Impact of combined hormonal contraceptives and metformin on metabolic syndrome in women with hyperandrogenic polycystic ovary syndrome and obesity: The COMET-PCOS randomized clinical trial

Background The risk-to-benefit ratio of using combined oral contraceptive pills (COCPs) and/or metformin for comprehensive management of polycystic ovary syndrome (PCOS) in women with obesity is unclear. As there is a lack of robust evidence on the impact of these first-line medications on cardiovascular disease (CVD) risk, we compared the effect of COCPs, metformin or both on prevalence of metabolic syndrome (MetS) in participants with hyperandrogenic PCOS and hypothesized that COCPs would increase prevalence of MetS while metformin would decrease prevalence of MetS. Methods and findings We conducted a multicenter, double-blind, double-dummy, randomized trial (COMET-PCOS) in participants between ages ≥18 and ≤40 years and body mass index (BMI) ≥25 kg/m² and ≤ 48 kg/m² with hyperandrogenic PCOS (defined by the Rotterdam criteria). Participants were randomized 1:1:1 to 24 weeks of low-dose COCPs (20 μg ethinyl estradiol/0.15 mg desogestrol), metforminXR (2,000 mg), or both (Combined). The primary outcome, assessed by intention-to-treat analysis, was the effect of the different treatment groups on the prevalence of MetS at the end of study. The analytical model included site, race, and the presence or absence of MetS at the screening visit as covariates. The secondary outcomes included changes in each component of MetS (TG, HDL-C, BP, WC, and fasting glucose levels) over the study period. Of the 240 participants randomly assigned, 20 out of 79 in the COCP group, 16 out of 81 in the metformin group, and 17 out of 80 in the combined group dropped out of the study. A total of 169 participants (70.4%) completed the trial between January 2018 and June 2023 (mean age: 29.5 years; mean BMI: 35.6kg/ m²; 70% were White and 23% were Black). The overall prevalence of MetS was 31% at baseline and comparable across groups. At the end of the study, the prevalence of MetS was 26.2% (17/65) in the metformin group, 28.6% (17/59) in the Combined group, and 28.8% (17/59) in COCP group with no significant difference in trend of MetS prevalence between groups (adjusted p=0.26). Waist circumference (mean change (MC) −2.23cm; 95% CI [−3.98, −0.49]; p=0.01), BMI (MC −0.49kg/ m²; 95% CI [−0.88, −0.10[; p=0.01), and android fat mass measured by DXA (MC −167g; 95% CI [−264, −71[; p<0.001) decreased in the COCP group over the study period whilst there was no statistically significant changes in these parameters in the metformin only group when compared to baseline.. In the metformin and Combined groups, the majority of participants (>64%) reported diarrhea, while 24.1% in the COCP group reported uterine bleeding. The main methodologic limitation of the study is the potential lack of power to detect differences in secondary outcomes. Conclusions In participants with hyperandrogenic PCOS and overweight/obesity, low-dose COCPs effectively managed PCOS symptoms without increasing prevalence of MetS. Our findings challenge the current practice of using metformin alone or with COCPs for lowering cardiometabolic risk.