Systematic review and meta-analysis of GLP-1 receptor agonists in heart failure: impact on 6-minute walk test performance

Background/Introduction Despite advances in heart failure (HF) pharmacotherapy, novel treatments are needed for its main subtypes - preserved (HFpEF), mildly reduced (HFmrEF), and reduced (HFrEF) left ventricular ejection fraction (LVEF). Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have shown promising cardioprotective effects. The 6-Minute Walk Test is a simple, low-cost, and reproducible measure of functional exercise capacity that sensitively reflects symptomatic and prognostic improvement, capturing real-world treatment response in patients with HF receiving medical therapy. Purpose We conducted a systematic review and meta-analysis assessing the impact of GLP-1 RAs, across the spectrum of LVEF, on 6-Minute Walk Test (6MWT) performance. Methods PubMed, Embase, Scopus and trial registries were searched up to December 2025, for randomised controlled trials (RCTs) involving adults with HF treated with GLP-1 RAs. Selection was strictly limited to studies whose participants had clearly defined HF and its subgroups. The main outcome of our study was change in performance between baseline and following treatment, for the 6MWT. Subgroup analyses were further performed by HF subtype. Pooled mean differences (MD, in metres) with 95% confidence intervals (CI) were calculated using random-effects models. Results Five RCTs (1858 participants) were included, with an overall low risk of bias. All were randomised, double-blinded, and placebo controlled. Both diabetics and non-diabetics were included, and all participants had a background of coronary artery disease. Mean or median body mass index (BMI) ranged between 28–42 across the groups. Four GLP-1 RAs were assessed (albiglutide, liraglutide semaglutide and tirzepatide). GLP-1 RAs significantly increased 6MWT performance in HF patients (MD: 18.09, 95% CI: 11.10–25.07) (Figure 1), especially for HFpEF (MD: 20.01, 95% CI: 11.86–28.17) and HFrEF (MD: 17.15, 95% CI: 1.92–32.39) patients (Figure 2). There was no significant heterogeneity between the studies. There were not enough studies to conclude for HFmrEF patients. Conclusions Treatment with GLP-1 RAs can be associated with improvements in 6MWT performance, in patients with HF, with the most pronounced effects seen in those with HFpEF. These findings suggest a potential role for GLP-1 RAs in enhancing functional capacity in HF beyond glycaemic control. Further dedicated, adequately powered trials are required to determine whether these results represent a class effect or are driven by specific agents, and to clarify their efficacy across all HF subtypes, including HFmrEF.