Efficacy & safety of sodium-glucose cotransporter-2 inhibitors in polycystic ovary syndrome: A meta-analysis with trial sequential analysis

Background & objectives Polycystic ovary syndrome (PCOS) is a common endocrinopathy characterised by menstrual irregularities, hirsutism, acne, obesity, infertility, and other features adversely affecting the quality of life of women of childbearing age. Besides lifestyle modifications, limited pharmacological treatments have been used to manage the symptoms of PCOS. This meta-analysis was conducted to evaluate a novel pharmacological approach, sodium glucose cotransporter-2 inhibitors (SGLT2i), in PCOS. Methods Electronic databases were searched systematically for literature published before November 2024. Randomised controlled trials (RCTs) evaluating SGLT2i alone or in combination in women diagnosed with PCOS, based on the Rotterdam criteria, were included in the meta-analysis. Preclinical studies, and non-randomised trials, were excluded. Quality of studies was assessed using RoB 2.0. Meta-analysis was performed for change in anthropometry, reproductive hormone levels, glycaemic and cardiometabolic indices. Adverse events (AEs) were also compared between the SGLT2i and control groups, using RevMan 5.4.1. Mean difference using the inverse-variance method and 95% confidence interval was used as a measure of effect size of continuous variables, while odds ratio (OR)using the Mantel-Haenszel method (M-H) with 95% confidence interval was calculated to analyse dichotomous variables. P value less than 0.5 was the cut-off for significance. Trial sequential analysis (TSA) was conducted to test the conventional and required information size (RIS) boundaries. The meta-analysis was registered in PROSPERO (CRD42024608736). Results Five RCTs with 'low' risk of bias, including 205 patients with PCOS, receiving SGLT2i (empagliflozin, licogliflozin, dapagliflozin, and canagliflozin alone and in combination with metformin) or control (placebo, metformin, or exenatide) were evaluated in the meta-analysis. SGLT2i significantly reduced total testosterone (mean difference=-0.10 [-0.19, -0.01], P=0.03), free androgen index (mean difference = -0.61 [-1.16, -0.05], P=0.03), and homeostasis model assessment-estimated insulin resistance (HOMA-IR) (mean difference = -0.38 [-0.75, -0.02], P=0.04). Total cholesterol (mean difference=0.13 [0.01, 0.26], P=0.04) and low-density cholesterol (MD=0.18 [0.06, 0.31], P=0.003) increased with SGLT2i use. Genitourinary AEs were more common in the SGLT2i group (OR=10.88 [1.33, 89.14], P= 0.03). On performing TSA, the Z-curve did not cross the RIS boundary of 80 per cent power. Interpretation & conclusions The findings of this meta-analysis suggest that SGLT2i improves the hormonal and glycaemic indices in patients with PCOS. It can prove to be a safe alternative in patients not responding to or intolerant of standard pharmacological treatments.