This randomized trial tested the effect of metformin on glycemic control and cardiac function in patients with heart failure (HF) and type 2 diabetes while evaluating intestinal effects on selected gut microbiome products reflected by trimethylamine-N-oxide (TMAO) and gut-derived incretins. Metformin treatment improved glycemic control and postprandial metabolism and enhanced postprandial glucagon-like peptide 1 (GLP-1) secretion but did not influence cardiac function or the TMAO levels. Metabolic effects of metformin in HF may be mediated by an improvement in intestinal endocrine function and enhanced secretion of the gut-derived incretin GLP-1.

Department of Cardiovascular Medicine Mayo Clinic Rochester MN

Institute for Clinical and Experimental Medicine Prague Czech Republic

Institute of Endocrinology Prague Czech Republic

Institute of Physiology of the Czech Academy of Sciences Prague Czech Republic

Physicians Committee for Responsible Medicine Washington DC

Zobrazit více v PubMed

McDonagh TA, Metra M, Adamo M, et al. .; ESC Scientific Document Group . 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2021;42:3599–3726 PubMed

Corrao G, Ghirardi A, Ibrahim B, Merlino L, Maggioni AP.. Burden of new hospitalization for heart failure: a population-based investigation from Italy. Eur J Heart Fail 2014;16:729–736 PubMed

Han Y, Xie H, Liu Y, Gao P, Yang X, Shen Z.. Effect of metformin on all-cause and cardiovascular mortality in patients with coronary artery diseases: a systematic review and an updated meta-analysis. Cardiovasc Diabetol 2019;18:96. PubMed PMC

Eurich DT, Weir DL, Majumdar SR, et al. . Comparative safety and effectiveness of metformin in patients with diabetes mellitus and heart failure: systematic review of observational studies involving 34,000 patients. Circ Heart Fail 2013;6:395–402 PubMed

Schernthaner G, Brand K, Bailey CJ.. Metformin and the heart: update on mechanisms of cardiovascular protection with special reference to comorbid type 2 diabetes and heart failure. Metabolism 2022;130:155160. PubMed

Miles JM, Rule AD, Borlaug BA.. Use of metformin in diseases of aging. Curr Diab Rep 2014;14:490. PubMed PMC

Napolitano A, Miller S, Nicholls AW, et al. . Novel gut-based pharmacology of metformin in patients with type 2 diabetes mellitus. PLoS One 2014;9:e100778. PubMed PMC

Forslund K, Hildebrand F, Nielsen T, et al. .; MetaHIT Consortium . Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature 2015;528:262–266 PubMed PMC

DeFronzo RA, Buse JB, Kim T, et al. . Once-daily delayed-release metformin lowers plasma glucose and enhances fasting and postprandial GLP-1 and PYY: results from two randomised trials. Diabetologia 2016;59:1645–1654 PubMed PMC

Tang WHW, Wang Z, Levison BS, et al. . Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med 2013;368:1575–1584 PubMed PMC

Tang WHW, Wang Z, Fan Y, et al. . Prognostic value of elevated levels of intestinal microbe-generated metabolite trimethylamine-N-oxide in patients with heart failure: refining the gut hypothesis. J Am Coll Cardiol 2014;64:1908–1914 PubMed PMC

Garin O, Ferrer M, Pont A, et al. . Disease-specific health-related quality of life questionnaires for heart failure: a systematic review with meta-analyses. Qual Life Res 2009;18:71–85 PubMed

Chen CH, Nakayama M, Nevo E, Fetics BJ, Maughan WL, Kass DA.. Coupled systolic-ventricular and vascular stiffening with age: implications for pressure regulation and cardiac reserve in the elderly. J Am Coll Cardiol 1998;32:1221–1227 PubMed

Borlaug BA, Redfield MM, Melenovsky V, et al. . Longitudinal changes in left ventricular stiffness: a community-based study. Circ Heart Fail 2013;6:944–952 PubMed PMC

Wohl P, Krusinová E, Hill M, et al. . Effect of telmisartan on selected adipokines, insulin sensitivity, and substrate utilization during insulin-stimulated conditions in patients with metabolic syndrome and impaired fasting glucose. Eur J Endocrinol 2010;163:573–583 PubMed

