This document summarizes a study that analyzed the risk and benefits of metformin use in diabetic patients undergoing secondary cardiovascular prevention. The study found that among 28,700 diabetic patients, those taking metformin had a 25% lower risk of all-cause mortality over 2 years compared to those not taking metformin, even after adjusting for differences in patient characteristics. Metformin use was associated with reduced mortality risk across most patient subgroups, with the largest benefits seen in those with a history of heart failure or those using insulin. The results suggest metformin may provide unexpected survival benefits in high-risk diabetic patients.

1. Metformine et mortalité chez 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

2. 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.

3. Holman R, New Engl J Med, 2008 Primary prevention and metformin:

6. Metformin Use is Restricted in High Risk Patients Dormandy JA, The Lancet. 2005T The ADVANCE Collaborative Group , The New Engl J Med. 2008 The Action to Control Cardiovascular Risk in Diabetes Study Group , The New Engl J Med. 2008 40% 60% ACCORD 39% 61% ADVANCE No Yes Metformin at baseline 43% 57% PROactive

7. 27,746 1,931 17,886 846 10,951 2,872 5,656 North 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 Patients from 5,473 Sites in 44 Countries www.reachregistry.org

10. Results: Baseline General Characteristics <.001 28.6 (5.9) 29.6 (6.0) BMI, kg/m 2 , mean (SD) <.001 99.6 (16.6) Waist, cm, mean (SD) .906 7997 (65.4) 4881 (65.5) Male sex, n (%) <.001 69.2 (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) <.001 Ethnic origin <.001 Region 102.0 (16.2) 76.0 (37.5) 78.3 (61.1) .003

11. 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.

12. Results: Survival according to Metformin Use Number at risk Metformin 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 cause Associées à Metformine

13. 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 341/7397 929/12 156 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

14. Results: Hazard Associated with Metformin Use According to Clinical Characteristics Age adjusted HR Metformin Use n/N Yes n/N No 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

15. Results: Hazard Associated with Metformin Use According to Clinical Characteristics History of Congestive 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/N Yes n/N No P Value

16. Results: Hazard Associated with Metformin Use According to Clinical Characteristics Renal Function At 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/N Yes n/N No P Value

17. Results: Hazard Associated with Metformin Use According 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/N Yes n/N No P Value

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19. Results: Hazard Associated with Metformin Use According 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/N Yes n/N No P Value

20. Results: Baseline General Characteristics Ethnic Origin Region North America Latin America Australia Japan Metformin Use: No W Europe W Europe Japan Australia Asia Asia E Europe E Europe Middle East Middle East Latin America Metformin Use: Yes Metformin Use: Yes Metformin Use: No Caucasian Hispanic East Asian South Asian Other Asian Black Other Hispanic East Asian South Asian Other Asian Black Other

21. metformin could be associated with 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