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Metformin Lowers Body Weight But Fails to Increase Insulin Sensitivity in Chronic Heart Failure Patients without Diabetes: a Randomized, Double-Blind, Placebo-Controlled Study

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Abstract

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.

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Availability of Data and Material

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgments

We are grateful for the excellent assistance provided by the medical laboratory technicians at the Medical Research Laboratory and at the Department of Cardiology, Aarhus University Hospital, Denmark.

Funding

This work was supported by the Danish Diabetes Academy supported by the Novo Nordisk Foundation (OL8201 to A.H.L. and H.W.), the Danish Council for Independent Research (4183-00384 to N.J.), NNF-Diabetes Excellence Project (NNF13OC0003882 to N.J.), the Arvid Nilsson Foundation (Dok 1780631 to A.H.L.), the Faculty of Health at Aarhus University (phd0115 to A.H.L.), the Danish Heart Foundation (15-R99-A5947-22932; 15-R99-A5947-22933 to A.H.L. and H.W.), Kirsten Anthonius Memorial Fund (to A.H.L.), the Health Research Fund of Central Denmark Region (to A.H.L.), the Augustinus Foundation (15-4919 to A.H.L.), the Aase and Ejnar Danielsen Foundation (10-001657 to A.H.L.), the Helga and Peter Korning Foundation (55027-100 to A.H.L.), and the Hede Nielsen Foundation (to A.H.L.).

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Authors and Affiliations

  1. Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark

    Anders Hostrup Larsen, Henrik Wiggers, Nichlas Riise Jespersen, Nils Henrik Hansson & Hans Erik Bøtker

  2. Department of Clinical Medicine, Medical Research Laboratory, Aarhus University Hospital, Aarhus, Denmark

    Anders Hostrup Larsen, Ole Lindgård Dollerup & Niels Møller

  3. Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark

    Ole Lindgård Dollerup

  4. Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Aarhus, Denmark

    Jørgen Frøkiær

  5. Department of Clinical Pharmacology, University of Southern Denmark, Odense C, Denmark

    Kim Brøsen

  6. Department of Clinical Epidemiology, Institute of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark

    Helene Nørrelund

  7. Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark

    Niels Møller

  8. Department of Clinical Pharmacology, Aarhus University Hospital, Aarhus, Denmark

    Niels Jessen

  9. Department of Biomedicine, Aarhus University, Aarhus, Denmark

    Niels Jessen

  10. Steno Diabetes Centre Aarhus, Aarhus University Hospital, Hedeager 3, DK-8200, Aarhus N, Denmark

    Niels Jessen

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  1. Anders Hostrup Larsen
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Contributions

N.J., H.W., H.N., K.B., J.F., N.M., and A.H.L. contributed to the study conception and/or design. Material preparation, data collection, and analysis were performed by A.H.L. The first draft of the manuscript was written by A.H.L. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Niels Jessen.

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Competing Interests

Merck KGaA (Darmstadt, Germany) provided the metformin (Glucophage XR®) and placebo tablets free of charge. Merck KGaA reviewed the manuscript for medical accuracy only before journal submission. The authors are fully responsible for the content of this manuscript, and the views and opinions described in the publication reflect solely those of the authors. H.W. has been the principal or a sub-investigator in studies involving the following pharmaceutical companies: MSD, Bayer, Daiichi-Sankyo, Novartis, Novo Nordisk, Sanofi-Aventis, and Pfizer. The other authors report no conflicts.

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Larsen, A.H., Wiggers, H., Dollerup, O.L. et al. 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 35, 491–503 (2021). https://doi.org/10.1007/s10557-020-07050-5

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