A Randomised, Double-Blind, Placebo-Controlled Trial of Metformin on Myocardial Efficiency in Insulin-Resistant Chronic Heart Failure Patients without Diabetes

Abstract

Abstract 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 11C-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-2·106; 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.