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GLP-1 receptor agonists versus metformin in PCOS: a systematic review and meta-analysis

Published:April 25, 2019DOI:https://doi.org/10.1016/j.rbmo.2019.04.017

      Abstract

      This meta-analysis aimed to evaluate the efficacy and safety of glucagon-like peptide 1 (GLP-1) receptor agonists for women with polycystic ovary syndrome (PCOS) by comparing their effect with that of metformin. Electronic databases (PubMed, EMBASE, Cochrane Library, WanFang Database, CNKI) dating from their establishment to June 2018 were searched to find all randomized controlled trials (RCTs) reporting the efficacy of GLP-1 receptor agonists versus metformin for patients with PCOS. Therapeutic variables included menstrual cycle, sex hormone and clinical manifestations, glucose metabolism and other metabolic indexes. Eight RCTs among 462 related articles were included in the meta-analysis. Compared with metformin, GLP-1 receptor agonists were more effective in improving insulin sensitivity (standard mean difference [SMD] –0.40, 95% confidence interval [CI] –0.74 to –0.06, P = 0.02) and reducing body mass index (SMD –1.02, 95% CI –1.85 to –0.19, P = 0.02) and abdominal girth (SMD –0.45, 95% CI –0.89 to –0.00, P = 0.05). GLP-1 receptor agonists were associated with a higher incidence of nausea and headache than metformin, but there were no significant differences in other data. Therefore, compared with metformin, GLP-1 receptor agonists might be a good choice for obese patients with PCOS, especially those with insulin resistance. The available evidence is, however, inconclusive given its moderate to low quality. More high-quality research is needed to assess the efficacy of a GLP-1 receptor agonist on women with PCOS.

      Keywords

      Introduction

      Polycystic ovary syndrome (PCOS) is a common reproductive endocrine metabolic disease, with various clinical manifestations (e.g. sparse or no ovulation, high-androgen symptoms and/or hyperandrogenaemia, polycystic ovaries and a metabolic disorder), often accompanied by obesity and insulin resistance, and an increase in the long-term risks of several concomitant diseases (e.g. type 2 diabetes mellitus, lipid metabolic disorder, cardiovascular disease, metabolic syndrome and endometrial carcinoma) (
      • Barthelmess E.K.
      • Naz R.K.
      Polycystic ovary syndrome: current status and future perspective.
      ). The main pathophysiological changes that occur in women with PCOS include hyperandrogenaemia, LH/FSH secretion disorder and insulin resistance. Some studies have reported that insulin resistance occurs in 70% of women with PCOS (
      • Farrell K.
      • Antoni M.H.
      Insulin resistance, obesity, inflammation, and depression in polycystic ovary syndrome: biobehavioral mechanisms and interventions.
      ) and is more likely to occur in obese individuals, particularly those with abdominal obesity (
      • Barber T.M.
      • Franks S.
      Adipocyte biology in polycystic ovary syndrome.
      ).
      As the aetiology of PCOS is unclear, its diagnosis and treatment remain controversial. At present, symptomatic treatment is dominant, mainly including regulation of the menstrual cycle, anti-hyperandrogenaemia therapy, weight control and management of insulin resistance metabolic disorders. Metformin is an effective insulin sensitizer and is currently recommended as a second-line therapy in some PCOS guidelines (
      • Legro R.S.
      • Arslanian S.A.
      • Ehrmann D.A.
      • Hoeger K.M.
      • Murad M.H.
      • Pasquali R.
      • Welt C.K.
      Diagnosis and treatment of polycystic ovary syndrome: an endocrine society clinical practice guideline.
      ). As specified in the 2017 guidelines of the American Society for Reproductive Medicine (ASRM), the ovulation rate can be increased by metformin alone in patients with PCOS (
      Practice Committee of the American Society for Reproductive Medicine
      Role of metformin for ovulation induction in infertile patients with polycystic ovary syndrome (PCOS): a guideline.
      ). In addition, in the latest recommendations, metformin is still recommended for adult women with PCOS for the treatment of weight, hormonal and metabolic conditions. At the same time, pharmacological anti-obesity agents should be considered to be an experimental therapy in women with PCOS for the purpose of improving fertility (
      • Teede H.J.
      • Misso M.L.
      • Costello M.F.
      • Dokras A.
      • Laven J.
      • Moran L.
      • Piltonen T.
      • Norman R.J.
      International PCOS Network. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome.
      ).
      Glucagon-like peptide 1 (GLP-1) is a peptide hormone secreted by intestinal L cells that promotes insulin secretion. It has various physiological effects, including improving insulin resistance, inhibiting appetite and food intake, delaying gastric emptying and reducing body weight (
      • Andersen A.
      • Lund A.
      • Knop F.K.
      • Vilsbøll T.
      Glucagon-like peptide 1 in health and disease.
      ). Some studies have shown that GLP-1 receptor agonists are superior to metformin for controlling body weight (
      • Elkind-Hirsch K.
      • Marrioneaux O.
      • Bhushan M.
      • Vernor D.
      • Bhushan R.
      Comparison of single and combined treatment with exenatide and metformin on menstrual cyclicity in overweight women with polycystic ovary syndrome.
      ,
      • Jensterle S.M.
      • Kocjan T.
      • Pfeifer M.
      • Kravos N.A.
      • Janez A.
      Short-term combined treatment with liraglutide and metformin leads to significant weight loss in obese women with polycystic ovary syndrome and previous poor response to metformin.
      ,
      • Wang F.F.
      • Wu Y.
      • Zhu Y.H.
      • Ding T.
      • Batterham R.L.
      • Qu F.
      • Hardiman P.J.
      Pharmacologic therapy to induce weight loss in women who have obesity/overweight with polycystic ovary syndrome: a systematic review and network meta-analysis.
      ), improving metabolic disorders and menstrual frequency, and significantly increasing the natural pregnancy rate in patients with PCOS (
      • Liu X.
      • Zhang Y.
      • Zheng S.Y.
      • Lin R.
      • Xie Y.J.
      • Chen H.
      • Zheng Y.X.
      • Liu E.
      • Chen L.
      • Yan J.H.
      • Xu W.
      • Mai T.T.
      • Gong Y.
      Efficacy of exenatide on weight loss, metabolic parameters and pregnancy in overweight/obese polycystic ovary syndrome.
      ). However, as these studies had small sample sizes and different quality levels, their conclusions differed. The present study compared the efficacy and safety of a GLP-1 receptor agonist with those of metformin in women with PCOS through a meta-analysis to provide evidence-based medical strategies for clinicians treating PCOS.

      Material and methods

      Search strategy

      The study employed electronic databases (PubMed, EMBASE, Cochrane Library, WanFang Database and CNKI [China National Knowledge Infrastructure]) searching from their inception date until June 2018. In addition, it also paid attention to the retrieval of unpublished literature and conference papers; retraced the references of the literature and employed a manual search. The following MeSH terms and their combinations were used: polycystic ovary syndrome, glucagon-like peptide 1 receptor agonist, exenatide, liraglutide, metformin and dimethylbiguanidine. The search was limited to randomized controlled trials (RCTs) in humans.

      Inclusion and exclusion criteria

      All RCTs reporting the efficacy and safety of GLP-1 receptor agonists compared with metformin for PCOS were included. The diagnosis of PCOS was based on the Rotterdam European Society for Human Reproduction and Embryology/ASRM standard (
      Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group
      Revised 2003 consensus on diagnostic criteria and longterm health risks related to polycystic ovary syndrome (PCOS).
      ) or the National Institute of Child Health and Human Development (NICHD) standard (
      • Zawadzki J.K.
      • Dunaif A.
      Diagnostic criteria for polycystic ovary syndrome: towards a rational approach.
      ) with no limit in terms of age, duration and ethnicity. Studies that were not published in English or Chinese were excluded. Studies without a control group or where GLP-1 receptor agonists and/ or metformin was combined with other treatments were also excluded.

      Outcomes of interest

      Outcomes of interest were planned a priori. The main outcomes were the index closely related to PCOS, including menstrual frequency, serum total testosterone and free androgen index (FAI), homeostasis model assessment of insulin resistance (HOMA-IR) scores and adverse events of nausea and headaches. Secondary outcomes were sex hormone-binding globulin (SHBG) and dehydroepiandrosterone sulphate (DHEA-S) concentrations, Ferriman–Gallwey scores, androstenedione, LH, fasting blood glucose (FBG) and fasting insulin (FINS) concentrations, body mass index (BMI), abdominal girth, triglyceride, total cholesterol, high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) concentrations, systolic blood pressure (SBP), diastolic blood pressure (DBP) and other types of adverse event.

      Data extraction

      Two authors (H.Y. and L.Y.J.) independently screened the literature, extracted the data and cross-checked them. Disagreements were resolved by discussion with the third author (H.B.).

