Pharmacoepidemiologic study on GLP-1RA use in patients with advanced HFrEF and obesity

ESC Heart Failure 2025 – In PRAISE-HFrEF among T2D patients with clinically severe HFrEF and BMI ≥30 kg/m², treatment with a GLP-1RA did not increase the risk of mortality or HF hospitalization compared with a dipeptidyl peptidase 4 inhibitor or sulfonyl urea.

This summary is based on the presentation of Varun Sundaram, MD, PhD (Cleveland, OH, USA) at the ESC Heart Failure Congress 2025 - PRAISE-HFrEF: Glucagon-like peptide-1 receptor agonism in heart failure with reduced ejection fraction and obesity.

Introduction and methods

Previously, a prespecified analysis of the SELECT (Semaglutide Effects on Cardiovascular Outcomes in People With Overweight or Obesity) trial showed semaglutide improved outcomes compared with placebo in patients with CVD and overweight or obesity but no diabetes who also had HFrEF (n=1347). However, this analysis was based on a relatively low incidence rate of HF hospitalizations (1.5% per year) in a HFrEF patient cohort with mild disease (<10% NYHA class III or IV HF symptoms; <45% on loop diuretics). Moreover, these findings are in contrast with results of small trials indicating potential safety concerns of GLP-1RAs in patients with clinically severe or advanced HFrEF.

The PRAISE-HFrEF study was a multicenter, observational, pharmacoepidemiologic study with an active-comparator, new-user design conducted at 170 Veteran Affairs Medical Centers in the US that investigated the efficacy and safety of GLP-1RA use in patients with clinically severe HFrEF and obesity. In this study, data were collected from 2729 T2D patients with HFrEF and BMI ≥30 kg/m² who received either a GLP-1RA (active treatment) or a dipeptidyl peptidase 4 (DPP-4) inhibitor or sulfonyl urea (comparator treatment) for the first time. Participants had to have active HF <12 months prior to treatment initiation, which was defined as: (1) hospitalization with a primary diagnosis of HF; (2) ongoing use of loop diuretics, and (3) elevated natriuretic peptide levels. Median follow-up duration was 3.3 years.

To balance baseline patient characteristics, inverse probability of treatment weighting (IPTW) was applied. The primary endpoint was the time to first HF hospitalization or all-cause mortality.

Main results

• In IPTW Cox regression analysis, the incidence of the primary endpoint did not differ between patients who were newly treated with a GLP-1RA (n=1228) and those with new initiation of a DPP-4 inhibitor or sulfonyl urea (n=1501) (HR: 0.92; 95%CI: 0.78–1.07; P=0.26) (in Cox proportional hazards analysis: HR: 0.97; 95%CI: 0.85–1.23; P=0.74).
• Among patients with BMI ≥40 kg/m² (n=880), the risk of the primary endpoint was lower in participants receiving a GLP-1RA compared with those taking the comparator treatment (HR: 0.45; 95%CI: 0.23–0.86), whereas there was no difference in risk among those with BMI 30.0–39.9 kg/m² (n=1849) (HR: 0.94; 95%CI: 0.78–1.14). However, there was no significant interaction by BMI category (P for interaction=0.10).
• Other subgroup analyses also showed consistent results across subgroups stratified by age, SGLT2 inhibitor use, or presence of CKD (all P for interaction>0.05).
• When the individual components of the primary endpoint were analyzed, there was no increased risk of all-cause mortality (HR: 0.89; 95%CI: 0.74–1.07) or HF hospitalization (modeled as repeating event after accounting for mortality as competing risk; HR: 0.97; 95%CI: 0.77–1.22).
• Patients in the GLP-1RA group lost more weight than those in the comparator group (–14.1% vs. –10.0%; P=0.0001).

Conclusion

In the pharmacoepidemiologic study PRAISE-HFrEF among patients with T2D, clinically severe HFrEF, and obesity, GLP-1RA use at diabetes management doses did not increase the risk of all-cause mortality or HF hospitalization compared with DPP-4 inhibitor or sulfonyl urea treatment.

- Our reporting is based on the information provided at the ESC Heart Failure Congress 2025 -