Sécurité cardiovasculaire du traitement de l`hyperglycémie dans le

Sécurité cardiovasculaire du traitement de
l’hyperglycémie dans le diabète de type 2
21 mai 2016 – LCB Michel P. HERMANS
MD (UCL) PhD (UCL & Oxford, UK) Dip. Natural Sciences (Open University, Milton Keynes, UK) Dip. Earth Sciences (Open University, Milton Keynes, UK) Dip. Human Geography (Open University, Milton Keynes, UK)
Dip. Environment (Open University, Milton Keynes, UK) PG CerNficate in Social Sciences (Open University, Milton Keynes, UK) Endocrinologie & NutriNon Cliniques universitaires St-­‐Luc Université Catholique de Louvain (epi) genetic factors
environmental
cardiometabolic RFs
standard RFs
overweight - obesity
age
metabolic syndrome
gender
gestational diabetes
IR / hyperinsulinemia
hypertension
pre-diabetes
chronic kidney disease
smoking
atherogenic dyslipidemia
LDL-C
Beta-cell failure
T2DM
chronic hyperglycemia (surrogate: HbA1c)
microvascular disease (DRP - PNP - DN)
macrovascular disease (CAD - PAD - CVD)
Risk Factors for Cardiovascular Disease
l  Modifiable
– 
Smoking
– 
Dyslipidaemia
l  Non-modifiable
•  LDL-C
•  low HDL-C
•  triglycerides
– 
HBP
– 
Diabetes
– 
Obesity
– 
Dietary factors, e.a. Hcy
– 
Thrombogenic factors
– 
Sedentarity
– 
Alcohol
– 
Personal history
of CHD
– 
Family history
of CHD
– 
Age
– 
Gender
Adapted from: Pyörälä K et al. Eur Heart J 1994;15:1300–1331.
Nutritional-physical activity imbalance
Proinflammatory state
muscle insulin resistance
Atherogenic
dyslipidemia
genetic &/or acquired mitochondrial
defects (density/function/biogenesis)
adipocyte dysregulation
↓ oxidation capacity: sarcopenia, fiber
type & distribution, ageing, obesity
↑ apoB-VLDL-TG
lipoproteins
↑ IR-inducing secretory products
and NEFAs; ↓ adiponectin
↑ glucose output
hepatic insulin
resistance
hepatic lipogenesis
NAFL, NAFLD, NASH
chronic hyperinsulinaemia
IFG-IGT / T2DM in predisposed individuals
Extra-Glycemic Effects of OAD
TZD
↑
↑
↑↑
↓ or ↔
MET
↓ or ↔
↔ or ↓
↑ or ↔
↓
SU/MG
↑
↔
↔
↔
Free fatty acids
Insulin resistance
PAI-I
CRP
Hypertension
↓↓↓
↓↓
↓
↓
↓
↓↓
↓
↓
↓
↔
↓
↔
↔
↔
↔
Microalbuminuria
↓
↔
↔
Weight
LDL-C
HDL-C
Triglycerides
TZD=thiazolidinedione, MET=metformin, SU=sulfonylurea, MG=meglitinide.
↑=increase, ↓=decrease, ↔=no effect.
Cardiovascular Effects of TZDs
↓
FFAs
↑
HDL-C
↓
Small, dense LDL
↓
PAI-1 levels and fibrinogen
↓
Triglycerides
↓
Blood pressure
↑
Endothelial function
↓
Microalbuminuria
Ovalle F et al. ADA; June 2001. Abstract 1896. Tack CJ et al. Diabetes Care. 1998;21:796-799.
Ghazzi MN et al. Diabetes. 1997;46:433-439. Parulkar AA et al. Ann Intern Med. 2001;134:61-71.
Imano E et al. Diabetes Care. 1998;21:2135-2139. Anand MM et al. Practical Diabetology. 1999;(June
23-27. Fonseca VA et al. J Clin Endocrinol Metab. 1998:83:3169-3176.
