Effect of semaglutide vs placebo on HbA1c, weight, mental health and SF-36: a randomized clinical trial in people with pre-diabetes, obesity and schizophrenia

Background: Individuals with schizophrenia face a 10 to 20-year reduction in life expectancy, primarily due to cardiovascular disease (CVD) and obesity-related type 2 diabetes (T2D). These risks may be exacerbated by treatment with second-generation antipsychotics (SGAs), which may cause obesity and thereby diminish quality of life (QoL). Semaglutide, a GLP-1 receptor agonist approved for obesity has demonstrated significant efficacy in promoting weight loss, and reducing the prevalence of T2D and risks for CVD. Therefore, this trial evaluated whether once-weekly semaglutide improves HbA1c, reduces weight, and enhances mental health and QoL in prediabetic, overweight/obese SGA-treated patients with schizophrenia.<br/><br/>Methods: We conducted a double-blind, randomized, placebo-controlled trial involving 154 adults, aged 18-60 years, with BMI ≥27 kg/m2, SGA-treated schizophrenia, and prediabetes (HbA1c: 39–47 mmol/mol). Participants were randomized (1:1) to receive once-weekly semaglutide or placebo, titrated to 1. 0 mg or maximally tolerated dose, over 30 weeks.<br/><br/>Outcomes: In total, 151 participants completed randomization (semaglutide group: 74; placebo group: 77). Intention-to-treat analysis demonstrated that semaglutide reduced HbA1c by 5. 07 mmol/mol (95% CI: -6. 05 to –4. 09) and body weight by 9. 21 kg (95% CI: -11. 68 to -6. 75) compared to placebo. Furthermore, 81% in the semaglutide group vs. 19% in the placebo group obtained an HbA1c &lt;39 mmol/mol (P &lt; 0. 001). The semaglutide group improved physical QoL scores (SF-36) by 3. 6 points (95% CI: 1. 4 to 5. 8), but changed neither mental QoL scores nor psychiatric symptoms outcomes. Finally, the semaglutide group had higher incidence of gastrointestinal symptoms, but experienced no worsening in somatic or mental serious adverse events.<br/><br/>Interpretation: Semaglutide appears safe as adjunct therapy for SGA-treated patients with schizophrenia, prediabetes, and overweight/obesity. During 30 weeks, semaglutide significantly improved glycemic control, promoted weight loss, and enhanced physical QoL without adversely affecting mental health. These findings highlight its potential role in mitigating cardiometabolic risks in this high-risk population.