Long-term semaglutide reduces diabetes risk

In a prespecified secondary analysis of the SELECT trial, long-term treatment with semaglutide allows more patients with prediabetes to regress to normoglycaemia while reducing progression to diabetes in some patients. However, semaglutide does not slow glycaemic progression over time.

By week 156, more patients taking semaglutide than placebo (69.5 percent vs 35.8 percent; p<0.0001) became normoglycaemic (HbA_1c <5.7 percent). A smaller proportion (1.5 percent vs 6.9 percent, respectively; p<0.0001) had biochemical diabetes (HbA_1c ≥6.5 percent). [Diabetes Care 2024;47:1350-1359]

Patients with lower HbA_1c at baseline were more likely to achieve normoglycaemia. Still, 47 percent of those with the most severe dysglycaemia were able to achieve normoglycaemia compared with 7 percent in the placebo group.

Semaglutide was associated with a 73-percent reduction in the risk of developing diabetes (hazard ratio [HR], 0.27). To prevent one case, 18.5 patients needed to be treated.

Both regression and progression were dependent on HbA_1c at baseline, with the magnitude of weight reduction important in mediating 24.5 percent of progression and 27.1 percent of regression.

“Overall, semaglutide improved glycaemic control in people with overweight or obesity who are at high risk of cardiovascular disease [CVD] but without diabetes,” said lead author Professor Steven Kahn from the University of Washington in Seattle, Washington, US at ADA 2024.

In the main SELECT trial published previously, semaglutide reduced the risk of major adverse cardiovascular events (MACE) by 20 percent in patients with CVD and overweight or obesity but without diabetes. Average BMI was 33.3 kg/m², HbA_1c was 5.8 percent, and age was 61.6 years. Overall, 66 percent had prediabetes at baseline. [N Engl J Med 2023;389:2221-2232]

Changes in glycaemia, body weight over time

In the prespecified secondary analysis, glycaemia was evaluated through 156 weeks. The nadir in mean HbA_1c was reached at 20 weeks, with semaglutide reducing mean HbA_1c to 5.45 percent vs 5.77 percent with placebo (p< 0.0001). Notably, HbA_1c decline was greatest in the group with the most severe dysglycaemia (HbA_1c 6 –<6.5 percent) at baseline.

After 156 weeks, semaglutide reduced mean HbA_1c to 5.51 percent vs 5.83 percent with placebo (p<0.0001). Compared with the week 20 results, there were statistically significant increases in mean HbA_1c by week 156 (0.07 percentage points and 0.06 percentage points in the semaglutide and placebo arms, respectively; p<0.0001 in each arm), with no statistically significant differences between arms (p=0.09).

Each glycaemic category had a progressive decline in glycaemic control over time.

Progression to diabetes was inversely associated with the amount of weight loss in both groups. However, mediation analysis showed that weight loss explained only about 30 percent of semaglutide benefits on glycaemia. “This might be due to semaglutide effects on beta-cell preservation, in addition to the improved insulin sensitivity with weight loss,” said Kahn.

Loss of beta-cell function

“There was a clear effect of semaglutide on lowering glycaemia, but importantly, HbA_1c increased over time at a similar rate in both semaglutide and placebo arms, indicating a clear progressive loss of beta-cell function,” commented Dr Shivani Misra from Imperial College London, UK, in an accompanying editorial. [Diabetes Care 2024;47:1322-1324]

However, Kahn said they did not measure insulin sensitivity or beta-cell function. Moreover, as 70 percent of the participants were male and 80 percent were White, he said the results should be interpreted cautiously for other groups.