Semaglutide 2.4 mg Shows Benefit as Treatment for Heart Failure with Obesity

Mikhail Kosiborod, MD
Credit: St. Luke's Mid America Heart Institute

The role of semaglutide 2.4 mg (Wegovy) could expand even further in the near future, as results of a study presented at the European Society of Cardiology (ESC) Congress 2023 suggest the GLP-1 receptor agonist could find a home in the management of heart failure with preserved ejection fraction (HFpEF).¹

Results of the STEP-HFpEF trial, which come less than a month after Novo Nordisk announced topline results from the SELECT trial, provide the latest evidence in support of a role in cardiovascular risk reduction for semaglutide 2.4 mg, with data indicating use was not only associated with improvements in symptoms and functional status, but could also reduce worsening heart failure events in people with HFpEF and obesity.^1,2

“To our knowledge, this is the first trial of a pharmacologic agent to specifically target obesity as a treatment strategy for HFpEF, and the magnitude of the benefits we observed is the largest seen with any agent in HFpEF,” said principal investigator Mikhail Kosiborod, a cardiologist at St. Luke’s Mid America Heart Institute and vice president of Research for Saint Luke’s Health System.³ “This will likely have a significant impact on clinical practice, especially since there is a dearth of efficacious therapies in this vulnerable patient group. We believe that these findings should also change the nature of the conversation about the role of obesity in HFpEF, as the STEP-HFpEF results clearly indicate that obesity is not simply a comorbidity in patients with HFpEF but a root cause and a target for therapeutic intervention.”

Few therapeutic agents have garnered the same level of attention as semaglutide in recent years. A staple in the management of type 2 diabetes due to its antihyperglycemic effects, the GLP-1 receptor agonist’s role in treatment algorithms underwent a major change after data from the phase 3 STEP program demonstrated use of a 2.4 mg dose was associated with significant weight loss in people with obesity, which led to a chronic weight management indication from the US Food and Drug Administration in June 2021.⁴

With STEP-HFpEF, investigators sought to test the hypothesis that treatment with semaglutide could improve symptoms, physical limitations and exercise function, in addition to weight loss, in patients with HFpEF and obesity. With this in mind, the Effect of Semaglutide 2.4 mg Once Weekly on Function and Symptoms in Subjects with Obesity-related Heart Failure with Preserved Ejection Fraction (STEP-HFpEF) trial was designed as a randomized, double-blind, placebo-controlled trial and conducted at 96 sites in 13 countries in Asia, Europe, and North and South America, with randomization occurring from March 2021-March 2022.¹

For inclusion in the trial, patients were required to have HFpEF and a body mass index (BMI) of 30 kg/m2 or greater. Of note, HFpEF was defined as having a left ventricular ejection fraction of at least 45%, NYHA function class II-IV symptoms, and a Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS) of less than 90 points. Patients were excluded if they had a patient-reported change in body weight of more than 5 kg within 90 days before screening or had a history of diabetes.¹

Patients included in the trial underwent randomization in a 1:1 ratio to either semaglutide 2.4 mg or placebo therapy for 52 weeks. The trial had dual primary endpoints defined as change from baseline in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS) and change in body weight. The trial also included multiple secondary endpoints such as change in the 6-minute walk distance, change in the C-reactive protein (CRP) level, and a hierarchical composite end point that included death, heart failure events, and differences in the change in the KCCQ-CSS and 6-minute walk distance.¹

Overall, 529 patients underwent randomization. Of these, 263 were randomized to semaglutide and 266 were randomized to placebo. Investigators pointed out 256 participants in the semaglutide arm and 254 patients in the placebo arm completed the trial. Investigators also pointed out the majority of participants were women (56.1%) and White (95.8%). The overall study cohort had a median age of 69 years, a median body weight of 105.1 kg, and a median BMI of 37 kg/m2, with 66% having a BMI of 35 kg/m2 or greater.¹

Investigators highlighted the cohort had a median KCCQ-CSS of 58.9, median 6-minute walk distance of 320.0 meters, median CRP level of 3.8 mg/L, median LVEF of 57.0%, and median NT-proBNP of 450.8 pg/mL. When examining baseline medication use, results suggested most participants received beta-blockers, diuretics, and renin–angiotensin system blockers, but only 34.8% received mineralocorticoid receptor antagonists and 3.6% received SGLT2 inhibitors.¹

Upon analysis, the mean change in the KCCQ-CSS was 16.6 points with semaglutide 2.4 mg and 8.7 points with placebo (estimated treatment difference [ETD], 7.8 points; 95% confidence interval [CI], 4.8 to 10.9; P < .001). For weight change, results suggested the mean percentage change in body weight was −13.3% with semaglutide 2.4 mg and −2.6% with placebo (ETD, −10.7 percentage points; 95% CI, −11.9 to −9.4; P < .001). The change in 6-minute walk distance also favored semaglutide 2.4 mg, with a mean change of 21.5 meters with semaglutide 2.4 mg compared to 1.2 meters with placebo (ETD, 20.3 meters; 95% CI, 8.6 to 32.1; P < .001).¹

Further analysis of secondary endpoints suggested semaglutide produced more wins than placebo for the hierarchical composite end point(win ratio, 1.72; 95% CI, 1.37 to 2.15; P < .001). Additionally, the mean percentage change in CRP level observed in the trial was −43.5% with semaglutide 2.4 mg and −7.3% with placebo therapy (estimated treatment ratio, 0.61; 95% CI, 0.51 to 0.72; P < .001). Results also suggested only 1 adjudicated heart failure event occurred among the semaglutide 2.4 mg group compared to 12 among the placebo group (Hazard ratio, 0.08; 95% CI, 0.00 to 0.42).¹

In a simultaneously published editorial, Yigal Pinto, MD, PhD, of Amsterdam University Medical Centers, celebrated the results of the STEP-HFpEF, but highlighted the findings created equally as many questions as it answered, which the medical community will need to answer if it hopes to apply the results moving forward.⁵

“The encouraging findings for semaglutide in patients with heart failure with preserved ejection fraction reported here potentially add a much needed extra option for these patients and provide another upstream treatment for patients with signs of this condition plus a high BMI,” Pinto wrote.⁵ “How these findings translate to hard end points remains to be established and will be important in determining the role of GLP-1 agonism as compared with SGLT2 inhibition in patients with heart failure with preserved ejection fraction.”

References:

1. Kosiborod MN, Abildstrøm SZ, Borlaug BA, et al. Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity. The New England Journal of Medicine. Published online August 25, 2023. doi:10.1056/NEJMoa2306963
2. Campbell P. Select trial shows semaglutide 2.4 mg could reduce cardiovascular risk. HCP Live. August 8, 2023. Accessed August 24, 2023. https://www.hcplive.com/view/select-trial-shows-semaglutide-2-4-mg-could-reduce-cardiovascular-risk.
3. Weight loss medication benefits patients with heart failure and obesity. European Society of Cardiology. Published online August 25, 2023.
4. Campbell P. Semaglutide (Wegovy) approved for chronic weight management in patients with obesity or overweight. HCP Live. June 4, 2021. Accessed August 24, 2023. https://www.hcplive.com/view/semaglutide-approved-for-chronic-weight-management-in-patients-with-obesity-or-overweight.
5. Pinto YM. Heart Failure with Preserved Ejection Fraction — A Metabolic Disease? The New England Journal of Medicine. Published online August 25, 2023. doi:10.1056/NEJMe2309294