Semaglutide benefits extend to HFpEF patients with T2D

The weight loss and heart failure (HF) benefits of semaglutide extend to patients with obesity-related HF with preserved ejection fraction (HFpEF) and type 2 diabetes (T2D) in the STEP-HFpEF DM trial, fuelling speculation that semaglutide may have cardiovascular effects beyond weight loss.

Semaglutide, given at a 2.4 mg dose, led to larger reductions in HF-related symptoms and physical limitations as measured by the 100-point Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS) compared with placebo (13.7 vs 6.4 points; p<0.001).

Weight loss was also greater with semaglutide than placebo (−9.8 percent vs −3.4 percent; p<0.001) at 1 year, reported Dr Mikhail Kosiborod from Saint Luke’s Mid America Heart Institute and the University of Missouri-Kansas City School of Medicine in Missouri, US at ACC.24.

“What we saw [in STEP-HFpEF DM] is quite fascinating,” he said. “The magnitude of benefit was very similar to what we saw in the first STEP-HFpEF trial of people without T2D.”

In the pooled analysis of the two trials, also presented at ACC.24 and published in April, semaglutide was superior to placebo, with a 7.5-point bigger KCCQ-CSS change and 8.4-percentage points more weight loss from baseline to 52 weeks vs placebo (p<0.0001 for both). [Lancet 2024;403:1635-1648]

Six-minute walk distance also improved with semaglutide (12.7 m gain) compared with placebo (1.6 m loss). CRP concentrations were significantly reduced with semaglutide vs placebo (p<0.0001 for all comparisons).

The investigators said the consistency of the findings between the two trials provides greater reassurance for semaglutide as “an effective treatment option” in patients with obesity-related HFpEF.

STEP-HFpEF DM trial

As patients with diabetes typically lose about 40 percent less weight on GLP-1 receptor agonists than nondiabetic patients, Kosiborod said the STEP-HFpEF DM trial was necessary because “if you believe that there could be differential treatment effects based on the degree of weight loss, you don’t want to combine these patients in the same trial.”

STEP-HFpEF DM enrolled 616 patients (median age 69 years, 44.3 percent female) with HFpEF (left ventricular ejection fraction ≥45 percent), a BMI of ≥30, and type 2 diabetes. They were randomly assigned to semaglutide, starting at the lowest dose (0.25 mg for 4 weeks), escalating to the maintenance dose (2.4 mg) by week 16, or placebo. Median BMI was 36.9, and median duration of T2D was 8 years.  [N Engl J Med 2024;390:1394-1407]

CRP concentrations were 42 percent lower with semaglutide at 52 weeks vs baseline, while the placebo group had a 12.8 percent reduction (p<0.0001). For NT-proBNP, the semaglutide group saw a 23.2 percent change vs a 4.6 percent change from baseline for the placebo group.

Hospitalizations or urgent HF-related visits occurred in 18 patients in the placebo group vs. seven in the semaglutide group (HR, 0.40). Semaglutide reduced HbA_1c levels (despite well-controlled glycaemia at baseline), without increasing clinically significant hypoglycaemia. Additionally, there was no increase in diabetic retinopathy events with semaglutide, which has been a potential concern for GLP-1 receptor agonists in diabetes.