Semaglutide improved insulin sensitivity, reduced insulin resistance, and lowered fasting glucose in adults with schizophrenia receiving second-generation antipsychotics, according to a 30-week double-blind randomized trial published in Diabetes Care. The study evaluated whether weight loss contributed to these metabolic changes in a population at high risk for antipsychotic-associated metabolic dysfunction.

The trial randomized 154 participants with overweight or obesity, schizophrenia and prediabetes to semaglutide (n=77) or placebo (n=77), with 141 participants (91.5%) completing follow-up. Complete insulin data were available for 131 cases. Baseline and end-of-study measures included fasting glucose, insulin, C-peptide, Homeostatic Model Assessment (HOMA) indices of β-cell function, insulin sensitivity, insulin resistance, and body weight.

Compared with placebo, semaglutide reduced fasting glucose by 0.87 mmol/L (95% confidence interval [CI], 0.59-1.15; P<0.001), improved insulin sensitivity by 8.60 (95% CI, 5.82-13.65; P=0.001), and reduced insulin resistance by 0.69 (95% CI, 0.20-1.00; P=0.006). Mean weight loss was 9.2 kg and significantly mediated improvements in insulin sensitivity (estimate 7.82; P=0.01) and insulin resistance (estimate -0.75; P=0.01).

Trends toward lower fasting insulin and C-peptide did not reach significance, and β-cell function remained largely unchanged. These findings suggest semaglutide may help address antipsychotic-related metabolic abnormalities primarily through weight reduction and improved insulin action.