Key Points:
- More than 80% of patients with HFpEF are overweight or obese, but there has not yet been a study examining the use of weight-loss agents in body weight reduction or HF symptomatology in HFpEF.
- In the Step-HFpEF study, subcutaneous once-weekly semaglutide was compared with placebo in patients with HFpEF and obesity. The two primary endpoints were change of KCCQ-CCS and body weight from baseline after 52 weeks of treatment.
- Semaglutide use resulted in a significant reduction in both heart failure symptomatology and body weight at 52 weeks.
At least 80% of patients with HFpEF are overweight or obese. Obesity likely contributes not only to ongoing HFpEF pathophysiology, but also to the burden of symptoms in heart failure. GLP-1 receptor agonists have shown great promise in treating obesity, but they have not yet been examined in the setting of HFpEF. In a breaking presentation at the 2023 ESC Congress today, Dr. Kosiborod (Saint Luke’s Health System, Kansas City) and his team presented their study: “STEP HFpEF: once-weekly semaglutide in people with HFpEF and obesity.” This study was simultaneously published in the New England Journal of Medicine.
The STEP-HFpEF trial (NCT04788511) was a randomized, international, multicenter, double-blind, placebo-controlled trial of HFpEF patients (EF >45%) and obesity (BMI>30kg/m2) and functional limitation (NYHA score II-IV and Kansas City Cardiomyopathy Questionnaire Clinical Summary Score [KCCQ-CCS] <90). Participants were also required to have at least ≥1 of the following: a) elevated filling pressures on invasive measurement, b) elevated natriuretic peptide (NP) levels with associated echocardiographic abnormalities; or c) HF hospitalization in the previous 12 months with ongoing echocardiographic abnormalities on diuretic requirement. Key exclusion criteria included diabetes (HbA1c >6.5%), prior or planned bariatric surgery, >5kg weight fluctuation within the 90 days prior to randomization, CV event <30 days of randomization, or sBP >160 mm Hg. The two primary endpoints were a) change in KCCQ-CSS score over 52 weeks and b) change in body weight over 52 weeks.
A total of 529 patients were 1:1 randomized to either subcutaneous once-weekly semaglutide (2.4mg) or placebo over 52 weeks. The median age was 69, and 56% were women. The median BMI was 37 kg/m2. Participants receiving semaglutide had a significantly greater reduction in KCCQ-CSS over 52 weeks compared to placebo (estimated treatment difference [ETD] 7.8 points, 95% CI 4.8-10.9 points, p<0.001). Participants receiving semaglutide also experienced significantly greater reduction in body weight over 52 weeks compared to placebo (ETD 10.7% body weight reduction, 95% CI 9.4%-11.9% reduction, p<0.001). Secondary endpoints included change in 6MWD at 52 weeks from baseline, which was also increased in the semaglutide group (ETD 20.3 meters, 95% CI 8.6-32.1 meters, p<0.001). Semaglutide users also had a higher win-ratio in the hierarchical composite endpoint of clinical benefit, time to death, number of HF events, time to first HF event, change in KCCQ-CSS, and change in 6MWD (stratified win ratio 1.72, 95% CI 1.37-2.15, p<0.001). Semaglutide also resulted in significant reduction in CRP (43.5% reduction, treatment ratio 0.61) and NT-proBNP (20.9% reduction, treatment ratio 0.84) relative to placebo. Semaglutide was generally well-tolerated, with 13.3% of participants experiencing adverse effects leading to discontinuation, of which 9.5% were gastrointestinal. There were fewer adverse events in the semaglutide group relative to placebo (13.3% vs 26.7%, p<0.001).
When discussing the clinical implications of the study at the ESC Congress press conference, Dr. Kosiborod stated: “I think that this study should change the conversation…it is very clear based on these results that in patients with HFpEF, obesity is not just a comorbidity—it appears to be the root cause of heart failure development and progression, and it should be treated as such and should be a target for intervention.”
