L26/O-010 Glucagon-like peptide-1 receptor agonists (GLP-1’s) for the improvement of cardiometabolic outcomes in women with polycystic ovarian syndrome (PCOS): a systematic review and network meta-analysis (NMA)

Abstract Study question Do GLP-1s, as a monotherapy or alongside metformin, improve cardiometabolic health outcomes for women with PCOS to a greater extent than metformin monotherapy? Summary answer GLP-1s (exenatide, liraglutide, semaglutide) significantly improved cardiometabolic outcomes compared to metformin monotherapy. However, the best results were seen with combined therapies (metformin+exenatide, metformin+liraglutide). What is known already Women with PCOS are at higher risk of developing metabolic syndrome and cardiovascular disease. Metformin is the recommended first line of treatment to improve insulin sensitivity with an associated weight loss of around 5%. GLP-1s produce a greater average weight losses of around 15-20% and similarly improve insulin sensitivity. GLP-1s are widely used in the treatment of Type 2 diabetes and more recently as a weight loss drug. A number of studies have now reported the use of GLP-1s in women with PCOS as monotherapy or in combination with metformin. Study design, size, duration A systematic review of RCTs was undertaken using the keywords ‘polycystic ovarian syndrome’, ‘GLP-1’, and ‘cardiometabolic outcomes’ between the years of 1946-2025. Excluded criteria included non-interventional studies, non PCOS cohorts, and non GLP-1 interventions. All eligible studies were included. Nine outcomes were reported in the review spanning anthropometric and metabolic measurements of health: BMI, waist circumference (WC), fat mass, HDL, LDL, HOMA IR, triglycerides and cholesterol. Direct and indirect evidence was used for the NMA. Participants/materials, setting, methods Participants were drawn from 14 RCTs: BMI (693 participants), WC (651), fat mass (359), HDL (506), LDL (506), HOMA IR (628), triglycerides (506) and cholesterol (506). No geographical restrictions were applied. Direct and indirect evidence was synthesised within a connected evidence network allowing estimation of relative treatment effects for all pairwise comparisons, including those not evaluated directly in head-to-head trials. Between-study heterogeneity was modelled using a random-effects framework with assessment of risk of bias. Main results and the role of chance Across 14 RCTs (n = 359-693 per outcome), GLP-1-based therapies demonstrated greater improvements across outcomes compared with metformin monotherapy. For BMI, liraglutide+metformin reduced BMI by 1.02 kg/m² vs metformin alone (95% CI -2.02 to -0.03). Semaglutide ranked best for BMI reduction (56.4% probability; SUCRA 77.7%), followed by liraglutide+metformin (19.6% probability; SUCRA 75.4%), while metformin ranked poorly (SUCRA 24.9%). For WC, liraglutide-based regimens favoured greater reductions compared with metformin, though estimates were imprecise; semaglutide ranked highest (81.9% probability; SUCRA 91.6%). For lipids, liraglutide+metformin reduced total cholesterol by 0.58 mmol/L (95% CI -0.97 to -0.20) and LDL cholesterol by 0.38 mmol/L (95% CI -0.76 to -0.00) versus metformin, ranking highest for LDL reduction (SUCRA 87.1%). Semaglutide (54.9%; SUCRA 88.8%) and liraglutide+metformin (44.1%; SUCRA 89.7%) ranked best for cholesterol reduction. For fat mass, liraglutide ranked best overall (71.3% probability; SUCRA 91.4%), followed by liraglutide+metformin (25.7% probability; SUCRA 74.9%), while metformin showed modest effects (SUCRA 46.9%). For HDL cholesterol, no GLP-1–based therapy showed a clear advantage over metformin. For HOMA-IR and triglycerides, effects favoured GLP-1–based therapies over metformin in direction, but estimates were imprecise. Overall, GLP-1–based therapies consistently ranked above metformin monotherapy for outcomes, although interpretation is limited by sparse head-to-head evidence. Limitations, reasons for caution Estimates for metformin vs placebo are informed by evidence within the GLP-1-containing-network rather than RCTs using metformin as interventional treatment within full historical metformin literature. Several outcomes relied heavily on indirect comparisons, sparse networks. Rankings should therefore be interpreted cautiously. Wider implications of the findings Metformin monotherapy is the standard treatment for PCOS with increased risk of cardiometabolic syndrome, however the improvement in outcomes is modest. GLP-1’s appear more effective than metformin monotherapy. However, some significantly greater improvements were seen with GLP-1+metformin combination therapy. Future studies should evaluate GLP-1 and GLP-1+metformin combination therapies. Trial registration number Yes