Effect of glucagon‐like peptide‐1 receptor agonists on heart failure outcomes and cardiovascular death across varying cardiovascular‐kidney‐metabolic comorbidity

Aims Effects of glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) on heart failure hospitalization (HFH) and cardiovascular (CV) death among patients with varying overlap of cardiovascular‐kidney‐metabolic (CKM) comorbidity are not well characterized. This study aimed to assess effects GLP‐1RAs on HFH and CV death across populations with varying type and number of CKM comorbidity. Methods and results Online databases were queried through November 2024 for primary and secondary analyses of clinical outcome trials of GLP‐1RAs in patients with heart failure (HF), type 2 diabetes mellitus (T2DM), chronic kidney disease (CKD), obesity, and combinations of these diseases. Primary outcome was a composite HFH or CV death. Secondary outcomes were first HFH and CV death. Hazard ratios (HRs), risk ratios (RRs), and their 95% confidence intervals (CI) were derived using random‐effects models. Fifteen trials ( n = 87 549) were included. Compared with placebo, GLP‐1RAs reduced the relative risk of composite HFH/CV death in HF (HR 0.81, 95% CI 0.69–0.96), T2DM (HR 0.85, 95% CI 0.78–0.93), and obesity (HR 0.70, 95% CI 0.58–0.86), with a non‐significant risk reduction in CKD (HR 0.79, 95% CI 0.61–1.01). GLP‐1RAs reduced the risk of HFH in T2DM (HR 0.89, 95% CI 0.80–0.99) and obesity (HR 0.63, 95% CI 0.45–0.87), with a non‐significant risk reduction among patients with HF (HR 0.85, 95% CI 0.69–1.04) and CKD (HR 0.82, 95% CI 0.64–1.06). GLP‐1RAs also significantly reduced CV death in HF (HR 0.88, 95% CI 0.77–0.99), T2DM (HR 0.85, 95% CI 0.78–0.93), and in obesity (HR 0.83, 95% CI 0.73–0.93), with a non‐significant risk reduction in CKD (HR 0.80, 95% CI 0.60–1.08). Effects were consistent across subgroups, except for HF with reduced ejection fraction (HFrEF), where GLP‐1RAs showed a non‐significant risk increase in HFH (HR 1.17, 95% CI 0.93–1.47) but significantly reduced CV death (HR 0.67, 95% CI 0.50–0.90). GLP‐1RAs were not associated with increased risk for serious adverse events (RR 0.94, 95% CI 0.89–1.00). Conclusions Glucagon‐like peptide‐1 receptor agonists reduce HFH and CV death across CKM conditions, with generally consistent effects in varying combinations of these diseases. The potential exception is among patients with HFrEF, where a reduction in risk of CV death, but a numeric increase in HFH, was observed. Definitive CV outcome trials are needed to definitively determine effects of GLP‐1RAs in patients with established HFrEF.