CLEVELAND – independently of baseline left-ventricular ejection fraction (LVEF).
The finding comes from a prespecified secondary analysis of the STEP-HFpEF trial of more than 500 nondiabetic patients with obesity and HF with an initial LVEF of 45% or greater.
They suggest that for patients with the obesity phenotype of HFpEF, semaglutide (Wegovy) could potentially join SGLT2 inhibitors on the short list of meds with consistent treatment effects whether LVEF is mildly reduced, preserved, or in the normal range.
That would distinguish the drug, a glucagon-like peptide-1 (GLP-1) receptor agonist, from mineralocorticoid receptor antagonists (MRA), sacubitril-valsartan (Entresto), and other renin-angiotensin-system inhibitors (RASi), whose benefits tend to taper off with rising LVEF.
The patients assigned to semaglutide showed significant improvement in both primary endpoints – change in Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) and change in body weight at 52 weeks – whether their baseline LVEF was 45%-49%, 50%-59%, or 60% or greater.
Results were similar for improvements in 6-minute walk distance (6MWD) and levels of NT-terminal pro–brain natriuretic peptide (NT-proBNP) and C-reactive protein, observed Javed Butler, MD, when presenting the analysis at the annual meeting of the Heart Failure Society of America, Cleveland.
Dr. Butler, of Baylor Scott and White Research Institute, Dallas, and the University of Mississippi, Jackson, is also lead author of the study, which was published on the same day in the Journal of the American College of Cardiology.
In his presentation, Dr. Butler singled out the NT-proBNP finding as “very meaningful” with respect to understanding potential mechanisms of the drug effects observed in the trial.
For example, people with obesity tend to have lower than average natriuretic peptide levels that “actually go up a bit” when they lose weight, he observed. But in the trial, “we saw a reduction in NT-proBNP in spite of the weight loss,” regardless of LVEF category.
John McMurray, MD, University of Glasgow, the invited discussant for Dr. Butler’s presentation, agreed that it raises the question whether weight loss was the sole semaglutide effect responsible for the improvement in heart failure status and biomarkers. The accompanying NT-proBNP reductions – when the opposite might otherwise have been expected – may point to a possible mechanism of action that is “something more than just weight loss,” he said. “If that were the case, it becomes very important, because it means that this treatment might do good things in non-obese patients or might do good things in patients with other types of heart failure.”
‘Vital reassurance’
More definitive trials are needed “to clarify safety and efficacy of obesity-targeted therapeutics in HF across the ejection fraction spectrum,” according to an accompanying editorial).
Still, the STEP-HFpEF analysis “strengthens the role of GLP-1 [receptor agonists] to ameliorate health status” for patients with obesity and HF with mildly reduced or preserved ejection fraction, write Muthiah Vaduganathan, MD, MPH, and John W. Ostrominski, MD, Brigham and Women’s Hospital and Harvard Medical School, both in Boston.
Its findings “provide vital reassurance” on semaglutide safety and efficacy in HF with below-normal LVEF and “tentatively support the existence of a more general, LVEF-independent, obesity-related HF phenotype capable of favorable modification with incretin-based therapies.”
The lack of heterogeneity in treatment effects across LVEF subgroups “is not surprising,” but “the findings reinforce that the benefits of this therapy in those meeting trial criteria do not vary by left ventricular ejection fraction,” Gregg C. Fonarow, MD, University of California, Los Angeles, Medical Center, said in an interview.
It remains unknown, however, “whether the improvement in health status, functional status, and reduced inflammation” will translate to reduced risk of cardiovascular death or HF hospitalization, said Dr. Fonarow, who isn’t connected to STEP-HFpEF.
It’s a question for future studies, he agreed, whether semaglutide would confer similar benefits for patients with obesity and HF with LVEF less than 45% or in non-obese HF patients.
Dr. McMurray proposed that future GLP-1 receptor agonist heart-failure trials should include non-obese patients to determine whether the effects seen in STEP-HFpEF were due to something more than weight loss. Trials in patients with obesity and HF with reduced LVEF would also be important.
“If it turns out just to be about weight loss, then we need to think about the alternatives,” including diet, exercise, and bariatric surgery but also, potentially, weight-loss drugs other than semaglutide, he said.