Semaglutide CV Benefits Irrespective of Weight Lost?

VENICE, Italy — Four-year data from the SELECT cardiovascular outcomes trial show that the anti-obesity drug semaglutide (Wegovy) leads to clinically significant and durable weight loss as well as improvements in waist circumference and waist circumference-to-height ratio (CHECK), in patients with preexisting cardiovascular disease (CVD), overweight or obesity, and without diabetes.

Participants lost a mean of 10.2% body weight and 7.7 cm from their waist circumference after 4 years, reported Donna Ryan, MD, clinical researcher in obesity medicine from Pennington Biomedical Research Centre, New Orleans, Louisiana, who presented the findings at the 2024 European Congress on Obesity (ECO), with the study published simultaneously in Nature Medicine

Also presenting data from the SELECT was John Deanfield, MD, cardiologist from University College London, United Kingdom. He reported on a secondary analysis showing that the CV benefits of the glucagon-like peptide 1 (GLP-1) agonist semaglutide are irrespective of weight lost or adiposity in the SELECT population at study baseline. 

Other experts including Professor Sir Martin Landray, MD, chief executive officer at Protas, urged caution in overextrapolating from “non-randomized assessments.” 

An earlier analysis of the SELECT CVD outcomes (primary outcomes) with semaglutide was published in The New England Journal of Medicine in November 2023 and reported by Medscape Medical News

Ryan highlighted the importance of long-term outcomes of semaglutide. “The SELECT trial was an excellent opportunity to look at the long-term effects of semaglutide on weight, in a very diverse population and over a long time — 4 years. And this was in patients who had preexisting cardiovascular disease — 30% had had a stroke and were a bit older and a bit sicker, with a substantial number over 65 and over 75. These are different to those we would usually treat for obesity,” Ryan told Medscape Medical News in an interview.

She also noted the importance around the primary outcome of the SELECT trial that aimed to explore semaglutide’s role in the secondary prevention of major adverse CV events (MACEs).

“Here we see that an obesity medication can reduce heart attack, stroke, and heart disease death in individuals with obesity who had had a prior heart attack, stroke, or peripheral artery disease but who did not have diabetes and the reduction was meaningful — by 20%,” she emphasized.

“This is a first. No weight loss medication has ever been shown to reduce cardiovascular events. Treatment for obesity has not been taken seriously as disease modifying until this study.”

A total of 17,604 patients from 41 countries with a body mass index (BMI) ≥ 27 (mean BMI was 33) and aged 45 years or older, the majority of whom were men (72%), were randomly assigned 1:1 to semaglutide, given by subcutaneous injection once weekly at a gradually escalating dose up to 2.4 mg daily by week 16, or placebo, for an average of 40 months. The primary CV endpoint was a composite of death from CV causes, nonfatal myocardial infarction (MI), or nonfatal stroke. 

Markers of obesity including body composition and fat distribution (waist circumference and waist circumference-to-height ratio, were measured rather than just BMI alone, to help clarify the effect of semaglutide on central abdominal fat, known to cause greater CV risk than general obesity.

“These participants are different to the people we usually have in weight management trials which usually include women and are younger than in this trial,” said Ryan. “This was such an interesting population to study in terms of weight and other anthropometrics.”

Ryan explained that in the SELECT study, they did not push patients to increase doses. “It’s not like a weight loss study. Why did people in SELECT lose less weight on average compared to weight loss studies? No one was trying to lose weight and our data shows people taking more of the drug do lose more weight,” explained Ryan. 

Per protocol, results showed that mean weight loss on semaglutide was -11.7% of body weight compared with -1.5% on placebo. “Weight loss was maintained at four years which was really excellent.” In the “in trial” analysis, Ryan reported that “slightly lower weight loss, but on average loss was 9-10% across 2, 3, and 4 years. These results are clinically significant and respectable.”

Over 40% No Longer Had Obesity at 2 Years

Turning to subgroups, Ryan reported that everyone was found to lose weight but that some lost more than others. Women lost more than men did (estimated treatment difference): -11.1% (95% CI, -11.56 to -10.66) vs -7.5% (95% CI, -7.78 to -7.23) with P < .0001. “We think this is due to greater exposure to drug levels. There was also an effect across age, but it was not clinically significant. Everyone was getting some effect of weight loss.”

