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Semaglutide Supports Long-Term Weight Loss, Reduces CV Risk Across BMI Subgroups


Analyses of the SELECT trial found mean weight loss of 10.2% sustained for 4 years and comparable CV benefit with weight loss greater or less than 5%, or even weight gain.

In 2 new analyses of data from the pivotal phase 3 SELECT cardiovascular outcomes trial, the glucagon-like peptide-1 (GLP-1) mimetic semaglutide, demonstrated sustained clinically significant long term weight loss and improvements in anthropometric measures as well as cardiovascular benefits regardless of initial baseline body mass index (BMI) or the amount of weight lost in adults with overweight or obesity, preexisting cardiovascular disease, and without diabetes.1,2

The findings from both analyses were presented at the European Congress on Obesity, May 12-15, in Venice, Italy.

The SELECT trial

The SELECT trial (October 2018 through June 2023) included 17 604 participants aged 45 years or older with preexisting CV disease and a BMI of 27 or more but with no history of type 2 diabetes.3 The geographically and ethnically/racially diverse population was drawn from 41 countries. SELECT participants were not enrolled in the study for the purpose of weight loss.

The cohort was randomly assigned to receive either subcutaneous semaglutide 2.4 mg or placebo. Mean follow up was approximately 40 months and the primary endpoint was a composite of major adverse CV events. Semaglutide was associated with a 20% relative reduction in risk of major adverse CV events (HR, 0.80; 95% CI, 0.72 to 0.90; P <. 001). Participants lost an average of 9.4% of bodyweight from baseline.3

Long-term weight loss with semaglutide

In the first prespecified analysis, simultaneously published in Nature Medicine, lead author Donna Ryan, MD, associate executive director for clinical research with the Pennington Biomedical Research Centre, New Orleans, Louisiana, and colleagues examined the effects of semaglutide on weight and on body mass index (BMI), waist circumference (WC), and waist-to-height ratio (WHtR) as surrogate markers for amount and location of body fat and evaluated semaglutide safety and tolerability, all by baseline BMI.1

The weight loss trajectory for participants in the semaglutide group over 4 years showed decline continued to week 65 and was sustained through week 208 at which point the semaglutide group had lost 10.2% of baseline bodyweight vs 1.5% in the placebo group.1

The average reduction of WC at week 208 among semaglutide-treated participants was 7.7 cm and 1.3 cm in the placebo group.1

By week 104, 41.2% of the semaglutide cohort reached WC below sex- and race-specific WC cutoff points vs 18% of the placebo group. Ryan and colleagues reported too that average WHtR was reduced by 6.9% in those receiving semaglutide vs 1% receiving placebo.1

Further, after 104 weeks, BMI category was improved for more than half (52.4%) of the semaglutide group compared to 15.7% of those receiving placebo. Moreover, the proportion of participants with obesity (BMI ≥30 kg/m2) at baseline fell from 71.0% to 43.3% in the semaglutide group versus 71.9% to 67.9% in the placebo group.1

Adverse event rates were lower across all BMI categories vs placebo.

“This degree of weight loss in such a large and diverse population suggests that it may be possible to impact the public health burden of multiple obesity-related illnesses,” Ryan said.

CV benefit independent of weight loss

The second prespecified analysis, led by Prof John Deanfield, director of the National Institute for Cardiovascular Outcomes Research, studied the relationship between time to first serious CV event and baseline weight, weight lost, WC, and WHtR after early treatment. At 20 weeks, when participants had reached full dose semaglutide, Deanfield and team reported comparable rates of serious CV events among semaglutide participants with weight loss of 5% or more, 5% or less, or even weight gain (HR, 0.67; 95% CI, 0.52-0.87 vs HR, 0.85; 95% CI, 0.72-1.00). Rates were also comparable, across baseline anthropometric subgroups, according to the study.2

"In this CV outcomes trial of semaglutide in patients with overweight or obesity but without diabetes, a reduction in MACE [major adverse cardiovascular events] was achieved regardless of the level of baseline adiposity. The magnitude of this treatment effect with semaglutide was also independent of the extent of achieved weight loss," Deanfield et al wrote. "This suggests alternative mechanisms of improved cardiovascular outcome beyond reduction in adiposity, which may benefit many patients on top of current guideline-directed care," the researchers concluded.2

1. Ryan, DH, Lingvay I, Deanfield J, et al. Long-term weight loss effects of semaglutide in obesity without diabetes in the SELECT trial. Nat Med (2024). DOI - 10.1038/s41591-024-02996-7,  https://www.nature.com/articles/s41591-024-02996-7
2. Deanfield J, Lingvay I, Kahn SK. Relevance of body weight and weight change on cardiovascular benefit with semaglutide: a prespecified analysis of the SELECT trial. Abstract presented at: European Congress on Obesity; May 12-15, 2024; Venice, Italy. GC4.351. Accessed May 14, 2024. https://karger.com/ofa/article-pdf/17/Suppl.%201/7/4225727/000538577.pdf
3. Lincoff AM, Brwon-Frandsen K, Colhoun HM, et al for the SELECT Trial Investigators. Semaglutide and cardiovascular outcomes in obesity without diabetes. N Engl J Med. 2023;389(24):2221-2232. doi:10.1056/NEJMoa230756

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