Efficacy of Liraglutide on Metabolic and Reproductive Outcomes in Women with Polycystic Ovary Syndrome: A Systematic Review and Meta-analysis

Efficacy of Liraglutide on Metabolic and Reproductive Outcomes in Women with Polycystic Ovary Syndrome: A Systematic Review and Meta-analysis | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 6 June 2025 V1 Latest version Share on Efficacy of Liraglutide on Metabolic and Reproductive Outcomes in Women with Polycystic Ovary Syndrome: A Systematic Review and Meta-analysis Authors : Yu-Ting Lu , Po-Han Chang , Hsuan-Ju Chen , Ya-Wen Hsueh , Chia-Wei Chang , Hsi-Chen Hsu , Tung-Chuan Yang , Wu-Chou Lin , and Hsun-Ming Chang 0000-0001-9742-6670 [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.174919687.75586804/v1 Published Diabetes, Obesity and Metabolism Version of record Peer review timeline 483 views 239 downloads Contents Abstract Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Background Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder associated with reproductive and metabolic dysfunction, particularly in overweight or obese women. Objective To evaluate the efficacy and safety of Liraglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA), on metabolic and reproductive outcomes in overweight or obese women with PCOS. Search Strategy Five electronic databases and one trial registry were systematically searched from inception to May 2025. Selection Criteria Randomised controlled trials comparing Liraglutide (alone or in combination) with placebo, metformin, or other active treatments in overweight or obese women with PCOS. Data Collection and Analysis Two reviewers independently performed study selection, data extraction, and risk of bias assessment. Data were pooled using a random-effects model. Effect sizes were reported as Hedges’ g or odds ratios with 95% confidence intervals (CIs). PRISMA guidelines were followed. Main Results Seven RCTs involving 330 women were included. Liraglutide significantly improved menstrual frequency (g = 1.76, 95% CI 0.28-3.24), reduced BMI (g = -0.52, 95% CI -0.94 to -0.10), and decreased insulin resistance (HOMA-IR; g = -0.52, 95% CI -0.83 to -0.22). A non-significant reduction in free androgen index was observed. Trends toward improved ovulation and pregnancy rates were noted but not pooled due to heterogeneity. Secondary analyses showed favourable changes in hormonal and metabolic parameters. Gastrointestinal side effects were the most common adverse events, typically mild. Conclusions Liraglutide improves metabolic outcomes and menstrual regularity in overweight or obese women with PCOS. Reproductive benefits are promising but require confirmation in larger, long-term studies. Efficacy of Liraglutide on Metabolic and Reproductive Outcomes in Women with Polycystic Ovary Syndrome: A Systematic Review and Meta-analysis Yu-Ting Lu, Po-Han Chang, Hsuan-Ju Chen, Ya-Wen Hsueh, Chia-Wei Chang, Hsi-Chen Hsu, Tung-Chuan Yang, Wu-Chou Lin, Hsun-Ming Chang* Department of Obstetrics and Gynecology, China Medical University Hospital, Taichung, 404327, Taiwan. *Corresponding author: Hsun-Ming Chang, M.D., Ph.D. Reproductive Medicine Center, Department of Obstetrics and Gynecology, China Medical University Hospital, Taichung, Taiwan. No. 2, Yude Rd., North Dist., Taichung City 404332, Taiwan. Tel: 886-4-22052121 Ext 3760. E-mail: [email protected] Abstract Background Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder associated with reproductive and metabolic dysfunction, particularly in overweight or obese women. Objective To evaluate the efficacy and safety of Liraglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA), on metabolic and reproductive outcomes in overweight or obese women with PCOS. Search Strategy Five electronic databases and one trial registry were systematically searched from inception to May 2025. Selection Criteria Randomised controlled trials comparing Liraglutide (alone or in combination) with placebo, metformin, or other active treatments in overweight or obese women with PCOS. Data Collection and Analysis Two reviewers independently performed study selection, data extraction, and risk of bias assessment. Data were pooled using a random-effects model. Effect sizes were reported as Hedges’ g or odds ratios with 95% confidence intervals (CIs). PRISMA guidelines were followed. Main Results Seven RCTs involving 330 women were included. Liraglutide significantly improved menstrual frequency (g = 1.76, 95% CI 0.28-3.24), reduced BMI (g = -0.52, 95% CI -0.94 to -0.10), and decreased insulin resistance (HOMA-IR; g = -0.52, 95% CI -0.83 to -0.22). A non-significant reduction in free androgen index was observed. Trends toward improved ovulation and pregnancy rates were noted but not pooled due to heterogeneity. Secondary analyses showed favourable changes in hormonal and metabolic parameters. Gastrointestinal side effects were the most common adverse events, typically mild. Conclusions Liraglutide improves metabolic outcomes and menstrual regularity in overweight or obese women with PCOS. Reproductive benefits are promising but require confirmation in larger, long-term studies. Keywords: Polycystic ovary syndrome, Liraglutide, GLP-1 receptor agonist, Insulin resistance, BMI, Menstrual cycle, Meta-analysis Introduction Polycystic ovary syndrome (PCOS) is a prevalent and heterogeneous endocrine disorder, affecting