Weight-Loss Drug Benefit Spans HFpEF, HFmrEF

CLEVELAND — Semaglutide 2.4 mg (Wegovy) improved outcomes across the range of moderately reduced and preserved ejection fraction in heart failure (HFmrEF, HFpEF) related to obesity, a prespecified secondary analysis of the STEP-HFpEF trial showed.

The benefits were consistent across subgroups, reported Javed Butler, MD, MPH, MBA, of the Baylor Scott and White Research Institute in Dallas, at the Heart Failure Society of America (HFSA) meeting and in the Journal of the American College of Cardiology.

For quality of life, semaglutide improved Kansas City Cardiomyopathy Questionnaire Clinical Summary Score by an average 5.0 points more than placebo in those with EF 45-49%, 9.8 points in the EF 50-59% patients, and 7.4 points with EF ≥60%, without a significant interaction (P=0.56).

The same was true for the other primary endpoint of body weight loss, which showed significant loss compared with placebo of 7.6 percentage points in those with EF 45-49%, 10.6 percentage points with EF 50-59%, and 11.9 percentage points with EF ≥60% (P=0.08 for interaction).

These findings, together with the overall positive results from the trial, “signify an initial paradigm-shifting step toward positioning semaglutide, and possibly other emerging incretin-based therapeutics and weight/metabolism-oriented approaches, at the center of obesity-related HFpEF management strategies,” according to the authors of an accompanying editorial.

Muthiah Vaduganathan, MD, MPH, and John W. Ostrominski, MD, both of Brigham and Women’s Hospital and Harvard Medical School in Boston, noted that obesity-related HFpEF “has emerged as among the most prevalent, debilitating, and deadly” phenotype of HFpEF.

Whereas the effects of beta-blockers, renin-angiotensin system inhibitors, angiotensin receptor-neprilysin inhibitors, and mineralocorticoid receptor antagonists drop off with higher EF, the GLP-1 receptor agonist semaglutide appears to be like SGLT2 inhibitors in consistent treatment effects across an LVEF range ≥45%, they pointed out.

That begs the question of whether the semaglutide benefit is just due to weight loss or if the drug does something more, noted HFSA late-breaking trial session discussant John McMurray, MD, PhD, of the University of Glasgow in Scotland. “Has it some other pharmacological action that is beneficial? Clearly, if that were the case, it becomes very important because it means that this treatment might do good things in non-obese patients and might do good things in patients with other types of heart failure.”

Whereas if it is just about weight loss, research is needed into diet and exercise and other pharmacological therapies like the novel oral GLP-1 receptor agonist orforglipron, dual GIP/GLP-1 receptor agonist tirzepatide (Mounjaro), and the novel triple GIP/GLP-1/glucagon receptor agonist retatrutide, he added.

McMurray agreed with Butler that one of the most interesting findings from the STEP-HFpEF secondary analysis was NT-proBNP, which decreased with semaglutide similarly across EF categories.

A diet-induced weight loss trial in a pretty similar patient population showed similar results as seen in STEP-HFpEF. While it didn’t have natriuretic peptide data, one other small randomized weight loss trial in HFpEF had shown an increase in levels as did observational data in patients undergoing bariatric surgery, McMurray noted.

“We found this result to be very meaningful in terms of our understanding of the mechanism of action” of semaglutide, Butler said, suggesting that its benefit goes beyond just weight loss.

As to whether the drug might find a place for obesity-related HF with reduced EF, the results offered “vital reassurance” regarding safety into the below-normal EF range as well, the editorialists noted. Prior data with GLP-1 receptor agonist exenatide (Byetta) had suggested potential harm in HF with reduced EF. Semaglutide, as in the main trial results, tended to be safer than placebo across the LVEF groups.

“Further, although more definitive studies are needed, the observation of treatment benefits on health status at LVEF <50% tentatively supports the existence of a more general, LVEF-independent, obesity-related HF phenotype capable of favorable modification with incretin-based therapies,” they concluded.

STEP-HFpEF included 529 HF patients with an LVEF of at least 45%, BMI of 30 or higher (median 37), and New York Heart Association functional class II, III, or IV symptoms, among other criteria. Participants were randomized to once-weekly semaglutide 2.4 mg delivered subcutaneously or placebo for 52 weeks along with lifestyle advice.

The prespecified secondary analysis included 85 patients with an LVEF of 45-49%, 215 in the 50-59% range, and 229 with LVEF ≥60%.

Limitations included the predominantly white population studied and lack of central laboratory measurement of LVEF, which could have introduced normal variability of clinical practice.