Wegovy beneficial in HFpEF regardless of diuretic use, cuts need for diuretics
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Key takeaways:
- Compared with placebo, Wegovy improved HF symptoms and physical limitations in patients with obesity-related HFpEF regardless of diuretic use.
- Wegovy also reduced the need for diuretics in this population.
In patients with the obesity phenotype of HF with preserved ejection, semaglutide 2.4 mg improved HF-related symptoms and physical limitations vs. placebo regardless of diuretic use, according to new data from the STEP-HFpEF trials.
In addition, semaglutide 2.4 mg (Wegovy, Novo Nordisk) reduced the need for diuretic use in this population compared with placebo, researchers reported at the European Society of Cardiology’s Heart Failure 2024 congress.
As Healio previously reported, in the STEP-HFpEF trial of patients with obesity-related HFpEF (defined as BMI > 30 kg/m2) but no diabetes and in the STEP-HFpEF DM trial of patients with obesity-related HFpEF and diabetes, semaglutide 2.4 mg was superior to placebo for improvement of HF symptoms and physical function. For the present analysis, the researchers stratified 1,145 patients from both trials according to diuretic use: no diuretics (n = 220), non-loop diuretics only (n = 223), loop diuretics < 40 mg per day (n = 219), loop diuretics 40 mg per day (n = 319) and loop diuretics > 40 mg per day (n = 174).
HFpEF and loop diuretics
“Patients with HFpEF frequently receive loop diuretics, which are first-line agents for decongestion but can cause electrolyte abnormalities, worsening kidney function and hypotension,” Subodh Verma, MD, cardiac surgeon and Canada Research Chair in Cardiovascular Surgery at the University of Toronto, who presented the results at the congress, told Healio. “In HFpEF, higher body mass index is associated with greater use and doses of loop diuretics. In patients with obesity-related HFpEF, loop diuretics appear to be less effective for decongestion and have an exaggerated unfavorable impact on kidney function, as compared with those that have HFpEF but no obesity.”
Across the subgroups, the percentage of women ranged from 41% to 55%, the percentage of white patients ranged from 80% to 98%, BMI ranged from 36.9 kg/m2 to 39.3 kg/m2 and left ventricular ejection fraction ranged from 55% to 60%.
The first primary endpoint of change in Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score at 52 weeks favored semaglutide 2.4 mg in all diuretic subgroups, with the magnitude of effect being greater in patients on loop diuretics (P for interaction across all five subgroups = .22; P for trend across all five subgroups = .02; adjusted mean difference vs. placebo in patients on loop diuretics, 9.3; 95% CI, 6.5-12.1; adjusted mean difference vs. placebo in patients not on loop diuretics, 4.7; 95% CI, 1.3-8.2; P for interaction = .042), according to the researchers.
The second primary endpoint of percentage change in body weight at 52 weeks favored semaglutide 2.4 mg regardless of diuretic group (P for interaction = .39; P for trend = .5), the researchers wrote.
The treatment effect of semaglutide 2.4 mg was consistent across diuretic subgroups in all secondary endpoints, including 6-minute walk distance, C-reactive protein, N-terminal pro-B type natriuretic peptide and a hierarchical composite endpoint incorporating outcomes related to death, HF events, change in KCCQ Clinical Summary Score and change in 6-minute walk distance, Verma and colleagues wrote.
Between baseline and 52 weeks, the average loop diuretic dose dropped 17% in patients assigned semaglutide 2.4 mg but rose 2.4% in those assigned placebo (P < .0001), and semaglutide 2.4 mg was more likely than placebo to prompt dose reduction (OR = 2.67; 95% CI, 1.7-4.18; P < .001) and less likely than placebo to prompt dose increase (OR = 0.35; 95% CI, 0.23-0.53; P < .001), according to the researchers.
Clinically meaningful results
“The majority of beneficial HF-related clinical effects and safety of semaglutide were consistent across diuretic groups, with greater magnitude of improvement in HF-related symptoms and physical limitations in patients taking loop diuretics,” Verma told Healio. “Semaglutide treatment led to a clinically meaningful and significant reduction in loop diuretic dose over the 52-week treatment period, which along with reductions in NT-pro BNP and fewer HF events, suggests disease-modifying effects in obesity-related HFpEF.”
Among users of diuretics at baseline, the semaglutide 2.4 mg group was more likely than the placebo group to discontinue diuretics by 52 weeks (HR = 2.69; 95% CI, 1.19-6.12; P = .02), and among nonusers of diuretics at baseline, the semaglutide 2.4 mg group was less likely than the placebo group to initiate diuretics by 52 weeks (HR = 0.29; 95% CI, 0.16-0.52; P < .001), the researchers found.
“Semaglutide has previously unrecognized and entirely novel effects to profoundly impact on patient symptoms, quality of life, and exercise capacity in people with obesity-related HFpEF,” Verma said. “Clinicians should be aware that people with overweight and obesity who are on loop diuretics have an even greater benefit on these parameters. The benefits are likely due to an effect of GLP-1 [receptor agonists] as a disease-modifying therapy. Currently, semaglutide 2.4 mg, while approved for the management of overweight/obesity and cardiovascular risk reduction, is not approved for the treatment of HFpEF. Obesity should no longer simply be considered a comorbidity in HFpEF, but a root cause of the disease, and a modifiable target of pharmacotherapy.”
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Sharma K, et al. Late-breaking clinical trials: LVAD, HFpEF and hypertrophic cardiomyopathy. Presented at: Heart Failure 2024; May 11-14, 2024; Lisbon, Portugal.
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