Sustained body weight loss with GLP-1RA in individuals with overweight or obesity
Once-Weekly Semaglutide in Adults with Overweight or Obesity
Introduction and methods
Obesity can lead to insulin resistance, hypertension, and dyslipidemia and is associated with type 2 diabetes, CV disease, and nonalcoholic fatty liver disease [1-3]. Lifestyle intervention, such as diet and exercise, is the standard approach for weight management, but challenging to sustain in the long run. Clinical guidelines suggest adjunctive pharmacotherapy, specifically for adults with a BMI of ≥30 kg/m² or ≥27 kg/m² in individuals with comorbidities [1,4,5]. Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), is approved as an adjunct to diet and exercise to improve glycemic control in adults with T2DM and to reduce MACE in adults with T2DM and established CVD . In a phase 2 trial, semaglutide induced weight loss in individuals with T2DM and in adults with obesity [7-9].
This phase 3 Semaglutide Treatment Effect in People with Obesity (STEP 1) study assessed the efficacy and safety of semaglutide versus placebo as an adjunct to lifestyle intervention to reduce bodyweight in individuals with overweight or obesity and without diabetes.
The STEP 1 trial was a multicenter, randomized, double-blind, placebo-controlled trial that enrolled individuals from June through November 2018. Adults (≥18 years) with one or more self-reported unsuccessful dietary efforts to lose weight and a BMI of ≥30 kg/m² or ≥27 kg/m² with at least one weight-related comorbidity were included in the study. Participants were randomized (2:1) to 2.4 mg of semaglutide (n=1306) administered subcutaneously once a week or placebo (n=655) in combination with lifestyle intervention. The coprimary endpoints were the percentage change in body weight from baseline to week 68 and the percentage of participants with bodyweight reduction of ≥5% at week 68. The supportive secondary endpoint of body composition (total fat, total lean body mass, and regional visceral fat mass) was analyzed in a subgroup of participants (n=140) that underwent dual-energy x-ray absorptiometry (DXA). Follow-up was 68 weeks.
- The estimated mean weight change at week 68 was -14.85% in patients treated with semaglutide compared to -2.41% in individuals with placebo. The estimated treatment difference between the two groups was -12.44% (95% CI: -13.37% to -11.51%, P<0.001).
- 86.4% (n=1047) participants in the semaglutide group reached a ≥5% bodyweight reduction from baseline to week 68 compared to 31.5% (n=182) of those with placebo (OR 11.2, 95% CI: 8.9 to 14.2, P<0.001).
- Of individuals receiving semaglutide, 69.1% (n=838) had a weight loss of ≥10% and 50.5% (n=612) of ≥15% compared to 12.0% (n=69) and 4.9% (n=28 in the placebo groups, respectively (OR for ≥10% weight loss: 14.7, 95% CI: 11.1 to 19.4, and OR for ≥15%: 19.3, 95% CI: 12.9 to 28.8, both P<0.001).
- Change in body weight was -15.3 kg in those receiving semaglutide and -2.6 kg in the placebo group (estimated treatment difference -12.7 kg; 95% CI: -13.7 to -11.7).
- The change in waist circumference was -13.54 cm in patients on semaglutide compared to -4.13 cm in patients using placebo. The estimated treatment difference was -9.42 cm (95% CI: -10.30 to -8.53, P<0.001).
- The SBP was more reduced in the semaglutide group compared to the placebo group ( 6.16 vs. 1.06 mm Hg, respectively). The estimated treatment difference was -5.10 mm Hg (95% CI: -6.34 to -3.87, P<0.001).
- SF-36 physical functioning score was more improved in patients using semaglutide compared to those receiving placebo (2.21 vs. 0.41, respectively). The treatment difference was 1.80 (95% CI: 1.18 to 2.42, P<0.001). The IWQOL-Lite-CT physical function score was also significantly improved in the semaglutide group compared to placebo (14.67 vs. 5.25, respectively, P<0.001) with a treatment difference of 9.43 (95% CI: 7.50 to 11.35).
- Total and abdominal visceral fat mass in individuals with semaglutide were reduced from baseline.
- The rate of gastrointestinal disorders (nausea, diarrhea, vomiting, and constipation) was higher in the semaglutide group compared to placebo (74.2% vs. 47.9%, respectively). Serious adverse events, such as serious gastrointestinal or hepatobiliary disorders, were more often reported with semaglutide than placebo (9.8% vs 6.4%, respectively). More participants discontinued their treatment in the semaglutide group due to adverse events (semaglutide 7.0% vs. placebo 3.1%). The majority of these events were gastrointestinal related.
The STEP 1 trial showed that adults with overweight or obesity without diabetes, who received semaglutide once-weekly in combination with lifestyle intervention had a significant and sustained body weight loss compared to placebo, with 86.4% of participants attaining at least 5% of weight loss after 68 weeks of treatment.