All-cause mortality and cardiovascular outcomes with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes and heart failure with reduced ejection fraction

Aravinthan Vignarajah; Peter Oro; Joseph El Dahdah; Nishanthi Vigneswaramoorthy; Amanda R Vest; Gautam Shah

doi:10.1016/j.ahjo.2025.100676

All-cause mortality and cardiovascular outcomes with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes and heart failure with reduced ejection fraction

Am Heart J Plus. 2025 Nov 13:60:100676. doi: 10.1016/j.ahjo.2025.100676. eCollection 2025 Dec.

Authors

Aravinthan Vignarajah¹, Peter Oro², Joseph El Dahdah¹, Nishanthi Vigneswaramoorthy³, Amanda R Vest⁴, Gautam Shah⁴

Affiliations

¹ Department of Medicine, Cleveland Clinic Fairview Hospital, Cleveland, OH, USA.
² Department of Internal Medicine, South Pointe Hospital - Cleveland Clinic, OH, USA.
³ Department of Medicine, SUNY Upstate Medical University Hospital, Syracuse, NY, USA.
⁴ Heart Vascular and Thoracic Institute, Cleveland Clinic, Cleveland, OH, USA.

Abstract

Background: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a popular first-line treatment option in managing Type 2 Diabetes Mellitus (T2DM) with cardiovascular co morbidities. Studies have established the benefit of GLP-1 RAs in improving cardiovascular (CV) outcomes in patients with T2DM. However, the impact of GLP-1 RAs on mortality and cardiovascular outcomes in patients with T2DM and Heart failure with reduced ejection fraction (HFrEF) remains uncertain.

Methods: This retrospective cohort study employed an active-comparator new-user design using the TriNetX Research Network database. Patients aged 18 years or older with T2DM and left ventricular ejection fraction of ≤40 % were identified for inclusion. Patients were classified into two groups: GLP-1 RAs users versus dipeptidyl peptidase 4 inhibitor (DPP4i) users. Propensity score matching (1:1) was conducted based on demographics, body mass index, comorbidities, glycated hemoglobin levels, medications and socioeconomic factors resulting in a matched cohort of 26,196 patients. Outcomes analyzed included all-cause mortality, acute myocardial infarction, cerebrovascular accident, and all-cause hospitalization.

Results: The GLP-1 RA user group demonstrated a reduced hazard ratio (HR, 95 % confidence interval) over 5 years compared with the DPP4i user group for all-cause mortality (0.62, 0.59-0.66, P < 0.001), all-cause hospitalization (0.71, 0.69-0.73, P < 0.001), acute myocardial infarction (0.87, 0.82-0.92, P < 0.001), heart failure exacerbation (0.83, 0.81-0.86, P < 0.001) and cerebrovascular accidents (0.85, 0.80-0.92, P < 0.001).

Conclusion: In patients with T2DM and HFrEF, GLP-1 RA therapy shows potential beneficial effects in reducing CV events over 5 years compared to control (DPP4i) group.

Keywords: Cardiovascular outcomes; Dipeptidyl peptidase-4 inhibitors (DPP4i); GLP-1 receptor agonists (GLP-1 RAs); Heart failure with reduced ejection fraction (HFrEF); Type 2 diabetes mellitus (T2DM).