      Risk of bias assessments and quality assessment

      Each original study was assessed by two authors (H.Y. and L.Y.J.) using Cochrane's risk of bias assessment tool for RCTs (
      • Higgins J.
      • Green S.E.
      Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0. The Cochrane Collaboration (Eds):.
      ). Seven domains related to risk of bias were assessed in each study, including random sequence generation, allocation concealment, blinding (blinding of participants and personnel, and blinding of outcome assessment), incomplete outcome data, selective reporting and other bias, represented by ‘low risk’, ‘unclear’ and ‘high risk’. The differences were discussed with the third author (H.B.).
      The overall quality of evidence was rated based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE), GRADE Working Group in 2000, www.gradepro.org, system into four categories: high, moderate, low and very low quality (
      • Guyatt G.
      • Oxman A.D.
      • Akl E.A.
      • Kunz R.
      • Vist G.
      • Brozek J.
      • Norris S.
      • Falck-Ytter Y.
      • Glasziou P.
      • DeBeer H.
      • Jaeschke R.
      • Rind D.
      • Meerpohl J.
      • Dahm P.
      • Schünemann H.J.
      GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables.
      ). Two authors (H.Y. and L.Y.J.) independently assessed the quality of the studies included.

      Statistical analysis

      Meta-analysis was performed using RevMan5.3 software, Version 5.3. The Nordic Cochrane Centre, The Cochrane Collaboration, 2014, Copenhagen. Dichotomous data were combined for meta-analysis using the Mantel/Haenszel model. Results were expressed as RR (Relative Risk) with 95% confidence interval (CI). The standard mean difference (SMD) was used to estimate continuous data, with 95% CI. Inter-study heterogeneity among the trials was assessed using the chi-squared test for analysis, combining I2 to determine the level of heterogeneity. Conclusions were based on random effect procedures to correct for unexplained heterogeneity of the studies. The random effects model uses a weighted average resulting in the assignment of more equal weights to all studies. The level of the meta-analysis was set to α = 0.05. Obvious clinical heterogeneity was treated by subgroup analysis or sensitivity analysis. If the heterogeneity was too large, only descriptive analysis was performed.
      Analysis of publication bias and analysis of meta-regression was to be performed if the number of studies was above 10.

      Results

      Literature identification

      The initial examination obtained 462 articles in total. After reading the titles, abstracts and full texts, eight RCTs (
      • Elkind-Hirsch K.
      • Marrioneaux O.
      • Bhushan M.
      • Vernor D.
      • Bhushan R.
      Comparison of single and combined treatment with exenatide and metformin on menstrual cyclicity in overweight women with polycystic ovary syndrome.
      ,
      • Fan X.X.
      • Yao Y.L.
      • Hu Y.J.
      Effect study of Exenatide on patients with polycystic ovary syndrome and type 2 diabetes in plateau area.
      ,
      • Gao L.H.
      • Zhang C.L.
      • Liu X.Y.
      • Liu J.
      • Zhong C.F.
      Pilot clinical study on the efficacy of liraglutide in treating polycystic ovary syndrome patients with type 2 diabetes mellitus.
      ,
      • Jensterle S.M.
      • Kocjan T.
      • Pfeifer M.
      • Kravos N.A.
      • Janez A.
      Short-term combined treatment with liraglutide and metformin leads to significant weight loss in obese women with polycystic ovary syndrome and previous poor response to metformin.
      ,
      • Jensterle M.
      • Kravos N.A.
      • Pfeifer M.
      • Kocjan T.
      • Janez A.
      A 12-week treatment with the long-acting glucagon-like peptide 1 receptor agonist liraglutide leads to significant weight loss in a subset of obese women with newly diagnosed polycystic ovary syndrome.
      ,
      • Jensterle M.
      • Salamun V.
      • Kocjan T.
      • Vrtacnik Bokal E.
      • Janez A.
      Short term monotherapy with GLP-1 receptor agonist liraglutide or PDE 4 inhibitor roflumilast is superior to metformin in weight loss in obese PCOS women: a pilot randomized study.
      ,
      • Lin W.H.
      Comparison of treatment with exenatide and metformin in overweight women with polycystic ovary syndrome.
      ,
      • Zheng S.Y.
      • Zhang Y.
      • Long T.
      • Lu J.H.
      • Liu X.
      • Yan J.H.
      • Chen L.
      • Gong Y.
      • Wang F.
      Short term monotherapy with exenatide is superior to metformin in weight loss, improving insulin resistance and inflammation in Chinese overweight/obese PCOS women.
      ) were included after excluding duplicates (50), unrelated references (199), animal experiments (36), reviews (107), studies with no control group (11) or non-randomized grouping (28) and not accordant with the inclusion criteria (32). The literature screening process and results are showed in Figure 1. The characteristics of the studies included are summarized in Table 1. A total of 375 women with PCOS were included, with 187 in the test groups and 188 in the control groups.
      Figure 1
      Figure 1Flow diagram of studies identified in the systematic review.
      *PubMed (n = 7), EMBASE (|n = 410), Cochrane Library (n = 6), CNKI (n = 10) and WanFang (n = 17).
      RCT, randomized controlled trial.
      Table 1Characteristics of studies included in the meta-analysis
      Author, yearNo. of cases

      (T/C)
      Age (years)

      (T/C)

      (mean ± SD)
      BMI (kg/m2)

      (T/C)

      (mean ± SD)
      BaselineInterventionsPeriod (weeks)Efficacy outcomes
      TC
      • Elkind-Hirsch K.
      • Marrioneaux O.
      • Bhushan M.
      • Vernor D.
      • Bhushan R.
      Comparison of single and combined treatment with exenatide and metformin on menstrual cyclicity in overweight women with polycystic ovary syndrome.
      20/2028.2 ± 1.1/27.7 ± 1.339.9 ± 1.5/41.3 ± 1.8ComparableEX (10 µg BID)MET (1.0 g BID)24Menstrual frequency, TT, SHBG, DHEA-S, FAI, HOMA-IR, BMI, AG, TC, TG, HDL-C, LDL-C
      • Jensterle S.M.
      • Kocjan T.
      • Pfeifer M.
      • Kravos N.A.
      • Janez A.
      Short-term combined treatment with liraglutide and metformin leads to significant weight loss in obese women with polycystic ovary syndrome and previous poor response to metformin.
      13/14ComparableLIRA (1.2 mg QD)MET (1.0 g BID)12Menstrual frequency, TT, DHEA-S, AND, HOMA-IR, BMI, AG, TC, TG, HDL-C, LDL-C, SBP, DBP
      • Jensterle M.
      • Kravos N.A.
      • Pfeifer M.
      • Kocjan T.
      • Janez A.
      A 12-week treatment with the long-acting glucagon-like peptide 1 receptor agonist liraglutide leads to significant weight loss in a subset of obese women with newly diagnosed polycystic ovary syndrome.
      17/1529.5 ± 7.7/25.3 ± 5.240.8 ± 6.1/38.2 ± 7.0ComparableLIRA (1.2 mg QD)MET (1.0 g BID)12Menstrual frequency, TT, SHBG, DHEA-S, FAI, F-G scores, AND, LH, HOMA-IR, BMI, AG, TC, TG, HDL-C, LDL-C, SBP, DBP
      • Jensterle M.
      • Salamun V.
      • Kocjan T.
      • Vrtacnik Bokal E.
      • Janez A.
      Short term monotherapy with GLP-1 receptor agonist liraglutide or PDE 4 inhibitor roflumilast is superior to metformin in weight loss in obese PCOS women: a pilot randomized study.
      15/15ComparableLIRA (1.2 mg QD)MET (1.0 g BID)12Menstrual frequency, TT, SHBG, DHEA-S, FAI, AND, FBG, FINS, HOMA-IR, BMI, AG
      • Zheng S.Y.
      • Zhang Y.
      • Long T.
      • Lu J.H.
      • Liu X.
      • Yan J.H.
      • Chen L.
      • Gong Y.
      • Wang F.
      Short term monotherapy with exenatide is superior to metformin in weight loss, improving insulin resistance and inflammation in Chinese overweight/obese PCOS women.
      41/4127.70 ± 3.41/28.16 ± 3.9229.18 ± 4.15/29.00 ± 4.10ComparableEX (10 µg BID)MET (1.0 g BID)12Menstrual frequency, TT, SHBG, DHEA-S, FAI, F-G scores, LH, FBG, FINS, HOMA-IR, BMI, AG, TC, TG, HDL-C, LDL-C,
      • Lin W.H.
      Comparison of treatment with exenatide and metformin in overweight women with polycystic ovary syndrome.
      12/13ComparableEX (10 µg BID)MET (0.5 g TID)12BMI, AG
      • Gao L.H.
      • Zhang C.L.
      • Liu X.Y.
      • Liu J.
      • Zhong C.F.
      Pilot clinical study on the efficacy of liraglutide in treating polycystic ovary syndrome patients with type 2 diabetes mellitus.
      32/3227.6 ± 4.5/–28.50 ± 0.62/–ComparableLIRA (1.2 mg QD)MET (0.5 g TID)12TT, LH, FBG, HOMA-IR, BMI
      • Fan X.X.
      • Yao Y.L.
      • Hu Y.J.
      Effect study of Exenatide on patients with polycystic ovary syndrome and type 2 diabetes in plateau area.
      37/3825.6 ± 3.2/27.6 ± 3.628.64 ± 3.16/28.11 ± 4.35ComparableEX (10 µg BID)MET (0.5 g TID)12TT, LH, FBG, FINS, HOMA-IR, BMI, TC, TG, HDL-C, LDL-C, SBP
      T, treatment group; C, control group; EX, exenatide; LIRA, liraglutide; MET, metformin; AG, abdominal girth; AND, androstenedione; BID, bis in die/twice day; QD, quaque die/once a day; TID; ter in die/three times a day; BMI, body mass index; DHEA-S, dehydroepiandrosterone sulphate; F-G scores, Ferriman–Gallwey scores; FAI, free androgen index; FBG, fasting blood glucose; FINS, fasting insulin; HDL-C, high-density lipoprotein cholesterol; HOMA-IR, ­homeostasis model assessment of insulin resistance; LDL-C, low-density lipoprotein cholesterol; SHBG, sex hormone-binding globulin; TG, triglyceride; TC, total cholesterol; TT, serum total testosterone.

