Wegovy Helps HFpEF Patients With Diabetes Mellitus

ATLANTA — Weight loss and heart failure benefits with semaglutide (Wegovy) extended to patients with obesity-related heart failure with preserved ejection fraction (HFpEF) who have type 2 diabetes, the STEP-HFpEF DM trial showed.

A 2.4-mg dose of the GLP-1 receptor agonist improved HF-related symptoms and physical limitations as measured with the Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score compared with the change over 1 year on placebo (13.7 vs 6.4 points on the 100-point KCCQ-CSS scale, P<0.001).

Patients also lost 6.4 percentage points more body weight with semaglutide over that period (−9.8% vs −3.4%, P<0.001), reported Mikhail N. Kosiborod, MD, of Saint Luke’s Mid America Heart Institute and the University of Missouri-Kansas City School of Medicine, at the American College of Cardiology annual meeting. The findings were also published in The New England Journal of Medicine.

The findings mirrored those of the similarly designed STEP-HFpEF trial in a population without type 2 diabetes. A pooled analysis of the two trials, also presented at the conference and published in The Lancet, showed a 7.5-point bigger KCCQ-CSS change and 8.4-percentage points more weight loss from baseline to 52 weeks compared with placebo (both P<0.0001).

Overall, the group concluded: “Consistency between the findings of the two trials provides greater reassurance that semaglutide is an efficacious treatment option with a favorable safety profile in a broad population” with HFpEF related to obesity.

Implications

Notably, KCCQ-CSS improvement was about the same between the two trials even though the weight loss was about 40% less in the patients with diabetes.

Session commentator Lee R. Goldberg, MD, MPH, of the University of Pennsylvania in Philadelphia, noted that the roughly 10% body weight loss with semaglutide was still about what might have been expected.

Kosiborod’s group pointed to use of insulin and insulin secretagogues as a potential reason for the attenuated body-weight reduction for the diabetes group but noted that it also “suggests that the mechanisms of benefit with semaglutide may extend beyond weight loss and may include direct effects on decongestion; vascular, skeletal muscle, and mitochondrial function; epicardial adipose tissue; inflammation; and insulin resistance, factors that (unlike weight loss) may be more pronounced in patients with type 2 diabetes than in those without type 2 diabetes.”

But because of that differential between the trials, they prove that the HF benefits are independent of weight loss, noted Erwan Donal, MD, PhD, of the University of Rennes in France, and colleagues in an accompanying comment in The Lancet.

“Semaglutide represents a major step forward in addressing major unmet needs in this vulnerable population, particularly in terms of improving exercise function and quality of life,” they wrote.

SGLT2 inhibitors have been the only disease-modifying therapy for HFpEF, but the researchers argued that the findings were suggestive for semaglutide as well in a large proportion of patients (some 80% of HFpEF patients have overweight or obesity). “Collectively, these results provide a signal for a potential reduction in clinical events, which requires further confirmation in heart failure outcome trials,” they wrote.

An additional question now is what would happen with combination SGLT2 inhibitor and GLP1 receptor agonist treatment, Donal’s group noted. Subgroup analysis showed consistent effects of semaglutide on HF-related outcomes with and without SGLT2 inhibitor use.

Trial Details

STEP-HFpEF DM included 616 adults who had heart failure with preserved ejection fraction (left ventricular ejection fraction ≥45%), a BMI of 30 or more, and type 2 diabetes with a hemoglobin A1c of no more than 10%. Patients also had to have at least one higher risk characteristic: elevated left ventricular filling pressures, elevated natriuretic peptide levels plus echocardiographic abnormalities, or heart failure hospitalization within the prior 12 months plus either echocardiographic abnormalities or ongoing treatment with diuretics.

Participants were randomly assigned to receive once-weekly semaglutide (dose ramped up to 2.4 mg over 16 weeks) or placebo for 52 weeks. Their median age was 69, 44.3% were female, and their median BMI was 36.9.

KCCQ-CSS and weight loss were co-primary endpoints.

Among the confirmatory secondary endpoints, change in the 6-minute walk distance from baseline to week 52 was a gain of 12.7 m in the semaglutide group compared with loss of 1.6 m in the placebo group (P=0.008). For a hierarchical composite endpoint of all-cause mortality, heart failure events, and hitting KCCQ-CSS and 6-minute walk distance thresholds, the “win” ratio was higher with semaglutide than with placebo (1.58, 95% CI 1.29-1.94, P<0.001).

The trial also affirmed safety in patients with type 2 diabetes, “who have unique potential vulnerabilities,” with fewer serious adverse events (AEs) overall (17.7% vs 28.8%, P=0.002), fewer cardiac disorder events (19 vs 40, P=0.004), and numerically fewer discontinuations due to serious AEs (1.9% vs 3.6%).

“Semaglutide reduced glycated hemoglobin levels (despite well-controlled glycemia at baseline) without an increase in clinically significant hypoglycemia,” the researchers noted. “Furthermore, there was no increase in diabetic retinopathy events with semaglutide, which has been a potential concern for GLP-1 receptor agonists in type 2 diabetes.”

One limitation was generalizability, Goldberg noted. He pointed to the relatively low proportion of women compared with their typical proportion of HFpEF cases and the small percentage of Black participants (4.2% in the semaglutide group and 1.6% in the placebo group).

Kosiborod responded by noting that the proportion was 26% among U.S.-enrolled patients but other enrolling countries had smaller Black populations.

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