The role of metformin (MET) in the treatment of patients with advanced HFrEF and type 2 diabetes mellitus (DM) is not firmly established. We studied the impact of MET on metabolic profile, quality of life (QoL) and survival in these patients. A total of 847 stable patients with advanced HFrEF (57.4 ± 11.3 years, 67.7% NYHA III/IV, LVEF 23.6 ± 5.8%) underwent clinical and laboratory evaluation and were prospectively followed for a median of 1126 (IQRs 410; 1781) days for occurrence of death, urgent heart transplantation or mechanical circulatory support implantation. A subgroup of 380 patients (44.9%) had DM, 87 of DM patients (22.9%) were treated with MET. Despite worse insulin sensitivity and more severe DM (higher BMI, HbA1c, worse insulin resistance), MET-treated patients exhibited more stable HF marked by lower BNP level (400 vs. 642 ng/l), better LV and RV function, lower mitral and tricuspid regurgitation severity, were using smaller doses of diuretics (all p < 0.05). Further, they had higher eGFR (69.23 vs. 63.34 ml/min/1.73 m2) and better QoL (MLHFQ: 36 vs. 48 points, p = 0.002). Compared to diabetics treated with other glucose-lowering agents, MET-treated patients had better event-free survival even after adjustment for BNP, BMI and eGFR (p = 0.035). Propensity score-matched analysis with 17 covariates yielded 81 pairs of patients and showed a significantly better survival for MET-treated subgroup (p = 0.01). MET treatment in patients with advanced HFrEF and DM is associated with improved outcome by mechanisms beyond the improvement of blood glucose control.

Department of Cardiology Institute for Clinical and Experimental Medicine IKEM Videnska 1958 9 140 21 Praha 4 Czech Republic

Department of Pathology Brigham and Women's Hospital Harvard Medical School Boston MA USA

Zobrazit více v PubMed

Lu HC, Parikh PP, Lorber DL. Phenformin-associated lactic acidosis due to imported phenformin. Diabetes Care. 1996;19:1449–1450. doi: 10.2337/diacare.19.12.1449. PubMed DOI

Salpeter SR, Greyber E, Pasternak GA, Salpeter EE. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst. Rev. 2010;2010:CD002967. doi: 10.1002/14651858.CD002967.pub4. PubMed DOI

Eurich DT, 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. doi: 10.1161/circheartfailure.112.000162. PubMed DOI

Crowley MJ, et al. Clinical outcomes of metformin use in populations with chronic kidney disease, congestive heart failure, or chronic liver disease: A systematic review. Ann. Intern. Med. 2017;166:191–200. doi: 10.7326/m16-1901. PubMed DOI PMC

Dludla PV, et al. Metformin and heart failure-related outcomes in patients with or without diabetes: A systematic review of randomized controlled trials. Heart Fail. Rev. 2021;26:1437–1445. doi: 10.1007/s10741-020-09942-y. PubMed DOI

Aguilar D, Chan W, Bozkurt B, Ramasubbu K, Deswal A. Metformin use and mortality in ambulatory patients with diabetes and heart failure. Circ. Heart Fail. 2011;4:53–58. doi: 10.1161/circheartfailure.110.952556. PubMed DOI PMC

MacDonald MR, et al. Treatment of type 2 diabetes and outcomes in patients with heart failure: A nested case-control study from the U.K. general practice research database. Diabetes Care. 2010;33:1213–1218. doi: 10.2337/dc09-2227. PubMed DOI PMC

Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet352, 854–865 (1998). PubMed

Shah DD, Fonarow GC, Horwich TB. Metformin therapy and outcomes in patients with advanced systolic heart failure and diabetes. J. Cardiac Fail. 2010;16:200–206. doi: 10.1016/j.cardfail.2009.10.022. PubMed DOI PMC

Cosentino F, et al. 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur. Heart J. 2020;41:255–323. doi: 10.1093/eurheartj/ehz486. PubMed DOI

Lang RM, et al. Recommendations for chamber quantification. Eur. J. Echocardiogr. 2006;7:79–108. doi: 10.1016/j.euje.2005.12.014. PubMed DOI

Aaronson KD, et al. Development and prospective validation of a clinical index to predict survival in ambulatory patients referred for cardiac transplant evaluation. Circulation. 1997;95:2660–2667. doi: 10.1161/01.cir.95.12.2660. PubMed DOI

