Efficacy and safety of saroglitazar as an add-on medication to metformin and lifestyle intervention in women with polycystic ovary syndrome: a randomised controlled clinical trial.

Polycystic Ovary Syndrome or PCOS is one of the most common endocrine disorders affecting women in the reproductive age group.WHO estimates that 8 to 13 percent of women in the reproductive age group are affected worldwide with PCOS while approximately 70 percent  cases remain undiagnosed. The global incidence of PCOS was reported as 1.55 million cases in 2017 representing a 4.47 percent rise from 2007 to 2017. In India, the prevalence of PCOS was 19.6 percent by Rotterdam 2003 criteria in a national cross-sectional survey conducted from 2018 to 2022. Despite its high prevalence, PCOS is often underdiagnosed and usually takes multiple visits or physicians to get identified which is a frustrating process for the patient. Delays in diagnosis may be linked to the progression of comorbidities, making it more difficult to implement lifestyle intervention, which is critical for the improvement of features of PCOS and quality of life.

The hallmark features of PCOS include hyperandrogenism, ovulatory dysfunction manifested as menstrual irregularities and oligo-anovulation and morphological polycystic ovaries. The syndrome is often accompanied by metabolic abnormalities such as obesity, dyslipidemia and insulin resistance or IR in a significant proportion of patients. Besides being the most frequent cause of anovulatory infertility, PCOS is associated with increased long-term risk of co-morbidities such as type 2 diabetes mellitus, non-alcoholic fatty liver disease, premenopausal cancer, premature vascular aging and cardiovascular complications.

Insulin resistance has been identified as a major hallmark in the pathogenesis of PCOS, which can aggravate hyperandrogenism. Hyperinsulinemia associated with IR contributes to increased LH-induced ovarian androgen synthesis and suppressed hepatic production of sex hormone binding globulin with a consequent rise in free testosterone levels. Evolving insights into the pathogenesis of PCOS have highlighted a pivotal role of IR, approximately 35 to 80 percent frequency in PCOS as a predisposing factor for hyperandrogenism, reproductive function abnormalities and metabolic derangements, thereby underscoring the need to manage IR in patients with PCOS.

   Emerging concepts revolving around the role of IR in the pathogenesis of PCOS have driven a shift in the therapeutic approach for PCOS towards interventions targeting IR such as insulin sensitizers, metformin and thiazolidinediones and other anti-diabetics like glucagon-like peptide 1 receptor agonists, dipeptidyl peptidase-4 inhibitors and sodium glucose co-transporter-2 inhibitors.

Metformin, a biguanide anti-diabetic agent, has demonstrated effectiveness in modifying the metabolic features of PCOS such as IR, obesity and impaired glucose metabolism, regularising menstrual cycles and inducing ovulation; consequently it is commonly prescribed off-label in PCOS. However, side-effects associated with metformin mainly gastro-intestinal discomfort such as nausea, vomiting, diarrhoea and abdominal pain may limit the drug’s use in certain patients. Also, there may be inadequate response to even high doses of metformin in some PCOS patients. Hence, evaluating the effect of other anti-diabetic drugs in combination with metformin is a research area of focus in recent times.

Saroglitazar, a novel anti-diabetic drug, belongs to the “glitazars” family of anti-diabetic drugs which are dual peroxisome proliferator-activated receptor agonists. It is the first drug in this class to obtain regulatory approval in India for the treatment of diabetic dyslipidemia, hypertriglyceridemia in type 2 diabetes patients, as add-on to metformin in type 2 DM and in non-cirrhotic nonalcoholic steatohepatitis. By virtue of being a potent dual protein activator, saroglitazar possesses suitable characteristics to treat many features of metabolic dysfunction such as IR, dyslipidemia, obesity as well as cardiovascular disorders. Hence, the therapeutic potential of saroglitazar in the management of PCOS, a disorder characterised by metabolic dysfunction and long term complications of type 2 DM, NAFLD and cardiovascular risk, is an area demanding investigation.