Paolisso G, Gambardella A, Marrazzo G, et al. . Metabolic and cardiovascular benefits deriving from beta-adrenergic blockade in chronic congestive heart failure. Am Heart J 1992;123:103–110 PubMed

Miller RA, Chu Q, Xie J, Foretz M, Viollet B, Birnbaum MJ.. Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP. Nature 2013;494:256–260 PubMed PMC

Melenovsky V, Benes J, Franekova J, et al. . Glucose homeostasis, pancreatic endocrine function, and outcomes in advanced heart failure. J Am Heart Assoc 2017;6:e005290. PubMed PMC

Wong AKF, Symon R, AlZadjali MA, et al. . The effect of metformin on insulin resistance and exercise parameters in patients with heart failure. Eur J Heart Fail 2012;14:1303–1310 PubMed

Larsen AH, Wiggers H, Dollerup OL, 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 2021;35:491–503 PubMed

Suskin N, McKelvie RS, Burns RJ, et al. . Glucose and insulin abnormalities relate to functional capacity in patients with congestive heart failure. Eur Heart J 2000;21:1368–1375 PubMed

Larsen AH, Jessen N, Nørrelund H, et al. . 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;22:1628–1637 PubMed

Ono K, Wada H, Satoh-Asahara N, et al. .; ABLE-MET Investigators . Effects of metformin on left ventricular size and function in hypertensive patients with type 2 diabetes mellitus: results of a randomized, controlled, multicenter, phase IV trial. Am J Cardiovasc Drugs 2020;20:283–293 PubMed PMC

Tang WHW, Hazen SL.. Microbiome, trimethylamine N-oxide, and cardiometabolic disease. Transl Res 2017;179:108–115 PubMed PMC

Trøseid M, Andersen GØ, Broch K, Hov JR.. The gut microbiome in coronary artery disease and heart failure: current knowledge and future directions. eBioMedicine 2020;52:102649. PubMed PMC

Bahne E, Sun EWL, Young RL, et al. . Metformin-induced glucagon-like peptide-1 secretion contributes to the actions of metformin in type 2 diabetes. JCI Insight 2018;3:e93936. PubMed PMC

Sun EW, Martin AM, Wattchow DA, et al. . Metformin triggers PYY secretion in human gut mucosa. J Clin Endocrinol Metab 2019;104:2668–2674 PubMed

Buse JB, DeFronzo RA, Rosenstock J, et al. . The primary glucose-lowering effect of metformin resides in the gut, not the circulation: results from short-term pharmacokinetic and 12-week dose-ranging studies. Diabetes Care 2016;39:198–205 PubMed

Maida A, Lamont BJ, Cao X, Drucker DJ.. Metformin regulates the incretin receptor axis via a pathway dependent on peroxisome proliferator-activated receptor-α in mice. Diabetologia 2011;54:339–349 PubMed

Cho YM, Kieffer TJ.. New aspects of an old drug: metformin as a glucagon-like peptide 1 (GLP-1) enhancer and sensitiser. Diabetologia 2011;54:219–222 PubMed

Cravalho CKL, Meyers AG, Mabundo LS, et al. . Metformin improves blood glucose by increasing incretins independent of changes in gluconeogenesis in youth with type 2 diabetes. Diabetologia 2020;63:2194–2204 PubMed

Kosiborod MN, Petrie MC, Borlaug BA, et al. .; STEP-HFpEF DM Trial Committees and Investigators . Semaglutide in patients with obesity-related heart failure and type 2 diabetes. N Engl J Med 2024;390:1394–1407 PubMed

Wallner M, Biber ME, Stolfo D, et al. . Glucagon-like peptide-1 receptor agonists use and associations with outcomes in heart failure and type 2 diabetes: data from the Swedish Heart Failure and Swedish National Diabetes registries. Eur Heart J Cardiovasc Pharmacother 2024;10:296–306 PubMed PMC

Zobrazit více v PubMed

figshare
10.2337/figshare.26838679