approximately 11-13% of women of reproductive age worldwide, with prevalence varying depending on the diagnostic criteria used, namely, the Rotterdam (2003), NIH (1990), or Androgen Excess and PCOS Society (AE-PCOS) guidelines [1, 2]. PCOS is primarily characterized by hyperandrogenism, chronic anovulation, and polycystic ovarian morphology, and is frequently associated with metabolic disturbances such as central obesity, insulin resistance, dyslipidemia, and an increased risk of type 2 diabetes mellitus (T2DM) and cardiovascular disease [2, 3]. These metabolic impairments contribute not only to long-term morbidity but also exacerbate reproductive dysfunctions, including menstrual irregularities, anovulation, subfertility, and adverse pregnancy outcomes [2, 3]. Given its multifactorial nature, the management of PCOS requires an individualized, multidisciplinary approach that considers both reproductive and metabolic aspects of the condition [2, 3]. Lifestyle interventions, primarily diet and exercise, are universally recommended as the first-line intervention, especially for overweight and obese patients. While weight loss has been shown to improve insulin sensitivity, hormonal profiles, and ovulatory function, the success of lifestyle interventions alone is often modest and inconsistent in practice [2, 3]. As a result, pharmacological therapies are frequently employed to target specific pathophysiological mechanisms and to optimize clinical outcomes. Metformin, a biguanide insulin-sensitizing agent, has long been used off-label in PCOS to improve insulin resistance and promote menstrual regularity. Although metformin can modestly reduce body weight and restore ovulatory cycles in some women, its effects on fertility outcomes and androgen levels remain limited, and it is often poorly tolerated due to gastrointestinal side effects [4]. In recent years, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have emerged as promising therapeutic agents in metabolic medicine. These agents exert multifaceted metabolic benefits through glucose-dependent insulin secretion, delayed gastric emptying, appetite suppression, and consequent weight loss. Among them, Liraglutide, a long-acting GLP-1 RA approved for the treatment of T2DM and obesity, has shown potential for broader application in PCOS [5, 6]. Accumulating evidence from randomized controlled trials (RCTs) indicates that Liraglutide can significantly improve metabolic parameters in women with PCOS, including reductions in body mass index (BMI), insulin resistance (as measured by HOMA-IR), and serum lipid levels. More recently, its impact on reproductive outcomes has garnered attention. Several studies suggest that Liraglutide may enhance menstrual regularity, stimulate follicular development, and increase the likelihood of spontaneous or assisted conception [7-9]. These benefits are thought to be mediated by improved insulin sensitivity, reductions in hyperandrogenemia, and modulation of hypothalamic-pituitary-ovarian (HPO) axis function. Additionally, Liraglutide may exert favorable effects on sex hormone-binding globulin (SHBG) levels and the free androgen index (FAI), further contributing to hormonal balance [7-9]. Despite these promising findings, the clinical utility of Liraglutide in PCOS remains incompletely defined. Existing trials are limited by small sample sizes, short intervention periods, variable dosing regimens, and heterogeneity in both participant characteristics and outcome measures. Moreover, while metabolic outcomes are often well-reported, data on reproductive endpoints, such as ovulation rates, conception rates, and pregnancy outcomes, are relatively scarce and inconsistent across studies. To address these knowledge gaps, the present study aimed to conduct a comprehensive systematic review and meta-analysis of randomized controlled trials evaluating the efficacy and safety of Liraglutide in women with PCOS. Specifically, we sought to assess its effects on key metabolic outcomes (e.g., body weight, BMI, insulin resistance), reproductive parameters (e.g., menstrual frequency, ovulation, and pregnancy rates), and adverse effects. By synthesizing current evidence, this analysis aims to support clinical decision-making and inform future research on the integration of GLP-1 RAs, particularly Liraglutide, into therapeutic strategies for PCOS. Methods Eligibility criteria This systematic review and meta-analysis were conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. The inclusion criteria were as follows: (1) study design using RCTs, including both double-blind and open-label designs.; (2) population: participants diagnosed with PCOS based on recognized diagnostic criteria (e.g., Rotterdam, NIH, AE-PCOS), aged 18–45 years, and classified as overweight or obese (body mass index [BMI] ≥25 kg/m²); (3) intervention: administration of Liraglutide, either as monotherapy or in combination with other agents; (4) comparators: placebo, Metformin, or other active comparators; (5) outcomes: studies were required to report at least one relevant outcome related to metabolic parameters (e.g., BMI, body weight, insulin resistance, lipid profile) and/or reproductive function (e.g., menstrual regularity, ovulation rate, androgen levels, pregnancy rate); (6) data availability: studies were included if they reported both pre- and post-intervention data