Metformine et mortalitéchez des diabétiques en prévention secondaire
Ronan Roussel, Florence Travert, Blandine Pasquet, Peter F. Wilson,Sidney C. Smith Jr, Shinya Goto, Philippe Ravaud, Michel Marre, Avi Porath,
Deepak L. Bhatt, Ph. Gabriel Steg, for the REACH investigators
Paris, France; Atlanta, Georgia, USA; Chapel Hill, North Carolina, USA;Isehara, Japan; Beer Sheva, Israel; and Boston, Massachusetts, USA
Roussel, Archives of Internal Medicine, 2010
Conflits d’intérêt potentiels :
J’ai reçu des soutiens financiers pour la recherche et des congrès et des contreparties financières pour des conférences de
sanofi-aventis, MSD Chibret, Servier, Roche et Novo Nordisk.
Holman R, New Engl J Med, 2008
Primary prevention and metformin:
Secondary CV Prevention in Diabetes:Unmet Needs
- Diabetes is associated with a doubling of CV risk, but also with an increased risk for cancer
- In the REACH Registry, fatality rates were higher in diabetic patients, despite as intensive treatment of risk factors as in non-diabetic patients
Krempf M, Am J Cardiol, 2010
The Emerging Risk Factors Collaboration, the Lancet, 2010
Established CV Disease
Metformin Use is Restricted in High Risk Patients
Dormandy JA, The Lancet. 2005TThe ADVANCE Collaborative Group, The New Engl J Med. 2008The Action to Control Cardiovascular Risk in Diabetes Study Group, The New Engl J Med. 2008
40%60%ACCORD
39%61%ADVANCE
NoYes
Metformin at baseline
43%57%PROactive
27,746
1,931
17,886
846
10,951
2,872
5,656North America
Latin America
Eastern Europe + North Asia
Middle East
Australia
Western Europe
S. Asia (incl. Japan)
*up to 15 patients / site (up to 20 in the US)
1. Bhatt DL et al. JAMA 2006;295:180-189.2. Ohman EM et al. Am Heart J 2006;151:786.e1-10.
Patient Recruitment: > 67,000 Patientsfrom 5,473 Sites in 44 Countries
www.reachregistry.org
Must include:
Signedwritten
informedconsent
Patients aged≥ 45 years
At least of four criteria1
• Documented cerebrovascular diseaseIschemic stroke or trans ischemic attack
• Documentedcoronary diseaseAngina, myocardial infarction, angioplasty /stent / bypass
3. Documented historicalor current intermittentclaudication associatedwith ABI < 0.9
4. At least atherothrombotic risk factors3
• Male aged ≥ 65 yearsor female aged ≥ 70 years
• Current smoking> 15 cigarettes/day
• Type 1 or 2diabetes
• Hypercholesterolemia• Diabetic nephropathy• Hypertension• ABI < 0.9 in either
leg at rest• Asymptomatic carotid
stenosis ≥ 70%• Presence of at least
one carotid plaque
ABI, ankle brachial index.Ohman EM et al. Am Heart J 2006;151:786.e1-10.
Inclusion Criteria of the REACH Registry
Total patients 67888
Aims of the Analysis
•Evaluation of the risk/benefit ratio associated with metformin in secondary cardiovascular prevention
We studied the baseline characteristics and 2-year outcomes of the subset of 28700 diabetic patients undergoing a secondary prevention strategy in
the international Reduction of Atherothrombosis for Continued Health (REACH) Registry.
•To assess whether metformin use was associated with a difference in mortality after adjustment for baseline differences and the propensity to receive metformin in patients with established coronary artery disease (CAD), cerebrovascular disease (CVD), or peripheral arterial disease (PAD).
Results: Baseline General Characteristics
<.00128.6 (5.9)29.6 (6.0)BMI, kg/m2, mean (SD)
<.00199.6 (16.6)Waist, cm, mean (SD)
.9067997 (65.4)4881 (65.5)Male sex, n (%)
<.00169.2 (9.5)67.1 (9.3)Age, y, mean (SD)
P Value
No(n = 12 234)
Yes(n = 7457)Characteristics
Metformin
eGFR (mL/min/1.73 m²)median (SD)
<.001Ethnic origin
<.001Region
102.0 (16.2)
76.0 (37.5)78.3 (61.1) .003
Results: Propensity Score
Confounding factors were taken into account using the propensity score method.