      Quality assessment

      The risk of bias assessment is presented in Table 2. The random sequence generation method used in most of the studies was clearly stated, but the concealment of allocation process was unclear for all the studies included. Unfortunately, it was clear that two studies (
      • Elkind-Hirsch K.
      • Marrioneaux O.
      • Bhushan M.
      • Vernor D.
      • Bhushan R.
      Comparison of single and combined treatment with exenatide and metformin on menstrual cyclicity in overweight women with polycystic ovary syndrome.
      ,
      • Lin W.H.
      Comparison of treatment with exenatide and metformin in overweight women with polycystic ovary syndrome.
      ) had not used blinding, and the others did not mention whether this had been employed. However, the laboratory results were objective and unlikely to be affected by the researchers’ knowledge of the participants. In this review, the loss rate of the studies ranged from 0% to 30%. Intention-to-treat analysis was performed on two studies (
      • Elkind-Hirsch K.
      • Marrioneaux O.
      • Bhushan M.
      • Vernor D.
      • Bhushan R.
      Comparison of single and combined treatment with exenatide and metformin on menstrual cyclicity in overweight women with polycystic ovary syndrome.
      ,
      • Jensterle M.
      • Kravos N.A.
      • Pfeifer M.
      • Kocjan T.
      • Janez A.
      A 12-week treatment with the long-acting glucagon-like peptide 1 receptor agonist liraglutide leads to significant weight loss in a subset of obese women with newly diagnosed polycystic ovary syndrome.
      ) with a high loss rate. Only Fan and colleagues’ study (
      • Fan X.X.
      • Yao Y.L.
      • Hu Y.J.
      Effect study of Exenatide on patients with polycystic ovary syndrome and type 2 diabetes in plateau area.
      ) showed evidence of other bias, which related to a specific geographical limitation (high-altitude areas).
      Table 2Risk of Bias Assessment in the RCTs
      Author, yearRandom sequence ­generationAllocation ­concealmentBlindingIncomplete outcome dataSelective reportingOther bias
      • Elkind-Hirsch K.
      • Marrioneaux O.
      • Bhushan M.
      • Vernor D.
      • Bhushan R.
      Comparison of single and combined treatment with exenatide and metformin on menstrual cyclicity in overweight women with polycystic ovary syndrome.
      Computer generated

      Low risk
      NA

      Unclear risk
      No blinding

      High risk
      Completed 70% + ITT

      Missing data with reasons given

      Low risk
      A-priori outcomes reported in main report

      Protocol available

      Low risk
      No bias identified

      Low risk
      • Jensterle S.M.
      • Kocjan T.
      • Pfeifer M.
      • Kravos N.A.
      • Janez A.
      Short-term combined treatment with liraglutide and metformin leads to significant weight loss in obese women with polycystic ovary syndrome and previous poor response to metformin.
      TRAND programme in Excel

      Low risk
      NA

      Unclear risk
      NA

      Unclear risk
      Completed 90%

      Missing data with reasons given

      Low risk
      A-priori outcomes reported in main report

      Protocol available

      Low risk
      No bias identified

      Low risk
      • Jensterle M.
      • Kravos N.A.
      • Pfeifer M.
      • Kocjan T.
      • Janez A.
      A 12-week treatment with the long-acting glucagon-like peptide 1 receptor agonist liraglutide leads to significant weight loss in a subset of obese women with newly diagnosed polycystic ovary syndrome.
      RAND programme in Excel

      Low risk
      NA

      Unclear risk
      NA

      Unclear risk
      Completed 87.5% + ITT

      Missing data with reasons given

      Low risk
      A-priori outcomes reported in main report

      Protocol available

      Low risk
      No bias identified

      Low risk
      • Jensterle M.
      • Salamun V.
      • Kocjan T.
      • Vrtacnik Bokal E.
      • Janez A.
      Short term monotherapy with GLP-1 receptor agonist liraglutide or PDE 4 inhibitor roflumilast is superior to metformin in weight loss in obese PCOS women: a pilot randomized study.
      NA

      Unclear risk
      NA

      Unclear risk
      NA

      Unclear risk
      Completed 88.9%

      Missing data with reasons given

      Low risk
      A-priori outcomes reported in main report

      Protocol not available

      Unclear risk
      No bias identified

      Low risk
      • Zheng S.Y.
      • Zhang Y.
      • Long T.
      • Lu J.H.
      • Liu X.
      • Yan J.H.
      • Chen L.
      • Gong Y.
      • Wang F.
      Short term monotherapy with exenatide is superior to metformin in weight loss, improving insulin resistance and inflammation in Chinese overweight/obese PCOS women.
      Computer generated

      Low risk
      NA

      Unclear risk
      NA

      Unclear risk
      Completed 77%

      Missing data with reasons given

      Unclear risk
      A-priori outcomes reported in main report

      Protocol not available

      Unclear risk
      No bias identified

      Low risk
      • Lin W.H.
      Comparison of treatment with exenatide and metformin in overweight women with polycystic ovary syndrome.
      Random number generated

      Low risk
      NA

      Unclear risk
      No blinding

      High risk
      Completed 88%

      Missing data with reasons given

      Low risk
      A-priori outcomes reported in main report

      Protocol available

      Low risk
      No bias identified

      Low risk
      • Gao L.H.
      • Zhang C.L.
      • Liu X.Y.
      • Liu J.
      • Zhong C.F.
      Pilot clinical study on the efficacy of liraglutide in treating polycystic ovary syndrome patients with type 2 diabetes mellitus.
      Random number generated

      Low risk
      NA

      Unclear risk
      NA

      Unclear risk
      Completed 96.9%

      Missing data with reasons given

      Low risk
      A-priori outcomes reported in main report

      Protocol not available

      Unclear risk
      No bias identified

      Low risk
      • Fan X.X.
      • Yao Y.L.
      • Hu Y.J.
      Effect study of Exenatide on patients with polycystic ovary syndrome and type 2 diabetes in plateau area.
      NA

      Unclear risk
      NA

      Unclear risk
      NA

      Unclear risk
      Completed 100%

      Low risk
      A-priori outcomes reported in main report

      Protocol not available

      Unclear risk
      All subjects limited to high-altitude areas

      High risk
      Blinding: blinding of participants and personnel, and blinding of outcome assessment.
      ITT, intention-to-treat analysis; NA, not available; RCT, randomized controlled trial.
      The quality assessment of the included studies using GRADE is presented in Table 3. The studies included are of moderate to low quality, the main problems being risk of bias and imprecision.
      Table 3Quality assessment
      Primary outcomesLimitationsInconsistencyIndirectnessImprecisionPublication biasQuality (GRADE)
      Assessed using the Grading of Recommendations Assessment, Development and Evaluation system (Guyatt et al., 2011). FAI, free androgen index; HOMA-IR, homeostasis model assessment of insulin resistance; TT, serum total testosterone.
      Menstrual frequencyNo serious limitationsNo serious inconsistencyNo serious indirectnessSerious imprecision
      Due to low total sample size and wide 95% confidence interval.
      UndetectedModerate
      TTNo serious limitationsNo serious inconsistencyNo serious indirectnessSerious imprecision
      Due to low total sample size and wide 95% confidence interval.
      UndetectedModerate
      FAINo serious limitationsNo serious inconsistencyNo serious indirectnessSerious imprecision
      Due to low total sample size and wide 95% confidence interval.
      UndetectedModerate
      HOMA-IR scoresNo serious limitationsNo serious inconsistencyNo serious indirectnessSerious imprecision
      Due to low total sample size and wide 95% confidence interval.
      UndetectedModerate
      NauseaSerious limitations
      Due to the absence of allocation concealment and blinding, subjective outcome indicators tend to have limitations.
      No serious inconsistencyNo serious indirectnessSerious imprecision
      Due to low total sample size and wide 95% confidence interval.
      UndetectedLow
      HeadacheSerious limitations
      Due to the absence of allocation concealment and blinding, subjective outcome indicators tend to have limitations.
      No serious inconsistencyNo serious indirectnessSerious imprecision
      Due to low total sample size and wide 95% confidence interval.
      UndetectedLow
      a Due to the absence of allocation concealment and blinding, subjective outcome indicators tend to have limitations.
      b Due to low total sample size and wide 95% confidence interval.
      c Assessed using the Grading of Recommendations Assessment, Development and Evaluation system (
      • Guyatt G.
      • Oxman A.D.
      • Akl E.A.
      • Kunz R.
      • Vist G.
      • Brozek J.
      • Norris S.
      • Falck-Ytter Y.
      • Glasziou P.
      • DeBeer H.
      • Jaeschke R.
      • Rind D.
      • Meerpohl J.
      • Dahm P.
      • Schünemann H.J.
      GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables.
      ).
      FAI, free androgen index; HOMA-IR, homeostasis model assessment of insulin resistance; TT, serum total testosterone.

