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

Abstract

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 (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. In both treatment arms mean nadir HbA1c for participants was at 20 weeks. Thereafter, HbA1c increased similarly in both arms, with a mean difference of -0.32 percentage points (95% CI -0.33 to -0.30; -3.49 mmol/mol [-3.66 to -3.32]) 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.

Graphical abstract

Figure 1

Changes over time in glycemia and body weight, and time-to-event analysis for progression to diabetes in all participants. The change over time in HbA_1c is illustrated in A and that in body weight in B. The cumulative incidence of diabetes, defined according to HbA_1c ≥6.5% (≥48 mmol/mol), in all participants is illustrated in C and for those with HbA_1c 6.0% to <6.5% (42 to <48 mmol/mol) at baseline in D. The number of participants sampled at each time point is provided. Error bars represent the SEM.

Figure 2

Bar graphs of glucose tolerance status at baseline, and 20, 52, 104, and 156 weeks, using observed data from the in-trial period. A: All participants. B: Subgroup with baseline HbA_1c 5.7% to <6.0% (39 to <42 mmol/mol). C: Subgroup with baseline HbA_1c 6.0% to <6.5% (42 to <48 mmol/mol). Normoglycemia was defined according to HbA_1c <5.7% (<39 mmol/mol) and diabetes according to HbA_1c ≥6.5% (≥48 mmol/mol). The number of participants sampled at each time point is provided. Participants who had died or who withdrew consent are excluded from the time of that occurrence. There were seven participants with HbA_1c 6.0% to <6.5% (42 to <48 mmol/mol) who were randomized in error.