Highlights
– Combined liraglutide plus metformin therapy produced larger improvements in glycaemic measures, insulin resistance and BMI than metformin alone in overweight/obese women with PCOS.
– The combination also yielded favorable changes in LH, FSH, total testosterone and lipid profiles.
– Treatment duration ≥16 weeks and absence of concurrent lifestyle intervention were associated with greater biochemical and hormonal improvements, but pooled estimates showed very high heterogeneity and overall low certainty of evidence.
Background: clinical context and unmet need
Polycystic ovary syndrome (PCOS) affects up to 8–13% of reproductive-age women depending on diagnostic criteria, and is commonly accompanied by overweight or obesity, insulin resistance and adverse cardiometabolic profiles. Obesity exacerbates hyperandrogenism, anovulation and metabolic risk in PCOS. Metformin has been widely used to target insulin resistance and improve ovulatory function, but its weight-loss effects are modest. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) such as liraglutide produce clinically meaningful weight reduction and improve glycaemic control in people with obesity and type 2 diabetes. Combining metformin and liraglutide could therefore offer additive or synergistic benefits for metabolic and reproductive outcomes in overweight or obese women with PCOS. The 2018 international PCOS guideline emphasizes weight management as a first-line strategy but leaves open the role of newer pharmacotherapies for specific patients with metabolic disease or failure to respond to lifestyle and first-line agents.
Study design and methods (what was done)
Ling et al. performed a systematic review and meta-analysis (Diabetes Obes Metab. 2025) of randomized controlled trials comparing liraglutide plus metformin versus metformin monotherapy in overweight or obese women with PCOS. Nineteen RCTs including 1,657 participants were identified from multiple databases (PubMed, EMBASE, Cochrane Library and major Chinese databases). Primary endpoints included glycaemic indices (fasting plasma glucose [FPG], 2-hour postprandial glucose, HbA1c), fasting insulin and HOMA-IR, body mass index (BMI), sex hormones (LH, FSH, total testosterone) and lipid profile (total cholesterol, triglycerides, LDL-C, HDL-C). The authors conducted subgroup analyses by treatment duration (≥16 weeks versus <16 weeks), concurrent lifestyle intervention (yes/no) and baseline BMI (overweight vs. obese). Standardized mean differences (SMDs) were calculated and heterogeneity quantified with I2 statistic. Risk of bias was assessed and GRADE used to rate overall evidence certainty.
Key findings and clinical interpretation
The pooled analyses found statistically significant and directionally consistent benefits of liraglutide plus metformin across multiple metabolic, hormonal and lipid outcomes compared with metformin alone. Key effect estimates (SMD, 95% CI; I2) reported were:
– Fasting plasma glucose: SMD -1.92 (95% CI -2.43 to -1.41); I2 = 95%.
– 2-hour postprandial glucose: -2.87 (-3.70 to -2.05); I2 = 97%.
– HbA1c: -2.91 (-3.84 to -1.98); I2 = 96%.
– HOMA-IR: -2.29 (-2.98 to -1.60); I2 = 97%.
– Fasting insulin: -0.75 (-1.41 to -0.09); I2 = 94%.
– BMI: -1.64 (-2.38 to -0.89); I2 = 97%.
– LH: -1.48 (-1.83 to -1.14); I2 = 85%.
– FSH: -1.17 (-1.62 to -0.73); I2 = 92%.
– Total testosterone: -0.66 (-1.30 to -0.03); I2 = 95%.
– Lipids: TC -2.34 (-3.67 to -1.01); TG -0.58 (-0.96 to -0.21); LDL-C -0.79 (-1.36 to -0.22); HDL-C increased 0.67 (0.21 to 1.13). Heterogeneity for lipid measures ranged from moderate to high (I2 79–98%).
Magnitude and clinical relevance
Effect sizes reported as SMDs are large for many outcomes, indicating consistent direction and moderate-to-large magnitude across trials. However, SMDs do not translate directly to clinical units without pooled mean differences; therefore clinicians should interpret magnitude cautiously. For weight, the reduction in BMI is consistent with an additive weight-loss effect when a GLP-1 RA is added to metformin, and aligns with prior evidence that liraglutide 3.0 mg yields clinically meaningful weight loss in people with obesity. Improvements in HOMA-IR and fasting glucose suggest enhanced insulin sensitivity, which is central to PCOS pathophysiology. Reductions in LH and total testosterone, though of smaller magnitude, are biologically plausible given weight loss and improved insulin signalling reduce ovarian androgen production.
Subgroup analyses
Results suggested that longer treatment duration (≥16 weeks) and trials without concurrent lifestyle interventions showed larger improvements in insulin resistance and reproductive hormones. Glycaemic benefits were more apparent in women classified as overweight rather than obese at baseline. Lipid improvements were consistent across subgroups. These subgroup signals may reflect differences in baseline metabolic status, treatment adherence, or dilution of effect when both arms received lifestyle counseling. Because subgroup analyses are observational and heterogeneity was high, these findings should be considered hypothesis-generating.
