Semaglutide shows significant weight loss and health benefits in four-year obesity study

In a recent study published in the journal Nature Medicine, an international team of researchers evaluated the effects of semaglutide on weight and anthropometric outcomes, as well as safety and tolerability, in adults with obesity but without diabetes, across different baseline body mass index (BMI) categories.

Study: Long-term weight loss effects of semaglutide in obesity without diabetes in the SELECT trial. Image Credit: Douglas Cliff / Shutterstock

Background 

The global prevalence of obesity (BMI ≥30 kg m−2) has nearly tripled since 1975. While BMI correlates with body fat on a population level, it may not accurately reflect fat amount or distribution in individuals. Excess body fat, particularly visceral and ectopic fat, drives cardiovascular (CV) disease (CVD) and contributes to chronic diseases like diabetes and cancer. Weight loss can reduce these effects, with modest loss improving CV risk factors and quality of life. Achieving significant weight loss with lifestyle changes alone is challenging, but medications like semaglutide have shown promise. Further research is needed to understand the long-term impacts, optimal dosing, and potential side effects of semaglutide in diverse populations with varying health profiles.

About the study 

The present study complies with ethical regulations and analyzes the Semaglutide Effects on Heart Disease and Stroke in Patients with Overweight or Obesity (SELECT) trial, a randomized, double-blind, placebo-controlled study. SELECT evaluated once-weekly subcutaneous semaglutide 2.4 mg versus placebo to reduce major adverse cardiac events in individuals with established CVD and overweight or obesity without diabetes. Approved by regulatory and ethical authorities, the trial included patients aged 45 years or older with a BMI of 27 kg/m−2 or higher and established CVD. All participants provided informed consent.

Designed by Novo Nordisk and an academic Steering Committee, the trial involved random assignment to semaglutide or placebo. The starting dose was 0.24 mg weekly, increasing every four weeks to a target of 2.4 mg. Dose adjustments were allowed based on tolerability. Investigators followed guidelines for medical treatment and lifestyle counseling to manage CVD, though counseling was not focused on weight loss.

Sex and race were self-reported, and body measurements followed specific protocols. Endpoints included changes in body weight, waist circumference (WC), waist-to-height ratio (WHtR), and the proportion achieving significant weight loss.

97.1% of the semaglutide group and 96.8% of the placebo group completed the trial, with 30.6% and 27.0% discontinuing treatment, respectively. Statistical analyses, based on the intention-to-treat principle, used covariance models and multiple imputation for missing data, with analyses performed using SAS software.

Study results 

The study enrolled 17,604 patients, 72.3% male, from 41 countries between October 2018 and March 2021, with a mean age of 61.6 years and a BMI of 33.3 kg/m−2. The baseline characteristics of the population have been previously reported. Notably, a higher proportion of Asian individuals was found in the lower BMI categories, and the proportion of women increased as the BMI category increased. Lower BMI categories were associated with a higher ratio of patients with normoglycemia and lower glycated hemoglobin levels. Although the proportions of patients with high cholesterol and smoking history were similar across BMI categories, the proportion of patients with high-sensitivity C-reactive protein levels increased with higher BMI categories.

The average percentage weight-loss trajectories with semaglutide and placebo over four years showed that weight loss continued to week 65 and was sustained through week 208. At week 208, the semaglutide group had a mean weight loss of 10.2%, compared to 1.5% in the placebo group. A first on-treatment analysis indicated a mean weight loss of 11.7% in the semaglutide group compared to 1.5% in the placebo group at week 208. At week 104, weight loss of ≥5%, ≥10%, ≥15%, ≥20%, and ≥25% was achieved by 67.8%, 44.2%, 22.9%, 11.0%, and 4.9% of those treated with semaglutide, respectively, compared to 21.3%, 6.9%, 1.7%, 0.6%, and 0.1% for those receiving placebo.

The change in WC mirrored the change in body weight, with an average reduction of 7.7 cm in the semaglutide group versus 1.3 cm in the placebo group at week 208. Within the SELECT population with a baseline BMI <35 kg/m−2, 15.0% of the semaglutide group and 14.3% of the placebo group were below sex- and race-specific WC cutoff points. By week 104, 41.2% of the semaglutide group fell below these cutoff points compared to 18.0% of the placebo group. At baseline, the mean WHtR was 0.66, which decreased by 6.9% in the semaglutide group compared to 1.0% in the placebo group by week 208.

At week 104, 52.4% of patients treated with semaglutide improved in their BMI category compared to 15.7% of those receiving placebo. The proportion of obese patients (BMI ≥30 kg/m−2) fell from 71.0% to 43.3% in the semaglutide group versus 71.9% to 67.9% in the placebo group. Safety and tolerability were also assessed, with semaglutide associated with lower rates of serious adverse events (SAEs) across all BMI categories. Rates of SAEs per 100 years of observation were lower in the semaglutide group compared to the placebo group, with no significant difference in hepatobiliary or gastrointestinal SAEs between the two groups.

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