Wegovy Scores HFpEF Benefits in People With Obesity

AMSTERDAM — Adults with heart failure with preserved ejection fraction (HFpEF) but without diabetes showed significant improvements in their heart failure-related symptoms and physical limitations, exercise function, and weight loss when treated with a weight-reducing dose of semaglutide for 52 weeks compared with placebo in the randomized STEP-HFpEF trial.

Dr Mikhail Kosiborod

The results, which also showed the treatment's safety in these patients, "indicate that treatment with semaglutide is a valuable therapeutic approach in the management of patients with HFpEF and obesity," Mikhail Kosiborod, MD, said at the 2023 Congress of the European Society of Cardiology.

The findings establish semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, as a second class of medication with proven efficacy and safety for people with HFpEF, joining two agents also proven beneficial for people with HFpEF, dapagliflozin (Farxiga) and empagliflozin (Jardiance), both from the class of sodium-glucose cotransporter 2 (SGLT2) inhibitors.

When administered at the approved dose for weight loss of 2.4 mg, injected subcutaneously weekly for 52 weeks, semaglutide (Wegovy) produced an average 7.8-point incremental improvement in patients' scores on the Kansas City Cardiomyopathy Questionnaire (KCCQ), a validated measure of symptoms and functional limitations, compared with controls who received placebo injections, as well as an average incremental weight loss from baseline compared with placebo of 10.7%. Both were significant effects compared with placebo and clinically meaningful benefits for the study's two primary endpoints.

Simultaneously with Kosiborod's report the results also appeared in a report posted online in The New England Journal of Medicine.

A 'Paradigm Shift' for Medical Weight Loss in Cardiology

The findings from this study with 529 randomized patients immediately propelled the weight-loss formulation of semaglutide into the ranks of agents used to treat and prevent cardiovascular disease events. This evolution in the indications for semaglutide will be driven not only by the STEP-HFpEF results but also by findings from the SELECT trial, which tested the same semaglutide weight-loss dose in people with obesity, established cardiovascular disease, and had positive top-line results for prevention of major cardiovascular adverse events, according to a release from Novo Nordisk earlier in August.

The STEP-HFpEF and SELECT results will trigger a "a paradigm shift" for cardiologists, who will now need to consider prescribing a weight-loss medication to many of their patients, agents that until now were not part of the usual pharmacologic toolbox for cardiologists, said Kosiborod, a cardiologist and codirector of the Haverty Cardiometabolic Center of Excellence at Saint Luke’s Mid America Heart Institute in Kansas City, Missouri. This shift will require education to bring the clinical cardiology community onboard, he added in an interview.

Given that semaglutide administered at this dose already has a US Food and Drug Administration-approved indication for weight loss in people with obesity or overweight plus at least one comorbidity, clinicians could immediately start using the treatment in people with obesity and HFpEF, said Kosiborod and other cardiologists.

Weekly semaglutide injections "could be considered a treatment option right now" for people with obesity and HFpEF, Kosiborod said during a press briefing.

Other experts agreed, especially because the STEP-HFpEF results confirmed that weight-loss treatment with semaglutide was safe in this population.

'A Terrific Win for Patients'

The new findings are "a terrific win and game changer for patients with HFpEF," commented Gregg C. Fonarow, MD, professor and co-chief of cardiology at the University of California, Los Angeles, who was not involved with the study.

"The magnitude of improvement in the patient-reported health status scores are large and impressive. These data support clinical use of this agent for individuals with HFpEF with a body mass index of 30 kg/m², patients who already fall within existing indications," Fonarow said in an interview.

"Given the improvements in clinical outcomes in the STEP-HFpEF and SELECT trials, cardiologists should be prescribing these medications to eligible patients without conditions," he added. "The perception of [semaglutide] needs to shift and be viewed as a component of the comprehensive medical therapies provided to individuals with established cardiovascular disease or HFpEF who also have elevated body mass index to improve their clinical outcomes."

