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September 7, 2026European Heart JournalOpen Access

GLP-1 RAs show no safety concerns in HFrEF subgroup analyses but require dedicated randomized trials.

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Why the study?

Do GLP-1 receptor agonists reduce morbidity and mortality in patients with HFrEF?

Population

Patients with heart failure with reduced ejection fraction (HFrEF), particularly those with obesity.

Design

Editorial

Key result

Existing data from subgroup analyses do not support safety concerns regarding GLP-1 receptor agonists in HFrEF, highlighting the need for a dedicated prospective randomized trial.

Authors

JBJawad H. ButtSSScott D. SolomonJMJohn J.V. McMurray

Discussion

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Overview

Subgroup data indicate no excess HF risk with GLP-1 RAs in HFrEF; challenges prior concerns but leaves open need for dedicated RCTs.

Key Points

  • Synthesize existing clinical evidence on the safety and efficacy of GLP-1 receptor agonists in heart failure with reduced ejection fraction (HFrEF) to evaluate the rationale for dedicated clinical trials.
  • Reviewed clinical outcome data from randomized trials of GLP-1 receptor agonists, including the SELECT trial (N=17,604 overall; n=1,347 with HFrEF), EXSCEL, FIGHT, and LIVE.
  • Evaluated cardiovascular mortality, worsening heart failure events, left ventricular ejection fraction (LVEF), heart rate changes, and weight loss across trial cohorts.
  • In the SELECT HFrEF subgroup (LVEF <50%), cardiovascular death occurred in 7% (46/666) with semaglutide versus 11% (76/681) with placebo (HR 0.63, 95% CI 0.43–0.91), while worsening heart failure occurred in 6% (36/666) versus 5% (35/681) (HR 1.08, 95% CI 0.68–1.72) over ~40 months median follow-up.
  • Dedicated small trials (FIGHT and LIVE) demonstrated no significant change in LVEF or NT-proBNP levels and only modest heart rate increases, but were underpowered for clinical endpoints.

Structured PICO

Do GLP-1 receptor agonists reduce morbidity and mortality in patients with HFrEF?

P
Population
Patients with heart failure with reduced ejection fraction (HFrEF), particularly those with obesity.
I
Intervention
Glucagon-like peptide 1-receptor agonists (GLP-1 RA)

There is a critical need for a dedicated, adequately powered randomized controlled trial to evaluate the safety and efficacy of GLP-1 receptor agonists in patients with HFrEF.

Limitations

  • Existing data are incomplete, inconsistent, and based on small trials or subgroups with few events.
  • Patients enrolled in available large trials are poorly characterized from a heart failure perspective.

Cite This Study

Butt et al. (2025) conducted a review in Heart failure with reduced ejection fraction (HFrEF) and obesity. Glucagon-like peptide 1-receptor agonists (GLP-1 RA) was evaluated. Existing data from subgroup analyses do not support safety concerns regarding GLP-1 receptor agonists in HFrEF, highlighting the need for a dedicated prospective randomized trial.

synapsesocial.com/papers/6a9e2d18fa5765b7effca53chttps://doi.org/10.1093/eurheartj/ehaf635
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Also Consider

Synapse has enriched 2 closely related papers on similar clinical questions. Consider them for comparative context:

  1. 1Effects of Liraglutide on Clinical Stability Among Patients With Advanced Heart Failure and Reduced Ejection Fraction2016 · 698 citations
  2. 2Tirzepatide for Heart Failure with Preserved Ejection Fraction and Obesity2024 · 940 citations