This score represents the probability of receiving metformin given an individual’s characteristics.
The list of co-variables was built in a two-step process. First, analyses were conducted to determine the variables associated with metformin prescription among all the available data variables.
The selected variables were then introduced in order to construct a multivariable logistic regression model.
The propensity score reached the quality requirements:
the likelihood associated with the model was strong (Wald test, P<.001)
the area under the ROC curve (0.72) exceeded the 0.7 threshold.
Results: Survival according to Metformin Use
Number at risk
Met
form
in
Yes
No
7397
12156
7234
11805
6848
10979
6119
9769
3340
5808
Hazard ratio: 0.67
95% CI: 0.59-0.75
P<0.0001
1270 fatality cases occurred.
28700 diabétiques DT2
-25% mortalité toute causeAssociées à Metformine
Results: Survival according to Metformin Use
Significant factors in univariate analysis:region, ethnic origin, education, employment, hypercholesterolemia, carotid surgery, atrial
fibrillation/flutter, congestive heart failure, aortic valve stenosis, abdominal aortic aneurysm, antiplatelet agents, anticoagulants, lipid-lowering agents, other cardiovascular agents, BMI, and SBP
No. of deaths/no. of patients
2-year mortality rate (95% CI)
Adjusted for sex and age
HR (95% CI)
HR (95% CI)
Adjusted for sex, age, propensity score, and significant factors
Metformin Use
No Yes
341/7397929/12 156
9.83(8.40-11.23)
6.33(5.24-7.41)
1
1
0.67(0.59-0.75)
0.76(0.65-0.89)
<.001
<.001
Results: Hazard Associated with Metformin UseAccording to Clinical Characteristics
Ageadjusted HR
Metformin Use
n/NYes
n/NNo
Favors metformin
P Value
P Value for interaction: p=0.07
78/2,987 176/3,859 0.63 p=0.008
191/3,791 532/6,768 0.77 p=0.016
71/ 598 220/1,492 0.92 p=0.605
Results: Hazard Associated with Metformin UseAccording to Clinical Characteristics
History ofCongestive Heart Failure
Favors metformin
P Value for interaction: p=0.39
221/6,002 488/9,120 0.80 p=0.034
116/1,220 419/2,790 0.69 p=0.006
adjusted HR
Metformin Use
n/NYes
n/NNo
P Value
Results: Hazard Associated with Metformin UseAccording to Clinical Characteristics
Renal FunctionAt Baseline
Favors metformin
P Value for interaction: p=0.12
14/118 90/455 1.06 p=0.890
86/1,572 336/3,388 0.64 p=0.003
188/4,442 379/6,326 0.89 p=0.302
adjusted HR
Metformin Use
n/NYes
n/NNo
P Value
Results: Hazard Associated with Metformin UseAccording to Clinical Characteristics
Insulin Use
Favors metformin
P Value for interaction: p=0.01
281/6,050 521/7,891 0.80 p=0.018
59/1,276 408/4,258 0.64 p=0.009
adjusted HR
Metformin Use
n/NYes
n/NNo
P Value
Merci de votre attention
Results: Hazard Associated with Metformin UseAccording to Clinical Characteristics
Gender
341/7,397 929/12,156 0.76 p<0.001
243/4,845 617/7,954 0.82 p=0.037
98/2,548 312/4,195 0.66 p=0.005
Favors metformin
P Value for interaction: p=0.07
adjusted HR
Metformin Use
n/NYes
n/NNo
P Value
Results: Baseline General Characteristics
EthnicOrigin
Region
North AmericaLatinAmerica
AustraliaJapan
Metformin Use: No
W Europe
W Europe
JapanAustralia
Asia
Asia
E Europe
E Europe
MiddleEast
MiddleEast
Latin America
Metformin Use: Yes Metformin Use: Yes
Metformin Use: No
Caucasian
Hispanic
East Asian
South Asian
Other Asian
BlackOther
Hispanic
East Asian
South AsianOther Asian
BlackOther
metformin could be associatedwith a better prognosis in older patients with diabetes
discharged after hospitalization for heart failure
Metformin: Unexpected Benefits?
Masoudi FA, Circulation. 2005;111(5):583-590
Adjusted mortality curves for patients hospitalized with heart failure and diabetes receiving prescription for metformin at hospital discharge and patients not treated with insulin-sensitizing drug.
HR=0.86, 95% CI 0.78 to 0.97