sept 2018 N=6,000 Cardiovascular Outcome Study of Linagliptin vs Glimepiride in Patients With Type 2 Diabetes Primary Outcome: Time to first occurrence of any component of the composite end point: CV death, nonfatal MI, nonfatal stroke, and hospitalization for unstable angina pectoris Vildagliptin Vildagliptin does not have an ongoing cardiovascular outcomes trial.

21 Gliptines et sécurité cardiovasculaire SAVOR & EXAMINE Pas d augmentation du risque CV avec les DPP-4I! Scirica BM et al., 2013 White MB et al., 2013

22 Caractéristiques des patients à risque accru d hypoglycémies Plus âgés Plus longue durée du diabète Repas régulièrement manqué Activité physique Prise d une posologie de médicament plus importante que celle prescrite 1. Henderson JN et al. Diabet Med. 2003;20: Miller CD et al. Arch Intern Med. 2001;161:

23 Conséquences des hypoglycémies chez le sujet diabétique Coût Qualité de vie Observance Morbi-mortalité cardiovasculaire très accrue si atcd hypo sévère ACCORD (+ 59 %) ADVANCE ( X 4) ORIGIN (+ 71 à 74 %) 1. Henderson JN et al. Diabet Med. 2003;20: Miller CD et al. Arch Intern Med. 2001;161:

24 Comparaison sulfamides -gliptines. Scheen, Rev Med Liège 2014;69:

25 Comparaison entre les différentes gliptines commercialisées en Belgique

26 Comparaison entre les différentes gliptines commercialisées en Belgique Differences Similarities Chemical structures in vitro selectivity Metabolism (changed/unchanged; active/inactive metabolite) Efficacy (HbA1c lowering) Tolerability Clinical safety profile Elimination (renal/hepatic) Preclinical toxicities Potency (therapeutic dose) Dosing frequency (once/twice daily) Use in special populations (eg impaired renal/hepatic function) Deacon CF, 2011

27 Caractéristiques pharmaco-cinétiques des différentes gliptines commercialisées Chemistry Metabolism Elimination route Sitagliptin β-amino acid-based Not appreciably metabolised Renal (~80% unchanged as parent) Vildagliptin Cyanopyrrolidine Hepatically hydrolysed to inactive metabolite (P 450 enzyme independent) Renal (22% as parent, 55% as metabolite) Saxagliptin Cyanopyrrolidine Hepatically metabolised to active metabolite (via P 450 3A4/5) Renal (12-29% as parent, 21-52% as metabolite) Alogliptin Modified pyrimidinedione Not appreciably metabolised Renal (>70% unchanged as parent) Linagliptin Xanthine-based Not appreciably metabolised Biliary (unchanged as parent); <6% via kidney

28 Caractéristiques pharmaco-cinétiques des différentes gliptines commercialisées Chemistry Metabolism Elimination route Sitagliptin β-amino acid-based Not appreciably metabolised Renal (~80% unchanged as parent) Vildagliptin Cyanopyrrolidine Hepatically hydrolysed to inactive metabolite (P 450 enzyme independent) Renal (22% as parent, 55% as metabolite) Saxagliptin Cyanopyrrolidine Hepatically metabolised to active metabolite (via P 450 3A4/5) Renal (12-29% as parent, 21-52% as metabolite) Alogliptin Modified pyrimidinedione Not appreciably metabolised Renal (>70% unchanged as parent) Linagliptin Xanthine-based Not appreciably metabolised Biliary (unchanged as parent); <6% via kidney

29 Caractéristiques pharmaco-cinétiques des différentes gliptines commercialisées Chemistry Metabolism Elimination route Sitagliptin β-amino acid-based Not appreciably metabolised Renal (~80% unchanged as parent) Vildagliptin Cyanopyrrolidine Hepatically hydrolysed to inactive metabolite (P 450 enzyme independent) Renal (22% as parent, 55% as metabolite) Saxagliptin Cyanopyrrolidine Hepatically metabolised to active metabolite (via P 450 3A4/5) Renal (12-29% as parent, 21-52% as metabolite) Alogliptin Modified pyrimidinedione Not appreciably metabolised Renal (>70% unchanged as parent) Linagliptin Xanthine-based Not appreciably metabolised Biliary (unchanged as parent); <6% via kidney

30 Efficacité/sécurité des gliptines au sein de populations spécifiques ( à risque ) Insuffisance rénale Insuffisance hépatique Légère (CrCl 50ml/min) Moderée (CrCl 30 - <50ml/min) Sévère/terminale (CrCl <30ml/min) Sitagliptine ½ dose ¼ dose* Légère/ modérée Vildagliptine ½ dose ½ dose * Saxagliptine ½ dose ½ dose* Alogliptine ½ dose ¼ dose* Linagliptine Sévère Actuellement non recommandée Actuellement non recommandée Actuellement non recommandée Actuellement non recommandée Actuellement non recommandée * Y compris patients dialysés

31 Une stratégie centrée sur le patient

32 Conclusions Individualiser Toutes les options: grande sécurité si utilisation appropriée Gliptines Excellente tolérance (et observance) prise de poids risque d hypoglycémie Protection cardiovasculaire?

33 Choix pour éviter des hypoglycémies

34 Choix pour réduire les coûts Choix pour éviter des hypoglycémies

35 Choix pour éviter une prise de poids

36 Percent Inhibition of DPP-4 Activity at 0 96h Following Administration of Drug for 5 Days 100 % Inhibition of DPP-4 (Mean + SEM Sita 100 mg qd Vilda 50 mg bid Saxa 5 mg qd Vilda 50 qd Pbo Hrs post last AM dose morning dose evening dose (Vildagliptin bid only)