In 2014, the United States Food and Drug Administration (FDA) approved liraglutide as the first GLP-1 receptor agonist (GLP-1RA) that can be used for obesity management in patients without diabetes [16]. In 2021, semaglutide followed with indications in obese patients (BMI above 30 kg/m²) or overweight patients (BMI above 27 kg/m²) with at least one adipose-based chronic diseases (ABCD) [17]. GLP-1RAs alone or combined with metformin have been investigated in several small studies with overweight/obese PCOS women [18]. Table 1 summarizes the clinical studies that measured the weight-reducing effects of GLP-1RAs in PCOS patients as one of their outcomes.

Additional insight was provided by a network meta-analysis including 23 studies and 951 women, which compared the effectiveness of liraglutide, orlistat, and metformin in promoting weight loss in PCOS women. Liraglutide monotherapy was superior in reducing body weight and waist circumference. Furthermore, its efficacy was the highest at the daily dose of 3 mg [19].

Beyond its weight loss effect, multiple studies provided additional insight into the metabolic benefits of GLP-1RAs in PCOS. Due to the high prevalence of prediabetes in PCOS, additional insights could be gained from a study in which metformin, exenatide, and their combination were studied to explore their effect on prediabetes remission rate. The remission rate of the combination group (64%) or exenatide group (56%) was significantly higher than that of the metformin group (32%), most likely due to the improvement of postprandial insulin secretion. It is also essential to notice that the effects of exenatide therapy persisted after 12 weeks of drug washout, suggesting possible cellular metabolic treatment legacy effect [37]. Furthermore, Yaribeygi et al. suggested that GLP-1RAs can also improve insulin sensitivity, by proposing eight potential molecular pathways [38].

In PCOS and its common comorbidities, circulating levels of adipose-secreted zinc-α2-glycoprotein (ZAG), an insulin-sensitizing cytokine, are considerably reduced [39,40]. A study on 82 PCOS women demonstrated that 12 weeks of twice a day exenatide 10 mcg or metformin 1000 mg significantly increased ZAG levels in both treatment arms compared to the baseline, without significant differences between the arms [36]. Further information on the metabolic effects was provided in a study evaluating the impact of exenatide on different metabolites in women with PCOS and matched controls [34]. The three-month trial demonstrated that triglycerides, HDL, LDL, total cholesterol, and branched-chain amino acid metabolism were improved following exenatide therapy [34].

Liraglutide administration in five patients with HAIR-AN syndrome, which represents an extreme case of PCOS with metabolic syndrome, resulted in a significant improvement in insulin resistance, adipose tissue amount, hyperandrogenemia, and the menstrual cycle regularity, despite minimal weight loss, therefore, the measured changes could be attributed to liraglutide action per se [41]. Additionally, a small study primarily investigated the liraglutide effect on liver fibrosis biomarkers in PCOS. Procollagen Type 3 amino-terminal peptide, which is a predictor of cirrhosis, was reduced after the intervention [42].

Despite menstrual regularity being an important treatment outcome in PCOS, the effect of GLP-1 levels or treatment with GLP-1RAs remains insufficiently studied. The first study to investigate the impact of GLP-1RA on the menstrual cyclicity randomized 42 oligo-ovulatory and overweight PCOS women to exenatide, metformin, or both. After 24 weeks, a significant improvement in the ovulation rate was demonstrated in all the groups, with the highest rate in the combination group and the lowest in the metformin-only group. Furthermore, the improvement in menstrual regularity was significantly correlated with a reduction in body weight, suggesting weight loss to be the primary driving factor behind the reproductive improvement [27]. A similar correlation between the change in menstrual frequency and BMI was found in a 26-week randomized, placebo-controlled trial that explored the effect of liraglutide 1.8 mg daily on ovarian function in 72 women with PCOS [43]. The bleeding ratio of 0.87 or above (calculated by the number of menstrual bleedings divided by the number of months in the study period) was achieved in 62% of women in the liraglutide group compared with 28% in the placebo group [43]. However, several additional studies with liraglutide in PCOS found unaltered menstrual rate despite reductions in body weight [20,21,29] and insulin resistance [28]. Potential explanations might include small sample sizes, short duration, and the low liraglutide dose [44].

