The efficacy and safety of novel antidiabetic agents in polycystic ovary syndrome: a network meta-analysis

Abstract Background Polycystic ovary syndrome (PCOS) is characterised by insulin resistance and hyperandrogenism; whether novel antidiabetic drugs differentially improve these metabolic and reproductive disturbances remains uncertain. We performed a network meta-analysis to simultaneously rank the efficacy and safety of sodium–glucose cotransporter-2 inhibitors (SGLT-2i), GLP-1 receptor agonists (GLP-1RAs) and DPP-4 inhibitors (DPP-4i) in women with PCOS. Methods We searched PubMed, Web of Science, Medline, Cochrane CENTRAL and Embase to 6 June 2025 for randomized controlled trials (RCTs) that compared SGLT-2i, GLP-1RAs or DPP-4i with placebo or active drugs in women ≥ 18 years with PCOS. Primary endpoints were Body Mass Index (BMI), homeostasis model assessment of insulin resistance (HOMA-IR), total testosterone (TT) and free androgen index (FAI); secondary endpoints included waist circumference (WC), Sex Hormone Binding Globulin (SHBG), fasting blood glucose (FBG), lipids and gastrointestinal adverse events. A frequentist random-effects network meta-analysis was conducted in Stata 15.1; treatments were ranked with SUCRA (0–100%) and certainty was appraised with CINeMA. Results 29 RCTs (1771 participants) were eligible. SGLT-2i yielded the largest reduction in BMI (mean difference vs. placebo − 4.26 kg m⁻², 95% CI − 6.01 to − 2.52; SUCRA 91%) and HOMA-IR (–2.56, − 4.53 to − 0.59; SUCRA 89%). The metformin plus GLP-1RAs combination produced the greatest decrease in TT (–1.35 ng mL⁻¹ vs. placebo, − 2.22 to − 0.48; SUCRA 85%) and FAI (–1.91, − 3.43 to − 0.40; SUCRA 82%), and also led improvements in WC, SHBG and FBG. SGLT-2i ranked first for lowering triglycerides (TG) and total cholesterol (TC). GLP-1RAs monotherapy carried the highest risk of nausea (OR 6.26–9.20), vomiting (OR up to 26.56) and abdominal pain, whereas metformin/DPP-4i markedly increased diarrhoea (OR 2 704 vs. placebo). No statistical inconsistency or publication bias was detected; certainty was high for selected contrasts but moderate to very low for most comparisons. Conclusions SGLT-2i provide the most favourable cardiometabolic profile as single agents for weight and insulin resistance in PCOS, whereas metformin combined with GLP-1RAs most effectively attenuates hyperandrogenism at the price of greater gastrointestinal intolerance. The low certainty of much of the evidence underscores the need for large, long-term RCTs to confirm these findings. Systematic review registration CRD420251045700.