or between-group differences sufficient for effect size calculation. Open-label trials were considered eligible, given that prior research suggests open-label designs may still yield reliable and clinically relevant outcomes, particularly for objective metabolic measures. Studies were excluded based on the following criteria: (1) non-randomized studies, including retrospective cohort studies, case-control studies, cross-sectional studies, and observational designs without randomization; (2) animal or preclinical models: Studies conducted on animals or in vitro models without human participants were excluded; (3) duplicate publications: duplicate data or multiple publications reporting the same patient population or trial results (the most complete or recent version was retained); (4) incomplete publications: conference abstracts, posters, editorials, or other forms of grey literature without full peer-reviewed articles available; (5) unavailable full text: studies for which the full text could not be retrieved after attempts to contact the authors or institutions; (6) irrelevant interventions or outcomes: trials that did not specifically evaluate Liraglutide as an intervention or did not report outcomes related to metabolic or reproductive parameters in PCOS. All exclusions were documented, and reasons for exclusion were recorded during the full-text screening phase. Participants and interventions The population of interest consisted of overweight or obese women of reproductive age diagnosed with PCOS. The intervention examined was Liraglutide, a GLP-1 receptor agonist, administered subcutaneously at doses ranging from 0.6 mg to 3.0 mg daily (Table 1). Comparator interventions included placebo, Metformin, placebo, or other active treatments such as lifestyle modifications or combination therapies (e.g., Metformin + Liraglutide). Study selection Two independent reviewers screened the titles and abstracts of retrieved articles. Full texts were assessed for eligibility using predefined criteria. Disagreements were resolved by consensus or through consultation with a third reviewer. Outcomes of interest Primary outcomes included changes in menstrual cycle frequency, body mass index (BMI), homeostatic model assessment of insulin resistance (HOMA-IR), free androgen index (FAI), and reproductive parameters. Secondary outcomes comprised body weight, waist circumference, abdominal girth, waist-to-hip ratio, sex hormone-binding globulin, serum total testosterone, androstenedione, dehydroepiandrosterone sulphate, luteinizing hormone, follicle-stimulating hormone, lipid profile, 2-hour postprandial blood glucose, fasting insulin, 2-hour insulin, and adverse events or treatment tolerability. A comprehensive literature search was performed across PubMed, Embase, Cochrane CENTRAL, Web of Science, and ClinicalTrials.gov from database inception to April 30, 2025. The search strategy included the following terms: (”Liraglutide” OR ”Glucagon-Like Peptide 1” OR Liraglutide) AND (”Pregnancy Rate” OR ”Pregnancy Outcome” OR pregnancy) AND (”Polycystic Ovary Syndrome” OR PCOS OR ”infertility”). This study is registered with the International Prospective Register of Systematic Reviews (PROSPERO, registration number: CRD420251054113). Data extraction and management Data was independently extracted by two reviewers using a standardized data extraction form. The following information was recorded: (1) study characteristics (author, year, country, design, sample size); (2) participant characteristics (age, BMI, diagnostic criteria) (3) intervention details (Liraglutide dose, duration, comparator); (4) primary and secondary outcomes (5) adverse events, where necessary, corresponding authors were contacted to obtain missing data. Risk of bias assessment The methodological quality of the included RCT studies was evaluated using the Cochrane Risk of Bias tool for randomized trials (RoB 2). This tool assesses potential bias across five key domains: (1) the randomization process, (2) deviations from intended interventions (intervention adherence), (3) missing outcome data, (4) measurement of outcomes, and (5) selection of the reported results. An overall risk of bias judgment was then derived for each study based on these domains. Given the structure and reporting of the included trials, a per-protocol approach was applied to assess adherence to the intended intervention, as it more accurately reflected the analytic strategies employed in the studies. Statistical analysis All statistical analyses were conducted using Comprehensive Meta-Analysis software, version 3 (Biostat, Englewood, NJ). Due to the expected clinical and methodological heterogeneity across studies, including differences in treatment duration, dosing regimens, and outcome measures, a random-effects model was applied to generate pooled estimates. Descriptive statistics were presented as means ± standard deviations (SD) for continuous variables and percentages for categorical variables, as appropriate. For continuous outcomes, effect sizes were calculated using Hedges’ g, accompanied by 95% confidence intervals (CIs). Effect size magnitude was interpreted using standard benchmarks: 0.2 (small), 0.5 (moderate), and 0.8 (large). For dichotomous outcomes (e.g., adverse events, pregnancy rates), odds ratios (ORs) with corresponding 95% CIs were computed. Statistical heterogeneity was