Effect of Glucagon-Like Peptide-1 Receptor Agonists on Heart Failure Outcomes and Cardiovascular Death Across Varying Cardiovascular-Kidney-Metabolic Comorbidity

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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.

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