Metformin Use and CV Outcomes Among Diabetes Patients

Study Questions:

What is the effect of metformin on cardiovascular (CV) outcomes and all-cause mortality in patients with type 2 diabetes mellitus (T2DM)?

Methods:

A post hoc analysis was conducted in SAVOR-TIMI 53, a multinational randomized controlled CV outcomes trial that compared the dipeptidyl peptidase-4 (DPP-4) inhibitor saxagliptin with placebo, enrolling 16,492 patients with T2DM and CV disease or elevated CV risk including prior heart failure (HF) and chronic kidney disease (CKD) with creatinine ≤6 mg/dl. Baseline biomarker samples were available in 12,156 subjects who were classified as Ever versus Never taking metformin during the trial period. Associations between metformin exposure and outcomes were estimated using Cox modeling for the composite endpoint of CV death, myocardial infarction (MI), or ischemic stroke as well as CV death and all-cause mortality with inclusion of biomarkers (N-terminal pro–B-type natriuretic peptide, high-sensitivity C-reactive protein, high-sensitivity troponin T) as covariates. Additional sensitivity analyses included propensity score matching and Cox multivariable models.

Results:

Of the 12,156 patients, 8,971 (74%) had metformin exposure, 1,611 (13%) had prior HF, and 1,332 (11%) had at least moderate CKD (estimated glomerular filtration rate [eGFR] <45 ml/min/1.73 m2). Of the patients with moderate to severe CKD, 1,078 (81%) had a baseline eGFR 30-<45 ml/min/1.73 m2, while 254 (19%) had an eGFR <30 ml/min/1.73 m2. At a median follow-up of 2.1 years, metformin use was associated with no difference in risk for the composite endpoint (hazard ratio inverse probability of treatment weighting [HRIPTW], 0.92; 95% confidence interval [CI], 0.76-1.11), but lower risk of all-cause mortality (HRIPTW, 0.75; 95% CI, 0.59-0.95), and lower risk of CV death (HRIPTW, 068; 95% CI, 0.51-0.91). In contrast to the overall population, metformin use was not associated with lower risk in patients with prior HF or CKD.

Conclusions:

In a cohort of 12,156 patients with T2DM and high CV risk, metformin use was associated with lower rates of all-cause mortality, including after adjustment for clinical variables and biomarkers, but not lower rates of the composite endpoint of CV death, MI, or ischemic stroke. This association was most apparent in patients without prior HF or moderate to severe CKD.

Perspective:

In the 2008 10-year follow-up of the United Kingdom study (Lancet 1998) of ‘intensive glucose control,’ compared to diet, the relatively small metformin group had a greater legacy effect reduction of diabetes outcomes, diabetes deaths, MI, and overall mortality, which were nearly twofold greater than sulfonylurea and insulin. Subsequent meta-analyses including the present study have not confirmed the benefit. Considering metformin is the hypoglycemic agent of first choice in TD2DM with and without atherosclerotic CV disease, and its lack of value in HF and CKD in this study, as the authors suggest, there is a need for an adequately powered randomized trial in these high-risk patients.

Clinical Topics: Diabetes and Cardiometabolic Disease, Heart Failure and Cardiomyopathies, Prevention, Acute Heart Failure, Heart Failure and Cardiac Biomarkers

Keywords: Atherosclerosis, Biological Markers, Brain Ischemia, C-Reactive Protein, Creatinine, Diabetes Mellitus, Type 2, Dipeptidyl Peptidase 4, Glomerular Filtration Rate, Glucose, Heart Failure, Hypoglycemic Agents, Insulin, Metabolic Syndrome X, Metformin, Myocardial Infarction, Natriuretic Peptide, Brain, Primary Prevention, Renal Insufficiency, Chronic, Stroke, Troponin T, Vascular Diseases


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