      Meta-analysis

      Primary outcomes

      The primary outcomes of the study related to efficacy (menstrual frequency, serum total testosterone concentration, FAI and HOMA-IR) and safety.
      For menstrual frequency, a total of five RCTs (
      • Elkind-Hirsch K.
      • Marrioneaux O.
      • Bhushan M.
      • Vernor D.
      • Bhushan R.
      Comparison of single and combined treatment with exenatide and metformin on menstrual cyclicity in overweight women with polycystic ovary syndrome.
      ,
      • Jensterle S.M.
      • Kocjan T.
      • Pfeifer M.
      • Kravos N.A.
      • Janez A.
      Short-term combined treatment with liraglutide and metformin leads to significant weight loss in obese women with polycystic ovary syndrome and previous poor response to metformin.
      ,
      • Jensterle M.
      • Kravos N.A.
      • Pfeifer M.
      • Kocjan T.
      • Janez A.
      A 12-week treatment with the long-acting glucagon-like peptide 1 receptor agonist liraglutide leads to significant weight loss in a subset of obese women with newly diagnosed polycystic ovary syndrome.
      ,
      • Jensterle M.
      • Salamun V.
      • Kocjan T.
      • Vrtacnik Bokal E.
      • Janez A.
      Short term monotherapy with GLP-1 receptor agonist liraglutide or PDE 4 inhibitor roflumilast is superior to metformin in weight loss in obese PCOS women: a pilot randomized study.
      ,
      • Zheng S.Y.
      • Zhang Y.
      • Long T.
      • Lu J.H.
      • Liu X.
      • Yan J.H.
      • Chen L.
      • Gong Y.
      • Wang F.
      Short term monotherapy with exenatide is superior to metformin in weight loss, improving insulin resistance and inflammation in Chinese overweight/obese PCOS women.
      ) were included. The results showed that there were no significant differences between the GLP-1 receptor agonist and metformin in terms of improving menstrual frequency (SMD 0.15, 95% CI –0.24 to 0.54], I2 = 36%) (Table 4 and Figure 2a).
      Table 4Summary of the meta-analysis of primary and secondary outcomes
      OutcomesNo. of studies includedNo. of cases
      Cases lost to follow-up were excluded.
      (T/C)
      Heterogeneity testMeta-analysis results
      PI2 (%)SMD (95% CI)P-value
      Effects on sex hormone and clinical manifestations
       Menstrual frequency584/87NS360.15 (–0.24 to 0.54)NS
       TT7153/155<0.00001880.64 (–0.08 to 1.35)NS
       SHBG473/73NS0–0.01 (–0.34 to 0.31)NS
       DHEA-S584/87NS0–0.07 (–0.37 to 0.23)NS
       FAI473/73NS30.11 (–0.22 to 0.44)NS
       F-G scores245/46NS00.11 (–0.30 to 0.52)NS
       AND339/41NS00.08 (–0.36 to 0.52)NS
       LH4114/1140.002800.02 (–0.58 to 0.63)NS
      Effects on glucose metabolism
       FBG4114/113<0.0000192–0.90 (–1.92 to 0.12)NS
       FINS382/83NS0–0.14 (–0.45 to 0.16)NS
       HOMA-IR scores6142/141NS48–0.40 (–0.74 to –0.06)0.02
      Effects on other metabolic indexes
       BMI8163/167<0.0000191–1.02 (–1.85 to –0.19)0.02
       AG694/99NS53–0.45 (–0.89 to –0.00)0.05
       TC5107/112<0.00001890.40 (–0.47 to 1.27)NS
       TG4
      Data from Jensterle and colleagues (Jensterle et al., 2014) could not be included as they were reported as median and interquartile range. T, treatment group; C, control group; AG, abdominal girth; AND, androstenedione; BMI, body mass index; DBP, diastolic blood pressure; DHEA-S, dehydroepiandrosterone sulphate; F-G scores, Ferriman–Gallwey scores; FAI, free androgen index; FBG, fasting blood glucose; FINS, fasting insulin; HDL-C, high-density lipoprotein cholesterol; HOMA-IR, homeostasis model assessment of insulin resistance; LDL-C, low-density lipoprotein cholesterol; SHBG, sex hormone-binding globulin; SBP, systemic blood pressure; TG, triglyceride; TC, total cholesterol; TT, serum total testosterone; NS, not statistically significant.
      96/98NS0–0.12 (–0.41 to 0.16)NS
       HDL-C5107/112NS0–0.22 (–0.49 to 0.05)NS
       LDL-C5107/1120.00178–0.35 (–0.96 to 0.25)NS
       SBP362/66NS0–0.20 (–0.55 to 0.15)NS
       DBP225/28NS0–0.11 (–0.65 to 0.44)NS
      a Cases lost to follow-up were excluded.
      b Data from Jensterle and colleagues (
      • Jensterle S.M.
      • Kocjan T.
      • Pfeifer M.
      • Kravos N.A.
      • Janez A.
      Short-term combined treatment with liraglutide and metformin leads to significant weight loss in obese women with polycystic ovary syndrome and previous poor response to metformin.
      ) could not be included as they were reported as median and interquartile range.
      T, treatment group; C, control group; AG, abdominal girth; AND, androstenedione; BMI, body mass index; DBP, diastolic blood pressure; DHEA-S, dehydroepiandrosterone sulphate; F-G scores, Ferriman–Gallwey scores; FAI, free androgen index; FBG, fasting blood glucose; FINS, fasting insulin; HDL-C, high-density lipoprotein cholesterol; HOMA-IR, homeostasis model assessment of insulin resistance; LDL-C, low-density lipoprotein cholesterol; SHBG, sex hormone-binding globulin; SBP, systemic blood pressure; TG, triglyceride; TC, total cholesterol; TT, serum total testosterone; NS, not statistically significant.
      Figure 2
      Figure 2Forest plot: comparison of menstrual frequency (A), serum total testosterone (B), free androgen index (C) and homeostasis model assessment of insulin resistance (D) comparing a glucagon-like peptide 1 (GLP-1) receptor agonist and metformin (MET). df, degrees of freedom; IV, Inverse variance methods.
      For serum total testosterone, a total of seven RCTs (
      • Elkind-Hirsch K.
      • Marrioneaux O.
      • Bhushan M.
      • Vernor D.
      • Bhushan R.
      Comparison of single and combined treatment with exenatide and metformin on menstrual cyclicity in overweight women with polycystic ovary syndrome.
      ,
      • Fan X.X.
      • Yao Y.L.
      • Hu Y.J.
      Effect study of Exenatide on patients with polycystic ovary syndrome and type 2 diabetes in plateau area.
      ,
      • Gao L.H.
      • Zhang C.L.
      • Liu X.Y.
      • Liu J.
      • Zhong C.F.
      Pilot clinical study on the efficacy of liraglutide in treating polycystic ovary syndrome patients with type 2 diabetes mellitus.
      ,
      • Jensterle S.M.
      • Kocjan T.
      • Pfeifer M.
      • Kravos N.A.
      • Janez A.
      Short-term combined treatment with liraglutide and metformin leads to significant weight loss in obese women with polycystic ovary syndrome and previous poor response to metformin.
      ,
      • Jensterle M.
      • Kravos N.A.
      • Pfeifer M.
      • Kocjan T.
      • Janez A.
      A 12-week treatment with the long-acting glucagon-like peptide 1 receptor agonist liraglutide leads to significant weight loss in a subset of obese women with newly diagnosed polycystic ovary syndrome.
      ,
      • Jensterle M.
      • Salamun V.
      • Kocjan T.
      • Vrtacnik Bokal E.
      • Janez A.
      Short term monotherapy with GLP-1 receptor agonist liraglutide or PDE 4 inhibitor roflumilast is superior to metformin in weight loss in obese PCOS women: a pilot randomized study.
      ,
      • Zheng S.Y.
      • Zhang Y.
      • Long T.
      • Lu J.H.
      • Liu X.
      • Yan J.H.
      • Chen L.
      • Gong Y.
      • Wang F.
      Short term monotherapy with exenatide is superior to metformin in weight loss, improving insulin resistance and inflammation in Chinese overweight/obese PCOS women.
      ) were included. No significant difference was found between the GLP-1 receptor agonist and metformin in terms of decreasing serum total testosterone concentration (SMD 0.64, 95% CI –0.08 to 1.35, I2 = 88%, P for heterogeneity <0.00001) (Figure 2b).
      For FAI, a total of four RCTs (
      • Elkind-Hirsch K.
      • Marrioneaux O.
      • Bhushan M.
      • Vernor D.
      • Bhushan R.
      Comparison of single and combined treatment with exenatide and metformin on menstrual cyclicity in overweight women with polycystic ovary syndrome.
      ,
      • Jensterle M.
      • Kravos N.A.
      • Pfeifer M.
      • Kocjan T.
      • Janez A.
      A 12-week treatment with the long-acting glucagon-like peptide 1 receptor agonist liraglutide leads to significant weight loss in a subset of obese women with newly diagnosed polycystic ovary syndrome.
      ,
      • Jensterle M.
      • Salamun V.
      • Kocjan T.
      • Vrtacnik Bokal E.
      • Janez A.
      Short term monotherapy with GLP-1 receptor agonist liraglutide or PDE 4 inhibitor roflumilast is superior to metformin in weight loss in obese PCOS women: a pilot randomized study.
      ,