There were two studies that addressed pregnancy rates in women with PCOS after an intervention with GLP-1RAs before conception, both reporting better pregnancy outcomes after the GLP-1RA withdrawal [31,32]. The first study included 176 overweight or obese women with PCOS and investigated the natural pregnancy rate in the following 12 weeks after a 12-week treatment with exenatide [32]. The study participants were randomized to receive either exenatide 10 mcg BID or metformin 1000 mg BID for the first 12 weeks, followed by metformin only for the second 12 weeks in which the natural pregnancy rate was tracked. In comparison to the metformin group, the participants receiving exenatide had significantly improved clinical variables after the first 12 weeks, including weight, total percentage of fat, HOMA-IR, and menstrual frequency. The study’s main outcome, the natural pregnancy rate following pre-treatment, was significantly higher in the exenatide group compared to the metformin group (43.6% versus 18.70%, respectively). Although the study was not designed to investigate the underlying mechanisms of this difference in the reproductive outcome, the authors proposed weight loss to most likely be the main contributor to the improved fertility [32]. The second study included 28 obese women with PCOS and explored intervention with low-dose liraglutide (1.2 mg QD) in combination with metformin. The combination of liraglutide and metformin was superior to metformin alone in increasing both the in vitro fertilization and cumulative (including spontaneous conception) pregnancy rates after pre-treatment in patients that were previously resistant to reproductive treatment. The pregnancy rate per embryo transfer was 85.7% in the combination group, compared to 28.6% in the metformin alone group. The cumulative pregnancy rate in 12 months was 69% in the combination compared to 36% in the metformin group. Those results could provide an additional perspective in understanding the direct reproductive effects of GLP-1RAs since both interventions resulted in comparable weight and visceral adipose tissue reductions, indicating other potential mechanisms of action beyond weight loss [31]. In addition, a case report of a 26-year-old infertile and obese PCOS woman reported successful pregnancy following 2-month preconception treatment with exenatide [45].

PCOS is known to be linked to adverse cardiovascular risk since insulin resistance is a vital factor in its pathogenesis, importantly leading to several cardiometabolic abnormalities [46]. In comparison to age and BMI-matched healthy controls, women with PCOS have a 30% increased risk of cardiovascular disease [47]. Whether PCOS is associated with subclinical and clinical atherosclerosis, independent of risk factors that commonly accompany the disorder, is unclear [46]. In recent years, cardiovascular outcomes trials have demonstrated that GLP-1RAs can significantly reduce cardiovascular events in individuals with Type 2 diabetes mellitus, however, the majority of available studies with GLP-1RAs in PCOS did not study cardiometabolic endpoints [48,49].

The first study that was designed to assess cardiometabolic endpoints was a 6-month controlled trial, which published its results in 2015. The effect of daily liraglutide 1.8 mg on weight loss and atherothrombosis markers was evaluated in a small group of PCOS women with obesity and controls. Liraglutide treatment was associated with a significant reduction in atherothrombosis markers in both groups, including inflammation, endothelial dysfunction, and clotting [28]. Two years later, the LIPT study (Liraglutide in PCOS on Markers of Vascular Thrombosis) reported effects of the same liraglutide dose in a 26-week study in 72 overweight PCOS women on markers of thromboembolism and cardiovascular disease. The trial demonstrated significant decreases in peak thrombin concentration and increases in time to start of thrombin generation and time to peak thrombin concentration. In addition, there was an improvement in fibrinolytic activity [50]. Additional cardiovascular biomarkers were reported by this research team in this study group a year later. Liraglutide treatment reduced the levels of the cardiovascular risk biomarkers for subclinical cardiovascular disease, midregional-pro-adrenomedullin by 25%, and midregional-pro-atrial natriuretic peptide by 6% (borderline significance) compared with placebo, whereas copeptin levels did not change [51]. The LIPT study also demonstrated reductions in liver fat content, visceral adipose tissue, and the prevalence of non-alcoholic fatty liver disease [23]. Furthermore, in a 4-month study that assessed the effect 16 weeks exenatide intervention on inflammation, endothelial dysfunction, and fibrinolytic activity in 30 overweight/obese women with PCOS, the treatment showed a significant reduction in the cardiovascular risk markers including cellular adhesion molecule 1, p-selectin as well as e-selectin, and an improvement in the C-reactive protein (CRP) [33].