Impact of oral contraceptives and metformin on advanced lipid phenotyping in polycystic ovary syndrome

CONTEXT: Combined oral contraceptives (OCPs) and metformin are commonly used in patients with polycystic ovary syndrome (PCOS), who are at elevated risk of dyslipidemia and cardiovascular disease (CVD), but their effects on advanced lipid phenotyping remain unclear. OBJECTIVE: To examine the impact of OCPs and metformin on (1) lipoproteins, (2) apolipoproteins, and (3) cholesterol efflux capacity (CEC, marker of HDL function). DESIGN: Secondary analysis of the COMET-PCOS randomized clinical trial. SETTING: Two tertiary care reproductive endocrinology clinics. PATIENTS OR OTHER PARTICIPANTS: Patients with hyperandrogenic PCOS and elevated BMI with paired serum samples for lipoprotein/apolipoprotein analysis (n = 180) and cholesterol efflux capacity (n = 129). INTERVENTION(S): 24 weeks of metformin, OCP, or OCP + metformin. MAIN OUTCOME MEASURE(S): Change in HDL particles (HDL-P), low-density lipoprotein particles (LDL-P), triglyceride-rich lipoprotein particles (TRL-P); apolipoproteins A-I, B, and C-III; and CEC. RESULTS: HDL-P concentration increased in the OCP and OCP + metformin arms, while atherogenic small LDL-P increased slightly. Metformin had a largely neutral effect on advanced lipid phenotyping. Cholesterol efflux capacity increased in the OCP arm, though this was attenuated when adjusting for change in ApoA-I (adjusted ratio of geometric means 1.08, 95% CI 0.99-1.17), which increased in all arms. CONCLUSIONS: In patients with PCOS and high metabolic risk, OCP use resulted in improved HDL-C function and a mixed effect on lipoproteins and apolipoproteins, with no clear benefit from metformin. These findings do not support or refute the cardiovascular risk-benefit of OCP use in PCOS and highlight the need for studies evaluating long-term clinical outcomes.