Safety and tolerability
The primary article did not provide pooled adverse-event rates in the summary. Classically, GLP-1 RAs have a predictable adverse-effect profile dominated by gastrointestinal symptoms (nausea, vomiting, diarrhoea), which commonly attenuate with time and dose escalation. Rare but important safety considerations include pancreatitis, gallbladder disease and theoretical medullary thyroid carcinoma risk observed in rodents. Conversely, liraglutide demonstrated cardiovascular risk reduction in the LEADER trial in people with type 2 diabetes, supporting cardiometabolic safety in higher-risk populations. In clinical practice for women of reproductive age, the teratogenic risk is not established but GLP-1 RAs are contraindicated in pregnancy and must be discontinued prior to conception; contraception counselling is essential.
Strengths and limitations of the evidence
Strengths: comprehensive database search including Chinese-language trials increased coverage; inclusion of randomized trials provides higher internal validity than observational data; consistent direction of effect across metabolic, hormonal and lipid outcomes supports biological plausibility.
Limitations: substantial statistical heterogeneity (I2 mostly >75%) across outcomes, variable trial quality and risk of bias, small sample sizes in many component RCTs, short follow-up durations in several studies, and lack of standardized outcome reporting (SMD rather than mean differences for many endpoints). These factors led the authors to rate the overall certainty of evidence as low. Importantly, critical patient-centered outcomes were underreported or absent: menstrual regularity and ovulation rates, fertility and pregnancy outcomes, long-term cardiometabolic events, and comprehensive adverse-event reporting were limited or inconsistently reported.
Mechanistic plausibility
Biologic rationale for combination therapy is clear. Metformin improves hepatic insulin sensitivity and reduces gluconeogenesis, with modest weight effects. Liraglutide reduces appetite and energy intake through central GLP-1 receptor activation and slows gastric emptying, producing substantial weight loss and attendant improvements in insulin sensitivity and lipids. Weight reduction and improved insulin signalling can lower ovarian androgen synthesis and normalize gonadotropin patterns, explaining improvements in LH, testosterone and FSH. Some experimental data also suggest direct effects of GLP-1 RAs on ovarian steroidogenesis, but clinical relevance remains to be fully defined.
Clinical implications and recommended approach
For overweight or obese women with PCOS who have persistent metabolic dysfunction or fail to achieve weight loss with lifestyle measures and metformin alone, adding a GLP-1 RA such as liraglutide may be considered to achieve greater weight loss, improved insulin sensitivity, better glycaemic indices and improved lipid and hormonal profiles. Clinicians must weigh benefits against common gastrointestinal side effects and reproductive planning: GLP-1 RAs should be stopped prior to conception and contraception discussed. Shared decision-making should address treatment goals (weight, glycaemia, ovulation, fertility) and patient preferences.
Research gaps and future directions
Key questions remain: what is the optimal dose and duration of combination therapy for reproductive outcomes (ovulation, pregnancy, live birth)? Are metabolic and hormonal improvements durable after treatment cessation? What is the long-term safety profile in reproductive-age women, especially regarding pregnancy planning and offspring outcomes? Large, multicenter RCTs with standardized endpoints (including patient-centered reproductive outcomes and robust safety reporting), longer follow-up, and economic evaluations are needed. Trials should also explore which patient subgroups derive the greatest net benefit (e.g., degree of obesity, baseline insulin resistance, fertility desire).
Conclusion
The 2025 systematic review and meta-analysis by Ling et al. synthesizes RCT data showing that liraglutide combined with metformin produces larger improvements in body weight, glycaemic control, insulin resistance, sex hormone indices and lipid profiles than metformin alone in overweight or obese women with PCOS. Despite promising and biologically plausible benefits, high heterogeneity, variable trial quality and limited safety and reproductive outcome data reduce the certainty of the evidence. Clinicians may consider combination therapy for selected patients prioritizing metabolic control and weight loss, but must counsel women regarding adverse effects and pregnancy planning. Larger, rigorous trials with standardized, patient-important outcomes are required to better define the role of GLP-1 RAs in PCOS care.
Funding and clinicaltrials.gov
The cited meta-analysis (Ling et al., 2025) did not report unified industry sponsorship in the summary provided here. Individual trials included within the meta-analysis likely varied in funding sources; readers should consult the full text and trial registries for details. Relevant registered studies of GLP-1 RAs in PCOS can be searched on clinicaltrials.gov for up-to-date trial status and protocols.
Selected references
1. Ling J, Wang T, Huang W, Zhen Y, Zhang M, Fang X, Song W, Du X. Combined liraglutide and metformin therapy in overweight or obese women with polycystic ovary syndrome: A systematic review and meta-analysis. Diabetes Obes Metab. 2025 Nov;27(11):6139-6153. doi: 10.1111/dom.70028. Epub 2025 Aug 26. PMID: 40855964; PMCID: PMC12515772.
2. Teede HJ, Misso ML, Costello MF, et al. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Hum Reprod. 2018;33(9):1602-1618.
3. Pi-Sunyer X, Astrup A, Fujioka K, et al. A randomized, controlled trial of 3.0 mg liraglutide for weight management. N Engl J Med. 2015;373(1):11-22.
4. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311-322.
Author note
This article is a synthesis and critical appraisal of the published systematic review and meta-analysis by Ling et al. (2025) and selected background literature. It aims to support clinicians and policy makers in interpreting the findings and applying them judiciously in clinical practice.
