The effect of olanzapine on diabetes related index in humans: a systematic review and meta-analysis of randomized controlled trials

BACKGROUND AND AIM: Olanzapine is a widely used second-generation antipsychotic with well-established efficacy in the treatment of schizophrenia, bipolar disorder, and related psychiatric conditions. However, its use has been consistently linked to metabolic adverse effects, particularly disturbances in glucose regulation. This systematic review and meta-analysis aimed to quantitatively evaluate the effects of olanzapine on key diabetes-related biomarkers, fasting blood sugar (FBS), fasting insulin, and glycated hemoglobin (HbA1c), in human populations, using evidence derived exclusively from randomized controlled trials (RCTs). METHODS: A comprehensive literature search was conducted in PubMed/MEDLINE, Scopus, Web of Science, and Embase from inception to July 1, 2025, without language or date restrictions. Eligible studies were RCTs involving human participants that compared olanzapine with placebo or no treatment and reported pre- and post-intervention data for FBS, fasting insulin, or HbA1c. Study quality was assessed using the Cochrane Risk of Bias 2 tool, and the certainty of evidence was evaluated using the GRADE framework. Pooled effect estimates were calculated as weighted mean differences (WMDs) with 95% confidence intervals (CIs) using random-effects models. Subgroup, sensitivity, and publication bias analyses were performed to explore heterogeneity and assess result robustness. RESULTS: Fifteen RCTs comprising 18 comparison arms were included in the meta-analysis. Olanzapine treatment was associated with a statistically significant increase in FBS (WMD: 2.618 mg/dL; 95% CI: 0.283 to 4.954) and fasting insulin levels (WMD: 3.636 µIU/mL; 95% CI: 1.964 to 5.307). In contrast, no significant change was observed in HbA1c levels (WMD: -0.029%; 95% CI: -0.284 to 0.226). Subgroup analyses suggested larger glycemic changes with higher doses (≥ 10 mg/day), longer treatment durations (≥ 12 weeks), and lower baseline body mass index, although these trends were not consistently statistically significant. Substantial heterogeneity was observed for FBS outcomes, whereas fasting insulin results were highly consistent across studies. CONCLUSION: Olanzapine use is associated with modest but significant elevations in FBS and insulin levels, indicating early disturbances in glucose homeostasis and a potential risk of insulin resistance, while effects on HbA1c remain inconclusive. Clinically, this highlights the need for routine monitoring of glucose and insulin levels, early lifestyle interventions, and consideration of pharmacologic strategies in high-risk patients to prevent progression to diabetes. These findings underscore the importance of proactive metabolic monitoring and individualized risk assessment in patients receiving olanzapine.