Background: Metformin reduces cardiovascular risk in patients with type 2 diabetes seemingly independent of lowering blood glucose concentration. We assessed the cardiovascular effects of metformin in individuals without type 2 diabetes.
Methods: We did a single-centre, double-blind, placebo-controlled trial at the Glasgow Clinical Research Facility (Glasgow, UK). We enrolled patients taking statins who did not have type 2 diabetes but who did have coronary heart disease and large waist circumferences. Participants were randomly assigned (1:1) by computer to either metformin (850 mg twice daily) or matching placebo in block sizes of four. Patients, investigators, trial staff, and statisticians were masked to treatment allocation. The primary endpoint was progression of mean distal carotid intima-media thickness (cIMT) over 18 months in the modified intention-to-treat population. Secondary endpoints were changes in carotid plaque score (in six regions), measures of glycaemia (HbA1c, fasting glucose, and insulin concentrations, and Homeostasis Model Assessment of Insulin Resistance [HOMA-IR]), and concentrations of lipids, high sensitivity C-reactive protein, and tissue plasminogen activator. The trial was registered at ClinicalTrials.gov, number NCT00723307.
Findings: We screened 356 patients, of whom we enrolled 173 (86 in the metformin group, 87 in the placebo group). Average age was 63 years. At baseline, mean cIMT was 0·717 mm (SD 0·129) and mean carotid plaque score was 2·43 (SD 1·55). cIMT progression did not differ significantly between groups (slope difference 0·007 mm per year, 95% CI -0·006 to 0·020; p=0·29). Change of carotid plaque score did not differ significantly between groups (0·01 per year, 95% CI -0·23 to 0·26; p=0·92). Patients taking metformin had lower HbA1c, insulin, HOMA-IR, and tissue plasminogen activator compared with those taking placebo, but there were no significant differences for total cholesterol, HDL-cholesterol, non-HDL-cholesterol, triglycerides, high sensitivity C-reactive protein, or fasting glucose. 138 adverse events occurred in 64 patients in the metformin group versus 120 in 60 patients in the placebo group. Diarrhoea and nausea or vomiting were more common in the metformin group than in the placebo group (28 vs 5).
Interpretation: Metformin had no effect on cIMT and little or no effect on several surrogate markers of cardiovascular disease in non-diabetic patients with high cardiovascular risk, taking statins. Further evidence is needed before metformin can be recommended for cardiovascular benefit in this population.
Funding: Chief Scientist Office (Scotland).
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