The effect of metformin on cardiovascular risk profile in patients without diabetes presenting with acute myocardial infarction: data from the Glycometabolic Intervention as adjunct to Primary Coronary Intervention in ST Elevation Myocardial Infarction (GIPS-III) trial

Chris P H Lexis, Anouk N A van der Horst-Schrivers, Erik Lipsic, Mattia A E Valente, Anneke C Muller Kobold, Rudolf A de Boer, Dirk J van Veldhuisen, Pim van der Harst, Iwan C C van der Horst, Chris P H Lexis, Anouk N A van der Horst-Schrivers, Erik Lipsic, Mattia A E Valente, Anneke C Muller Kobold, Rudolf A de Boer, Dirk J van Veldhuisen, Pim van der Harst, Iwan C C van der Horst

Abstract

Objective: In patients with diabetes mellitus, metformin treatment is associated with reduced mortality and attenuation of cardiovascular risk. As a subanalysis of the Glycometabolic Intervention as adjunct to Primary Coronary Intervention in ST Elevation Myocardial Infarction (GIPS-III) study, we evaluated whether metformin treatment in patients with ST-segment elevation myocardial infarction (STEMI) without diabetes improves the cardiovascular risk profile.

Methods: A total of 379 patients, without known diabetes, presenting with STEMI were randomly allocated to receive metformin 500 mg twice daily or placebo for 4 months.

Results: After 4 months, the cardiovascular risk profile of patients receiving metformin (n=172) was improved compared with placebo (n=174); glycated hemoglobin (5.83% (95% CI 5.79% to 5.87%) vs 5.89% (95% CI 5.85% to 5.92%); 40.2 mmol/mol (95% CI 39.8 to 40.6) vs 40.9 mmol/mol (40.4 to 41.2), p=0.049); total cholesterol (3.85 mmol/L (95% CI 3.73 to 3.97) vs 4.02 mmol/L (95% CI 3.90 to 4.14), p=0.045); low-density lipoprotein cholesterol (2.10 mmol/L (95% CI 1.99 to 2.20) vs 2.3 mmol/L (95% CI 2.20 to 2.40), p=0.007); body weight (83.8 kg (95% CI 83.0 to 84.7) vs 85.2 kg (95% CI 84.4 to 86.1), p=0.024); body mass index (26.8 kg/m(2) (95% CI 26.5 to 27.0) vs 27.2 kg/m(2) (95% CI 27.0 to 27.5), p=0.014). Levels of fasting glucose, postchallenge glucose, insulin, high-density lipoprotein cholesterol, and blood pressure were similar in both groups.

Conclusions: Among patients with STEMI without diabetes, treatment with metformin for 4 months resulted in a modest improvement of the cardiovascular risk profile compared with placebo.

Trial register number: NCT01217307.

Keywords: Cardiac Function; Cardiovascular Disease Risk; Cardiovascular Risk Factors; Metformin.

Figures

Figure 1
Figure 1
Change in markers of glycometabolism and cardiovascular risk profile. Absolute changes in (95% CI) the metformin and placebo groups in glycated hemoglobin (HbA1c) concentration (A), insulin levels (B), body weight (C), total cholesterol (D), low-density lipoprotein (LDL)-cholesterol (E), and high-density lipoprotein (HDL)-cholesterol (F) were analyzed using analysis of covariance.
Figure 2
Figure 2
Change in glycated hemoglobin (HbA1c) over time. Trajectories of change in HbA1c over time (95% CI) were analyzed using linear mixed-effects model, showing different trajectories between the two treatment groups (p=0.031).
Figure 3
Figure 3
Oral glucose tolerance testing during hospitalization and at 4 months after infarction. Bar and whisker plots demonstrating blood glucose concentrations during hospitalization (A) and at 4 months (B). Each plot shows fasting blood glucose concentration left of the dotted line, and 120 min postchallenge glucose concentration right of the dotted line. The bars represent median (p50) and IQR (p25 and p75) and the whiskers p5 and p95.

