STEP-HFpEF: Semaglutide 2.4 mg Eases Symptoms and Cuts Weight in Obesity-Related Heart Failure

In the STEP-HFpEF trial, once-weekly semaglutide 2.4 mg improved heart-failure symptoms and physical function and produced substantial weight loss over 52 weeks in patients with heart failure with preserved ejection fraction and obesity.

Heart failure with preserved ejection fraction — HFpEF — now accounts for roughly half of all heart-failure cases, and the majority of patients with it live with overweight or obesity. Yet for years, treatment options were remarkably thin. Until recently, no therapy had clearly improved outcomes in HFpEF, and management consisted mainly of diuretics to relieve fluid overload and control of contributing conditions such as hypertension. The arrival of SGLT2 inhibitors, shown in the EMPEROR-Preserved and DELIVER trials to reduce heart-failure hospitalizations in HFpEF, was the first real pharmacological advance — but symptom burden and functional limitation remained largely unaddressed, particularly in patients whose disease is closely intertwined with obesity.

The link between obesity and HFpEF is not merely statistical. Excess visceral fat expands plasma volume, promotes systemic inflammation, and contributes to stiffening of the heart muscle — mechanisms that plausibly drive the breathlessness, edema, and exercise intolerance that define the condition. That made weight reduction a rational therapeutic target, but one that diet and exercise programs alone had rarely achieved at a meaningful, sustained scale in this older, chronically ill population.

The STEP-HFpEF trial, led by Mikhail Kosiborod of Saint Luke’s Mid America Heart Institute and published in the New England Journal of Medicine in 2023, asked a direct question: in patients with obesity-related HFpEF, does targeting the obesity itself with semaglutide 2.4 mg improve symptoms and function?

What the researchers did

The international, randomized, double-blind, placebo-controlled phase 3 trial enrolled 529 patients with HFpEF — defined by a left ventricular ejection fraction of at least 45 percent — and a body-mass index of 30 or higher. Participants were assigned to once-weekly semaglutide 2.4 mg or placebo for 52 weeks, on top of their existing heart-failure therapy.

The trial had two primary endpoints: the change in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS), a 100-point measure of heart-failure symptoms and physical limitation where higher scores mean better health, and the percentage change in body weight. Secondary endpoints included the change in six-minute walk distance and a hierarchical composite of death, heart-failure events, and symptom improvement.

What they found

Both primary endpoints favored semaglutide decisively. The KCCQ-CSS improved by an average of 16.6 points with semaglutide versus 8.7 points with placebo — an estimated difference of 7.8 points. For context, a 5-point change on this scale is generally considered clinically meaningful, so the placebo-subtracted effect exceeds that threshold.

Body weight fell by 13.3 percent with semaglutide, compared with 2.6 percent with placebo — a magnitude consistent with the STEP obesity program, now demonstrated in a heart-failure population.

Functional capacity moved in parallel. Six-minute walk distance increased by 21.5 meters on semaglutide versus 2.4 meters on placebo. Participants on semaglutide also fared better on the hierarchical composite endpoint that combined death, heart-failure events, and thresholds of symptom and walking improvement.

The investigators concluded that among patients with HFpEF and obesity, semaglutide 2.4 mg led to larger reductions in heart-failure symptoms and physical limitations, greater improvements in exercise function, and greater weight loss than placebo.
Kosiborod et al., N Engl J Med 2023 (STEP-HFpEF)

Notably, serious adverse events were less frequent with semaglutide than with placebo, a pattern also seen in the SELECT cardiovascular outcomes trial. A confirmatory sister trial, STEP-HFpEF DM, subsequently tested the same approach in patients with obesity-related HFpEF and type 2 diabetes and reported consistent results.

Limitations

The findings apply to a specific population: HFpEF accompanied by obesity. Whether patients with HFpEF who are not obese would benefit is unknown, and the trial says nothing about heart failure with reduced ejection fraction, where the treatment landscape and physiology differ.

The endpoints were symptoms, function, and weight — not hospitalizations or death. The trial was not powered to show that semaglutide prevents heart-failure hospitalizations or prolongs life in this population, and larger outcomes trials are needed to answer that question. One year of follow-up also cannot establish durability beyond the treatment period, and the STEP program’s extension data in obesity suggest that weight — and possibly symptom benefit — returns substantially when treatment stops.

Finally, the trial was funded and analyzed by Novo Nordisk, the manufacturer of semaglutide. That is standard for regulatory development, but independent replication and health-system data on cost and access will shape how broadly these results translate into practice.