She added that individuals with a higher BMI at baseline lost more weight than the lowest BMI, which was 27-30. “We’d expect this to be the case because people with the lower BMI get greater exposure to the drug.”

At baseline, participants were categorized according to whether they had normal weight, overweight, obesity class I, obesity class II, or obesity class III. The breakdown was similar in the semaglutide and placebo groups. “At 2 years, 12% of individuals who were randomized to semaglutide were now at normal BMI, and 44.6% no longer had obesity. Results were superior to placebo.”

Overall, adverse events were fewer in those patients treated with semaglutide compared with placebo, and this was primarily driven by reduction in cardiovascular events, reported Ryan. “Individuals across all baseline levels of BMI had the same response.”

Semaglutide CV Benefit According to Baseline Weight and Weight Lost

Deanfield reported on the relationship between weight measures at baseline as well as weight change after early treatment (to week 20) and CV outcomes. “We wanted to know whether the particular groups of patients would benefit more from semaglutide,” Deanfield said. 

“For all the groups based on baseline BMI, body weight, waist circumference and so on, there was absolutely no relationship between baseline adiposity and the [CV] benefits patients received,” he said, adding that benefit was the similar across the lower BMIs and the higher.

Looking specifically at weight change after 20 weeks (when full dose is reached) and time to first MACE event, Deanfield found that in semaglutide patients, there was no difference according to whether patients lost 5% or more body weight or under 5% body weight/gained weight (hazard ratio, 0.67; 95% CI, 0.52-0.87 vs hazard ratio, 0.85; 95% CI, 0.72-1.00). 

“This suggests alternative mechanisms of improved CV outcomes with semaglutide beyond reduction in adiposity,” remarked Deanfield. “Many patients with overweight and obesity and not just those who lose weight, may receive CV benefit from semaglutide.”

Alternative mechanisms might include positive impacts on blood sugar, blood pressure, or inflammation, as well as direct effects on the heart muscle and blood vessels, or a combination of one or more of these, according to Deanfield. 

“These drugs were developed for type 2 diabetes and glycemic control, then obesity and translating through this pathway, we see the real excitement is in change to the outcome of important diseases, and here specifically we are looking at cardiometabolic diseases, but other diseases might benefit too, including kidney disease and neurological diseases,” said Deanfield. 

Naveed Sattar, PhD, professor of metabolic medicine at the University of Glasgow, Scotland, commented on the results, reflecting on CV benefits and weight loss, and pointing out that they, “suggest the direct effect of semaglutide on the heart and blood vessels may be most responsible for its benefits on MACE but they cannot discount an additive benefit, even if small, of the weight loss on benefits seen.”

“That said, the weight benefit remains important irrespective of any MACE impact as weight loss is likely the key factor responsible for other benefits including on heart failure outcomes and, importantly, on measures of quality of life in this trial,” he added. “From a wider perspective, drugs that have direct effects on disease processes but also give weight loss are likely to be key in the future to help stem or reverse the worrying rates of multimorbidity now being seen in countries like the UK.”

Landray added that “The results are important since they suggest that, if the drug were affordable and widely available, then it could be used to reduce the risk of cardiovascular events among a very broad range of people who already have cardiovascular disease in order to prevent future cardiovascular events, much like we do with statins and treatments for blood pressure.”

However, Landray pointed out that this is a “subsidiary analysis of a large randomized trial” and that he is reasonably convinced of the treatment effects for people with different levels of BMI at baseline, but cautioned: “I am much less convinced about the appropriateness of the analyses based on the level of weight loss achieved.”

Ryan declares having received consulting honoraria from Altimmune, Amgen, Biohaven, Boehringer Ingelheim, Calibrate, Carmot Therapeutics, CinRx, Eli Lilly, Epitomee, Gila Therapeutics, IFA Celtics, Novo Nordisk, Pfizer, Rhythm, Scientific Intake, Wondr Health, and Zealand Pharma; she declares she received stock options from Calibrate, Epitomee, Scientific Intake, and Xeno Bioscience. Deanfield declares having received consulting honoraria from Amgen, Boehringer Ingelheim, Merck, Pfizer, Aegerion, Novartis, Sanofi, Takeda, Novo Nordisk, and Bayer and research grants from British Heart Foundation, MRC (UK), NIHR, PHE, MSD, Pfizer, Aegerion, Colgate and Roche. 

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