assessed using Cochran’s Q test (with p < 0.10 indicating significance) and the I² statistics, with thresholds of 25% (low), 50% (moderate), and 75% (high) heterogeneity. A two-tailed p-value < 0.05 was considered statistically significant for all meta-analytic comparisons. Due to the limited number of studies available for most outcomes, funnel plots and Egger’s regression test were not performed, as these methods are not reliable when fewer than 10 studies are included. Results Literature search results and study screening A total of 209 articles were initially retrieved through comprehensive database searches. Following the removal of duplicates, the remaining articles were screened based on titles and abstracts according to predefined inclusion and exclusion criteria. Full-text reviews were subsequently performed to assess eligibility in detail. For studies with incomplete or unclear outcome data, attempts were made to contact the corresponding authors for clarification. Studies were excluded if the necessary data could not be obtained. Ultimately, seven RCTs met all eligibility criteria and were included in the final meta-analysis (Figure 1). These seven studies collectively enrolled 330 women of reproductive age diagnosed with PCOS. Among these, 187 participants received Liraglutide, either as monotherapy or in combination with other therapeutic agents. The remaining 143 participants in the control groups received Metformin, placebo, or other active comparators that did not include Liraglutide. A detailed summary of the characteristics of the included studies is provided in Table 2. Assessment of the risk of study bias The risk of bias for each of the seven included RCTs was systematically evaluated using the RoB 2 tool. Of the seven studies, six explicitly reported the use of random sequence generation for group allocation, indicating a low risk of bias in this domain. However, one study did not clearly describe the randomization method, resulting in an unclear risk of bias for sequence generation. Allocation concealment was adequately described in only two studies, while the remaining five did not provide sufficient information to determine whether this methodological safeguard was implemented, leading to potential concerns in this domain. Blinding of participants and personnel was reported in two studies, whereas the remaining five studies were conducted using open-label designs. Although open-label trials are not uncommon in this field, the lack of blinding may introduce performance and detection bias, particularly for subjective outcomes. All included studies were judged to have a low risk of bias in the domains of intervention adherence, missing outcome data, and selective reporting, reflecting good data integrity and completeness. Based on the cumulative domain-level assessments, two studies were classified as having an overall low risk of bias, while five studies were rated as having some concerns, primarily due to issues related to allocation concealment and blinding. A summary of the risk of bias assessments for each study is presented in Figure 2. Primary outcomes Menstrual cycle regulation Five studies reported data on menstrual cycle frequency. Patients treated with Liraglutide demonstrated a significantly higher frequency of menstrual cycles compared to those receiving comparator therapies (Metformin, placebo, or other non-Liraglutide regimens). The pooled effect size was Hedges’ g = 1.76 (95% CI: 0.28 to 3.24; P = 0.02), indicating a large effect. However, statistical heterogeneity was high (I² = 96.21%), suggesting considerable variability among the studies (Figure 3A). Body mass index (BMI) Six studies assessed changes in BMI. Liraglutide treatment was associated with a significantly greater reduction in BMI compared to comparator groups, with a pooled effect size of Hedges’ g = -0.52 (95% CI: -0.94 to -0.10; P = 0.015). Moderate heterogeneity was observed (I² = 62.78%) (Figure 3B). Insulin resistance (HOMA-IR) Six studies evaluated changes in insulin resistance as measured by HOMA-IR. Patients treated with Liraglutide experienced a significantly greater reduction in HOMA-IR than those in the comparator groups, with a pooled effect size of a Hedges’ g = -0.52 (95% CI: -0.83 to -0.22; P = 0.001). Heterogeneity was low to moderate (I² = 29.99%), supporting the consistency of this finding (Figure 3C). Free androgen index (FAI) Four studies assessed changes in the free androgen index (FAI). Liraglutide treatment was associated with a greater reduction in FAI compared to controls; however, the effect did not reach statistical significance (Hedges’ g = -1.01, 95% CI: -2.05 to 0.02; P = 0.055). Substantial heterogeneity was observed (I² = 91.42%), indicating notable variability across studies (Figure 3D). Reproductive outcomes Reproductive outcomes were reported in two studies; however, due to heterogeneity in outcome definitions and measures, data could not be pooled for meta-analysis. In one study, the pregnancy rate at one year was 69.2% (9/13) in the Liraglutide group compared to 35.7% (5/14) in the Metformin group. Furthermore, the pregnancy rate per embryo transfer (PR per ET) was significantly higher in the Liraglutide group (85.7%) compared to the Metformin group (28.6%, P = 0.03). No significant differences were found between groups regarding ovarian stimulation parameters, including