Effects of metformin on microvascular function and exercise tolerance in women with angina and normal coronary arteries - A randomized, double-blind, placebo-controlled study

OBJECTIVES This study sought to determine whether metformin improves vascular function or myocardial ischemia in nondiabetic subjects. BACKGROUND Metformin prevents diabetes and may reduce coronary events in patients with diabetes, but effects on microvascular function and angina are not clear. METHODS We conducted an 8-week double-blind, randomized, placebo-controlled study of metformin 500 mg twice a day in 33 nondiabetic women with a prior history of normal coronary angiography but two consecutive positive (ST-segment depression >= 1 mm) exercise tolerance tests. All parameters were measured at baseline and at 8 weeks, together with an in vivo assessment of forearm (skin) microvascular function using laser Doppler imaging combined with iontophoresis. RESULTS In comparison with placebo (n = 17), metformin recipients (n = 16) showed significant reductions in weight and in homeostatic model assessment for insulin resistance (p < 0.05, intention to treat). Endothelium-dependent microvascular responses improved significantly with metformin (2-way repeated analysis of variance, p = 0.0003), but responses with placebo were unchanged (p = 0.50). A comparison of change in acetylcholine responses between metformin and placebo recipients was significant, whether analyzed by a 2-way analysis of variance (p < 0.0001) or change in area under curves (mean change +392 perfusion units, 95% confidence interval [Cl] 20 to 764). Endothelium-independent responses were not altered. Maximal ST-segment depression (-0.84 mm, 95% Cl -1.49 to -0.20, p = 0.013), Duke score (6.1 U, 95% Cl 1.8 to 10.5, p = 0.008), and chest pain incidence (-0.11 episodes/day, 95% CI -0.22 to 0.00, p = 0.056) improved in metformin relative to placebo recipients. CONCLUSIONS Metformin may improve vascular function and decrease myocardial ischemia in nondiabetic women with chest pain and angiographically normal coronary arteries. Larger controlled trials of longer duration are warranted.