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

1. Low-dose combined hormonal contraceptives managed symptoms of polycystic ovary syndrome without increasing the prevalence of metabolic syndrome among participants with hyperandrogenic PCOS (polycystic ovarian syndrome) and overweight/obesity.

Evidence Rating Level: 2 (Good)

Combined oral contraceptive pills (COCPs) have been used as first-line treatment for polycystic ovarian syndrome (PCOS) for decades. However, COCP use may increase blood pressure,  triglyceride levels, and cardiovascular disease (CVD) risk, especially for those with obesity and hyperandrogenic PCOS. Metformin is commonly prescribed to treat PCOS due to the role of insulin resistance in hyperandrogenism development. However, metformin has been found to be less effective than COCPs in managing PCOS. Combining metformin with COCP may improve outcomes. Studies examining the combined effect of these medications on CVD risk, especially metabolic syndrome (MetS), among women with hyperandrogenic PCOS are lacking. This study thus compared the impact of COCPs, metformin, and the combination of both on MetS in hyperandrogenic PCOS individuals with overweight/obesity. This multicenter, double-blind, randomized trial (COMET-PCOS) recruited participants between the ages of 18 and 40 years and body mass index (BMI) 25 and 48 kg/m2 with hyperandrogenic PCOS in Pennsylvania, USA, from January 15, 2018, to June 28, 2023. 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 was the prevalence of MetS at the end of the study, defined as the last completed standard visit ≥16 weeks or an early termination visit after 12 weeks. Of the 240 participants randomized, 169 participants (70.4%) completed the trial (mean age: 29.5 years; mean BMI: 35.6 kg/m2), of which 59 were in the COCP group, 65 in the metformin group, and 63 were in the combined group. At baseline, the prevalence of MetS was 31% and comparable across groups. At the end of the study, the prevalence of MetS was 28.8% (17/59) in the COCP group, 26.2% (17/65) in the metformin group, and 28.6% (17/59) in the Combined group. Between-group differences were non-significant. At the end of the study, the COCP group showed a decrease in waist circumference (mean change (MC) −2.23 cm; 95% CI [−3.98, −0.49]), BMI (MC −0.49 kg/m2; 95% CI [−0.88, −0.10]), and android fat mass (MC −167 g; 95% CI [−264, −71]) compared to baseline. These parameters did not change in the metformin-only group. The majority of participants (>64%) in the metformin and combined groups reported diarrhea, while 24.1% in the COCP group reported uterine bleeding. Overall, this study found that low-dose COCPs managed PCOS symptoms without increasing the prevalence of MetS among participants with hyperandrogenic PCOS and overweight/obesity. These results support the use of low-dose COCPs alone as first-line therapy for PCOS treatment in this population. Future longitudinal studies are needed to confirm this study’s findings.

Click here to read this study in PLOS One

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