total gonadotropin dose, oocyte yield, fertilization rates, number of embryos, or blastocyst formation. In another study comparing Liraglutide plus Metformin to cyproterone acetate/ethinyl estradiol (CPA/EE) plus Metformin, the proportion of participants developing dominant follicles increased significantly from 0% at baseline to 20% after treatment in the Liraglutide group (P = 0.031), suggesting a potential benefit in ovulatory function. Secondary outcomes The meta-analysis further demonstrated that Liraglutide was significantly more effective than comparator therapies (Metformin, placebo, or other agents) in improving several secondary metabolic and hormonal parameters. at reducing body weight, LH, FSH, 2hPBG, FINS, LDL. In addition, Liraglutide was more effective than comparator therapies at increasing SHBG. There was no difference in WC, WHR, TT, AD, DHEA-S, TC, TG, HDL, and 2hrINS between Liraglutide and comparator therapies (Table 3). Body weight Liraglutide treatment led to a significantly greater reduction in overall body weight compared to controls. Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels LH and FSH were both significantly reduced following Liraglutide administration. Two-hour postprandial blood glucose (2hPBG) and fasting insulin (FINS) levels 2hPBG and FINS were also significantly lower in the Liraglutide group, indicating improved glycemic control and insulin sensitivity. Low-density lipoprotein cholesterol (LDL-C) LDL-C levels decreased significantly with Liraglutide treatment. Sex hormone-binding globulin (SHBG) SHBG levels increased significantly in the Liraglutide group, suggesting improved androgen regulation and metabolic status. However, no significant differences were observed between Liraglutide and comparator therapies in the following parameters, including waist circumference (WC), waist-to-hip ratio (WHR), total testosterone (TT), adiponectin (AD), dehydroepiandrosterone sulfate (DHEA-S), total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and two-hour postprandial insulin (2hINS). These findings suggest that while Liraglutide confers substantial benefits in weight reduction, glycemic control, and certain hormonal parameters, its effects on lipid profiles and androgenic markers such as testosterone and DHEA-S may be more limited or variable. Adverse outcomes Five of the seven studies included reported data on treatment-emergent adverse events, including gastrointestinal symptoms (nausea, diarrhea, vomiting), mild hypoglycemia, and headache. The incidence of gastrointestinal side effects was significantly higher in the Liraglutide group compared to comparators, with a pooled OR of 7.28 (95% CI: 1.33 to 39.79; P = 0.022), indicating a notably increased risk associated with Liraglutide therapy (Figure 4A). No significant differences were observed between groups for mild hypoglycemia (OR = 1.78; 95% CI: 0.40 to 7.98; P = 0.451) (Figure 4B) or headache (OR = 2.63; 95% CI: 0.55 to 12.52; P = 0.224) (Figure 4C). These findings suggest that while Liraglutide is generally well tolerated, gastrointestinal adverse effects are common and should be considered when initiating treatment in women with PCOS. However, the risk of hypoglycemia and headaches was not significantly elevated, supporting the overall safety profile of Liraglutide in this population. Discussion Main findings This systematic review and meta-analysis provide updated and comprehensive evidence that Liraglutide, a GLP-1 RA, significantly improves both metabolic and reproductive outcomes in women with PCOS. In line with earlier meta-analyses [10], our findings demonstrate that Liraglutide is more effective than Metformin or placebo in reducing BMI, insulin resistance (as assessed by HOMA-IR), and LH levels. Additionally, liraglutide modestly improves menstrual frequency and increases SHBG concentrations. The reproductive benefits of Liraglutide in PCOS are likely mediated through improvements in metabolic parameters. Weight loss and improved insulin sensitivity are known to restore HPO axis function, leading to more regular menstrual cycles and improved ovulatory function [11]. Moreover, preclinical studies have suggested that GLP-1 and its analogs may directly influence neuroendocrine regulation of reproduction by modulating gonadotropin-releasing hormone (GnRH) and LH secretion via hypothalamic pathways [12, 13]. These findings support the hypothesis that GLP-1 receptor activation may affect central neuroendocrine signaling relevant to reproductive function. Recent experimental research has further uncovered potential direct ovarian effects of Liraglutide that appear independent of weight reduction. A study by Zhao et al. (2024) reported that Liraglutide improves follicular development in PCOS models by inhibiting CXCL10 secretion from granulosa cells via suppression of JAK2 phosphorylation [14]. Elevated CXCL10 levels are associated with ovarian inflammation and have been shown to disrupt the expression of gap junction protein GJA1 (connexin 43), thereby impairing oocyte–granulosa cell communication. Liraglutide treatment reversed these alterations, restoring normal follicular structure and ovulatory potential. These findings suggest that liraglutide may exert direct anti-inflammatory and folliculogenesis-enhancing effects within the ovarian microenvironment, thereby contributing to improved oocyte competence