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
Prévalence du diabète de type 2 en Belgique: + 33% en 6 ans Sweden 7.3% 460,000 Belgium 2003 1 4.2% (315,000) 2009 2 5.6% (420.000) 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 1883-06-10 1: Prevalence data, 2003 2: Thalès data 2009 Sources: American Diabetes Association, 2008, www.diabetes.org; Centers for Disease Control, 2008, www.cdc.gov Adapted from IDF E-Atlas. Available at www.eatlas.idf.org. Accessed 9 March 2007.
Source: 2005 2008 National Health and Nutrition Examination Survey.
Source: 2007 2009 National Health Interview Survey.
Prévention des complications
La place des biguanides dans le traitement du diabète sucré. Journées de Diabétologie de l Hôtel-Dieu 1974, pages 129-150. 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.
Le premier choix = Metformine (sauf contre-indications) En comparaison avec le traitement conventionnel (patients obèses, UKDPS) 32% réduction du risque des complications diabétiques p=0.0023 42% réduction du risque des décès liés au diabète p=0.017 36% réduction de la mortalité toutes causes p=0.011 39% réduction du risque des infarctus du myocarde p=0.01 UKPDS 34. Lancet 1998; 352: 854-65.
En deuxième ligne? Nombreuses combinaisons possibles
En deuxième ligne? Nombreuses combinaisons possibles?
Sulfamides et gliptines actuellement commercialisés en Belgique A. Scheen, Rev Med Liège 2014;69:476-484
Comment faire son choix? Preuves scientifiques (EBM) Mécanisme d action Efficacité Tolérance et sécurité Coût Aspects individuels
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!
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)
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
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
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
HbA 1c avec sitagliptine ou Glipizide ajouté à la metformine: Efficacité comparable 8.2 HbA 1c, % ±SE 8.0 7.8 7.6 7.4 7.2 7.0 6.8 6.6 6.4 6.2 Sulfonylurea a + metformin (n=411) Sitagliptin b + metformin (n=382) 0 6 12 18 24 30 38 46 52 Weeks Nauck MA et al., 2007
Comparaison Sitagliptine + Metformine vs Glipizide + Metformine Poids corporel Hypoglycémies Body weight (kg ± SE) 3 2 1 0-1 -2 Glipizide + metformin Sitagliptin + metformin Incidence (%) 50 40 30 20 10 32% P<0.001 5% -3 0 12 24 38 52 Weeks 0 Week 52 Glipizide + metformin Sitagliptin + metformin Nauck MA et al., 2007
Gliptines et affections pancréatiques 19 Pancreatic Safety of Incretin-Based Drugs FDA and EMA Assessment N Engl J Med 2014;379:794-97 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.
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.
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
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;20:1016 1021. 2. Miller CD et al. Arch Intern Med. 2001;161:1653 1659.
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;20:1016 1021. 2. Miller CD et al. Arch Intern Med. 2001;161:1653 1659.
Comparaison sulfamides -gliptines. Scheen, Rev Med Liège 2014;69:476-484
Comparaison entre les différentes gliptines commercialisées en Belgique
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
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
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
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
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
Une stratégie centrée sur le patient
Conclusions Individualiser Toutes les options: grande sécurité si utilisation appropriée Gliptines Excellente tolérance (et observance) prise de poids risque d hypoglycémie Protection cardiovasculaire?
Choix pour éviter des hypoglycémies
Choix pour réduire les coûts Choix pour éviter des hypoglycémies
Choix pour éviter une prise de poids
Percent Inhibition of DPP-4 Activity at 0 96h Following Administration of Drug for 5 Days 100 % Inhibition of DPP-4 (Mean + SEM 80 60 40 Sita 100 mg qd Vilda 50 mg bid Saxa 5 mg qd Vilda 50 qd Pbo 20 0 0 12 24 36 48 96 Hrs post last AM dose morning dose evening dose (Vildagliptin bid only)