GLP-1 receptor agonists added to guideline-directed medical therapy in heart failure with reduced ejection fraction: a propensity score-matched analysis

Background Guideline-directed medical therapy (GDMT) remains the cornerstone of treatment for heart failure with reduced ejection fraction (HFrEF). GLP-1 receptor agonists (GLP-1RAs) have demonstrated cardiovascular benefit in high-risk populations, yet their impact on myocardial recovery in HFrEF remains unclear. This study aimed to evaluate clinical outcomes in HFrEF patients receiving GDMT alone versus GDMT combined with a GLP-1RA. Methods Using the TriNetX federated research network, we conducted a retrospective cohort study of adult patients with a diagnosis of HfrEF from December 2017-December 2022. Patients receiving GDMT alone were compared to those receiving GDMT plus a GLP-1RA. One-to-one propensity score matching (577 patients per group) was performed to balance baseline covariates including demographic information, comorbidities, and medications such as antiarrhythmics. Patients were followed for up to 4 years. Primary outcomes included all-cause mortality, myocardial infarction, stroke, acute heart failure exacerbation, and left ventricular ejection fraction (LVEF) recovery to above 40% on most recent follow-up echocardiography. Results After propensity score matching, baseline characteristics were well-balanced between groups (n=577 per group). No statistically significant differences were observed between GDMT and GDMT+GLP-1RA groups with respect to all-cause mortality (HR: 1.32, CI=0.94-1.95, p=0.10), myocardial infarction (HR: 1.01, CI=0.78-1.31, p=0.96), stroke (HR: 1.09, CI=0.77-1.53, p=0.63), or acute heart failure exacerbation (HR: 1.14, CI=0.94-1.37, p=0.17). However, a significantly greater proportion of patients in the GDMT+GLP-1RA group demonstrated LVEF recovery to above 40% on most recent follow-up compared to GDMT alone (HR: 0.80, CI=0.64-0.99, p=0.04). Conclusions The addition of a GLP-1RA to GDMT in HFrEF patients was associated with a significantly higher rate of ejection fraction recovery, suggesting a potential role for GLP-1RAs in promoting reverse cardiac remodelling. These findings warrant further investigation in prospective trials to clarify the mechanistic and clinical implications of GLP-1RA therapy in this population.