les nouveaux anti-diabétiques oraux: comment faire le …€¦ · les nouveaux anti-diabétiques...
TRANSCRIPT
Les nouveaux anti-diabétiques oraux: comment faire le bon choix ?
Pr Nicolas PAQUOT
Département de Médecine Interne Service de Diabétologie, Nutrition et
Maladies métaboliques
3ème Journée Liégeoise de Diabétologie Samedi 15 novembre 2014
Sources: American Diabetes Association, 2008, www.diabetes.org; Centers for Disease Control, 2008, www.cdc.gov
Prévalence du diabète de type 2 en Belgique: + 33% en 6 ans
Germany 10.2%
6.3 million
Sweden 7.3%
460,000
Italy 6.6%
2.9 million
Netherlands 3.7%
432,000
Belgium 20031
4.2% (315,000) 20092
5.6% (420.000)
France 6.2%
2.7 million
Spain 9.9%
3.0 million
Adapted from IDF E-Atlas. Available at www.eatlas.idf.org. Accessed 9 March 2007. 1: Prevalence data, 2003 2: Thalès data 2009
ME
422H
Q09
PM06
5(6)
- N
S 1
883-
06-1
0
Régime et exercice physique
ECHEC
Sujets obèses Sujets de poids normal
ÉCHEC ÉCHEC
+ BIGUANIDE (METFORMINE)
+ INSULINO-SÉCRÉTEUR (SULFAMIDÉ)
+ BIGUANIDE
ÉCHEC ÉCHEC
+ INSULINE
+ INSULINO-SÉCRÉTEUR (SULFAMIDÉ)
Luyckx A, Daubresse JC, Carpentier JL & Lefèbvre P.
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
• 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.
Le premier choix = Metformine (sauf contre-indications)
Sulfamides et gliptines actuellement commercialisés en Belgique
A. Scheen, Rev Med Liège 2014;69:476-484
• Preuves scientifiques (EBM) • Mécanisme d’action • Efficacité • Tolérance et sécurité • Coût • Aspects individuels
Comment faire son choix ?
Na+
Na+ K+
K+
K+
K+
GLUT2
Ca2+
Voltage-gated Ca2+ channel
KIR
Pancreatic ß cell
Insulin granules
Ca2+
Ca2+ Ca2+ -
Sulfonylureas -
Vm
Sécrétion d’insuline indépendamment de la glycémie !
Glucose
Canaux potassiques également
dans le cœur !
Sulfamidés: mécanisme d’action
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
Release of active incretins GLP-1 and GIPa
Blood glucose in fasting and postprandial states
Ingestion of food
Glucagon from alpha cells (GLP-1)
Hepatic glucose production
GI tract
DPP-4 enzyme
Inactive GLP-1
Insulin from beta cells (GLP-1 and GIP)
Glucose-dependent
Glucose-dependent
Pancreas
Inactive GIP
Beta cells Alpha cells
Peripheral glucose uptake
DPP-4 Inhibitors: An Incretin-Based Glucose-Dependent Mechanism for Improving Glycemic Control
Release of active incretins GLP-1 and GIPa
Blood glucose in fasting and postprandial states
Ingestion of food
Glucagon from alpha cells (GLP-1)
Hepatic glucose production
GI tract
DPP-4 enzyme
Inactive GLP-1
X DPP-4 inhibitor
Insulin from beta cells (GLP-1 and GIP)
Glucose-dependent
Glucose-dependent
Pancreas
Inactive GIP
Beta cells Alpha cells
Peripheral glucose uptake
DPP-4 Inhibitors: An Incretin-Based Glucose-Dependent Mechanism for Improving Glycemic Control
Release of active incretins GLP-1 and GIPa
Blood glucose in fasting and postprandial states
Ingestion of food
Glucagon from alpha cells (GLP-1)
Hepatic glucose production
GI tract
DPP-4 enzyme
Inactive GLP-1
X DPP-4 inhibitor
Insulin from beta cells (GLP-1 and GIP)
Glucose-dependent
Glucose-dependent
Pancreas
Inactive GIP
Beta cells Alpha cells
Peripheral glucose uptake
GLP-1 analogues
Sulfonylureaa + metformin (n=411) Sitagliptinb + metformin (n=382)
HbA
1c, %
±SE
Weeks
6.2
6.4
6.6
6.8
7.0
7.2
7.4
7.6
7.8
0 6 12 18 24 30 38 46 52
8.0
8.2
HbA1c avec sitagliptine ou Glipizide ajouté à la metformine: Efficacité comparable
Nauck MA et al., 2007
Glipizide + metformin Sitagliptin + metformin
Hypoglycémies
P<0.001
32%
5%
0
10
20
30
40
50
Week 52
Inci
denc
e (%
)
Poids corporel
Body
wei
ght (
kg ±
SE)
Glipizide + metformin
Sitagliptin + metformin
-3
-2
-1
0
1
2
3
0 12 24 38 52
Weeks
Nauck MA et al., 2007
Comparaison Sitagliptine + Metformine vs Glipizide + Metformine
19
Gliptines et affections pancréatiques 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.
20
Sitagliptin TECOS
Start: Dec 2008 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 EXAMINE
Start: Sept 2009 Projected completion: May 2015 N=5,400
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 SAVOR
Start: May 2010 Projected completion: June 2014 N=16,500
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.
Etudes en cours
Etudes à visée cardiovasculaire actuellement en cours avec les gliptines (inhibiteurs de la DPP-4)
SAVOR & EXAMINE
Scirica BM et al., 2013 White MB et al., 2013
Pas d’augmentation du risque CV avec les DPP-4I !
Gliptines et sécurité cardiovasculaire
• 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.
Caractéristiques des patients à risque accru d’hypoglycémies
• 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.
Conséquences des hypoglycémies chez le sujet diabétique
Deacon CF, 2011
Differences Similarities
Chemical structures Efficacy (HbA1c lowering)
in vitro selectivity Tolerability
Metabolism (changed/unchanged; active/inactive metabolite) 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)
Comparaison entre les différentes gliptines commercialisées en Belgique
Chemistry Metabolism Elimination route
Sitagliptin β-amino acid-based Not appreciably metabolised Renal (~80% unchanged as parent)
Vildagliptin Cyanopyrrolidine Hepatically hydrolysed to inactive metabolite (P450 enzyme independent)
Renal (22% as parent, 55% as metabolite)
Saxagliptin Cyanopyrrolidine Hepatically metabolised to active metabolite (via P450 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 (P450 enzyme independent)
Renal (22% as parent, 55% as metabolite)
Saxagliptin Cyanopyrrolidine Hepatically metabolised to active metabolite (via P450 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 (P450 enzyme independent)
Renal (22% as parent, 55% as metabolite)
Saxagliptin Cyanopyrrolidine Hepatically metabolised to active metabolite (via P450 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
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)
Légère/ modérée Sévère
Sitagliptine √ ½ dose ¼ dose* √ Actuellement non recommandée
Vildagliptine √ ½ dose ½ dose * √ Actuellement non recommandée
Saxagliptine √ ½ dose ½ dose* √ Actuellement non
recommandée
Alogliptine √ ½ dose ¼ dose* √ Actuellement non recommandée
Linagliptine √ √ √ √ Actuellement non
recommandée
* Y compris patients dialysés
• Individualiser • Toutes les options: grande sécurité si
utilisation appropriée – Gliptines
• Excellente tolérance (et observance) • prise de poids • risque d’hypoglycémie • Protection cardiovasculaire ?
Conclusions