Inzucchi SE, Masoudi FA, McGuire DK. Metformin in heart failure. Diabetes Care. 2007;30:e129. doi: 10.2337/dc07-1686. PubMed DOI

Tseng CH. Metformin use is associated with a lower risk of hospitalization for heart failure in patients with type 2 diabetes mellitus: A retrospective cohort analysis. J. Am. Heart Assoc. 2019;8:e011640. doi: 10.1161/jaha.118.011640. PubMed DOI PMC

Bergmark BA, et al. Metformin use and clinical outcomes among patients with diabetes mellitus with or without heart failure or kidney dysfunction: Observations from the SAVOR-TIMI 53 trial. Circulation. 2019;140:1004–1014. doi: 10.1161/circulationaha.119.040144. PubMed DOI

Inzucchi SE, et al. Insulin-sensitizing antihyperglycemic drugs and mortality after acute myocardial infarction: Insights from the National Heart Care Project. Diabetes Care. 2005;28:1680–1689. doi: 10.2337/diacare.28.7.1680. PubMed DOI

Masoudi FA, et al. Thiazolidinediones, metformin, and outcomes in older patients with diabetes and heart failure: An observational study. Circulation. 2005;111:583–590. doi: 10.1161/01.cir.0000154542.13412.b1. PubMed DOI

Eurich DT, Majumdar SR, McAlister FA, Tsuyuki RT, Johnson JA. Improved clinical outcomes associated with metformin in patients with diabetes and heart failure. Diabetes Care. 2005;28:2345–2351. doi: 10.2337/diacare.28.10.2345. PubMed DOI

Evans JM, et al. Effect of Metformin on mortality in patients with heart failure and type 2 diabetes mellitus. Am. J. Cardiol. 2010;106:1006–1010. doi: 10.1016/j.amjcard.2010.05.031. PubMed DOI

Roussel R, et al. Metformin use and mortality among patients with diabetes and atherothrombosis. Arch. Intern. Med. 2010;170:1892–1899. doi: 10.1001/archinternmed.2010.409. PubMed DOI

Andersson C, et al. Metformin treatment is associated with a low risk of mortality in diabetic patients with heart failure: A retrospective nationwide cohort study. Diabetologia. 2010;53:2546–2553. doi: 10.1007/s00125-010-1906-6. PubMed DOI

Romero SP, et al. Metformin therapy and prognosis of patients with heart failure and new-onset diabetes mellitus. A propensity-matched study in the community. Int. J. Cardiol. 2013;166:404–412. doi: 10.1016/j.ijcard.2011.10.141. PubMed DOI

Tinetti ME, McAvay G, Trentalange M, Cohen AB, Allore HG. Association between guideline recommended drugs and death in older adults with multiple chronic conditions: Population based cohort study. BMJ (Clin. Res. Ed.) 2015;351:h4984. doi: 10.1136/bmj.h4984. PubMed DOI PMC

Weir DL, McAlister FA, Senthilselvan A, Minhas-Sandhu JK, Eurich DT. Sitagliptin use in patients with diabetes and heart failure: A population-based retrospective cohort study. JACC. Heart Fail. 2014;2:573–582. doi: 10.1016/j.jchf.2014.04.005. PubMed DOI

Eurich DT, et al. Metformin treatment in diabetes and heart failure: When academic equipoise meets clinical reality. Trials. 2009;10:12. doi: 10.1186/1745-6215-10-12. PubMed DOI PMC

Owen MR, Doran E, Halestrap AP. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem. J. 2000;348(Pt 3):607–614. doi: 10.1042/bj3480607. PubMed DOI PMC

El-Mir MY, et al. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J. Biol. Chem. 2000;275:223–228. doi: 10.1074/jbc.275.1.223. PubMed DOI

Kanamori H, et al. Metformin enhances autophagy and provides cardioprotection in δ-sarcoglycan deficiency-induced dilated cardiomyopathy. Circ. Heart Fail. 2019;12:e005418. doi: 10.1161/circheartfailure.118.005418. PubMed DOI

Larsen AH, 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. doi: 10.1002/ejhf.1656. PubMed DOI

Wu H, et al. Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. Nat. Med. 2017;23:850–858. doi: 10.1038/nm.4345. PubMed DOI

He K, et al. The effect of metformin therapy on incidence and prognosis in prostate cancer: A systematic review and meta-analysis. Sci. Rep. 2019;9:2218. doi: 10.1038/s41598-018-38285-w. PubMed DOI PMC

