AIMS: To examine whether on-treatment changes in kidney function and cardiometabolic markers are associated with the magnitude of heart failure (HF) risk reduction across large-scale trials of glucagon-like peptide-1 receptor agonists (GLP-1RAs).
MATERIALS AND METHODS: We searched PubMed and Embase from inception to 29 January 2026 for randomised, placebo-controlled GLP-1RA trials enrolling ≥ 1000 adults with type 2 diabetes and/or overweight or obesity and a follow-up of at least one year. The primary outcome was clinical HF events (hospitalisation for HF, with or without urgent HF visits). We pooled hazard ratios (HRs) using random-effects meta-analysis and performed mixed-effects meta-regression to test whether between-group changes in annualised estimated glomerular filtration rate (eGFR) improvement, body weight, systolic blood pressure (SBP), and heart rate were associated with the treatment effect on clinical HF events.
RESULTS: Eleven trials were included (90 867 participants; 2863 clinical HF events). GLP-1RAs reduced the risk of clinical HF events (HR 0.86, 95% CI 0.80 to 0.93, p < 0.001, I = 2.1%). In meta-regression, annualised eGFR improvement was significantly associated with greater HF risk reduction (p = 0.009); at the trial level, each 1 mL/min/1.73 m/year greater improvement in eGFR corresponded to a 21% lower hazard of clinical HF events (95% CI 7% to 32%). In contrast, changes in body weight, SBP, and heart rate were not associated with HF risk reduction. 2 2
CONCLUSIONS: Across large-scale GLP-1RA trials, greater annualised eGFR improvement was associated with larger reductions in clinical HF events. Annualised eGFR change may serve as a useful marker of HF benefit with GLP-1RAs.
