SELECT trial: Further analysis shows preventative effects of semaglutide on type 2 diabetes development

The SELECT (Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity) trial previously showed that the GLP-1 receptor agonist semaglutide was effective in reducing the risk of major adverse cardiovascular events in people with cardiovascular disease (CVD) and overweight or obesity, but without type 2 diabetes (Lincoff et al, 2023).

Further prespecified analyses of SELECT data presented at the 2024 ADA Scientific Sessions demonstrated that semaglutide also had beneficial effects on glycaemia, reducing the risk of developing type 2 diabetes and increasing the likelihood of reverting to normoglycaemia in those with prediabetes.

Among the large study population of 17 604 participants, average BMI was 33.3 kg/m², HbA_1c 5.8% (40 mmol/mol) and age 61.6 years. Overall, 66% of participants had prediabetes at baseline. Results showed that the semaglutide group had a significant reduction in HbA_1c of 0.31% (3.4 mmol/mol) at 20 weeks and, thereafter, HbA_1c gradually increased, in parallel, in both the semaglutide and placebo arms. Notably, the effect on HbA_1c was greatest in the group with the most severe dysglycaemia (HbA_1c 6.0% to <6.5%) at baseline.

At the 3-year follow-up, 306 people in the semaglutide group had progressed to type 2 diabetes, compared with 1059 in the placebo group (hazard ratio 0.27; 95% CI 0.24–0.31). This effect was independent of body weight and BMI at baseline; however, it was significantly affected by HbA_1c at baseline, with the greatest efficacy in those with prediabetes at study initiation (although the effect was still significant in those with normoglycaemia).

Semaglutide also increased the likelihood of reversion from prediabetes to normoglycaemia, with the proportion of participants with prediabetes falling from 66% at baseline to 24% at 20 weeks and 31% at 3 years. In contrast, prediabetes rates in the placebo group were more or less stable throughout. Those with lower HbA_1c at baseline were more likely to achieve normoglycaemia; nonetheless, 47% of those with the most severe dysglycaemia at baseline were still able to achieve normoglycaemia at 3 years (compared with around 7% in the placebo group).

Unsurprisingly, progression to type 2 diabetes was inversely associated with the amount of weight lost in both groups; however, mediation analysis suggested that weight loss explained only about 30% of the beneficial effects of semaglutide on glycaemia. The authors proposed that this might be due to benefits of semaglutide in terms of beta-cell preservation, in addition to the improved insulin sensitivity resulting from weight loss.

It should be noted that these results were in people with established CVD, and it remains uncertain whether they would extend to people without CVD. Furthermore, 70% of participants were male and 80% were of White ethnicity, so the results should be interpreted cautiously in other groups.

Results were simultaneously published in Diabetes Care.