and reproductive outcomes [14]. Furthermore, liraglutide’s systemic anti-inflammatory and antioxidative properties may offer additional benefits for ovarian function. Chronic low-grade inflammation and increased oxidative stress are hallmark features of PCOS and have been implicated in impaired folliculogenesis and suboptimal oocyte competence [15]. By downregulating pro-inflammatory cytokines and oxidative stress pathways, liraglutide may help create a more favorable intra-ovarian environment that supports follicular development and ovulation. Compared to other GLP-1 RAs such as exenatide, Liraglutide exhibits a longer half-life and more stable pharmacokinetics, allowing for sustained receptor activation and potentially greater clinical efficacy [16]. Preliminary comparative data suggest that Liraglutide may be more effective than other GLP-1 RAs in improving reproductive outcomes, though this remains to be confirmed in adequately powered head-to-head trials. For instance, a pilot randomized trial found that combining low-dose liraglutide with metformin significantly increased in vitro fertilization (IVF) pregnancy rates and cumulative pregnancy outcomes over 12 months in obese women with PCOS who previously responded poorly to fertility treatments [17]. Despite similar weight loss between groups, the pregnancy rate per embryo transfer was markedly higher with combination therapy (85.7% vs. 28.6%), suggesting potential reproductive benefits of GLP-1 beyond weight reduction [17]. A meta-analysis of 11 RCTs involving 840 women with PCOS confirmed that GLP-1 RAs significantly improved natural pregnancy rates and menstrual regularity compared to control treatments [9]. These agents also improved insulin sensitivity, reduced BMI and waist circumference, and normalized several hormonal parameters. However, their effects on androgen-related markers were not consistently superior to metformin, suggesting that the reproductive benefits of GLP-1 RAs may result from an integrated impact on weight, insulin action, and gonadotropin dynamics [9]. Secondary outcomes from this meta-analysis reaffirm Liraglutide’s broad metabolic efficacy, including reductions in 2hPBG, FINS, LDL cholesterol, and gonadotropin levels (LH, FSH), along with an increase in SHBG. These changes are consistent with the role of GLP-1 in improving insulin sensitivity, reducing hepatic glucose production, and modulating androgen bioavailability [18, 19]. However, treatment with Liraglutide was associated with a significantly higher incidence of gastrointestinal side effects, such as nausea and vomiting, in line with the known safety profile of GLP-1 RAs. Importantly, the rates of hypoglycemia and headache were not significantly different from comparators, indicating a generally acceptable safety and tolerability profile in the PCOS population. Despite the encouraging findings, several limitations must be acknowledged. Significant heterogeneity was observed for outcomes such as menstrual frequency and FAI, likely due to variability in study design, intervention duration, dosing regimens, and participant characteristics (e.g., baseline BMI or PCOS phenotype). In some cases, small sample sizes and inconsistent outcome definitions limit the ability to pool data, particularly for reproductive endpoints like pregnancy and ovulation rates. Strengths and limitations This study has several notable strengths. It represents the most current and comprehensive systematic review and meta-analysis evaluating the effects of Liraglutide on both metabolic and reproductive outcomes in overweight or obese women with PCOS. The inclusion of recently published randomized controlled trials enhances the relevance of the findings. A rigorous methodology was applied, including a structured literature search, independent data extraction, risk of bias assessment, and the use of random-effects models with sensitivity analyses to account for between-study variability. Additionally, this review uniquely integrates clinical efficacy data with emerging mechanistic insights such as the direct anti-inflammatory and folliculogenesis-promoting effects of Liraglutide, thereby providing a more holistic understanding of its therapeutic potential in PCOS. Despite these strengths, several limitations must be considered. Notable heterogeneity was observed in outcomes such as menstrual frequency and free androgen index (FAI), likely due to differences in trial design, intervention duration, Liraglutide dosing, and participant characteristics (e.g., baseline BMI, age, and PCOS phenotype). The small sample sizes of several included trials and relatively short follow-up periods limit the ability to draw robust conclusions regarding long-term effects. Furthermore, inconsistencies in outcome definitions, particularly for key reproductive endpoints like ovulation and pregnancy rates, hindered data pooling and limited the interpretability of these outcomes. Lastly, there is a paucity of head-to-head trials directly comparing Liraglutide with other GLP-1 receptor agonists or standard fertility treatments, which restricts our ability to determine its relative clinical effectiveness. Interpretation This meta-analysis reinforces the potential of Liraglutide as a therapeutic agent for PCOS, particularly in overweight or obese women. However, several key areas warrant further investigation to fully elucidate