Metformin Shows No Cardiovascular Benefit in HFrEF: Met-HeFT Trial Findings

Metformin did not significantly affect cardiovascular outcomes in patients with heart failure with reduced ejection fraction (HFrEF) and diabetes, prediabetes, or increased diabetes risk, according to results from the Met-HeFT trial and an accompanying meta-analysis presented in a Hot Line session at the European Society of Cardiology (ESC) Congress 2026 in Munich, Germany.1,2

Metformin is the most commonly prescribed oral antidiabetic medication worldwide. Type 2 diabetes and heart failure frequently coexist, but whether metformin offers cardioprotective benefit beyond glucose lowering had not previously been tested in a large, randomized trial.3

The rationale for testing metformin in heart failure stemmed largely from observational data. A 2020 systematic review and meta-regression analysis found metformin use was associated with reduced mortality across both reduced and preserved ejection fraction heart failure populations, with an even greater apparent protective effect in HFpEF specifically.4

Henrik Wiggers, MD, principal investigator of Met-HeFT and professor at Aarhus University Hospital, explained the evidence gap motivating the trial in a press release: "Observational studies and small, short-term trials suggest that metformin may have cardioprotective effects beyond glucose lowering in patients with heart failure, but whether metformin improves cardiovascular outcomes has not been tested in a large long-term randomised trial," he noted.1

Met-HeFT Trial Design and Primary Results

The investigator-initiated, double-blind Met-HeFT trial was conducted at 23 centers in Denmark as part of DANHEART, a factorial trial including the H-HeFT trial of hydralazine-isosorbide dinitrate in chronic heart failure, presented separately at the same congress. Eligible patients had symptomatic chronic heart failure, a left ventricular ejection fraction of up to 40%, and type 2 diabetes, prediabetes, or increased risk of developing type 2 diabetes. Investigators randomly assigned 940 participants in a 1:1 ratio to metformin or placebo; the mean age was 70 years, and 16% of patients were female.1

During a mean follow-up of 3.7 years, there was no significant difference between metformin and placebo for the primary end point, a composite of death, worsening heart failure, acute myocardial infarction, or stroke (25.1% vs 23.4%; hazard ratio [HR], 1.10; 95% CI, 0.84-1.42; P = .48). Metformin also did not significantly affect secondary end points, including all-cause death, unplanned heart failure events, new-onset diabetes, or change in the cardiac strain marker NT-proBNP.1

As a limitation, Wiggers noted only around 10% of participants had confirmed type 2 diabetes, with most instead having prediabetes or insulin resistance. "Our lack of enrolment of patients with type 2 diabetes likely reflected the existing widespread use of metformin and the reluctance of patients and clinicians to discontinue ongoing metformin treatment, which was a requirement for inclusion," he said.1

Met-HeFT Meta-Analysis and Clinical Implications

Anders Hostrup Larsen, MD, of Goedstrup Hospital, presented a companion meta-analysis of randomized, placebo-controlled trials of metformin in established heart failure and ischemic heart disease, incorporating Met-HeFT data alongside 2 other heart failure trials (n = 1077 patients total) and 4 ischemic heart disease trials (n = 1123 patients).2

"The meta-analysis came to the same conclusion as the Met-HeFT trial," Larsen said. "There was no significant difference in cardiovascular outcomes with metformin in patients with heart failure and a reduced ejection fraction, and we also showed no significant effect in established ischaemic heart disease."

Summarizing the evidence, Wiggers said metformin remains a safe and effective glucose-lowering therapy despite the null cardiovascular finding: "Metformin was not associated with any harm and it still remains beneficial in terms of glucose lowering, but our analyses indicate no significant evidence for any independent cardioprotective benefits," Wiggers said.1

The results contrast with the dedicated outcome trials underlying SGLT2 inhibitor use in HFrEF, where agents such as dapagliflozin and empagliflozin have demonstrated reductions in cardiovascular death and heart failure hospitalization regardless of diabetes status. Met-HeFT indicates metformin's role in this population remains limited to glycemic management rather than heart failure-specific risk reduction.

References

1. European Society of Cardiology. No significant evidence for protection against cardiovascular outcomes with metformin in heart failure. Published August 30, 2026. Accessed August 30, 2026.

2. Larsen AH, et al. Met-HeFT meta-analysis: metformin in heart failure and ischemic heart disease: a systematic review and meta-analyses. Presented at: ESC Congress 2026; August 30, 2026; Munich, Germany.

3. Chaudhary S, Kulkarni A. Metformin: past, present, and future. Curr Diab Rep. 2024;24:119-130.

4. Halabi A, Sen J, Huynh Q, Marwick TH. Metformin treatment in heart failure with preserved ejection fraction: a systematic review and meta-regression analysis. Cardiovasc Diabetol. 2020;19:124. doi:10.1186/s12933-020-01100-w