STEP-HFpEF DM Trial Hints at Semaglutide HF Effects Beyond Pounds Shed

The results are suggestive of disease-modifying benefits of semaglutide independent of weight loss, says Mikhail Kosiborod.

STEP-HFpEF DM Trial Hints at Semaglutide HF Effects Beyond Pounds Shed

ATLANTA, GA—In a finding that sheds some light on just how semaglutide helps the heart, patients with obesity-related heart failure with preserved ejection fraction (HFpEF) and type 2 diabetes see significant improvement in symptoms and physical limitations after a year of therapy on semaglutide, despite losing less weight than patients who don’t have diabetes, the STEP-HFpEF DM trial shows.

The findings, presented here at the American College of Cardiology 2024 Scientific Session, will inevitably fuel speculation that the glucagon-like peptide-1 (GLP-1) inhibitor may have cardiovascular effects beyond weight loss.

“What we saw I think is quite fascinating,” lead investigator Mikhail Kosiborod, MD (Saint Luke’s Mid America Heart Institute, Kansas City, MO), told TCTMD. “The magnitude of benefit was very similar to what we saw in the first STEP-HFpEF trial in people without diabetes.”

The STEP-HFpEF study lent support to the idea that more was at play than weight loss, with positive shifts seen in C-reactive protein (CRP) and NT-proBNP with once-weekly semaglutide (Wegovy; Novo Nordisk). Those results were not entirely unexpected in light of the SELECT trial data showing a 20% reduction in the risk of major adverse cardiovascular events when added to standard care in adults with overweight or obesity who were not diabetic.

Knowing that patients with diabetes typically lose about 40% less weight on GLP-1 receptor agonists than nondiabetic patients, Kosiborod said the STEP-HFpEF DM trial was necessary because “if you believe that there could be differential treatment effects based on the degree of weight loss, you don't want to combine these patients in the same trial.”

In the study, which was also simultaneously published in the New England Journal of Medicine, patients on semaglutide had greater mean change from baseline in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS) as well as greater mean change in body weight compared with patients on placebo. They also saw greater gains in 6-minute walk distance.

“This is a really important message for the field. Of course, weight loss is important. That is one of the factors behind what we are observing,” Kosiborod noted. “But this trial clearly suggests that weight loss is not everything here [and] that there are most likely weight-loss-independent benefits of semaglutide that are disease modifying.”


For the study, 616 HFpEF patients (median age 69 years; 44% women) were randomized to once-weekly semaglutide starting at the lowest dose (0.25 mg for 4 weeks), escalating to the maintenance dose (2.4 mg) by week 16, or placebo. Median body mass index (BMI) was 36.9, with 64% of participants having a BMI of 35 or higher, and median duration of diabetes was 8 years. In addition to diuretics, renin-angiotensin system blockers, and beta-blockers, approximately one-third of patients were also on mineralocorticoid receptor antagonists and sodium-glucose cotransporter 2 inhibitors.

Approximately 15% of patients in each group prematurely discontinued the study treatment. By the end of the study period, 80% who had been assigned to semaglutide were still on the weekly maintenance dose.

This trial clearly suggests that weight loss is not everything here. Mikhail Kosiborod

At 52 weeks, the mean change in KCCQ-CSS was 13.7 points in the semaglutide groups and 6.4 points in the placebo group. Percentage bodyweight change was 9.8% and 3.4%, respectively (P < 0.001 for both comparisons).

The 6-minute walk test results showed a gain of 12.7 m in the semaglutide group and a loss of 1.6 m in the placebo group (P = 0.008).

An analysis of the hierarchical composite endpoint showed a greater stratified win ratio for semaglutide than placebo (1.58; 95% CI 1.29-1.94). The findings held for most key components of the hierarchical composite endpoint, driven by a 15-point difference in the KCCQ-CSS.

CRP levels were 42% lower in semaglutide patients at 52 weeks compared with baseline, while the placebo group saw a 12.8% reduction (P < 0.001). For NT-proBNP, the semaglutide group started with a median level of 477.8 pg/mL and saw a 23.2% change, compared with just a 4.6% change from baseline for the placebo group.

Hospitalizations or urgent HF-related visits occurred in 18 patients in the placebo group versus seven patients in the semaglutide group (HR 0.40; 95% CI 0.15-0.92).

Serious adverse events and adverse events of special interest, which included hypoglycemia and diabetic retinopathy, occurred in 17.7% of semaglutide users versus 28.8% of those who received placebo (P = 0.002). Treatment discontinuation due to any serious adverse event occurred at rates of 10.6% with semaglutide and 8.2% with placebo. Fully 6.5% of discontinuations in the GLP-1 group were do to gastrointestinal adverse events—a common complaint with these agents.

Strongly Suggestive Data

The benefits of semaglutide on KCCQ-CSS are “larger than we've seen with any previous intervention ever studied in HFpEF,” Kosiborod told TCTMD.

In the paper, the investigators hypothesize than the weight-loss-independent benefits of semaglutide in HFpEF “may include direct effects on decongestion; vascular, skeletal muscle, and mitochondrial function; epicardial adipose tissue; inflammation; and insulin resistance, factors that (unlike weight loss) may be more pronounced in patients with type 2 diabetes than in those without type 2 diabetes.”

Kosiborod said while the data are probably not sufficient to be absolutely definitive, particularly given the small numbers, “the fact that you see the same signal in two independent trials in different patient populations is very strongly suggestive that it's not an accident that you see fewer events in the semaglutide group than the placebo group.”

As for what this means for patients like those in the studies, that remains to be seen, but he added that the data suggest that semaglutide treatment should be studied for longer in this patient population to see if the signal of improvement continues with treatment duration.

“Older people in particular with HFpEF are the ones that typically have the most debilitating symptoms, and they're also the ones that value improvement of those symptoms [and in] quality of life over quantity of life,” Kosiborod said. “It’s not like we have lots of treatments for this type of heart failure. We have very few that have been proven effective. What we hope data like this actually will do is compel payers to reconsider their stance on covering obesity medications.”

Additional data are forthcoming from a pooled analysis of STEP-HFpEF and STEP-HFpEF DM, and will be presented here tomorrow. That analysis is expected to give further insight into the benefits and tolerance of semaglutide across subgroups.

  • Kosiborod MN, Petrie MC, Borlaug BA, et al. Semaglutide in patients with obesity-related heart failure and type 2 diabetes. N Engl J Med. 2024;Epub ahead of print.

  • The trial was sponsored by Novo Nordisk.
  • Kosiborod reports consultancy/advisory board participation for 35Pharma, Alnylam, Amgen, Applied Therapeutics, Arrowhead Pharmaceuticals, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Dexcom, Eli Lilly, Esperion Therapeutics, Imbria Pharmaceuticals, Janssen, Lexicon Pharmaceuticals, Merck, Novo Nordisk, Pharmacosmos, Pfizer, Regeneron, Sanofi, scPharmaceuticals, Structure Therapeutics, Vifor Pharma, and Youngene Therapeutics; research grants from AstraZeneca, Boehringer Ingelheim, and Pfizer; and honoraria from Astra Zeneca, Boehringer Ingelheim, and Novo Nordisk.