Two trials of the of glucagon-like peptide-1 (GLP-1) receptor agonist semaglutide show similar improvement in heart failure (HF) symptoms and weight loss in patients with a BMI >30 who have heart failure with preserved ejection fraction (HFpEF) with or without diabetes. HFpEF is the most common phenotype of HF in the world and is increasingly common as obesity grows more common, noted Mikhail N. Kosiborod, MD, the Ben McAllister Endowed Chair in Cardiovascular Research, Saint Luke’s Health System and Professor of Medicine, University of Missouri-Kansas City.

The initial results of STEP-HFpEF (HFpEF patients without diabetes) and STEP-HFpEF-DM (HFpEF patients with diabetes), showed a combined Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) improvement of 7.5 points and body weight reduction of 8.4 percent versus placebo over 52 weeks. The STEP-HFpEF and STEP-HFpEF-DM Trials—Targeting Obesity to Treat Heart Failure on Sunday afternoon, June 23, offered the first dive into diabetes-specific results from the trials.

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STEP-HFpEF-DM evaluated the effects of semaglutide in 616 patients by three categories of baseline A1C: <6.5 percent, 6.5 percent­–< 7.5 percent, and ≥7.5 percent. Patients had a median A1C at baseline of 6.8 percent and a mean BMI of about 38. Most patients, 59.7 percent, were 65–75 years old, 44.3 percent were female, and 84.3 percent were white.

“There was no impact of baseline A1C on KCCQ benefits,” said Melanie J. Davies, CBE, MB, ChB, MD, FRCP, FRCGP, FMedSci, Professor of Diabetes Medicine, University of Leicester, Leicester, United Kingdom. “And the same observation applies to body weight advantages.”

Baseline A1C likewise had no effect on improvements in six-minute walk distance, C-reactive protein high-sensitivity (hsCRP), or N-terminal prohormone of brain natriuretic peptide (NTproBNP).

The overall reduction in A1C with semaglutide was 0.8 percent, Dr. Davies reported, with increasing reductions as baseline A1C increased.  

Patients in the semaglutide arm were less likely to initiate any diabetes medication and more likely to discontinue any diabetes medication. There were numerically fewer hypoglycemic events in the semaglutide arm.

“Semaglutide significantly reduced A1C, but its HF benefits are likely driven by mechanisms beyond glycemia, including both weight loss-related and weight loss-independent effects,” Dr. Davies said.

The mechanisms by which semaglutide benefits HF are not clear. While semaglutide has similar HFpEF benefits regardless of diabetes, the mean weight loss in STEP-HFpEF was 10.7 percent compared to 6.4 percent in STEP-HFpEF-DM, nearly 40 percent lower.

“There is something more than weight loss at work,” said Javed Butler, MD, MPH, MBA, President, Baylor Scott and White Research Institute, the Maxwell A. and Gayle H. Clampitt Endowed Chair, Baylor Scott and White Health, and Distinguished Professor of Medicine, University of Mississippi.

There were other differences as well. Patients with higher baseline NTproBNP benefited more than those with lower levels. Those with New York Heart Association (NYHA) Functional Classification III or IV HF showed greater benefit than those with NYHA Class II. Patients with atrial fibrillation had greater benefits than those without. Patients on loop diuretics showed greater benefit than those not on the agents.

Semaglutide lowered NTproBNP versus placebo regardless of weight lost during the trial. And while numbers were small, semaglutide showed longer time to first HF event and time to first HF event or CV death.

Better understanding of the mechanisms of action for semaglutide are needed, but the more important message is that the drug can treat HF patients today.

“We are in a war with HF,” said Subodh Verma, MD, PhD, FRCSC, Professor and Cardiac Surgeon, University of Toronto, Canada Research Chair in CV Surgery, and Chair of the CardioLink Trials Platform, St. Michael’s Hospital, Toronto, Canada. “It represents a recalcitrant burden and we have very few options. Between 80–90 percent of HFpEF is co-existent with obesity, an area in which we have had no previous tools.”

The STEP-HFpEF program is poised to transform clinical practice, Dr. Verma continued. The magnitude of benefit is large and includes all KCCQ domains. The trial was not designed to evaluate clinical events, but the data show major reductions in time to first HF and/or CV death.

Semaglutide benefits both male and female patients with greater benefits in women. The drug also triggers early improvement in NYHA class. Analysis of both female benefit and NYHA improvements were published simultaneously in the Journal of the American College of Cardiology.

“STEP-HF marks the beginning of a new era in the management of the obesity phenotype of HFpEF—arguably the most prevalent form of HFpEF globally—by changing the conversation about the role of obesity in the development and progression of HFpEF from a comorbidity to a root cause and treatment target,” Dr. Verma said.