      • Zheng S.Y.
      • Zhang Y.
      • Long T.
      • Lu J.H.
      • Liu X.
      • Yan J.H.
      • Chen L.
      • Gong Y.
      • Wang F.
      Short term monotherapy with exenatide is superior to metformin in weight loss, improving insulin resistance and inflammation in Chinese overweight/obese PCOS women.
      ) were included. Results showed that no significant difference between the GLP-1 receptor agonist and metformin in terms of decreasing FAI (SMD 0.11, 95% CI –0.22 to 0.44, I2 = 3%). (Figure 2c).
      For HOMA-IR, a total of six RCTs (
      • Elkind-Hirsch K.
      • Marrioneaux O.
      • Bhushan M.
      • Vernor D.
      • Bhushan R.
      Comparison of single and combined treatment with exenatide and metformin on menstrual cyclicity in overweight women with polycystic ovary syndrome.
      ,
      • Fan X.X.
      • Yao Y.L.
      • Hu Y.J.
      Effect study of Exenatide on patients with polycystic ovary syndrome and type 2 diabetes in plateau area.
      ,
      • Gao L.H.
      • Zhang C.L.
      • Liu X.Y.
      • Liu J.
      • Zhong C.F.
      Pilot clinical study on the efficacy of liraglutide in treating polycystic ovary syndrome patients with type 2 diabetes mellitus.
      ,
      • Jensterle M.
      • Kravos N.A.
      • Pfeifer M.
      • Kocjan T.
      • Janez A.
      A 12-week treatment with the long-acting glucagon-like peptide 1 receptor agonist liraglutide leads to significant weight loss in a subset of obese women with newly diagnosed polycystic ovary syndrome.
      ,
      • Jensterle M.
      • Salamun V.
      • Kocjan T.
      • Vrtacnik Bokal E.
      • Janez A.
      Short term monotherapy with GLP-1 receptor agonist liraglutide or PDE 4 inhibitor roflumilast is superior to metformin in weight loss in obese PCOS women: a pilot randomized study.
      ,
      • Zheng S.Y.
      • Zhang Y.
      • Long T.
      • Lu J.H.
      • Liu X.
      • Yan J.H.
      • Chen L.
      • Gong Y.
      • Wang F.
      Short term monotherapy with exenatide is superior to metformin in weight loss, improving insulin resistance and inflammation in Chinese overweight/obese PCOS women.
      ) were included. Results showed that the GLP-1 receptor agonist had a greater effect in terms of improving insulin resistance than metformin (SMD –0.40, 95% CI –0.74 to –0.06 P = 0.02, I2 = 48%). (Figure 2d).
      • Jensterle S.M.
      • Kocjan T.
      • Pfeifer M.
      • Kravos N.A.
      • Janez A.
      Short-term combined treatment with liraglutide and metformin leads to significant weight loss in obese women with polycystic ovary syndrome and previous poor response to metformin.
      study (
      • Jensterle S.M.
      • Kocjan T.
      • Pfeifer M.
      • Kravos N.A.
      • Janez A.
      Short-term combined treatment with liraglutide and metformin leads to significant weight loss in obese women with polycystic ovary syndrome and previous poor response to metformin.
      ) could not be included as it reported data as median and interquartile range, whereas the other six studies reported mean ± SD.
      For the meta-analysis of safety, a total of eight RCTs (
      • Elkind-Hirsch K.
      • Marrioneaux O.
      • Bhushan M.
      • Vernor D.
      • Bhushan R.
      Comparison of single and combined treatment with exenatide and metformin on menstrual cyclicity in overweight women with polycystic ovary syndrome.
      ,
      • Fan X.X.
      • Yao Y.L.
      • Hu Y.J.
      Effect study of Exenatide on patients with polycystic ovary syndrome and type 2 diabetes in plateau area.
      ,
      • Gao L.H.
      • Zhang C.L.
      • Liu X.Y.
      • Liu J.
      • Zhong C.F.
      Pilot clinical study on the efficacy of liraglutide in treating polycystic ovary syndrome patients with type 2 diabetes mellitus.
      ,
      • Jensterle S.M.
      • Kocjan T.
      • Pfeifer M.
      • Kravos N.A.
      • Janez A.
      Short-term combined treatment with liraglutide and metformin leads to significant weight loss in obese women with polycystic ovary syndrome and previous poor response to metformin.
      ,
      • Jensterle M.
      • Kravos N.A.
      • Pfeifer M.
      • Kocjan T.
      • Janez A.
      A 12-week treatment with the long-acting glucagon-like peptide 1 receptor agonist liraglutide leads to significant weight loss in a subset of obese women with newly diagnosed polycystic ovary syndrome.
      ,
      • Jensterle M.
      • Salamun V.
      • Kocjan T.
      • Vrtacnik Bokal E.
      • Janez A.
      Short term monotherapy with GLP-1 receptor agonist liraglutide or PDE 4 inhibitor roflumilast is superior to metformin in weight loss in obese PCOS women: a pilot randomized study.
      ,
      • Lin W.H.
      Comparison of treatment with exenatide and metformin in overweight women with polycystic ovary syndrome.
      ,
      • Zheng S.Y.
      • Zhang Y.
      • Long T.
      • Lu J.H.
      • Liu X.
      • Yan J.H.
      • Chen L.
      • Gong Y.
      • Wang F.
      Short term monotherapy with exenatide is superior to metformin in weight loss, improving insulin resistance and inflammation in Chinese overweight/obese PCOS women.
      ) were included, of which two RCTs (
      • Gao L.H.
      • Zhang C.L.
      • Liu X.Y.
      • Liu J.
      • Zhong C.F.
      Pilot clinical study on the efficacy of liraglutide in treating polycystic ovary syndrome patients with type 2 diabetes mellitus.
      ,
      • Fan X.X.
      • Yao Y.L.
      • Hu Y.J.
      Effect study of Exenatide on patients with polycystic ovary syndrome and type 2 diabetes in plateau area.
      ) cannot be combined with other studies for metaquantitative analysis. Meta-analysis of the remaining six RCTs (
      • Elkind-Hirsch K.
      • Marrioneaux O.
      • Bhushan M.
      • Vernor D.
      • Bhushan R.
      Comparison of single and combined treatment with exenatide and metformin on menstrual cyclicity in overweight women with polycystic ovary syndrome.
      ,
      • Jensterle S.M.
      • Kocjan T.
      • Pfeifer M.
      • Kravos N.A.
      • Janez A.
      Short-term combined treatment with liraglutide and metformin leads to significant weight loss in obese women with polycystic ovary syndrome and previous poor response to metformin.
      ,
      • Jensterle M.
      • Kravos N.A.
      • Pfeifer M.
      • Kocjan T.
      • Janez A.
      A 12-week treatment with the long-acting glucagon-like peptide 1 receptor agonist liraglutide leads to significant weight loss in a subset of obese women with newly diagnosed polycystic ovary syndrome.
      ,
      • Jensterle M.
      • Salamun V.
      • Kocjan T.
      • Vrtacnik Bokal E.
      • Janez A.
      Short term monotherapy with GLP-1 receptor agonist liraglutide or PDE 4 inhibitor roflumilast is superior to metformin in weight loss in obese PCOS women: a pilot randomized study.
      ,
      • Lin W.H.
      Comparison of treatment with exenatide and metformin in overweight women with polycystic ovary syndrome.
      ;
      • Zheng S.Y.
      • Zhang Y.
      • Long T.
      • Lu J.H.
      • Liu X.
      • Yan J.H.
      • Chen L.
      • Gong Y.
      • Wang F.
      Short term monotherapy with exenatide is superior to metformin in weight loss, improving insulin resistance and inflammation in Chinese overweight/obese PCOS women.
      ) showed that the incidence of adverse events of nausea and headache using GLP-1 receptor agonists was higher than that of metformin, the difference being statistically significant (both P = 0.04) (Table 5).
      Table 5The meta-analysis of safety
      Type of adverse eventsNo. of studies includedNo. of cases
      Cases lost to follow-up were excluded. NS, not statistically significant; RR, relative risk.
      (T/C)
      Heterogeneity testMeta-analysis results
      PI2 (%)RR (95% CI)P-value
      Nausea596/101NS291.88 (1.02–3.46)0.04
      Diarrhoea596/1010.04590.59 (0.11–3.28)NS
      Bloating261/61NS00.56 (0.12–2.52)NS
      Vomiting485/87NS02.46 (0.87–7.01)NS
      Cramping (gastrointestinal)261/61NS01.67 (0.23–12.24)NS
      Headache459/62NS04.83 (1.10–21.13)0.04
      Stomach ache375/75NS00.56 (0.12–2.54)NS
      Constipation489/89NS61.00 (0.30–3.37)NS
      Fatigue261/61NS550.99 (0.04–23.27)NS
      Dizziness255/55NS07.00 (0.90–54.25)NS
      Migraine120/200.33 (0.01–7.72)NS
      Hot flushes120/200.33 (0.01–7.72)NS
      Hypoglycaemia335/40NS82.64 (0.70–9.97)NS
      Insomnia114/143.00 (0.13–67.91)NS
      a Cases lost to follow-up were excluded.NS, not statistically significant; RR, relative risk.