References

    1. Steg PG, James SK, Atar D et al. , Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC). ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J 2012;33:2569–619. 10.1093/eurheartj/ehs215
    1. Timmer JR, Ottervanger JP, de Boer MJ et al. . Primary percutaneous coronary intervention compared with fibrinolysis for myocardial infarction in diabetes mellitus: results from the Primary Coronary Angioplasty vs Thrombolysis-2 trial. Arch Intern Med 2007;167:1353–9. 10.1001/archinte.167.13.1353
    1. van der Horst IC, Nijsten MW, Vogelzang M et al. . Persistent hyperglycemia is an independent predictor of outcome in acute myocardial infarction. Cardiovasc Diabetol 2007;6:2 10.1186/1475-2840-6-2
    1. Timmer JR, van der Horst IC, Ottervanger JP et al. , Zwolle Myocardial Infarction Study Group. Prognostic value of admission glucose in non-diabetic patients with myocardial infarction. Am Heart J 2004;148:399–404. 10.1016/j.ahj.2004.04.007
    1. Timmer JR, Hoekstra M, Nijsten MW et al. . Prognostic value of admission glycosylated hemoglobin and glucose in nondiabetic patients with ST-segment-elevation myocardial infarction treated with percutaneous coronary intervention. Circulation 2011;124:704–11. 10.1161/CIRCULATIONAHA.110.985911
    1. Norhammar A, Tenerz A, Nilsson G et al. . Glucose metabolism in patients with acute myocardial infarction and no previous diagnosis of diabetes mellitus: a prospective study. Lancet 2002;359:2140–4. 10.1016/S0140-6736(02)09089-X
    1. Inzucchi SE, Bergenstal RM, Buse JB et al. . Management of hyperglycemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 2012;55:1577–96. 10.1007/s00125-012-2534-0
    1. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998;352:854–65. 10.1016/S0140-6736(98)07037-8
    1. Holman RR, Paul SK, Bethel MA et al. . 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008;359:1577–89. 10.1056/NEJMoa0806470
    1. Mellbin LG, Malmberg K, Norhammar A et al. . DIGAMI 2 Investigators. The impact of glucose lowering treatment on long-term prognosis in patients with type 2 diabetes and myocardial infarction: a report from the DIGAMI 2 trial. Eur Heart J 2008;29:166–76. 10.1093/eurheartj/ehm518
    1. Mellbin LG, Malmberg K, Norhammar A et al. . DIGAMI 2 Investigators. Prognostic implications of glucose-lowering treatment in patients with acute myocardial infarction and diabetes: experiences from an extended follow-up of the Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) 2 Study. Diabetologia 2011;54:1308–17. 10.1007/s00125-011-2084-x
    1. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837–53. 10.1016/S0140-6736(98)07019-6
    1. Knowler WC, Barrett-Connor E, Fowler SE et al. , Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393–403. 10.1056/NEJMoa012512
    1. Orchard TJ, Temprosa M, Barrett-Connor E et al. . Diabetes Prevention Program Outcomes Study Research Group. Long-term effects of the Diabetes Prevention Program interventions on cardiovascular risk factors: a report from the DPP Outcomes Study. Diabet Med 2013;30:4655.
    1. Ramachandran A, Snehalatha C, Mary S et al. . Indian Diabetes Prevention Programme (IDPP). The Indian Diabetes Prevention Programme shows that lifestyle modification and metformin prevent type 2 diabetes in Asian Indian subjects with impaired glucose tolerance (IDPP-1). Diabetologia 2006;49:289–97. 10.1007/s00125-005-0097-z
    1. Yang W, Liu J, Shan Z et al. . Acarbose compared with metformin as initial therapy in patients with newly diagnosed type 2 diabetes: an open-label, non-inferiority randomised trial. Lancet Diabetes Endocrinol 2014;2:46–55. 10.1016/S2213-8587(13)70021-4
