SAT-133 Addition of Metformin Does Not Alter Metabolic Impact of Combined Oral Contraceptive Pills in Hyperandrogenic Women with Polycystic Ovary Syndrome: Findings from COMET-PCOS Trial

Abstract Disclosure: C.M. Stetter: None. W.C. Dodson: None. C. Coutifaris: None. OBJECTIVE: Combined oral contraceptive pills (COCPs) are used as first-line treatment for polycystic ovary syndrome (PCOS), which is associated with increased cardiovascular disease (CVD) risk even at a young age. Some studies suggest a detrimental effect of COCPs on metabolic parameters, but their impact in women with a hyperandrogenic phenotype who are overweight or obese remains controversial. Moreover, it is unclear if use of Metformin alone or in combination with COCPs alters this impact. This study aimed to compare the effect of COCPs, Metformin, and COCP+Metformin on metabolic parameters. MATERIALS AND METHODS: This was a double-blind, placebo-controlled randomized clinical trial performed at 2 U.S. sites. 240 women with hyperandrogenic PCOS and BMI ≥25kg/m2 were randomized to 6 months of continuous COCPs (20ug ethinyl estradiol/0.15mg desogestrel) (n=79), extended-release 2000mg/day Metformin (n=81), or a combination (COCP+Metformin) (n=80). Outcomes included changes from baseline in 2-hour oral glucose tolerance test (GTT) results, waist circumference (WC), android fat mass on DEXA scan, and lipoproteins using NMR. Linear mixed models were fit to assess differences between treatment arms with respect to changes from the start to end of the study. RESULTS: Mean age was 29.5±5.2 years, and mean BMI was 35.6±5.7kg/m2. 24% identified as Black. In the COCP and COCP+Metformin arms, mean BMI (-0.49kg/m2, 95% CI -0.88 - -0.10 for OCP; -0.47, 95% CI -0.85 - -0.09 for OCP+Metformin) and WC (-2.2cm, 95% CI -3.98 - -0.49 for OCP; -2.4, 95% CI -4.1 - -0.8 for OCP+Metformin) decreased during the study. COCPs also resulted in decreased android fat (-167g, 95% CI -264 - -71). There were no changes in BMI, WC, or android fat mass in the Metformin group. Insulin sensitivity (HOMA-IR and Matsuda’s index) or fasting and 2-hour insulin in any of the 3 arms. 2-hour glucose increased (ratio of geometric means (RGM) 1.13, 95% CI 1.05-1.22) in the COCP group, and addition of Metformin did not mitigate this (RGM 1.15, 95% CI 1.07-1.23 for COCP+Metformin). Apo A1 and total HDL particles (anti-atherogenic) increased in the COCP and COCP+Metformin groups compared to the Metformin group (p<0.01). There were no differences in changes in Apo B (atherogenic) between groups. Total LDL and small-LDL particles increased in the COCP group (p<0.01), with no improvement with addition of Metformin. Participants receiving Metformin experienced more gastrointestinal side effects than those in the COCP alone arm (p<0.001). CONCLUSIONS: In this study including a high-risk PCOS phenotype, COCPs had favorable effects on obesity measures and mixed effects on lipids and glucose tolerance. Metformin alone or in combination with COCPs did not result in significant improvements. Our findings support the use of COCPs as first-line therapy in the hyperandrogenic PCOS phenotype and suggest that Metformin is of limited benefit. Presentation: Saturday, July 12, 2025