Risk of diabetes mellitus with olanzapine compared to clozapine: A systematic review and meta-analysis.

Aim: Olanzapine and clozapine are second-generation antipsychotics commonly associated with metabolic side effects. In Japan, olanzapine is designated as "principally contraindicated" for patients with diabetes, while clozapine is "used with caution," despite similar pharmacological profiles. This study compares the risk of new-onset diabetes mellitus between olanzapine and clozapine using adjusted effect estimates from observational studies. Methods: We conducted a systematic review and meta-analysis of observational studies published between 2000 and 2025 that reported diabetes-related outcomes in patients treated with olanzapine or clozapine. Adjusted odds ratios (aORs) and hazard ratios (HRs) were synthesized using a random-effects model. In the absence of direct comparative data, the Bucher method was employed for indirect comparisons using a shared comparator. Results: Sixteen studies were included. Meta-analysis of seven HR-based studies revealed a significantly lower risk of new-onset diabetes in the olanzapine group compared to clozapine (pooled HR = 0.73, 95% confidence interval [CI]: 0.63-0.85). On the other hand, the odds ratio (OR)-based analysis (nine studies) showed no significant difference (pooled OR = 0.85, 95% CI: 0.66-1.09). Sensitivity analysis with only aORs and subgroup analysis by follow-up duration revealed no significant differences. Conclusion: This study provides preliminary evidence that olanzapine is associated with a lower or at least comparable risk of new-onset diabetes relative to clozapine. Considering that olanzapine is more tightly regulated than clozapine in clinical practice in Japan, these findings indicate the need for further confirmatory studies and accumulation of robust evidence to inform potential regulatory reclassification.