Anselmino LE, et al. Repositioning metformin and propranolol for colorectal and triple negative breast cancers treatment. Sci. Rep. 2021;11:8091. doi: 10.1038/s41598-021-87525-z. PubMed DOI PMC

Meijers WC, et al. Heart failure stimulates tumor growth by circulating factors. Circulation. 2018;138:678–691. doi: 10.1161/circulationaha.117.030816. PubMed DOI

Banke A, et al. Incidence of cancer in patients with chronic heart failure: A long-term follow-up study. Eur. J. Heart Fail. 2016;18:260–266. doi: 10.1002/ejhf.472. PubMed DOI

Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N. Engl. J. Med. 2008;359:1577–1589. doi: 10.1056/NEJMoa0806470. PubMed DOI

Cameron AR, et al. Anti-inflammatory effects of metformin irrespective of diabetes status. Circ. Res. 2016;119:652–665. doi: 10.1161/circresaha.116.308445. PubMed DOI PMC

Mohan M, et al. A randomized controlled trial of metformin on left ventricular hypertrophy in patients with coronary artery disease without diabetes: The MET-REMODEL trial. Eur. Heart J. 2019;40:3409–3417. doi: 10.1093/eurheartj/ehz203. PubMed DOI PMC

Santos-Gallego CG, et al. Empagliflozin ameliorates adverse left ventricular remodeling in nondiabetic heart failure by enhancing myocardial energetics. J. Am. Coll. Cardiol. 2019;73:1931–1944. doi: 10.1016/j.jacc.2019.01.056. PubMed DOI

Coll AP, et al. GDF15 mediates the effects of metformin on body weight and energy balance. Nature. 2020;578:444–448. doi: 10.1038/s41586-019-1911-y. PubMed DOI PMC

Benes J, et al. The role of GDF-15 in heart failure patients with chronic kidney disease. Can. J. Cardiol. 2019;35:462–470. doi: 10.1016/j.cjca.2018.12.027. PubMed DOI

Monzo L, et al. Myocardial ketone body utilization in patients with heart failure: The impact of oral ketone ester. Metab. Clin. Exp. 2021;115:154452. doi: 10.1016/j.metabol.2020.154452. PubMed DOI

Nielsen R, et al. cardiovascular effects of treatment with the ketone body 3-hydroxybutyrate in chronic heart failure patients. Circulation. 2019;139:2129–2141. doi: 10.1161/circulationaha.118.036459. PubMed DOI PMC

Konopka AR, et al. Hyperglucagonemia mitigates the effect of metformin on glucose production in prediabetes. Cell Rep. 2018;23:2532. doi: 10.1016/j.celrep.2018.05.027. PubMed DOI PMC

Landstedt-Hallin L, Englund A, Adamson U, Lins PE. Increased QT dispersion during hypoglycaemia in patients with type 2 diabetes mellitus. J. Intern. Med. 1999;246:299–307. doi: 10.1046/j.1365-2796.1999.00528.x. PubMed DOI

Rector TS, Kubo SH, Cohn JN. Validity of the Minnesota living with heart failure questionnaire as a measure of therapeutic response to enalapril or placebo. Am. J. Cardiol. 1993;71:1106–1107. doi: 10.1016/0002-9149(93)90582-w. PubMed DOI

Benes J, et al. The effect of three major co-morbidities on quality of life and outcome of patients with heart failure with reduced ejection fraction. ESC Heart Fail. 2021 doi: 10.1002/ehf2.13227. PubMed DOI PMC

McMurray JJV, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N. Engl. J. Med. 2019;381:1995–2008. doi: 10.1056/NEJMoa1911303. PubMed DOI

Packer M, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N. Engl. J. Med. 2020;383:1413–1424. doi: 10.1056/NEJMoa2022190. PubMed DOI

Anker SD, et al. Effect of empagliflozin on cardiovascular and renal outcomes in patients with heart failure by baseline diabetes status: Results from the EMPEROR-reduced trial. Circulation. 2021;143:337–349. doi: 10.1161/circulationaha.120.051824. PubMed DOI PMC

Gebrie D, Getnet D, Manyazewal T. Cardiovascular safety and efficacy of metformin-SGLT2i versus metformin-sulfonylureas in type 2 diabetes: Systematic review and meta-analysis of randomized controlled trials. Sci. Rep. 2021;11:137. doi: 10.1038/s41598-020-80603-8. PubMed DOI PMC