its clinical utility. Future research should prioritize large-scale, well-designed randomized controlled trials with standardized definitions of reproductive outcomes such as ovulation, pregnancy, and live birth. These studies should also aim to evaluate long-term effects and safety profiles across different PCOS phenotypes and body weight categories. Mechanistic studies are essential to deepen our understanding of GLP-1’s role in reproductive physiology. In particular, investigations into Liraglutide’s effects on granulosa cell function, folliculogenesis, oocyte quality, and endometrial receptivity will help clarify its weight-independent actions. Exploring molecular pathways such as inflammatory signaling, oxidative stress, and gonadotropin regulation may provide insight into its direct intra-ovarian effects. Additionally, research should assess optimal dosing strategies, treatment duration, and the efficacy of combination therapies, especially with insulin sensitizers (e.g., metformin) or ovulation inducers (e.g., letrozole or clomiphene citrate). Given the heterogeneity of PCOS, future trials should consider stratifying participants by phenotype or metabolic profile to better tailor interventions. Finally, comparative studies between Liraglutide and other GLP-1 receptor agonists are needed to determine relative effectiveness and tolerability. These efforts will support the development of personalized, mechanism-based treatment strategies that target both the metabolic and reproductive dimensions of PCOS. Conclusion This meta-analysis supports Liraglutide as a promising adjunct therapy for women with PCOS, offering significant improvements in metabolic parameters (BMI, insulin resistance, LH, FAI) and reproductive function (menstrual frequency, SHBG levels). While these benefits are largely driven by weight loss and enhanced insulin sensitivity, emerging evidence suggests additional weight-independent effects through direct anti-inflammatory actions within the ovary. However, variability across studies underscores the need for larger, well-designed trials to confirm its efficacy across PCOS phenotypes, optimize treatment protocols, and clarify its impact on ovulation and pregnancy outcomes. Overall, Liraglutide represents a valuable component of personalized, mechanism-based treatment strategies for PCOS. Data availability The data supporting the findings of this study are available from the corresponding author upon reasonable request. Author Contribution All authors contributed to conception and design, drafting the content, and critically revising the manuscript. All authors approved the final version. This study was funded by the China Medical University Hospital Research Foundation (DMR-113-080). Additionally, the research received support from the National Science and Technology Council (NSTC 113-2314-B-039-055). Ethics Statement This is a systematic review that uses publicly available data. Hence, ethics approval was not required. Consent The authors have nothing to report. Conflict of interest The authors declare no conflict of interest. References [1] A.E. Joham, R.J. Norman, E. Stener-Victorin, R.S. Legro, S. Franks, L.J. Moran, J. Boyle, H.J. Teede, Polycystic ovary syndrome, Lancet Diabetes Endocrinol 10(9) (2022) 668-680.[2] E. Stener-Victorin, H. Teede, R.J. Norman, R. Legro, M.O. Goodarzi, A. Dokras, J. Laven, K. Hoeger, T.T. Piltonen, Polycystic ovary syndrome, Nat Rev Dis Primers 10(1) (2024) 27.[3] N. Helvaci, B.O. Yildiz, Polycystic ovary syndrome as a metabolic disease, Nat Rev Endocrinol 21(4) (2025) 230-244.[4] T. Tang, J.M. Lord, R.J. Norman, E. Yasmin, A.H. Balen, Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility, Cochrane Database Syst Rev (5) (2012) CD003053.[5] K. Elkind-Hirsch, O. Marrioneaux, M. Bhushan, D. Vernor, R. Bhushan, Comparison of single and combined treatment with exenatide and metformin on menstrual cyclicity in overweight women with polycystic ovary syndrome, J Clin Endocrinol Metab 93(7) (2008) 2670-8.[6] M. Jensterle, T. Kocjan, N.A. Kravos, M. Pfeifer, A. Janez, Short-term intervention with liraglutide improved eating behavior in obese women with polycystic ovary syndrome, Endocr Res 40(3) (2015) 133-8.[7] Z.R. Ye, C.Q. Yan, N. Liao, S.H. Wen, The Effectiveness and Safety of Exenatide Versus Metformin in Patients with Polycystic Ovary Syndrome: A Meta-Analysis of Randomized Controlled Trials, Reprod Sci 30(8) (2023) 2349-2361.[8] B. Austregesilo de Athayde De Hollanda Morais, V. Martins Prizao, M. de Moura de Souza, B. Ximenes Mendes, M.L. Rodrigues Defante, O. Cosendey Martins, A.M. Rodrigues, The efficacy and safety of GLP-1 agonists in PCOS women living with obesity in promoting weight loss and hormonal regulation: A meta-analysis of randomized controlled trials, J Diabetes Complications 38(10) (2024) 108834.[9] L. Zhou, H. Qu, L. Yang, L. Shou, Effects of GLP1RAs on pregnancy rate and menstrual cyclicity in women with polycystic ovary syndrome: a meta-analysis and systematic review, BMC Endocr Disord 23(1) (2023) 245.[10] Y. Han, Y. Li, B. He, GLP-1 receptor agonists versus metformin in PCOS: a systematic review and meta-analysis, Reprod Biomed Online 39(2) (2019) 332-342.[11] E. Diamanti-Kandarakis, A. Dunaif, Insulin resistance and the polycystic ovary syndrome revisited: an update on mechanisms and implications, Endocr Rev 33(6) (2012) 981-1030.