Beneficial effects of GLP-1RA in obesity-related HFpEF irrespective of diuretic use


ESC Heart Failure 2024 – Semaglutide improved KCCQ-CSS in patients with obesity-related HFpEF compared with placebo irrespective of diuretic use and dose, with more pronounced effects in patients receiving loop diuretics at baseline.

This summary is based on the presentation of Subodh Verma, MD, PhD (Toronto, ON, Canada) at ESC Heart Failure 2024 - Semaglutide therapy and diuretic use in obesity-related HFpEF: insights from the STEP-HFpEF programme.

Introduction and methods

Patients with HFpEF are often prescribed loop diuretics for decongestion. Loop diuretics appear to be less effective and have and exaggerated negative effect on kidney function in patients with obesity-related HFpEF. In the STEP-HFpEF programme, treatment with semaglutide improved HF-related symptoms, physical limitations and exercise function, and led to greater weight loss compared with placebo.

The aim of this prespecified analysis of pooled data from the STEP-HFpEF programme was to (1) investigate the efficacy and safety of semaglutide across baseline diuretic groups, and (2) investigate the effects of semaglutide on changes in loop diuretic use and dose over 52 weeks.

The STEP-HFpEF programme comprises of two RCTs (STEP-HFpEF, n=529; STEP-HFpEF DM, n=617) in which adults with HFpEF and obesity (BMI ≥30 kg/m²) were randomized to semaglutide 2.4 mg subcatenous once weekly or matching placebo for 52 weeks, in addition to standard care. Loop diuretics, thiazide diuretics, and MRA’s, but not SGLT2 inhibitors, were considered diuretics. This analysis stratified patients into 5 different groups based on baseline diuretics use: no diuretic (n=220), non-loop diuretics only (n=223), loop diuretic dose <40 mg/d (n=219), loop diuretic dose of 40 mg/d (n=309), and loop diuretic dose >40 mg/d (n=174).

The dual primary outcomes were change in KCCQ – Clinical Summary Score (CSS) and percent change in body weight from baseline to 52 weeks.

Main results

Efficacy of semaglutide

  • At week 52, semaglutide improved KCCQ-CSS across all baseline diuretic subgroups compared with placebo, with the greatest improvements in the group with the highest loop diuretic dose (difference of 3.2 points [95%CI: -1.8-8.2] in the no diuretics group; 6.2 points [95%CI: 1.4-11.1] in the non-loop diuretic only group; 7.9 points [95%CI: 2.9-12.9] in the loop diuretic dose <40 mg/d group; 8.9 points [95%CI: 4.7-13.0] in the loop diuretic dose =40 mg/d group; and 11.6 points [95%CI: 6.0-17.2] om the loop diuretic dose >40 mg/d group; P for interaction=0.22; P value for trend=0.02).
  • Semaglutide had a consistent beneficial effect on body weight (P for interaction=0.39), 6-minute walk distance (P for interaction=0.70), the hierarchical composite endpoint (P for interaction=0.24), CRP (P for interaction=0.76), and NT-proBNP (P for interaction=0.54) across all 5 diuretic subgroups compared with placebo.

Changes in loop diuretic use and dose

  • Semaglutide reduced loop diuretic dose from baseline to 52 weeks compared with placebo (estimated treatment difference: -11.8 mg/d; 95%CI: -16.8 to -6.8; P<0.0001).
  • Compared with patients in the placebo group, patients in the semaglutide group were more likely to have a decrease in loop diuretics dose (OR: 2.67; 95%CI: 1.70-4.18; P<0.001) and less likely to have a diuretic dose increase (OR: 0.23; 95%CI: 0.23-0.53; P<0.001).
  • Treatment with semaglutide was associated with lower initiation of new loop diuretic among baseline non-users compared with placebo (HR: 0.29; 95%CI: 0.16-0.52; P<0.001), and higher discontinuation of loop diuretic among baseline users (HR: 2.69; 95%CI: 1.19-6.12).


In this prespecified analysis of the STEP-HFpEF programme, treatment with semaglutide versus placebo improved KCCQ-CSS across all diuretics subgroups, with more pronounced effects in patients receiving loop diuretics at baseline. Semaglutide’ effect on body weight, exercise function, and biomarkers of inflammation and congestion were consistent across diuretic subgroups. Moreover, treatment with semaglutide reduced loop diuretic use and dose from baseline to 52 weeks compared with placebo.

- Our reporting is based on the information provided at ESC Heart Failure 2024 -

The findings of this study were simultaneously published in Eur Heart J.

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