Semaglutide Has Similar Benefits in Women and Men With HFpEF

Among patients who have obesity-related heart failure with preserved ejection fraction (HFpEF), once-weekly semaglutide 2.4 mg (Wegovy; Novo Nordisk) induces greater weight loss in women than in men when compared to placebo. Patients of both sexes, however, derive similar benefits in terms HF-related symptoms and physical limitations, according to a pooled analysis of the STEP-HFpEF and STEP-HFpEF DM trials.

That supports accumulating evidence, researchers say, that at least some of the positive effects of the glucagon-like peptide-1 (GLP-1) receptor agonist in this population are independent of the number of pounds shed.

Lead investigator Subodh Verma, MD, PhD (Unity Health Toronto, University of Toronto, Canada), reported the new analysis at the recent 2024 American Diabetes Association Scientific Sessions. The findings were published simultaneously online in the Journal of the American College of Cardiology.

Sex-based analyses like this one are particularly important in HFpEF, Verma told TCTMD, because the condition is more prevalent in women; there are differences between the sexes in terms of HF pathophysiology, clinical course, prognosis, and response to certain drug therapies; and the impact of visceral adiposity in HFpEF is magnified in women.

Of note, this is the first analysis exploring potential sex differences in a clinical trial focusing on patients with obesity-related HFpEF, which is the most common phenotype in the United States. These patients tend to have a disproportionate burden of symptoms and physical limitations, and Verma said it’s imperative to find therapies that not only improve prognosis, but also improve quality of life, exercise capacity, and signs and symptoms of HF.

In that context, data from the STEP-HFpEF program provide “the first insights into a potential therapy in the obesity-related HFpEF phenotype, for which we have not previously had any dedicated studies per se,” he said. “It really sends a clear message that the benefit of semaglutide is entirely consistent across all of the various subgroups that we’ve studied, but very importantly by sex.”

The STEP-HFpEF Program

For the analysis, the investigators pooled data from STEP-HFpEF in patients without diabetes and STEP-HFpEF DM in patients with type 2 diabetes. Both trials included patients with obesity-related HFpEF, defined by an LVEF of 45% or great, a body mass index (BMI) of 30 kg/m² or higher, and a Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score below 90 points.

Of the 1,145 total patients, 49.7% were women. Compared with their male counterparts, women had a higher BMI, LVEF, and C-reactive protein level, a lower likelihood of atrial fibrillation or coronary artery disease, and worse HF symptoms and physical limitations. NT-proBNP levels were not significantly different by sex.

It really sends a clear message that the benefit of semaglutide is entirely consistent across all of the various subgroups that we’ve studied, but very importantly by sex. Subodh Verma

The dual primary endpoints of the analysis were the change in KCCQ clinical summary score and the percentage change in body weight, with some differences observed by sex. Women had a greater drop in body weight than did men (9.6% vs 7.2%; P = 0.006 for interaction), consistent with prior trials of GLP-1 receptor agonists. Even so, the mean increase in KCCQ score was similar in women and men (7.6 vs 7.5 points; P = 0.94 for interaction).

Also improving to a similar extent in women and men were other secondary endpoints, including 6-minute walk distance, levels of C-reactive protein and NT-proBNP, and a hierarchical composite endpoint that incorporated all-cause death, HF events, and changes in KCCQ score and 6-minute walk distance (P = NS for all interactions).

Rates of serious adverse events and serious cardiac disorders were lower with semaglutide versus placebo irrespective of sex.

Is Semaglutide a Heart Drug?

Harlan Krumholz, MD (Yale School of Medicine, New Haven, CT), incoming editor-in-chief of JACC, pointed out to TCTMD that there have been limited therapeutic options for patients with obesity-related HFpEF.

Because studies of GLP-1 receptor agonists in other contexts have shown differences in response by sex and because HFpEF disproportionately affects women, it was worth exploring within the STEP-HFpEF program whether semaglutide had differential effects by sex, he said, adding that there have also been questions about whether the drug’s benefits are solely related to weight loss.

Across multiple studies now, “it seems as if there’s evidence emerging that this isn’t just about the weight loss, but it actually is about mechanics of the heart and the way in which the heart functions,” Krumholz said. And this analysis, showing greater weight loss in women but similar benefits across sexes, represents “more evidence that these may be heart drugs: that they’re improving heart health maybe directly, not just in a way that’s tracking with the weight loss but in ways that seem to be independent to some extent of the weight loss.”

It seems as if there’s evidence emerging that this isn’t just about the weight loss. Harlan Krumholz

Krumholz said he was pleased to see that the benefits of semaglutide were similar in both women and men. “Increasingly, we’re not going to be thinking about these just as anti-obesity drugs. They do treat obesity, but they’re also heart health drugs and in the proper setting, they’re having powerful effects on improving cardiovascular health,” he said, citing the populations of patients with HFpEF and, based on SELECT, atherosclerotic cardiovascular disease.

Senior author Mikhail Kosiborod, MD (Saint Luke’s Mid America Heart Institute, Kansas City, MO), said it wasn’t surprising to see that women lost more weight than men considering the findings of prior trials. In addition, even though “it’s fair to say that weight loss is likely an important factor behind the heart failure benefits that we see,” there is emerging evidence from multiple studies that there’s more to it, he added. He pointed out, for instance, that there was less weight lost in semaglutide-treated patients in STEP-HFpEF DM than in STEP-HFpEF, but that the impact on HF outcomes was similar in both trials.

“We already had a number of hints that weight loss does not explain everything and there are probably weight loss-independent effects of semaglutide at play here,” Kosiborod said. “So to this question of whether it’s the weight loss or the drugs, the answer is probably both are important.”

For Verma, getting to the exact mechanism of benefit “is more of an academic exercise because at the end of the day, for the patient in the trenches who is really suffering with heart failure with preserved ejection faction in the context of obesity-related heart failure and is limited with symptoms and physician function, the mechanism of benefit is less relevant to them as long as it is leading to an improvement in clinical signs and symptoms.”

Increasing Adoption

Despite the positive results of trials of semaglutide and other GLP-1 receptor agonists indicating benefits beyond just weight loss, patients are still finding it difficult to access the drugs.

Krumholz said multiple factors are playing into that, including high cost, spotty insurance coverage, and drug shortages. But importantly, use of these drugs for a purpose other than weight loss is a paradigm shift, and it will take time for cardiologists to start thinking about obesity as a comorbidity that should be treated to promote cardiovascular health, he indicated. “Right now, we have to fight hard for our patients for them to be able to get it, afford it, and have it be accessible to them.”

So to this question of whether it’s the weight loss or the drugs, the answer is probably both are important. Mikhail Kosiborod

Kosiborod acknowledged that access to these medications is a challenge for both clinicians and patients, and he said one of the solutions for overcoming those obstacles is to continue building the evidence around their benefits for patients with obesity-related complications like HF or atherosclerotic CVD.

“Treating the root cause, treating that key driver of all these complications [obesity], is critically important, but we have to prove that by treating it you’re producing tangible benefits for the patients,” Kosiborod said, adding that he hopes mounting data will influence payers to make these types of drugs more available.

What is happening now, Kosiborod said, is a paradigm shift in how the medical community is thinking about HFpEF—ie, that it is a cardiometabolic disease. “I think this opens up an entirely new avenue of clinical research with various anti-obesity strategies in this patient population, which is super exciting,” he said. “It’s great news for the patients and the clinicians taking care of them, and I think it’s great news for the clinical trial community because I think we’ve discovered something absolutely fundamental about what the future treatment paradigm is going to look like for this very, very vulnerable patient population.”