Semaglutide drives ‘substantial’ improvements in heart failure symptoms: STEP-HFpEF
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Key takeaways:
- Semaglutide 2.4 mg significantly reduced HF symptom burden among adults with HF with preserved ejection fraction and obesity.
- Semaglutide was also tied to improvements in body weight and 6-minute walk distance.
In adults with HF with preserved ejection fraction and obesity, semaglutide 2.4 mg significantly improved HF-related symptoms and physical limitations and was associated with greater weight loss compared with placebo, researchers reported.
In an analysis of more than 500 adults with HFpEF and obesity, researchers also found that participants who received semaglutide 2.4 mg (Wegovy, Novo Nordisk) increased their 6-minute walk distance, experienced reductions in C-reactive protein and had fewer adverse events compared with those who received placebo, Mikhail Kosiborod, MD, FACC, FAHA, cardiologist at Saint Luke’s Mid America Heart Institute and professor of medicine at the University of Missouri-Kansas City School of Medicine, said during a presentation at the European Society of Cardiology Congress.
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Among people with HFpEF in the U.S., about 80% have overweight or obesity, Kosiborod said during an interview. Those with the obesity/HFpEF phenotype experience an especially high burden of debilitating symptoms, including exercise intolerance, shortness of breath and edema.
“This has a substantial impact on their daily quality of life and, until now, we have had very little to offer these patients,” Kosiborod told Healio. “It is a huge unmet clinical need. These outcomes — patient symptoms, physical limitations and quality of life — are extraordinarily important. Well-designed studies have shown patients value improvements in their symptoms and daily function as highly as survival.
“Obesity may be the root cause in terms of the development and progression of HFpEF, but until now, we have had no clinical trials of any pharmacologic therapies specifically targeting obesity as a treatment for HFpEF,” Kosiborod told Healio. “This is the first trial to ever do that.”
Symptom improvements, weight loss
Kosiborod and colleagues analyzed data from 529 adults with HFpEF and a BMI of 30 kg/m2 or higher, randomly assigned once-weekly semaglutide 2.4 mg or placebo for 52 weeks. The dual primary endpoints were change from baseline in the Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score, ranging from 0 to 100 (higher scores indicating fewer symptoms and limitations) and change in body weight.
Secondary endpoints included change in 6-minute walk test distance and a hierarchical composite endpoint that included death, HF events and differences in the change in KCCQ clinical summary score and 6-minute walk distance, as well as change in CRP level.
The findings were simultaneously published in The New England Journal of Medicine.
The mean change in KCCQ clinical summary score was 16.6 points for participants who received semaglutide and 8.7 points for those who received placebo, for an estimated difference of 7.8 points (95% CI, 4.8-10.9; P < .001). Mean percentage change in body weight was –13.3% for those who received semaglutide and –2.6% for those who received placebo, for an estimated difference of –10.7 percentage points (95% CI, –11.9 to –9.4; P < .001).
The mean change in 6-minute walk distance was 21.5 m with semaglutide and 1.2 m with placebo, for an estimated difference of 20.3 m (95% CI, 8.6-32.1; P < .001).
In the analysis of the hierarchical composite endpoint, semaglutide produced more wins than placebo (win ratio, 1.72; 95% CI, 1.37-2.15; P < .001). The mean percentage change in CRP level was –43.5% with semaglutide and –7.3% with placebo, for an estimated treatment ratio of 0.61 (95% CI, 0.51-0.72; P < .001).
Serious adverse events were less common among participants who received semaglutide vs. placebo (13.3% vs. 26.7%; P < .001); with researchers noting that the between-group difference primarily reflected the lower number of CV events in the semaglutide group compared with placebo (2.7% vs. 11.3%; P < .001).
“This is the largest benefit on patient symptoms and physical limitations as well as exercise function that we have ever seen with any drug in HFpEF, so it is extremely substantial,” Kosiborod told Healio. “This is three times the magnitude of effect seen in trials of other treatments for HFpEF. These are impressive results.”
Kosiborod said all reported responder analyses in the trial, even those examining large improvements in the KCCQ clinical summary score, consistently showed superiority of semaglutide to placebo, adding that participants who received semaglutide had more than double the odds of having such benefits.
Kosiborod called the absolute magnitude of the increase in the 6-minute walk distance “notable,” adding the findings were similar to that observed in trials of exercise training in patients with HFpEF and HF with reduced EF.
“Collectively, our results indicate that semaglutide may represent a valuable therapeutic approach in the management of HFpEF in patients with obesity,” the researchers wrote in NEJM.
‘Much needed option’ for HFpEF with obesity
In a related editorial published in NEJM, Yigal M. Pinto, MD, PhD, professor of heart failure and arrhythmias at Amsterdam University Medical Center, wrote that the “encouraging findings” for semaglutide “potentially add a much-needed extra option” for people with HFpEF and elevated BMI.
“How these findings translate to hard endpoints 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,” Pinto wrote.
Data from STEP-HFpEF follow the four phase 3 STEP trials, also reported by Healio, each with the same coprimary endpoints of percentage change in body weight and weight reduction of at least 5% from baseline to 68 weeks compared with placebo. Those studies each demonstrated significant weight loss in adults with overweight or obesity.
References:
- Kosiborod MN, et al. N Engl J Med. 2023;doi:10.1056/NEJMoa2306963.
- Pinto YM. N Engl J Med. 2023;doi:10.1056/NEJMe2309294.
Perspective
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Sean Pinney, MD, FACC, FAST, FHFSA
These results provide hope for patients with heart failure and preserved ejection fraction. The addition of semaglutide led to favorable reductions in weight and improvements in quality of life and exercise capacity. Coupled with the beneficial reduction in inflammatory markers, it is safe to say that semaglutide is directly impacting the underlying biology of those patients with the obesity phenotype of HFpEF.
Some may argue that the improvement in walk distance was modest, but it appears similar to reported values with dapagliflozin. Two limitations that stand out is the underrepresentation of minority populations enrolled in this trial and the low rate of SGLT2 inhibitor use. Now we need to know what effect GLP-1 receptor agonists will have in concert with SGLT2 inhibitors, medications of proven benefit in HFpEF. We also need additional studies to understand what salutary effects these agents will have on CV structure and function.
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Kosiborod MN, et al. Hot line 1. Presented at: European Society of Cardiology Congress; Aug. 25-28, 2023; Amsterdam (hybrid meeting).
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