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 ≥45 years, body mass index ≥27 kg/m2, with preexisting cardiovascular disease but without diabetes (HbA1c <6.5%) were randomized to receive subcutaneous semaglutide (2.4 mg weekly) or placebo. Major glycemic outcomes were HbA1c, and proportions achieving biochemical normoglycemia (HbA1c <5.7%) and progressing to biochemical diabetes (HbA1c >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. On both treatment arms, mean nadir HbA1c was at 20 weeks. Thereafter, it increased similarly in both arms with a mean difference of -0.32% (95% CI: -0.33% to -0.30%; -3.49 mmol/mol [-3.66; -3.32]) 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 NNT 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.