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

Eur J Heart Fail. 2020 Sep;22(9):1628-1637. doi: 10.1002/ejhf.1656. Epub 2019 Dec 21.

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 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 ·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.

Keywords: Heart failure; Insulin resistance; Metformin; Mitochondrial function; Myocardial efficiency; Myocardial oxygen consumption.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Diabetes Mellitus*
  • Double-Blind Method
  • Heart Failure* / drug therapy
  • Humans
  • Hypoglycemic Agents / therapeutic use
  • Insulin
  • Metformin / therapeutic use*
  • Stroke Volume

Substances

  • Hypoglycemic Agents
  • Insulin
  • Metformin