Semaglutide and diuretic use in obesity-related heart failure with preserved ejection fraction: a pooled analysis of the STEP-HFpEF and STEP-HFpEF-DM trials

Author:

Shah Sanjiv J1,Sharma Kavita2,Borlaug Barry A3ORCID,Butler Javed45ORCID,Davies Melanie67,Kitzman Dalane W8,Petrie Mark C9,Verma Subodh10,Patel Shachi11,Chinnakondepalli Khaja M11,Einfeldt Mette N12,Jensen Thomas J12,Rasmussen Søren12,Asleh Rabea13ORCID,Ben-Gal Tuvia14,Kosiborod Mikhail N11ORCID

Affiliation:

1. Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine , Chicago, IL , USA

2. Division of Cardiology, The Johns Hopkins University School of Medicine , Baltimore, MD , USA

3. Department of Cardiovascular Medicine, Mayo Clinic , Rochester, MN , USA

4. Baylor Scott and White Research Institute , Dallas, TX , USA

5. Department of Medicine, University of Mississippi , Jackson, MS , USA

6. Diabetes Research Centre, University of Leicester , Leicester , UK

7. NIHR Leicester Biomedical Research Centre , Leicester , UK

8. Department of Internal Medicine, Sections on Cardiovascular Medicine and Geriatrics/Gerontology, Wake Forest University School of Medicine , Winston-Salem, NC , USA

9. School of Cardiovascular and Metabolic Health, University of Glasgow , Glasgow , UK

10. Division of Cardiac Surgery, Li Ka Shing Knowledge Institute of St Michael’s Hospital, Unity Health Toronto, University of Toronto , Toronto, ON , Canada

11. Department of Cardiovascular Disease, Saint Luke’s Mid America Heart Institute , Kansas City, MO , USA

12. Novo Nordisk A/S , Søborg , Denmark

13. Heart Institute, Hadassah University Medical Center, Faculty of Medicine, Hebrew University of Jerusalem , Jerusalem , Israel

14. Heart Failure Unit, Cardiology Department, Rabin Medical Center, Faculty of Medicine, Tel Aviv University , Tel Aviv , Israel

Abstract

Abstract Background and Aims In the STEP-HFpEF trial programme, treatment with semaglutide resulted in multiple beneficial effects in patients with obesity-related heart failure with preserved ejection fraction (HFpEF). Efficacy may vary according to baseline diuretic use, and semaglutide treatment could modify diuretic dose. Methods In this pre-specified analysis of pooled data from the STEP-HFpEF and STEP-HFpEF-DM trials (n = 1145), which randomized participants with HFpEF and body mass index ≥ 30 kg/m2 to once weekly semaglutide 2.4 mg or placebo for 52 weeks, we examined whether efficacy and safety endpoints differed by baseline diuretic use, as well as the effect of semaglutide on loop diuretic use and dose changes over the 52-week treatment period. Results At baseline, across no diuretic (n = 220), non-loop diuretic only (n = 223), and loop diuretic [<40 (n = 219), 40 (n = 309), and >40 (n = 174) mg/day furosemide equivalents] groups, there was progressively higher prevalence of hypertension and atrial fibrillation; and greater severity of obesity and heart failure. Over 52 weeks of treatment, semaglutide had a consistent beneficial effect on change in body weight across diuretic use categories (adjusted mean difference vs. placebo ranged from −8.8% [95% confidence interval (CI) −10.3, −6.3] to −6.9% [95% CI −9.1, −4.7] from no diuretics to the highest loop diuretic dose category; interaction P = .39). Kansas City Cardiomyopathy Questionnaire clinical summary score improvement was greater in patients on loop diuretics compared to those not on loop diuretics (adjusted mean difference vs. placebo: +9.3 [6.5; 12.1] vs. +4.7 points [1.3, 8.2]; P = .042). Semaglutide had consistent beneficial effects on all secondary efficacy endpoints (including 6 min walk distance) across diuretic subgroups (interaction P = .24–.92). Safety also favoured semaglutide vs. placebo across the diuretic subgroups. From baseline to 52 weeks, loop diuretic dose decreased by 17% in the semaglutide group vs. a 2.4% increase in the placebo group (P < .0001). Semaglutide (vs. placebo) was more likely to result in loop diuretic dose reduction (odds ratio [OR] 2.67 [95% CI 1.70, 4.18]) and less likely dose increase (OR 0.35 [95% CI 0.23, 0.53]; P < .001 for both) from baseline to 52 weeks. Conclusions In patients with obesity-related HFpEF, semaglutide improved heart failure-related symptoms and physical limitations across diuretic use subgroups, with more pronounced benefits among patients receiving loop diuretics at baseline. Reductions in weight and improvements in exercise function with semaglutide vs. placebo were consistent in all diuretic use categories. Semaglutide also led to a reduction in loop diuretic use and dose between baseline and 52 weeks. Clinical Trial Registration NCT04788511 and NCT04916470.

Funder

Novo Nordisk

Publisher

Oxford University Press (OUP)

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