Effect of Semaglutide on Regression and Progression of Glycemia in People With Overweight or Obesity but Without Diabetes in the SELECT Trial

OBJECTIVE To determine whether semaglutide slows progression of glycemia in people with cardiovascular disease and overweight or obesity but without diabetes. RESEARCH DESIGN AND METHODS In a multicenter, double-blind trial, participants aged ≥45 years, with BMI ≥27 kg/m², and with preexisting cardiovascular disease but without diabetes (HbA_1c <6.5%) were randomized to receive subcutaneous semaglutide (2.4 mg weekly) or placebo. Major glycemic outcomes were HbA_1c and proportions achieving biochemical normoglycemia (HbA_1c <5.7%) and progressing to biochemical diabetes (HbA_1c ≥6.5%). RESULTS Of 17,604 participants, 8,803 were assigned to semaglutide and 8,801 to placebo. Mean ± SD intervention exposure was 152 ± 56 weeks and follow-up 176 ± 40 weeks. In both treatment arms mean nadir HbA_1c for participants was at 20 weeks. Thereafter, HbA_1c increased similarly in both arms, with a mean difference of 20.32 percentage points (95% CI 20.33 to 20.30; 23.49 mmol/mol [23.66 to 23.32]) and with the difference favoring semaglutide throughout the study (P < 0.0001). Body weight plateaued at 65 weeks and was 8.9% lower with semaglutide. At week 156, a greater proportion treated with semaglutide were normoglycemic (69.5% vs. 35.8%; P < 0.0001) and a smaller proportion had biochemical diabetes by week 156 (1.5% vs. 6.9%; P < 0.0001). The number needed to treat was 18.5 to prevent a case of diabetes. Both regression and progression were dependent on glycemia at baseline, with the magnitude of weight reduction important in mediating 24.5% of progression and 27.1% of regression. CONCLUSIONS In people with preexisting cardiovascular disease and overweight or obesity but without diabetes, long-term semaglutide increases regression to biochemical normoglycemia and reduces progression to biochemical diabetes but does not slow glycemic progression over time.