Impact of once-weekly subcutaneous semaglutide 2.4 mg on metabolic syndrome in the 2-year, randomised controlled STEP 5 trial

Metabolic syndrome (MetS) is associated with an increased risk of cardiovascular disease and type 2 diabetes. Obesity is a key driver of MetS. In the STEP 5 trial, treatment with once-weekly subcutaneous semaglutide 2.4 mg resulted in 15.2% weight loss after 104 weeks vs 2.6% with placebo. This post hoc analysis of STEP 5 investigated the effect of 2 years of treatment with semaglutide on MetS. 304 adults with overweight/obesity (body mass index [BMI] ≥30 kg/m2, or ≥27 kg/m2 with ≥1 weight-related comorbidity), without diabetes, were randomised 1:1 to semaglutide 2.4 mg or placebo (both plus diet and physical activity) for 104 weeks. We assessed MetS prevalence at baseline and weeks 52 and 104, and weight loss from baseline to week 104 (<10%/≥10%). MetS was defined as the presence of ≥3 National Cholesterol Education Program Adult Treatment Panel III criteria. Results are based on observed data from the in-trial period. P values were from a chi-square test of proportions. Analyses were not adjusted for multiplicity. There were 89 participants with MetS at baseline in the semaglutide group and 79 in the placebo group. The proportions of participants with remission of MetS at weeks 52 and 104 were significantly greater with semaglutide vs placebo (p<0.01; Figure A). Similarly, the proportions of participants without MetS at baseline who developed it by weeks 52 and 104 were significantly lower with semaglutide vs placebo (p<0.01; Figure B). When considering the degree of weight loss (<10%/≥10%) in both the semaglutide and placebo groups, semaglutide led to a higher rate of MetS remission in participants with <10% weight loss than placebo at both 52 weeks (57.9% vs 25.0%) and 104 weeks (39.5% vs 15.3%). Weight loss of ≥10% led to higher MetS remission rates, which were similar in semaglutide- and placebo-treated participants (63.0% vs 66.7%, respectively, at 52 weeks; 71.1% vs 83.3% at 104 weeks). A greater proportion of participants treated with once-weekly subcutaneous semaglutide 2.4 mg achieved remission of MetS, and fewer developed incident MetS, compared with placebo. These benefits were maintained over 2 years of semaglutide treatment. These results suggest that the positive effects of semaglutide on MetS could potentially impact the progression to type 2 diabetes and cardiovascular disease while individuals are taking the drug. However, these data should be interpreted with caution due to the small participant numbers involved.