Objective: To evaluate the efficacy of insulin sensitizers on menstrual frequency, sex hormone and metabolic parameters in overweight women with PCOS. Methods: We searched multiple databases from inception to September 2019 for RCTs. Network meta-analysis was conducted using multivariate random effects method. Results: 14 trials reporting on 619 women were included. Compared with metformin, metformin + TZDs was more superior in menstrual recovery (WMD 3.68, 95% CrI 1.65 to 8.20), metformin + GLP-1 receptor agonists was more effective in decreasing AND (WMD -2.53, 95% CrI -3.96 to -1.09), both metformin + GLP-1 receptor agonists (WMD 9.22, 95% CrI 5.46 to 12.98) and metformin + TZDs (WMD 4.30, 95% CrI 0.78 to 7.82) were more effective in increasing SHBG, while TZDs was less effective in decreasing BMI (WMD 1.69, 95% CrI 0.72 to 2.66). Compared with GLP-1 receptor agonists, metformin + GLP-1 receptor agonists was associated with higher SHBG (WMD 7.80, 95% CrI 4.75 to 10.85), lower FT (WMD -1.77, 95% CrI -3.25 to -0.29), lower AND (WMD -2.70, 95% CrI -3.91 to -1.50) and lower FG (WMD -0.41, 95% CrI -0.73 to -0.08). Conclusion: For overweight women with PCOS, both metformin combined with GLP-1 receptor agonists and metformin combined with TZDs appear superior to monotherapy in improving hyperandrogenemia. Metformin combined with TZDs could be particularly effective in promoting the recovery of menstruation. Metformin combined with GLP-1 receptor agonists has additional advantage in improving fasting glucose when compared with GLP-1 receptor agonists alone. TZDs is inferior to metformin in decreasing BMI.

FIGURE S1. Funnel plot for the improvement of menstrual frequency (a) FIGURE S2. Funnel plot for the improvement of menstrual frequency (b) FIGURE S3. Funnel plot for the improvement of TT (total testosterone) FIGURE S4. Funnel plot for the improvement of FT (free testosterone) FIGURE S5. Funnel plot for the improvement of SHBG (sex hormone binding globulin) FIGURE S6. Funnel plot for the improvement of AND (androstenedione) FIGURE S7. Funnel plot for the improvement of FG (fasting glucose) FIGURE S8. Funnel plot for the improvement of FINS (fasting insulin) FIGURE S9. Funnel plot for the improvement of BMI (body mass index) FIGURE S10. Funnel plot for the improvement of WC (waist circumference) FIGURE S11. Forest plot for the improvement of menstrual frequency (a) FIGURE S12. Forest plot for the improvement of menstrual frequency (b) FIGURE S13. Forest plot for the improvement of TT (total testosterone) FIGURE S14. Forest plot for the improvement of FT (free testosterone) FIGURE S15. Forest plot for the improvement of SHBG (sex hormone binding globulin) FIGURE S16. Forest plot for the improvement of AND (androstenedione) FIGURE S17. Forest plot for the improvement of FG (fasting glucose) FIGURE S18. Forest plot for the improvement of FINS (fasting insulin) FIGURE S19. Forest plot for the improvement of BMI (body mass index) FIGURE S20. Forest plot for the improvement of WC (waist circumference)