Semaglutide scores again, this time for HFpEF in obese

Once weekly injection of semaglutide causes weight loss in obese patients with heart failure with preserved ejection fraction (HFpEF), with positive shifts in symptoms and improvements in physical limitations in the STEP-HFpEF trial presented at ESC 2023.

Semaglutide is approved for chronic weight management in overweight or obese adults with high blood pressure, type 2 diabetes, or high cholesterol and previously, for glycaemic control in people with diabetes, but not for HFpeF.

Traditionally, cardiologists have had concerns about weight loss in HF patients, believing that obesity was protective, a phenomenon known as the “obesity paradox.” The STEP-HFpEF results negated that notion.

The dual primary endpoints of weight loss and improvements in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS) were better with semaglutide-treated patients than placebo-treated controls. [N Engl J Med 2023;doi:10.1056/NEJMoa2306963]

“This is the largest KCCQ clinical summary score benefit ever seen with any drug in HFpEF,” said principal investigator Dr Mikhail Kosiborod from Saint Luke’s Mid America Heart Institute, Kansas City, Missouri, US, during the ESC 2023 Hot Line session. “This should give semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, an important role in the management of HFpEF.”

Kosiborod shared that the majority of HFpEF patients are overweight or obese, and this phenotype has unique clinical and haemodynamic features that convey a high burden of symptoms and functional impairment. Currently, there are no approved therapies specifically targeting the combination of HFpEF and obesity.

STEP-HF population

The trial randomly assigned 529 obese patients with a left ventricular ejection fraction ≥45 percent and impaired function to weekly subcutaneous injections of semaglutide 2.4 mg or placebo over a 16-week dose-escalation period, followed by another 36 weeks of treatment. Follow-up was between weeks 52 and 57. Most patients had NYHA class II HF.

As the drug is approved in adults with diabetes, those with known diabetes or HbA_1c ≥6.5 percent were excluded from the trial, and so were individuals with prior or planned bariatric surgery.

At 52 weeks, KCCQ-CSS improved in both groups, but was greater with semaglutide at 16.6 points vs 8.7 points with placebo, for a difference of 7.8 points.

“The benefits on KCCQ were evident as early as the first 20 weeks and continued to improve from there,” Kosiborod reported.

Other trials of SGLT2 inhibitors in HF have reported a KCCQ-CCS score difference of 2–3 points, except for dapagliflozin in PRESERVED-HF, which showed a 5.8-point difference.

Body weight dropped by 13.3 percent in patients treated with semaglutide vs 2.6 percent with placebo. Six-minute walk distance improved by 21.5 and 1.2 metres in favour of semaglutide. Mean percent reduction in C-reactive protein (CRP) – a measure of systemic inflammation – was also greater with semaglutide (43.5 percent vs 7.3 percent), as was the reduction in N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels from baseline (20 percent vs roughly 5 percent with placebo).

Data first of a kind

Typically, the higher the BMI the lower the NT-proBNP, said Kosiborod. “We never had data about what happens to NT-proBNP in patients with HF who are obese and with elevated NT-proBNP at baseline. This is the first data of its kind to show that patients treated with semaglutide had a significantly greater reduction in NT-proBNP despite pretty massive weight loss.”

Serious adverse events were lower with semaglutide than placebo (13.3 percent vs 26.7 percent), driven primarily by the lower rate of cardiac disorders with semaglutide than placebo (2.7 percent vs 11.3 percent). However, 13. 3 percent and 5.3 percent of patients, respectively, discontinued treatment due to adverse events, predominantly related to gastrointestinal events.

Whether the weight loss is what is driving the benefit or other effects of semaglutide are at play, Kosiborod has this to say: “STEP-HFpEF is the first trial to demonstrate what happens when you target obesity in people, who we believe, have obesity-mediated HFpEF. I think it’s not just the weight loss but the weight loss-related effects that happen simultaneously.”

He added that this concept is supported by indications of a decongestive effect, plus the NT-proBNP results, and the observed signal for fewer cardiac events in semaglutide-treated patients.

Obesity a disease that should be treated

In an accompanying editorial, Dr Yigal Pinto from Amsterdam UMC, University of Amsterdam, the Netherlands said the encouraging findings for semaglutide in STEP-HFpEF potentially add a much-needed extra option and provide another upstream treatment for obese patients with HFpEF. However, he called for studies with hard cardiovascular endpoints in the future.

Kosiborod however said the current trial is designed for regulatory approval of new indications based on HFpEF symptoms and improvements in physical functioning, not hard outcomes. Most patients, he added, would already qualify for semaglutide based on obesity alone.

His parting words were obesity is no longer a cosmetic issue. “Obesity is a disease that needs to be treated, just like any chronic disease.”