    1. Diabetes Prevention Program Research Group. Long-term safety, tolerability, and weight loss associated with metformin in the Diabetes Prevention Program Outcomes Study. Diabetes Care 2012;35:731–7. 10.2337/dc11-1299
    1. Johnson JA, Simpson SH, Toth EL et al. . Reduced cardiovascular morbidity and mortality associated with metformin use in subjects with type 2 diabetes. Diabet Med 2005;22:497–502. 10.1111/j.1464-5491.2005.01448.x
    1. Preiss D, Lloyd SM, Ford I et al. . Metformin for non-diabetic patients with coronary heart disease (the CAMERA study): a randomised controlled trial. Lancet Diabetes Endocrinol 2014;2:116–24. 10.1016/S2213-8587(13)70152-9
    1. Fontbonne A, Charles MA, Juhan-Vague I et al. , BIGPRO Study Group. The effect of metformin on the metabolic abnormalities associated with upper-body fat distribution. Diabetes Care 1996;19:920–6. 10.2337/diacare.19.9.920
    1. The Diabetes Prevention Program Research Group. Role of insulin secretion and sensitivity in the evolution of type 2 diabetes in the diabetes prevention program: effects of lifestyle intervention and metformin. Diabetes 2005;54:2404–14. 10.2337/diabetes.54.8.2404
    1. Lexis CP, van der Horst IC, Lipsic E et al. , GIPS-III Investigators. Effect of metformin on left ventricular function after acute myocardial infarction in patients without diabetes: the GIPS-III randomized clinical trial. JAMA 2014;311:1526–35. 10.1001/jama.2014.3315
    1. Lexis CP, van der Horst IC, Lipsic E et al. , GIPS-III Investigators. Metformin in non-diabetic patients presenting with ST elevation myocardial infarction: rationale and design of the glycometabolic intervention as adjunct to primary percutaneous intervention in ST elevation myocardial infarction (GIPS)-III trial. Cardiovasc Drugs Ther 2012;26:417–26. 10.1007/s10557-012-6413-1
    1. American Diabetes Association. Standards of medical care in diabetes—2014. Diabetes Care 2014;37:S14–80. 10.2337/dc14-S014
    1. Rydén L, Grant PJ, Anker SD et al. . ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Task Force on diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and developed in collaboration with the European Association for the Study of Diabetes (EASD). Eur Heart J 2013;34:3035–87. 10.1093/eurheartj/eht108
    1. Di Angelantonio E, Gao P, Khan H et al. , for The Emerging Risk Factors Collaboration. Glycated hemoglobin measurement and prediction of cardiovascular disease. JAMA 2014;311:1225–33. 10.1001/jama.2014.1873
    1. van der Horst IC, Zijlstra F, van ‘t Hof AW, et al. ., Zwolle Infarct Study Group . Glucose-insulin-potassium infusion inpatients treated with primary angioplasty for acute myocardial infarction: the glucose-insulin-potassium study: a randomized trial. J Am Coll Cardiol 2003;42:784–91.
    1. Malmberg K, Rydén L, Wedel H et al. , DIGAMI 2 Investigators. Intense metabolic control by means of insulin in patients with diabetes mellitus and acute myocardial infarction (DIGAMI 2): effects on mortality and morbidity. Eur Heart J 2005;26:650–61. 10.1093/eurheartj/ehi199
    1. Díaz R, Goyal A, Mehta SR et al. . Glucose-insulin-potassium therapy in patients with ST-segment elevation myocardial infarction. JAMA 2007;298:2399–405. 10.1001/jama.298.20.2399
    1. The Diabetes Prevention Program Research Group. Factors associated with diabetes onset during metformin versus placebo therapy in the Diabetes Prevention Program. Diabetes 2007;56:1153–9. 10.2337/db06-0918

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