Dr Nancy K. Sweitzer

Historically, cardiologists have had a concern that weight loss was potentially harmful in people with heart failure and that obesity was protective, a phenomenon known as the "obesity paradox," but the STEP-HFpEF data help disprove that notion, commented Nancy K. Sweitzer, MD, PhD, a heart failure specialist and vice chair of clinical research in the Department of Medicine at Washington University in St. Louis, Missouri, who also was not involved in the study.

No Signal of an Obesity Paradox

"There's been a concern in the heart failure community to use weight-loss strategies in people with heart failure because of this, but this evidence provides a lot of confidence that it's safe to use this weight-loss treatment. The results show that patients feel better and lose weight with no signal of harm," Sweitzer said in an interview.

The "encouraging findings" for semaglutide in patients with HFpEF "potentially add a much needed extra option for these patients and provide another upstream treatment for patients with signs of this condition plus a high body mass index," commented Yigal M. Pinto, MD, PhD, in an editorial that accompanied the published report. "How these findings translate to hard end points remains to be established and will be important in determining the role of GLP-1 agonism," wrote Pinto, a professor and heart failure specialist at Amsterdam University Medical Center, Amsterdam, the Netherlands.

But Kosiborod said that the improvement seen in the KCCQ score was itself an important benefit for patients. "Heart failure is defined clinically based on symptoms," he noted, and results in prior studies documented that patients value improvements in symptoms and physical limitations even more than they value "hard endpoints" such as survival.

The new findings, which indicate that two different and expensive classes of medications are now standard-of-care for many people with HFpEF and obesity — the SGLT2 inhibitors and the GLP-1 receptor agonist semaglutide — also raise concerns over patient access and affordability, as many US insurers have a history of requiring prior authorization, high copays, or coverage denials for these two medical classes.

But Sweitzer and Kosiborod both said that the insurance-coverage climate seems, in just the past couple of years or so, to have dramatically improved, although it's still not ideal.

Prior Authorization Hoops Have Decreased

"We still have prior-authorization hoops to jump through, but I expect these will continue to decrease over time as evidence for clinical benefits [from weight loss] continues to accumulate," said Sweitzer.

And "the SELECT data mean that cardiologists will need to become comfortable prescribing GLP-1 receptor agonists," she added.

"It's not okay for insurers to say we are not going to cover weight-loss medications because it's a cosmetic indication," said Kosiborod. "Obesity appears to be very important in the pathogenesis and progression of heart failure, and if patients derive substantial benefit, they should have access to this treatment."

The improvements in KCCQ score, as well as in several secondary and exploratory endpoints including a significant reduction in C-reactive protein (an indication of a potent anti-inflammatory effect), an average 20 m increase in 6-minute walk distance, a significant average drop in N-terminal pro-brain natriuretic peptide, and a drop in heart failure hospitalizations or urgent heart failure visits (although the trial was not powered to show differences in clinical events), "were the largest benefits in these outcomes we've seen" compared with any other medical intervention in people with HFpEF, he noted.

"About 80% of US patients with HFpEF have obesity or overweight," Kosiborod noted. Using semaglutide on these patients "is an issue of access and insurance coverage. My hope is that these and other data will favorably change this," he said.

A related trial with a similar design, STEP-HFpEF DM, is still in progress and testing the same semaglutide treatment in adults with HFpEF, obesity, and type 2 diabetes, noted Kosiborod, who is also lead investigator for that study. He said those results will likely become available before the end of 2023.

The study was funded by Novo Nordisk, the company that markets semaglutide (Wegovy). Kosiborod has been a consultant and advisor to and has received honoraria from Novo Nordisk. He has also been a consultant to numerous other companies, received research grants from AstraZeneca, Boehringer Ingelheim, and Pfizer, honoraria from AstraZeneca, and is a stockholder in Artera Health and Saghmos Therapeutics. Fonarow has been a consultant to Abbott, Amgen, AstraZeneca, CHF Solutions, Cytokinetics, Edwards, Janssen, Medtronic, Merck, Novartis, and Regeneron. Sweitzer reports no relevant financial relationships.

New Engl J Med. Published online August 25, 2023. Abstract.

ESC Congress 2023. Hot Line 1. Presented August 25, 2023.

Mitchel L. Zoler is a reporter with Medscape and MDedge based in the Philadelphia region. @mitchelzoler.

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