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Results for Semaglutide Show Obesity Is a “Root Cause” of HFpEF; Payer Coverage Needed, Kosiborod Says


Patients who took the therapy lost weight and recorded some of the best gains in quality of life and physical improvement ever seen in this type of a study.

Giving semaglutide (Wegovy, Novo Nordisk) to patients with obesity and a type of hard-to-treat heart failure not only helped them lose weight, gain physical function, and greatly improve their quality of life, but it also demands a rethinking of the role of obesity in this condition, according to the lead investigator who studied the drug in these patients.

Patients in the STEP-HFpEF trial had heart failure with preserved ejection fraction (HFpEF), which did not even have FDA-approved treatments before 2021. Results presented Friday at the European Society of Cardiology (ESC) 2023 Congress in Amsterdam show that semaglutide, a once-weekly glucagon-like peptide-1 (GLP-1) receptor agonist, brought patients with HFpEF and overweight or obesity a net weight loss that was 10.7% greater than placebo, along with one of the largest gains ever seen on a well-known quality of life scale, the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS).

The patients in the trial who took semaglutide also made gains on a 6-minute walk test and showed improvements on important biomarker measures, relative to the placebo group, that suggest reduced inflammation. The findings were also reported in The New England Journal of Medicine.1

HFpEF occurs when the heart pumps normally but is too stiff to properly fill with blood; evidence suggests it can be brought on by other chronic conditions that damage the heart’s capacity to function.



There are no therapies specifically approved to treat obesity-related HFpEF, even though 80% of the US patients with this type of heart failure are overweight or obese, according to STEP-HFpEF principal investigator Mikhail Kosiborod, MD, of Saint Luke's Mid America Heart Institute, Kansas City. Kosiborod said the trial should “change the conversation about the role of obesity in HFpEF” and have an impact on clinical practice.

In a press conference prior to Friday's presentation, Kosiborod spoke directly to the challenges some patients have had receiving payer coverage for obesity medications—and said he hoped these results would “change the conversation.”

“I personally don't think that it's OK to say, ‘Well, we're not going to cover it because obesity is a cosmetic issue.’ Clearly, it is not. It clearly appears to be very important in the pathophysiology and progression of heart failure.”

Methods and Results of STEP HFpEF

The STEP-HFpEF results presented at ESC are from the first of 2 randomized trials involving patients with obesity and HFpEF: these results are for patients without type 2 diabetes (529 patients); a separate trial, STEP-HFpEF DM (617 patients), will show results for patients with T2D.

In the trial presented Friday, patients received a 2.4-mg dose of semaglutide given subcutaneously for 52 weeks. To enroll, patients had to be at least 18 years of age and have a left ventricular ejection fraction of at least 45%, a body mass index of at least 30 kg/m2, and New York Heart Association functional class II to IV symptoms and a KCCQ-CSS score of less than 90 points (scores range from 0 to 100, with higher scores indicating fewer symptoms and limitations). In addition, they had to have a 6-minute walk test of at least 100 m and at least of the following: elevated left ventricular filling pressure, elevated natriuretic peptide levels plus echocardiographic abnormalities, or heart failure hospitalization within the past 12 months.

The dual primary end points were the mean change in the KCCQ-CSS and weight loss. The increase was 16.6 points with semaglutide and 8.7 points with placebo (estimated difference, for the net increase of 7.8 points; 95% CI, 4.8-10.9; P < .001). The mean change in body weight was –13.3% on semaglutide and –2.8% on placebo, for an estimated difference of –10.7 percentage points (95% CI, –11.9% to –9.4%, P < .001).

In addition to the results for the primary end points, results for secondary end points were as follows:

  • Patients who took semaglutide experienced a mean change in the 6-minute walk distance of 21.5 m compared with 1.2 m with placebo, for an estimated difference of 20.3 m (95% CI, 8.6-32.1; P < .001)
  • In the analysis of the hierarchical composite end point, semaglutide produced more wins than placebo, for a win ratio of 1.72 (95% CI, 1.37-2.15; P < .001)
  • In the mean measure of C-reactive protein, the percentage change for patients taking semaglutide was –43.5% with semaglutide and –7.3% with placebo (estimated treatment ratio, 0.61; 95% CI, 0.51-0.72; P < .001).
  • Fewer participants reported serious adverse events in the semaglutide group (35 participants, 13.3%) compared with the placebo group (71 participants, 26.7%).

At the press conference, Kosiborod also highlighted an exploratory end point: the change in NT-proBNP at 52 weeks was –20.9% for semaglutide and –5.3% for placebo. He also noted that 1 patient in the semaglutide group and 12 in the placebo group experienced an adjudicated event of heart failure hospitalization or urgent visit (hazard ratio 0.08, 95% CI 0.00 to 0.42).

In an accompanying editorial to the NEJM paper, Yigal M. Pinto, MD, wrote that it remains to be seen whether these findings translate into “hard end points,” to determine whether a GLP-1 receptor agonist or an sodium glucose co-transporter 2 (SGLT2) inhibitor is the best weapon against heart failure.2 Kosiborod said from a patient point of view, that’s beside the point. Patients highly value symptom relief, he said—some surveys show more than survivorship itself. And Kosiborod, who has studied SGLT2 inhibitors extensively, noted that the 2 drug classes have separate mechanisms of action and it’s perfectly fine to use them together in certain patients.

“We Have to Take This Seriously”

In response to a question from The American Journal of Managed Care®, Kosiborod said it’s clear that this study, along with other recent results, should “change the conversation” about payer coverage for obesity medications generally and for semaglutide in in particular. (Topline results for the 17,000-patient SELECT trial show the drug met its mark in preventing major cardiovascular events.)

“It's very, very clear based on the results of this study, [that] in patients with heart failure—this type of heart failure—typical obesity is not just a coexisting condition, it's not just a comorbidity, that it appears to be the root cause of heart failure progression, both in development and progression, for many of these patients. It should be treated as such, and it should also be a target for intervention."

If patients can benefit from semaglutide, he continued, they should have access to the therapy. Referring to the improvements in quality of life and physical function, “This is the largest benefit on these types of outcomes,” Kosiborod said, “that we've seen with any pharmaceutical intervention in this patient population. So, I think we have to take this very seriously.”


1. Kosiborod MN, Abildstrom SZ, Borlaug BA, et al; STEP-HFpEF trial committee and investigators. Semaglutide in patients with heart failure with preserved ejection fraction and obesity. N Engl J Med. Published August 25, 2023. doi:10.1056/NEJMoa2306963

2. Pinto YM. Heart Failure with preserved ejection fraction — a metabolic disease? N Engl J Med. Published August 25, 2023. doi:10.1056/NEJMe2309294

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