RECORD
Rosiglitazone Evaluated for
Cardiovascular Outcome and
Regulation of Glycaemia in Diabetes
Baseline characteristics
Background metformin
Background sulfonylurea
+rosiglitazone +sulfonylurea
Participants (n)
+rosiglitazone +metformin
1117
1105
1103
1122
57 ± 8
57 ± 8
60 ± 8
60 ± 8
54
53
49
51
6.1 ± 4
6.3 ± 4
7.9 ± 6
7.9 ± 5
7.8 ± 0.7
7.8 ± 0.7
8.0 ± 0.7
8.0 ± 0.7
33 ± 5
33 ± 5
30 ± 4
30 ± 4
15.3
14.8
19.2
20.1
Stable angina (%)
9.4
7.8
11.1
12.8
Myocardial infarction (%)
4.5
5.6
4.9
4.6
Age (year)
Sex (male, %)
Duration of diabetes (year)
HbA1c (%)
BMI (kg/m2)
Ischaemic heart disease (%)
Mean ± SD
Cardiovascular death, myocardial
infarction
10
Rosiglitazone
154 events
Cumulative
Metformin/SU 165 events
incidence
or
HR: 0.93 (95% CI 0.74,1.15) p=0.50
(%, SE)
8
stroke
6
4
2
0
0
People at risk
Rosiglitazone 2220
Metformin/SU 2227
1
2
3
Time (years)
4
5
2121
2135
2052
2057
1982
1978
1912
1901
1852
1816
6
994
970
Cardiovascular death
Rosiglitazone 60 events
Metformin/SU 71 events
10
Cumulative
incidence
(%, SE)
8
HR: 0.84 (95% CI 0.59,1.18) p=0.32
6
4
2
0
0
People at risk
Rosiglitazone 2220
Metformin/SU 2227
1
2
3
Time (years)
4
5
6
2139
2148
2084
2085
2032
2025
1972
1965
1918
1893
1042
1017
Stroke, fatal and non-fatal
Rosiglitazone 46 events
Metformin/SU 63 events
10
Cumulative
incidence
(%, SE)
8
HR: 0.72 (95% CI 0.49,1.06) p=0.10
6
4
2
0
0
People at risk
Rosiglitazone 2220
Metformin/SU 2227
1
2
3
Time (years)
4
5
6
2132
2142
2070
2068
2009
1998
1947
1930
1891
1851
1024
991
Heart failure, fatal and non-fatal
Rosiglitazone 61 events
Metformin/SU 29 events
10
Cumulative
incidence
(%, SE)
8
HR: 2.10 (95% CI 1.35,3.27) p=0.001
6
4
2
0
0
People at risk
Rosiglitazone 2220
Metformin/SU 2227
1
2
3
Time (years)
4
5
2130
2146
2069
2078
2008
2014
1994
1949
1884
1877
6
1017
1012
Les récentes études sur les nouveaux
hypoglycémiants se sont avérées neutres du
point de vue du critère d'évaluation CV principal
HR : 1,0
(IC à 95% : 0,89 –
1,12)
SAVOR-TIMI 53
HR : 0,96
(IC à 95% : LS ≤1,16)
EXAMINE
2013
Inhibiteurs de la
DPP-4*
Lixisénatide
HR : 0,98
(IC à 95% : 0,88 –
1,09)
TECOS
2014
HR : 1,02
(IC à 95% : 0,89 –
1,17)
2015
ELIXA
EMPA-REG OUTCOME®
Empagliflozine
CV, cardiovasculaire ; HR, hazard ratio ; DPP-4, dipeptidyl peptidase-4
*Saxagliptine, alogliptine, sitagliptine
Adapté de Johansen OE. World J Diabetes 2015;6:1092-96
BE/EMP /00061 09/2015
22
Data from EXAMINE Subanalyses CV Mortality in Pa.ents with Type 2 Diabetes and Recent Acute Coronary Syndromes from the EXAMINE Trial William B. White, et All JACC, April1,Volume 63, N
°12, 1152-­‐248-­‐A24 BE/EMP /00061 09/2015
28
Conclusions AugmentaNon de l'excréNon de glucose AugmentaNon de l'excréNon de sodium DiminuNon de la glycémie HbA1c 0,6 à 1 % Perte de calories Poids 2 à 3 kg DiminuNon de la charge sodée Pression artérielle 3 à 5 mmHg BE/EMP/ 00062 10/2015 Critère d’évaluation principal :
MACE à 3 points
HR 0,86
(IC à 95,02% : 0,74 – 0,99)
p=0,0382*
Fonction d'incidence cumulée. MACE, événement indésirable cardiovasculaire majeur ; HR, hazard ratio.
* Des tests bilatéraux de supériorité ont été réalisés (signification statistique indiquée si p≤0,0498)
BE/EMP /00061 09/2015
30
Décès CV
HR 0,62
(IC à 95% : 0,49 – 0,77)
p<0,0001
Fonction d'incidence cumulée. HR, hazard ratio
BE/EMP /00061 09/2015
31
Hospitalisation pour insuffisance cardiaque
HR 0,65
(IC à 95% : 0,50 – 0,85)
p=0,0017
Fonction d'incidence cumulée. HR, hazard ratio
BE/EMP /00061 09/2015
32
Mortalité toutes causes confondues
HR 0,68
(IC à 95% : 0,57 – 0,82)
p<0,0001
Estimation de Kaplan-Meier. HR, hazard ratio
BE/EMP /00061 09/2015
33
Slide No 41
Liraglutide
A human GLP-1 analogue
for the once-daily treatment of
type 2 diabetes