GLP-1 receptor agonists reduce HF worsening events in HFpEF but show no benefit in HFrEFGLP-1 drugs help heart failure with preserved ejection fraction

This meta-analysis evaluated the efficacy and safety of GLP-1 receptor agonists in a large cohort of 11,234 patients diagnosed with heart failure (HF) with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF). The study aimed to determine if these agents provide distinct benefits across different heart failure phenotypes.

The primary outcome measured was the occurrence of HF worsening events. In the HFpEF population, GLP-1 receptor agonists demonstrated a significant reduction in these events, reporting an effect size of 0.67 (95% CI 0.50-0.89). Conversely, in the HFrEF population, no benefit was observed for reducing HF worsening events, with an effect size of 1.23 (95% CI 0.89-1.69).

Secondary outcomes further differentiated the impact of GLP-1 receptor agonists between the two groups. In patients with HFpEF, treatment led to improved NT-proBNP levels (0.85 ratio), an increase in 6-minute walk distance by 17.6 m, and an improvement in Kansas City Cardiomyopathy Questionnaire scores by 7.4 points. Additionally, systolic blood pressure decreased by 3.6 mmHg in the HFpEF group. A composite of HF worsening events or cardiovascular death was also significantly reduced in HFpEF patients (effect size 0.76; 95% CI 0.64-0.90).

Safety and tolerability data indicated that GLP-1 receptor agonists were associated with gastrointestinal adverse events. These gastrointestinal issues were identified as the most frequent cause of drug discontinuation, specifically noted with a risk ratio of 3.12 (95% CI 1.28-7.63). While these side effects are common to the class, they represent a significant factor in treatment adherence.

These results provide high certainty for findings regarding HFpEF and moderate certainty for HFrEF. The data suggests that while GLP-1 receptor agonists may offer clinical, functional, and biomarker improvements specifically for those with preserved ejection fraction, the evidence does not support similar benefits for patients with reduced ejection fraction. This distinction is critical for personalized treatment pathways in heart failure management.

Methodological limitations include the reported gastrointestinal intolerance which can impact long-term compliance. The study highlights a clear divergence in clinical outcomes based on ejection fraction status. Future research may need to investigate why GLP-1 receptor agonists fail to show benefit in HFrEF patients or if specific dosages or combinations could alter these results.

Clinically, these findings suggest that GLP-1 receptor agonists are a promising intervention for HFpEF patients to improve functional outcomes and reduce worsening events. However, clinicians should not expect similar efficacy in the HFrEF population based on current evidence. Patients must be counseled regarding potential gastrointestinal side effects which remain the primary cause of discontinuation.