AMSTERDAM — The more weight patients lost while on weekly semaglutide treatment in the STEP-HFpEF trial, the better their outcomes, suggesting that weight loss by itself was a major reason why the treatment improved a broad range of prespecified study outcomes, including symptoms and physical limitations, exercise capacity, and inflammation, new analyses from the trial show.
Dr Mikhail Kosiborod
At the 2023 Congress of the European Society of Cardiology where he presented these new findings, Mikhail N. Kosiborod, MD, also posited that weight loss produced by weekly subcutaneous injections of 2.4 mg semaglutide (Wegovy) for 52 weeks in the study does not fully explain the multiple mechanisms that may be involved in producing this intervention’s effects in the STEP-HFpEF trial.
His report earlier at the Congress and in a simultaneously published report of the trial’s primary outcomes established a role for medically induced weight loss in managing patients with obesity-phenotype HFpEF in a total of 529 randomized individuals with HFpEF and obesity but without diabetes.
The new analyses showed that for one of the two primary endpoints — the change from baseline in patients’ assessment on the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ), the placebo-adjusted average change was a 16.1-point improvement in the 51 people with a 5%–10% weight loss during the 1-year study, and a 21.6-point improvement in the 58 who had at least a 20% weight loss, a between-group average 5.5 point difference that represents a clinically meaningful incremental improvement in this validated metric of symptoms and functional limitations.
Similar weight-related differences in benefit also occurred for the secondary outcomes of changes from baseline in 6-minute walk distance and in levels of C-reactive protein (CRP), a measure of systemic inflammation.
In an adjusted regression model, every 10% drop from baseline body weight was significantly linked with a 6.4-point improvement in KCCQ score, a 14.4 meter improvement in 6-minute walk distance, and a 28% relative reduction from baseline in CRP, reported Kosiborod, a cardiologist and co-director of the Haverty Cardiometabolic Center of Excellence at Saint Luke’s Mid America Heart Institute in Kansas City, Missouri.
These new, prespecified analyses also showed that people with obesity and HFpEF responded roughly the same to semaglutide treatment compared with placebo-treated controls regardless of their starting BMI, including people with class 1 (30-34 kg/m2), class 2 (35-39 kg/m2), and class 3 (≥40 kg/m2) obesity.
Simultaneously with Kosiborod’s report at the Congress, these findings also appeared in a report posted online in Nature Medicine.
Not Every Benefit Was Fully Mediated by Weight Loss
These analyses “do not tell us how much of the benefit was mediated by weight loss, but the data do say that the more weight a person lost, the more benefit they got,” Kosiborod explained in an interview. “That is not the same as saying that everything is mediated by weight. It doesn’t say that nothing beyond weight loss matters.”
He and his associates are planning a mediation analysis of data from STEP-HFpEF that will more directly address this issue.
“It’s likely that people who lost more weight with semaglutide also had greater benefits from other effects of semaglutide at the same time. Weight loss is a good surrogate marker” for the range of effects that a person receives from treatment with semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, Kosiborod said.
“GLP-1 receptor agonists may have direct effects on atherosclerosis, as well as other effects that are uncoupled from weight loss,” such as proven anti-inflammatory effects, he added.
Another exploratory effect from semaglutide treatment in the study and reported by Kosiborod was a significant reduction in serum levels of N-terminal pro brain natriuretic peptide, an association never previously seen with weight loss in people with heart failure.
Dr John Deanfield
“The outcomes we’ve already seen in STEP-HFpEF were largely symptomatic, which are extraordinarily important, but there may be a completely different relationship between weight and clinical events,” commented John E. Deanfield, PhD, a professor of cardiology at University College Hospital, London, who was not involved in the study.
Deanfield noted that important prognostic markers such as cholesterol levels and blood pressure reductions are usually not temporally related to weight loss. “The idea that [the benefits seen in STEP-HFpEF] are purely from weight loss is something we need to be careful about,” he said.
Dr Naveed Sattar
“My gut feeling is that at least 75% of the effect [in STEP-HFpEF} was due to weight loss,” commented Naveed Sattar, PhD, professor of metabolic medicine at the University of Glasgow, who was not associated with the research.
STEP-HFpEF 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. Deanfield has been a consultant to Novo Nordisk as well as to Aegerion, Amgen, Bayer, Boehringer Ingelheim, Merck, Novartis, Pfizer, Sanofi, and Takeda, and has received research funding from Aegerion, Colgate, MSD, Pfizer, and Roche. Sattar has been a consultant to Novo Nordisk as well as to Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Lilly, Novartis, Pfizer, and Roche Diagnostics.
European Society of Cardiology Congress 2023. Presented August 27, 2023.
New Engl J Med. Published online August 25, 2023. Abstract
Nat Med. Published online August 27, 2023. Full text
Mitchel L. Zoler is a reporter with Medscape and MDedge based in the Philadelphia region. @mitchelzoler
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