      Secondary outcomes

      Results showed that GLP-1 receptor agonists had a greater effect in reducing BMI (SMD –1.02, 95% CI –1.85 to –0.19, P = 0.02, I2 = 91%, P for heterogeneity <0.00001) (
      • Elkind-Hirsch K.
      • Marrioneaux O.
      • Bhushan M.
      • Vernor D.
      • Bhushan R.
      Comparison of single and combined treatment with exenatide and metformin on menstrual cyclicity in overweight women with polycystic ovary syndrome.
      ,
      • Fan X.X.
      • Yao Y.L.
      • Hu Y.J.
      Effect study of Exenatide on patients with polycystic ovary syndrome and type 2 diabetes in plateau area.
      ,
      • Gao L.H.
      • Zhang C.L.
      • Liu X.Y.
      • Liu J.
      • Zhong C.F.
      Pilot clinical study on the efficacy of liraglutide in treating polycystic ovary syndrome patients with type 2 diabetes mellitus.
      ,
      • Jensterle S.M.
      • Kocjan T.
      • Pfeifer M.
      • Kravos N.A.
      • Janez A.
      Short-term combined treatment with liraglutide and metformin leads to significant weight loss in obese women with polycystic ovary syndrome and previous poor response to metformin.
      ,
      • Jensterle M.
      • Kravos N.A.
      • Pfeifer M.
      • Kocjan T.
      • Janez A.
      A 12-week treatment with the long-acting glucagon-like peptide 1 receptor agonist liraglutide leads to significant weight loss in a subset of obese women with newly diagnosed polycystic ovary syndrome.
      ,
      • Jensterle M.
      • Salamun V.
      • Kocjan T.
      • Vrtacnik Bokal E.
      • Janez A.
      Short term monotherapy with GLP-1 receptor agonist liraglutide or PDE 4 inhibitor roflumilast is superior to metformin in weight loss in obese PCOS women: a pilot randomized study.
      ,
      • Lin W.H.
      Comparison of treatment with exenatide and metformin in overweight women with polycystic ovary syndrome.
      ,
      • Zheng S.Y.
      • Zhang Y.
      • Long T.
      • Lu J.H.
      • Liu X.
      • Yan J.H.
      • Chen L.
      • Gong Y.
      • Wang F.
      Short term monotherapy with exenatide is superior to metformin in weight loss, improving insulin resistance and inflammation in Chinese overweight/obese PCOS women.
      ) and abdominal circumference (SMD –0.45, 95% CI –0.89 to –0.00, P = 0.05; I2 = 53%) (
      • Elkind-Hirsch K.
      • Marrioneaux O.
      • Bhushan M.
      • Vernor D.
      • Bhushan R.
      Comparison of single and combined treatment with exenatide and metformin on menstrual cyclicity in overweight women with polycystic ovary syndrome.
      ,
      • Jensterle S.M.
      • Kocjan T.
      • Pfeifer M.
      • Kravos N.A.
      • Janez A.
      Short-term combined treatment with liraglutide and metformin leads to significant weight loss in obese women with polycystic ovary syndrome and previous poor response to metformin.
      ,
      • Jensterle M.
      • Kravos N.A.
      • Pfeifer M.
      • Kocjan T.
      • Janez A.
      A 12-week treatment with the long-acting glucagon-like peptide 1 receptor agonist liraglutide leads to significant weight loss in a subset of obese women with newly diagnosed polycystic ovary syndrome.
      ,
      • Jensterle M.
      • Salamun V.
      • Kocjan T.
      • Vrtacnik Bokal E.
      • Janez A.
      Short term monotherapy with GLP-1 receptor agonist liraglutide or PDE 4 inhibitor roflumilast is superior to metformin in weight loss in obese PCOS women: a pilot randomized study.
      ,
      • Lin W.H.
      Comparison of treatment with exenatide and metformin in overweight women with polycystic ovary syndrome.
      ,
      • Zheng S.Y.
      • Zhang Y.
      • Long T.
      • Lu J.H.
      • Liu X.
      • Yan J.H.
      • Chen L.
      • Gong Y.
      • Wang F.
      Short term monotherapy with exenatide is superior to metformin in weight loss, improving insulin resistance and inflammation in Chinese overweight/obese PCOS women.
      ) than metformin (Supplemental Figures 1 and 2). There were no significant differences for the other data (e.g. SHBG, DHEA-S, Ferriman–Gallwey scores, androstenedione, LH, FBG, FINS, triglyceride, total cholesterol, HDL-C, LDL-C, SBP and DBP) between two groups (see Table 4).
      There was no difference in adverse reactions such as diarrhoea, bloating, vomiting, gastrointestinal cramping, stomach ache or constipation (see Table 5).

      Subgroup analysis

      Due to the high heterogeneity of serum total testosterone results, a subgroup analysis was performed according to the different methodologies used. Elkind-Hirsch and colleagues (
      • Elkind-Hirsch K.
      • Marrioneaux O.
      • Bhushan M.
      • Vernor D.
      • Bhushan R.
      Comparison of single and combined treatment with exenatide and metformin on menstrual cyclicity in overweight women with polycystic ovary syndrome.
      ) used a specific chemiluminescence immunoassay (Diagnostic Products, Los Angeles, USA). whereas Jensterle and co-workers (
      • Jensterle S.M.
      • Kocjan T.
      • Pfeifer M.
      • Kravos N.A.
      • Janez A.
      Short-term combined treatment with liraglutide and metformin leads to significant weight loss in obese women with polycystic ovary syndrome and previous poor response to metformin.
      ,
      • Jensterle M.
      • Kravos N.A.
      • Pfeifer M.
      • Kocjan T.
      • Janez A.
      A 12-week treatment with the long-acting glucagon-like peptide 1 receptor agonist liraglutide leads to significant weight loss in a subset of obese women with newly diagnosed polycystic ovary syndrome.
      ,
      • Jensterle M.
      • Salamun V.
      • Kocjan T.
      • Vrtacnik Bokal E.
      • Janez A.
      Short term monotherapy with GLP-1 receptor agonist liraglutide or PDE 4 inhibitor roflumilast is superior to metformin in weight loss in obese PCOS women: a pilot randomized study.
      ) used coated-tube radioimmunoassay (DiaSorin, Salluggia, Italy or Diagnostic Products Corporation). Gao and colleagues (
      • Gao L.H.
      • Zhang C.L.
      • Liu X.Y.
      • Liu J.
      • Zhong C.F.
      Pilot clinical study on the efficacy of liraglutide in treating polycystic ovary syndrome patients with type 2 diabetes mellitus.
      ) used chemiluminescence, but the methods employed by the others studies (
      • Fan X.X.
      • Yao Y.L.
      • Hu Y.J.
      Effect study of Exenatide on patients with polycystic ovary syndrome and type 2 diabetes in plateau area.
      ,
      • Lin W.H.
      Comparison of treatment with exenatide and metformin in overweight women with polycystic ovary syndrome.
      ,
      • Zheng S.Y.
      • Zhang Y.
      • Long T.
      • Lu J.H.
      • Liu X.
      • Yan J.H.
      • Chen L.
      • Gong Y.
      • Wang F.
      Short term monotherapy with exenatide is superior to metformin in weight loss, improving insulin resistance and inflammation in Chinese overweight/obese PCOS women.
      ) were unknown. The studies were divided into those using coated-tube radioimmunoassay as group A and those using other methods of measurement as group B. The results of the subgroup analysis suggested that the heterogeneity was due to the differences in measurement method. No significant difference was found between GLP-1 receptor agonists and metformin in group A (Supplemental Figure 3).

