Metabolic disturbances are common in individuals with schizophrenia receiving second-generation antipsychotic therapy. A 30-week double-blind randomized trial published in Diabetes Care evaluated the effects of semaglutide on insulin sensitivity, insulin resistance, β-cell function, and glucose regulation in adults with overweight or obesity and schizophrenia who had prediabetes and were receiving second-generation antipsychotics.

The trial randomized 154 participants to semaglutide (n = 77) or placebo (n = 77), and 141 individuals (91.5%) completed the study. Participants were 56% women and had a mean age of 38.3 years. Complete insulin-related metabolic data were available for 131 participants. Baseline and follow-up assessments included fasting glucose, insulin, C-peptide, body weight, β-cell function using the Homeostasis Model Assessment (HOMA2), insulin sensitivity (HOMA2), and the HOMA index for insulin resistance.

Compared with placebo, semaglutide reduced fasting glucose by −0.87 mmol/L (95% CI −1.15 to −0.59; P < 0.001). Insulin sensitivity improved by 8.60 (95% CI 5.82 to 13.65; P = 0.001). Insulin resistance declined by −0.69 (95% CI −1.00 to −0.20; P = 0.006). Participants receiving semaglutide experienced a mean weight loss of 9.2 kg. Mediation analysis showed that weight loss partly explained improvements in insulin sensitivity (estimate 7.82; P = 0.01) and insulin resistance (estimate −0.75; P = 0.01).

Reductions in fasting insulin and C-peptide and the increase in β-cell function were not statistically significant. Overall, semaglutide improved insulin sensitivity, reduced insulin resistance, lowered fasting glucose, and produced substantial weight loss, while β-cell function remained largely unchanged.