Effect of semaglutide 2.4 mg once weekly on 10-year type 2 diabetes risk in adults with overweight or obesity.

OBJECTIVE: In the Semaglutide Treatment Effect in People with obesity (STEP) trials, once-weekly subcutaneous semaglutide 2.4 mg plus lifestyle intervention reduced body weight and improved cardiometabolic parameters in adults with obesity (or overweight with weight-related comorbidities). Effects on the risk of developing type 2 diabetes (T2D) require investigation. METHODS: STEP 1 (68 weeks) and 5 (104 weeks) randomized participants to semaglutide 2.4 mg or placebo. STEP 4 included a 20-week semaglutide run-in followed by randomization to 48 weeks of continued semaglutide or withdrawal (placebo). Ten-year T2D risk scores were calculated post hoc using Cardiometabolic Disease Staging. RESULTS: In STEP 1 (N = 1583), relative risk score reductions were greater with semaglutide versus placebo (semaglutide: -61.1%; placebo: -12.9%; p < 0.0001). These reductions were maintained to week 104 in STEP 5 (N = 295; semaglutide: -60.0%; placebo: 3.5%; p < 0.0001). Risk scores during the STEP 4 run-in period (N = 776) were reduced from 20.6% to 11.1% and further to 7.7% at week 68 with continued semaglutide, increasing to 15.4% with withdrawal (relative risk score change: semaglutide: -32.1%; placebo: +40.6%; p < 0.0001). Risk score reductions mirrored weight loss. CONCLUSIONS: Cardiometabolic Disease Staging risk assessment suggests that once-weekly semaglutide 2.4 mg may substantially lower 10-year T2D risk in people with overweight or obesity.