A randomised, double‐blind, placebo‐controlled trial of metformin on myocardial efficiency in insulin‐resistant chronic heart failure patients without diabetes

AIMS: The present study tested the hypothesis that metformin treatment may increase myocardial efficiency (stroke work/myocardial oxygen consumption) in insulin-resistant patients with heart failure and reduced ejection fraction (HFrEF) without diabetes. METHODS AND RESULTS: Thirty-six HFrEF patients (ejection fraction 37 +/- 8%; median age 66 years) were randomised to metformin (n = 19) or placebo (n = 17) for 3 months in addition to standard heart failure therapy. The primary endpoint was change in myocardial efficiency expressed as the work metabolic index (WMI), assessed by (11) C-acetate positron emission tomography and transthoracic echocardiography. Compared with placebo, metformin treatment (1450 +/- 550 mg/day) increased WMI [absolute mean difference, 1.0 mmHg.mL.m(-2) .10(6) ; 95% confidence interval (CI) 0.1 to 1.8; P = 0.03], equivalent to a 20% relative efficiency increase. Patients with above-median plasma metformin levels displayed greater WMI increase (25% vs. -4%; P = 0.02). Metformin reduced myocardial oxygen consumption (-1.6 mL O2 .100 g(-1) .min(-1) ; P = 0.014). Cardiac stroke work was preserved (-2 J; 95% CI -11 to 7; P = 0.69). Metformin reduced body weight (-2.2 kg; 95% CI -3.6 to -0.8; P = 0.003) and glycated haemoglobin levels (-0.2%; 95% CI -0.3 to 0.0; P = 0.02). Changes in resting and exercise ejection fraction, global longitudinal strain, and exercise capacity did not differ between groups. CONCLUSION: Metformin treatment in non-diabetic HFrEF patients improved myocardial efficiency by reducing myocardial oxygen consumption. Measurement of circulating metformin levels differentiated responders from non-responders. These energy-sparing effects of metformin encourage further large-scale investigations in heart failure patients without diabetes.