Semaglutide improves heart failure symptoms and weight in adults with type 2 diabetes and obesity-related HFpEF

In a 52-week randomized trial, once-weekly semaglutide 2.4 mg improved heart failure symptoms and physical function, and led to greater weight loss, than placebo in adults who had both obesity-related heart failure with preserved ejection fraction (HFpEF) and type 2 diabetes ^[1].

The trial enrolled 616 participants with HFpEF, a body-mass index of 30 or more, and type 2 diabetes. They were assigned to semaglutide or placebo for one year. The study was funded by Novo Nordisk and registered as NCT04916470 ^[1]. Semaglutide is the molecule in Ozempic, Wegovy and Rybelsus.

What the trial measured

The two main measures were change in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS), a 0-to-100 scale where higher scores mean fewer symptoms and physical limits, and change in body weight ^[1].

On the symptom score, the mean change was 13.7 points with semaglutide and 6.4 points with placebo, an estimated difference of 7.3 points (95% confidence interval, 4.1 to 10.4; P<0.001). Mean body weight fell 9.8% with semaglutide and 3.4% with placebo, an estimated difference of 6.4 percentage points (95% CI, 7.6 to 5.2 in the negative direction; P<0.001) ^[1].

Three other measures also favored semaglutide: the change in six-minute walk distance (estimated difference, 14.3 meters; 95% CI, 3.7 to 24.9; P=0.008); a composite measure that included death, heart failure events, and differences in symptom score and walk distance (win ratio, 1.58; 95% CI, 1.29 to 1.94; P<0.001); and change in C-reactive protein, a marker of inflammation (estimated treatment ratio, 0.67; 95% CI, 0.55 to 0.80; P<0.001) ^[1].

Serious adverse events were reported in 55 participants (17.7%) in the semaglutide group and 88 (28.8%) in the placebo group ^[1]. The published summary does not break down which specific serious events occurred, and it does not report whether deaths or heart failure hospitalizations fell on their own, apart from the combined measure.

Why it matters for patients

In HFpEF, the heart's measured pumping fraction is preserved, but people often have breathlessness, fatigue and limited exercise capacity. Obesity and type 2 diabetes are common in this group and are tied to a high symptom burden, and the trial authors note that no approved therapies specifically target obesity-related HFpEF in people with type 2 diabetes ^[1].

The symptom-score difference of 7.3 points sits above the range often described as noticeable to patients, while the average 14.3-meter difference in six-minute walk distance is small. The trial ran for one year, so results beyond 12 months have not been reported. Because the participants all had type 2 diabetes as well as obesity-related HFpEF, it is not established from this trial alone whether the same pattern holds for people with obesity-related HFpEF who do not have diabetes. A separate pooled analysis combining this trial with the earlier STEP-HFpEF trial has also been published ^[1].

Whether insurers cover semaglutide for a heart failure diagnosis has not been disclosed, and no labeling change for an HFpEF indication has been reported.

What happens next

The results were published on April 18, 2024 ^[1]. Longer-term follow-up, effects on death or hospitalization separately, and any regulatory action to add heart failure to semaglutide's approved uses have not been reported. Novo Nordisk sponsored the trial, and the published comment letters and author reply that followed appeared in the New England Journal of Medicine in July 2024 ^[1].