      Discussion

      This meta-analysis aimed to determine the value of GLP-1 receptor agonists as a treatment for PCOS. A GLP-1 receptor agonist was found to be superior to metformin for improving insulin sensitivity and reducing the BMI and abdominal girth of women with PCOS. GLP-1 receptor agonists had similar effects on menstrual frequency, serum total testosterone, FAI, SHBG, DHEA-S, Ferriman–Gallwey scores, androstenedione, LH, FBG, FINS, triglycerides, total cholesterol and blood pressure when compared with metformin. The incidence rates of nausea and headache were higher than in the metformin group, but those of stomach ache, vomiting, bloating, diarrhoea and constipation did not differ compared with the GLP-1 receptor agonist group. None of the evidence could be graded as high quality. Nonetheless, some ideas have emerged that deserve consideration in clinical practice. In particular, the reassuring data on GLP-1 receptor agonists for improving insulin sensitivity are supported by moderate quality evidence.
      The aetiology of PCOS is unknown. Many scholars have concluded that it is a multigene hereditary disease caused by interactions between environmental factors and several minor genes (e.g. high-androgen-related genes, insulin effect-related genes and chronic inflammatory factor genes) (
      • Franks S.
      • Gharani N.
      • Waterworth D.
      • Batty S.
      • White D.
      • Williamson R.
      • McCarthy M.
      Genetics of Polycystic Ovary Syndrome.
      ,
      • Martínez-garcía M.Á.
      • Gambineri A.
      • Alpañés M.
      • Sanchón R.
      • Pasquali R.
      • Escobar-Morreale H.F.
      Common variants in the sex hormone-binding globulin gene (SHBG) and polycystic ovary syndrome (PCOS) in Mediterranean women.
      ). These studies have suggested that peripheral insulin resistance and hyperinsulinaemia occur in 40–60% of women with PCOS (particularly those with abdominal obesity). Metformin is the first-choice drug for improving insulin resistance in patients with PCOS as it inhibits the synthesis and output of hepatic glycogen, increases glucose uptake/utilization by the peripheral tissues and improves insulin sensitivity. Lee and colleagues (
      • Lee Y.S.
      • Park M.S.
      • Choung J.S.
      • Kim S.S.
      • Oh H.H.
      • Choi C.S.
      • Ha S.Y.
      • Kang Y.
      • Kim Y.
      • Jun H.S.
      Glucagon-like peptide-1 inhibits adipose tissue macrophage infiltration and inflammation in an obese mouse model of diabetes.
      ) showed that a GLP-1 receptor agonist directly inhibits the inflammatory pathway by reducing macrophage infiltration to increase the insulin sensitivity of fat, muscle, and liver tissues; it also improves insulin resistance through a series of indirect mechanisms (
      • Taher J.
      • Baker C.L.
      • Cuizon C.
      • Masoudpour H.
      • Zhang R.
      • Farr S.
      • Naples M.
      • Bourdon C.
      • Pausova Z.
      • Adeli K.
      2014. GLP-1 receptor agonism ameliorates hepatic VLDL overproduction and de novo lipo-genesis in insulin resistance.
      ), for example changing energy utilization efficiency, reducing fat synthesis and increasing lipolysis in the liver, obstructing a fructose-induced lipid metabolic disorder based on the parasympathetic nervous system, and inhibiting the excessive production of very low density lipoprotein in the liver. The conclusions of the current study overwhelmingly support the idea that metformin and a GLP-1 receptor agonist both increased insulin sensitivity and improved insulin resistance in patients with PCOS, with the latter demonstrating greater efficacy.
      Metformin directly inhibits the activity of P450c-17a, resulting in reduced androgen secretion by thecal cells and the adrenal glands of women with PCOS (
      • Attia G.R.
      • Rainey W.E.
      • Carr B.R.
      Metformin directly inhibits androgen production in human thecal cells.
      ,
      • Palomba S.
      • Falbo A.
      • Russo T.
      • Orio F.
      • Tolino A.
      • Zullo F.
      Systemic and local effects of metformin administration in patients with polycystic ovary syndrome (PCOS) relationship to the ovulatory response.
      ). Metformin can also promote the synthesis of SHBG and indirectly decrease plasma androgen concentration (
      • Diamanti-Kandarakis E.
      • Kouli C.
      • Tsianateli T.
      • Bergiele A.
      Therapeutic effects of metformin on insulin resistance and hyperandrogenism in polycystic ovary syndrome.
      ,
      • Nestler J.E.
      • Jakubowicz D.J.
      Decreases in ovarian cytochrome P450c17 alpha activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome.
      ). A definitive mechanism for how the GLP-1 receptor agonist influences androgens is unclear. However, animal experiments have shown that exenatide can reduce serum testosterone concentration and improve hyperandrogenism in PCOS (
      • Sun L.
      • Ji C.
      • Jin L.
      • Bi Y.
      • Feng W.
      • Li P.
      • Shen S.
      • Zhu D.
      Effects of exenatide on metabolic changes, sexual hormones, inflammatory cytokines, adipokines, and weight change in a DHEA-Treated rat model.
      ,
      • Zhen C.
      • Wang Z.H.
      • Shan L.L.
      • Wang L.P.
      Therapeutic effect of glucagon-like peptide-1 analogue-Exenatide on polycystic ovary syndrome rats.
      ). A systematic review also showed that serum testosterone was the only variable that decreased significantly after 3 months of treatment with GLP-1 receptor agonists (
      • Niafar M.
      • Pourafkari L.
      • Porhomayon J.
      • Nader N.
      A systematic review of GLP-1 agonists on the metabolic syndrome in women with polycystic ovaries.
      ). The results of the current meta-analysis revealed no significant difference between the GLP-1 receptor agonist and metformin in terms of decreasing serum total testosterone and FAI.
      Menstrual disorders and symptoms of sterility occur in about 98% of women with PCOS, and are one of their foremost worries (
      • Roe A.H.
      • Prochaska E.
      • Smith M.
      • Sammel M.
      • Dokras A.
      Using the androgen excess-PCOS society criteria to diagnose polycystic ovary syndrome and the risk of metabolic syndrome in adolescents.
      ). Body weight can be reduced by both metformin and GLP-1 receptor agonists, which improves insulin resistance, reduces androgen concentrations, restores the menstrual cycle and induces ovulation. Animal experiments indicate that liraglutide regulates the ovarian phosphoinositide 3-kinase (PI3K)/AKT pathway to affect FoxO1 (forkhead box protein O1) phosphorylation and the development of ovarian follicles (
      • Yang H.Y.
      The study of GLP-1 analogue in PI3K/AKT/FoxO1 pathway in the ovaries of rats with polycystic ovary sydrome.
      ). This meta-analysis revealed no significant difference between the GLP-1 receptor agonist and metformin in terms of improving menstrual frequency.
      Excess body weight is a key phenotype of PCOS as 60–70% of women with PCOS are characterized as obese or overweight (
      • Leo V.D.
      • Marca A.L.
      • Petraglia F.
      Insulin-lowering agents in the management of polycystic ovary syndrome.
      ), and a 5–10% weight loss has been shown to improve reproductive and metabolic outcomes in women with PCOS (
      • Clark A.M.
      • Thornley B.
      • Tomlinson L.
      • Galletley C.
      • Norman R.J.
      Weight loss in obese infertile women results in improvement in reproductive outcome for all forms of fertility treatment.
      ,
      • Huber-Buchholz M.M.
      • Carey D.G.
      • Norman R.J.
      Restoration of reproductive potential by lifestyle modification in obese polycystic ovary syndrome: role of insulin sensitivity and luteinizing hormone.
      ). The weight loss effects of metformin are, however, disputed and have been best documented in obese rather than lean women with PCOS. GLP-1 receptor agonists bind with the receptor in various regions of the hypothalamus (e.g. the arcuate nuclei) to inhibit appetite, increase the sensation of satiety and reduce food intake (
      • Hayes M.R.
      • Mietlicki-Baase E.G.
      • Kanoski S.E.
      • De Jonghe B.C
      Incretins and amylin: neuroendocrine communication between the gut, pancreas, and brain in control of food intake and blood glucose.
      ). Receptor binding also delays gastric emptying and bowel movements (
      • Smits M.M.
      • Tonneijck L.
      • Muskiet M.H.
      • Kramer M.H.
      • Cahen D.L.
      • van Raalte D.H.
      Gastrointestinal actions of glucagon-like peptide-1-based therapies: glycaemic control beyond the pancreas.
      ) and reduces body weight through a central mechanism mediated mainly by the vagus nerve. In addition, one study (
      • Inoue K.
      • Maeda N.
      • Kashine S.
      • Fujishima Y.
      • Kozawa J.
      • Hiuge-Shimizu A.
      • Okita K.
      • Imagawa A.
      • Funahashi T.
      • Shimomura I.
      Short-term effects of liraglutide on visceral fat adiposity, appetite, and food preference: a pilot study of obese Japanese patients with type 2 diabetes.
      ) showed that the GLP-1 receptor agonist liraglutide reduced fat accumulation in the viscera by acting on invariant natural killer T cells, increasing the browning of white adipose tissue and enhancing FGF-21 (fibroblast growth factor 21) expression in adipose tissue.
      Women with PCOS are also more likely to suffer with hypertension, hyperlipidaemia, fatty liver and an increased cardiovascular risk. Metabolic syndrome can be effectively improved by both metformin and GLP-1 receptor agonists (
      • Derosa G.
      • Maffioli P
      GLP-1 agonists exenatide and liraglutide: a review about their safety and efficacy.
      ,
      • Zhou J.
      • Massey S.
      • Story D.
      • Li L.
      Metformin: An Old Drug with New Applications.
      ). As shown by the results of the current meta-analysis, a GLP-1 receptor agonist more effectively reduced BMI and abdominal circumference in women with PCOS compared with metformin. However, the effects on reducing various metabolic indices, for example SBP, DBP, total cholesterol and triglycerides, were not significantly different.
      In terms of adverse events, the most common adverse event of metformin and GLP-1 receptor agonists relate to the gastrointestinal tract. Studies have, however, shown that nausea caused by GLP-1 receptor agonists usually diminishes with time and may be related to fluctuations in the maximum plasma concentrations (Cmax) of the drug (
      • Fineman M.S.
      • Shen L.Z.
      • Taylor K.
      • Kim D.D.
      • Baron A.D.
      Effectiveness of progressive dose-escalation of exenatide (exendin-4) in reducing dose-limiting side effects in subjects with type 2 diabetes.
      ,
      • Yoo B.K.
      • Triller D.M.
      • Yoo D.J.
      Exenatide: A new option for the treatment of type 2 diabetes.
      ). Headache is a relatively special adverse event, which is closely related to patient compliance. The incidence rates of nausea and headache were higher with a GLP-1 receptor agonist than with metformin. It is worth noting that, in all the studies reporting this on this event (
      • Jensterle S.M.
      • Kocjan T.
      • Pfeifer M.
      • Kravos N.A.
      • Janez A.
      Short-term combined treatment with liraglutide and metformin leads to significant weight loss in obese women with polycystic ovary syndrome and previous poor response to metformin.
      ,
      • Jensterle M.
      • Kravos N.A.
      • Pfeifer M.
      • Kocjan T.
      • Janez A.
      A 12-week treatment with the long-acting glucagon-like peptide 1 receptor agonist liraglutide leads to significant weight loss in a subset of obese women with newly diagnosed polycystic ovary syndrome.
      ,
      • Jensterle M.
      • Salamun V.
      • Kocjan T.
      • Vrtacnik Bokal E.
      • Janez A.
      Short term monotherapy with GLP-1 receptor agonist liraglutide or PDE 4 inhibitor roflumilast is superior to metformin in weight loss in obese PCOS women: a pilot randomized study.
      ), a low dose of liraglutide of 1.2 mg quaque die/once a day was used. The adverse effects of the high dose (1.8 mg), which was not used in any of the studies included in this meta-analysis, might be worse.
      The current study had several strengths. No prior meta-analysis on this issue has been as large, up to date or comprehensive. The results of a systematic evaluation in 2015 showed that the BMI and serum total testosterone concentrations of women with PCOS decreased after administering a GLP-1 receptor agonist for 3 months (
      • Niafar M.
      • Pourafkari L.
      • Porhomayon J.
      • Nader N.
      A systematic review of GLP-1 agonists on the metabolic syndrome in women with polycystic ovaries.
      ). However, no head-to-head comparison with other drugs was performed, and drug-related adverse reactions were not assessed in that systematic evaluation. Metformin is a commonly used therapeutic drug approved by the US Food and Drug Administration for women with PCOS and a metabolic disorder. In the present study, the efficacy and safety of a GLP-1 receptor agonist for PCOS were further evaluated by comparison with metformin, which has well-established efficacy.
      Some limitations of this study should, however, be addressed. The effect of GLP-1 receptor agonists on reducing abdominal girth was limited compared with that of metformin. The difference was statistically significant but lay at the edge of statistical significance. Further analysis is needed with an expanded sample size. The possible causes of the heterogeneity found in the literature were analysed. First, very few clinical studies have been conducted on PCOS, and still fewer studies met the inclusion criteria of the current analysis. All the studies included had small sample sizes, and the ‘grey literature’ was not included, causing a possible selection bias. Second, although publication bias may have occurred in the studies included, such a bias could not be assessed using a funnel plot due to the small sample size. Third, the study populations differed: a European population was studied by Elkind-Hirsch and colleagues (
      • Elkind-Hirsch K.
      • Marrioneaux O.
      • Bhushan M.
      • Vernor D.
      • Bhushan R.
      Comparison of single and combined treatment with exenatide and metformin on menstrual cyclicity in overweight women with polycystic ovary syndrome.
      ) and Jensterle and colleagues (
      • Jensterle S.M.
      • Kocjan T.
      • Pfeifer M.
      • Kravos N.A.
      • Janez A.
      Short-term combined treatment with liraglutide and metformin leads to significant weight loss in obese women with polycystic ovary syndrome and previous poor response to metformin.
      ,
      • Jensterle M.
      • Kravos N.A.
      • Pfeifer M.
      • Kocjan T.
      • Janez A.
      A 12-week treatment with the long-acting glucagon-like peptide 1 receptor agonist liraglutide leads to significant weight loss in a subset of obese women with newly diagnosed polycystic ovary syndrome.
      ,
      • Jensterle M.
      • Salamun V.
      • Kocjan T.
      • Vrtacnik Bokal E.
      • Janez A.
      Short term monotherapy with GLP-1 receptor agonist liraglutide or PDE 4 inhibitor roflumilast is superior to metformin in weight loss in obese PCOS women: a pilot randomized study.
      ) and an Asian population in the other four studies (
      • Fan X.X.
      • Yao Y.L.
      • Hu Y.J.
      Effect study of Exenatide on patients with polycystic ovary syndrome and type 2 diabetes in plateau area.
      ,
      • Gao L.H.
      • Zhang C.L.
      • Liu X.Y.
      • Liu J.
      • Zhong C.F.
      Pilot clinical study on the efficacy of liraglutide in treating polycystic ovary syndrome patients with type 2 diabetes mellitus.
      ,
      • Lin W.H.
      Comparison of treatment with exenatide and metformin in overweight women with polycystic ovary syndrome.
      ,
      • Zheng S.Y.
      • Zhang Y.
      • Long T.
      • Lu J.H.
      • Liu X.
      • Yan J.H.
      • Chen L.
      • Gong Y.
      • Wang F.
      Short term monotherapy with exenatide is superior to metformin in weight loss, improving insulin resistance and inflammation in Chinese overweight/obese PCOS women.
      ), including one study by Fan and co-workers (
      • Fan X.X.
      • Yao Y.L.
      • Hu Y.J.
      Effect study of Exenatide on patients with polycystic ovary syndrome and type 2 diabetes in plateau area.
      ) on women from high-altitude areas. Fourth, the studies included did not adopt a blinding method and or allocation concealment, and the intention-to-treat analytical method was adopted by only two studies (
      • Elkind-Hirsch K.
      • Marrioneaux O.
      • Bhushan M.
      • Vernor D.
      • Bhushan R.
      Comparison of single and combined treatment with exenatide and metformin on menstrual cyclicity in overweight women with polycystic ovary syndrome.
      ,
      • Jensterle M.
      • Kravos N.A.
      • Pfeifer M.
      • Kocjan T.
      • Janez A.
      A 12-week treatment with the long-acting glucagon-like peptide 1 receptor agonist liraglutide leads to significant weight loss in a subset of obese women with newly diagnosed polycystic ovary syndrome.
      ). Fifth, the dosing regimen and follow-up duration were not the same in the different studies, which may have affected the clinical efficacy and occurrence of adverse reactions. Finally, the methodology was limited in some studies, and the evaluation indices were not the same.