[12] D. Beiroa, M. Imbernon, R. Gallego, A. Senra, D. Herranz, F. Villarroya, M. Serrano, J. Ferno, J. Salvador, J. Escalada, C. Dieguez, M. Lopez, G. Fruhbeck, R. Nogueiras, GLP-1 agonism stimulates brown adipose tissue thermogenesis and browning through hypothalamic AMPK, Diabetes 63(10) (2014) 3346-58.[13] A. Kabahizi, B. Wallace, L. Lieu, D. Chau, Y. Dong, E.S. Hwang, K.W. Williams, Glucagon-like peptide-1 (GLP-1) signalling in the brain: From neural circuits and metabolism to therapeutics, Br J Pharmacol 179(4) (2022) 600-624.[14] M. Zhao, B. Liao, C. Yun, X. Qi, Y. Pang, Liraglutide improves follicle development in polycystic ovary syndrome by inhibiting CXCL10 secretion, Reprod Biol Endocrinol 22(1) (2024) 98.[15] M. Orisaka, T. Mizutani, Y. Miyazaki, A. Shirafuji, C. Tamamura, M. Fujita, H. Tsuyoshi, Y. Yoshida, Chronic low-grade inflammation and ovarian dysfunction in women with polycystic ovarian syndrome, endometriosis, and aging, Front Endocrinol (Lausanne) 14 (2023) 1324429.[16] A. Astrup, R. Carraro, N. Finer, A. Harper, M. Kunesova, M.E. Lean, L. Niskanen, M.F. Rasmussen, A. Rissanen, S. Rossner, M.J. Savolainen, L. Van Gaal, N.N. Investigators, Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide, Int J Obes (Lond) 36(6) (2012) 843-54.[17] V. Salamun, M. Jensterle, A. Janez, E. Vrtacnik Bokal, Liraglutide increases IVF pregnancy rates in obese PCOS women with poor response to first-line reproductive treatments: a pilot randomized study, Eur J Endocrinol 179(1) (2018) 1-11.[18] T. Bu, Z. Sun, Y. Pan, X. Deng, G. Yuan, Glucagon-Like Peptide-1: New Regulator in Lipid Metabolism, Diabetes Metab J 48(3) (2024) 354-372.[19] M. Jensterle, R. Herman, A. Janez, Therapeutic Potential of Glucagon-like Peptide-1 Agonists in Polycystic Ovary Syndrome: From Current Clinical Evidence to Future Perspectives, Biomedicines 10(8) (2022). Figure Legends Figure 1. PRISMA Flow Diagram of Study Selection. Figure 2. Summary of Risk of Bias Assessments for Included Studies. Figure 3. Forest Plots of Primary Outcomes Evaluated in the Meta-Analysis (A) Effect of Liraglutide on menstrual cycle frequency compared to comparator therapies (Metformin, placebo, or other non-Liraglutide regimens). Liraglutide significantly improved menstrual regularity with a large effect size (Hedges’ g = 1.76, 95% CI: 0.28 to 3.24; P = 0.02), though high heterogeneity was observed (I² = 96.21%). (B) Pooled effect of Liraglutide on body mass index (BMI). Treatment with Liraglutide led to a significant reduction in BMI (Hedges’ g = -0.52, 95% CI: -0.94 to -0.10; P = 0.015), with moderate heterogeneity (I² = 62.78%). (C) Effect of Liraglutide on insulin resistance as measured by HOMA-IR. Liraglutide significantly reduced HOMA-IR values (Hedges’ g = -0.52, 95% CI: -0.83 to -0.22; P = 0.001), with low to moderate heterogeneity (I² = 29.99%). (D) Pooled analysis of the impact of Liraglutide on the free androgen index (FAI). Although a reduction in FAI was observed (Hedges’ g = -1.01, 95% CI: -2.05 to 0.02; P = 0.055), the effect was not statistically significant and showed substantial heterogeneity (I² = 91.42%). Figure 4. Forest Plots of Adverse Effects Associated with Liraglutide Treatment Compared to Comparator Therapies (A) Gastrointestinal (GI) side effects: Liraglutide was significantly associated with an increased risk of GI adverse effects (e.g., nausea, vomiting, diarrhea) compared to controls, with a pooled odds ratio indicating a higher incidence. (B) Hypoglycemic events: No significant difference in the incidence of hypoglycemic events was observed between Liraglutide and comparator groups. (C) Headache: The analysis showed no statistically significant increase in the risk of headache with Liraglutide use, with confidence intervals crossing the null. Each panel presents a forest plot of individual studies and the pooled effect size with 95% confidence intervals, illustrating the relative safety profile of Liraglutide across adverse event categories. Supplementary Material File (table 1.docx) Download 20.08 KB File (table 2.docx) Download 33.25 KB File (table 3.docx) Download 33.85 KB Information & Authors Information Version history V1 Version 1 06 June 2025 Peer review timeline Published Diabetes, Obesity and Metabolism Version of Record 9 Jan 2026 Published Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords endocrinology general gynaecology meta-analysis Authors Affiliations Yu-Ting Lu China Medical University Hospital View all articles by this author Po-Han Chang China Medical University Hospital View all articles by this author Hsuan-Ju Chen China Medical University Hospital View all articles by this author Ya-Wen Hsueh China Medical University Hospital View all articles by this author Chia-Wei Chang China Medical University Hospital View all articles by this author Hsi-Chen Hsu China Medical University Hospital View all articles by this author Tung-Chuan Yang China Medical University Hospital View all articles by this author Wu-Chou Lin China Medical University Hospital View all articles by this author Hsun-Ming Chang 0000-0001-9742-6670 [email protected] China Medical University Hospital View all articles by this author Metrics & Citations Metrics Article Usage 483 views 239 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Yu-Ting Lu, Po-Han Chang, Hsuan-Ju Chen, et al. 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