TY - JOUR

T1 - Metformin Lowers Body Weight But Fails to Increase Insulin Sensitivity in Chronic Heart Failure Patients without Diabetes

T2 - a Randomized, Double-Blind, Placebo-Controlled Study

AU - Larsen, Anders Hostrup

AU - Wiggers, Henrik

AU - Dollerup, Ole Lindgard

AU - Jespersen, Nichlas Riise

AU - Hansson, Nils Henrik

AU - Frokiaer, Jorgen

AU - Brøsen, Kim

AU - Norrelund, Helene

AU - Bøtker, Hans Erik

AU - Møller, Niels

AU - Jessen, Niels

PY - 2021

Y1 - 2021

N2 - 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.

AB - 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.

KW - Metformin

KW - Heart failure

KW - Insulin sensitivity

KW - Hyperinsulinemic euglycemic clamp

KW - HEPATIC GLUCOSE-PRODUCTION

KW - SKELETAL-MUSCLE

KW - SUBSTRATE METABOLISM

KW - OBESE

KW - RESISTANCE

KW - ROSIGLITAZONE

KW - TROGLITAZONE

KW - HOMEOSTASIS

KW - INHIBITION

KW - MECHANISM

U2 - 10.1007/s10557-020-07050-5

DO - 10.1007/s10557-020-07050-5

M3 - Journal article

C2 - 32770520

VL - 35

SP - 491

EP - 503

JO - Cardiovascular Drugs and Therapy

JF - Cardiovascular Drugs and Therapy

SN - 0920-3206

ER -