      Conclusions

      In conclusion, our meta-analysis provides evidence that a GLP-1 receptor agonist is superior to metformin for improving insulin sensitivity. However, no significant difference was shown between the GLP-1 receptor agonist and metformin in terms of improving menstrual frequency and decreasing serum total testosterone and FAI. In addition, close attention should be paid to its adverse reactions (e.g. nausea and headache) in clinical applications. Overall, the available evidence is not of high quality, and more multicentre, randomized, controlled studies with a larger sample size and rigorous design are expected in the future to offer more objective clinical data for guiding the clinical treatment of women with PCOS.

      Acknowledgement

      This work was supported by a grant from National Natural Science Foundation of China (grant no. 81570765).

      Appendix. Supplementary materials

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      Biography

      Bing He is a Doctor of Medicine, PhD supervisor and Professor. Since 2003, she has worked in the Department of Endocrinology, Shengjing Hospital of China Medical University, Shenyang, China, participating in a number of national and provincial science projects. Her latest research is on the diagnosis and treatment of polycystic ovary syndrome.
      Key message
      This meta-analysis, including eight studies, on the efficacy and safety of a glucagon-like peptide 1 (GLP-1) receptor agonist versus metformin for polycystic ovary syndrome patients found that, compared with metformin, GLP-1 receptor agonists were more effective in reducing body mass index and abdominal girth and improving insulin sensitivity. However, more high-quality studies are needed.