Novel interventional therapies to improve cardiovascular risk in women with polycystic ovary syndrome

Introduction: Polycystic ovary syndrome (PCOS) is associated with a diverse range of endocrine, metabolic and cardiovascular risk factors. Low vitamin D in PCOS is associated with multiple cardiovascular risk factors and vitamin D replacement therapy has been suggested as a promising alternative for the prevention and treatment of PCOS. Empagliflozin; a sodium-glucose cotransporter 2 (SGLT2) inhibitor, has been shown to have several favourable effects on inflammatory and cardiovascular risk factors in both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) patients and could potentially be a treatment option in women with PCOS. Methods: The first study was a randomized, double-blind, placebo-controlled trial with an objective to determine the effect of vitamin D supplementation on liver fibrosis markers. Forty overweight and obese women with PCOS were randomization to either vitamin D 3200 IU daily or placebo for 3 months. The second trial was a randomised open-label parallel study to look at the effects of empagliflozin versus metformin on hormonal, metabolic and cardiovascular risk factors in women with PCOS. Forty overweight and obese women with PCOS were randomization to either empagliflozin 25mg or metformin 1500mg daily for 3 months. Results: For vitamin D treatment, there were significant reductions in individual liver fibrosis markers [hyaluronic acid (HA), N-terminal pro-peptide type-III pro-collagen (PIIINP), tissue inhibitor of metalloproteinase-1 (TIMP-1)] and their cumulative enhanced liver fibrosis (ELF) score was associated with a significant improvement in alanine aminotransferase (ALT) levels in patients randomized to vitamin D, whereas there were no changes in any of these parameters in the placebo group. There were no changes in free androgen index (FAI), insulin resistance (Homeostasis model assessment-insulin resistance; HOMA-IR), other anthropometric, inflammatory and body composition parameters in either group. There were no significant changes in endothelial microparticles (EMPs) in the vitamin D group as compared to the placebo group. In the second study, there were significant reductions in anthropometric and body composition parameters in patients randomized to empagliflozin while patients on metformin had significant increases in these parameters as compared to baseline. Between groups comparisons at the end of the study showed that the percentage reductions in anthropometric and body composition parameters were statistically significant in the empagliflozin group as compared to the metformin group. There was significant reduction in total testosterone levels in the metformin group only but not in the empagliflozin group. There were no significant changes in FAI, HOMA-IR, reactive hyperaemic index (RHI), fasting lipids and other hormonal and metabolic markers in both the groups. However, there were significant increases in cluster of differentiation 54 (CD54) and cluster of differentiation 62 (CD62) microparticles in the empagliflozin group and cluster of differentiation (CD106) microparticles in both the empagliflozin and metformin groups. Conclusions: Direct beneficial effects of vitamin D supplementation on markers of hepatic fibrosis were seen in overweight and obese women with PCOS shown by a reduction in the ELF score and its constituent liver fibrosis markers (HA, PIIINP, TIMP-1). However, vitamin D supplementation did not improve endothelial function as suggested by no significant changes in EMPs in the vitamin D group as compared to the placebo group. In the second trial, empagliflozin improved anthropometric and body composition indices after three months of treatment. However, there was significant increase in CD54 and CD62 microparticles after empagliflozin and CD106 microparticles after both empagliflozin and metformin treatments suggesting that the effects of empagliflozin and metformin could be partly mediated through modulation of endothelial function. This research work suggests both vitamin D and SGLT2 inhibition (empagliflozin) as potential treatment options in women with PCOS for improving future cardiovascular risk.