Preconception incretin therapy reduces pregnancy and cardiometabolic outcomes in polycystic ovary syndrome

BACKGROUND: Polycystic ovary syndrome (PCOS), now polyendocrine metabolic ovarian syndrome (PMOS), is associated with reproductive and cardiometabolic complications. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) receptor agonists (RAs) improve obesity-related outcomes, but their impact on pregnancy outcomes in PMOS remains unclear. METHODS: We conducted a target trial emulation using the TriNetX global federated health research network. Women ≥18 years with PCOS/PMOS receiving pre-conception GLP-1/dual GLP-1/GIP RA therapy (liraglutide, semaglutide or tirzepatide) were compared with metformin. Propensity score matching (1:1) accounted for demographics, anthropometrics, comorbidities and medications. The primary outcome was a composite of adverse pregnancy outcomes (hypertensive, glycaemic, placental, delivery, labour, foetal growth, preterm and early pregnancy complications) over two years. Individual pregnancy endpoints, major adverse cardiovascular events (MACE) and type 2 diabetes (T2D) were exploratory secondary outcomes. Cox regression generated hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: After matching, 48,126 patients were included per group. Pre-conception GLP-1/GIP RA use was associated with lower risk of the composite pregnancy outcome (HR 0.38; 95% CI 0.34-0.41). Exploratory analyses also demonstrated lower risks of individual pregnancy endpoints, MACE (HR 0.88; 95% CI 0.81-0.95) and T2D (HR 0.31; 95% CI 0.30-0.33). Associations varied across some sensitivity analyses. CONCLUSION: Pre-conception GLP-1/GIP RA use in women with PCOS/PMOS was associated with lower risks of adverse pregnancy outcomes and cardiometabolic disease compared with metformin, consistent with potential benefits of pre-conception metabolic optimisation. This study cannot evaluate in-pregnancy safety or efficacy, and these findings do not support GLP-1/GIP RA use during gestation.