Purpose: The glucose-lowering drug metformin has recently been shown to reduce myocardial oxygen consumption and increase myocardial efficiency in chronic heart failure (HF) patients without diabetes. However, it remains to be established whether these beneficial myocardial effects are associated with metformin-induced alterations in whole-body insulin sensitivity and substrate metabolism.
Methods: Eighteen HF patients with reduced ejection fraction and without diabetes (median age, 65 (interquartile range 55-68); ejection fraction 39 ± 6%; HbA1c 5.5 to 6.4%) were randomized to receive metformin (n = 10) or placebo (n = 8) for 3 months. We studied the effects of metformin on whole-body insulin sensitivity using a two-step hyperinsulinemic euglycemic clamp incorporating isotope-labeled tracers of glucose, palmitate, and urea. Substrate metabolism and skeletal muscle mitochondrial respiratory capacity were determined by indirect calorimetry and high-resolution respirometry, and body composition was assessed by bioelectrical impedance analysis. The primary outcome measure was change in insulin sensitivity.
Results: Compared with placebo, metformin treatment lowered mean glycated hemoglobin levels (absolute mean difference, - 0.2%; 95% CI - 0.3 to 0.0; p = 0.03), reduced body weight (- 2.8 kg; 95% CI - 5.0 to - 0.6; p = 0.02), and increased fasting glucagon levels (3.2 pmol L-1; 95% CI 0.4 to 6.0; p = 0.03). No changes were observed in whole-body insulin sensitivity, endogenous glucose production, and peripheral glucose disposal or oxidation with metformin. Equally, resting energy expenditure, lipid and urea turnover, and skeletal muscle mitochondrial respiratory capacity remained unaltered.
Conclusion: Increased myocardial efficiency during metformin treatment is not mediated through improvements in insulin action in HF patients without diabetes.
Clinical trial registration: URL: https://clinicaltrials.gov . Unique identifier: NCT02810132. Date of registration: June 22, 2016.
Keywords: Heart failure; Hyperinsulinemic euglycemic clamp; Insulin sensitivity; Metformin.