Larsen 2020 Cardiovasc Drugs Ther

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Larsen AH, Wiggers H, Dollerup OL, Jespersen NR, Hansson NH, Frøkiær J, Brøsen K, Nørrelund H, Bøtker HE, Møller N, Jessen N (2020) Metformin lowers body weight but fails to increase insulin sensitivity in chronic heart failure patients without diabetes: a randomized, double-blind, placebo-controlled study. Cardiovasc Drugs Ther [Epub ahead of print].

» PMID: 32770520

Larsen Anders Hostrup, Wiggers Henrik, Dollerup Ole Lindgaard, Jespersen Nichlas Riise, Hansson Nils Henrik, Froekiaer Joergen, Broesen Kim, Noerrelund Helene, Boetker Hans Erik, Moeller Niels, Jessen Niels (2020) Cardiovasc Drugs Ther

Abstract: 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.

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.

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.

Increased myocardial efficiency during metformin treatment is not mediated through improvements in insulin action in HF patients without diabetes.

Keywords: Heart failure, Hyperinsulinemic euglycemic clamp, Insulin sensitivity, Metformin Bioblast editor: Plangger M O2k-Network Lab: DK Aarhus Boetker HE


Labels: MiParea: Respiration, Patients, Pharmacology;toxicology  Pathology: Cardiovascular, Diabetes 

Organism: Human  Tissue;cell: Skeletal muscle  Preparation: Permeabilized tissue 


Coupling state: LEAK, OXPHOS, ET  Pathway: N, NS, ROX  HRR: Oxygraph-2k 

2020-08