*2.4.1. Lifestyle intervention in PCOS*

Recent clinical practice guidelines recommend lifestyle modification as the first-line intervention in obese PCOS [42]. Low glucose index diet and hypocaloric diet lead to decrease in body mass index (BMI), waist circumference and waist-to-hip ratio [39]. Modification of lifestyle is associated with an important reduction in testosterone and an increase in serum sex hormone-binding globulin (SHBG) levels, leading to reduced free androgen index [43– 45]. Furthermore, beneficial effect of appropriate lifestyle on metabolic abnormalities, such as a decrease in serum insulin and fasting glucose levels, an improvement in insulin resistance (IR) and decline in diastolic blood pressure, is known [43–45]. Lifestyle changes also lead to improvement of fertility function [39, 46, 47]. Two small studies in PCOS proved the impact of dietary intervention on ghrelin, whereas no studies evaluated the impact of lifestyle intervention on incretin hormones in this population [17, 48]. However, the treatment goals with lifestyle intervention are usually hardly achievable and nonsustainable in everyday life.

#### *2.4.2. Metformin in PCOS*

Metformin as an established treatment in PCOS with many potential roles, including attenuating IR and direct blocking ovarian androgen production, has inconsistently demonstrated weight reduction. The absolute weight loss that was best documented in obese rather in lean women with PCOS had been about 2.7 kg, representing less than 5% of weight reduction [49, 50]. No benefit regarding weight reduction was recognized when metformin was added on lifestyle changes. In a small study with 19 lean and 21 obese PCOS patients, the impact of metformin on incretin hormones was demonstrated with the increase of GLP-1 during OGTT with 8-month metformin intervention [35].

## *2.4.3. GLP-1 receptor agonists in PCOS*

group were also reported [37]. Contrary, another group found higher fasting GLP-1 levels in PCOS patients; while at the end of OGTT, GLP-1 levels did not differ between groups [36].

Also studies concerning the GLP-1 response in PCOS patients in relation to body weight are not conclusive. Some authors demonstrated no difference in GLP-1 between lean and obese patients with PCOS during OGTT, whereas others reported lower levels of GLP-1 in obese PCOS patients compared to lean age-matched PCOS patients and healthy lean con-

There are only few studies evaluating GIP levels in women with PCOS. Compared with BMI- and age-matched controls, most of them demonstrated no difference in fasting GIP levels [20, 33–35, 38], yet some have found increased fasting GIP [21]. The results of postprandial GIP levels in PCOS compared to matched controls are more inconsistent. While some studies did not find differences in GIP levels [34], other found increased [21, 38] or decreased

Weight reduction is substantial for improvement of hyperandrogenism and reproductive function in obese women with PCOS [4, 39]. Furthermore, weight loss has beneficial effects on all cardiovascular risk factors, including glycemic control, hypertension and hyperlipidemia

Recent clinical practice guidelines recommend lifestyle modification as the first-line intervention in obese PCOS [42]. Low glucose index diet and hypocaloric diet lead to decrease in body mass index (BMI), waist circumference and waist-to-hip ratio [39]. Modification of lifestyle is associated with an important reduction in testosterone and an increase in serum sex hormone-binding globulin (SHBG) levels, leading to reduced free androgen index [43– 45]. Furthermore, beneficial effect of appropriate lifestyle on metabolic abnormalities, such as a decrease in serum insulin and fasting glucose levels, an improvement in insulin resistance (IR) and decline in diastolic blood pressure, is known [43–45]. Lifestyle changes also lead to improvement of fertility function [39, 46, 47]. Two small studies in PCOS proved the impact of dietary intervention on ghrelin, whereas no studies evaluated the impact of lifestyle intervention on incretin hormones in this population [17, 48]. However, the treatment goals with lifestyle intervention are usually hardly achievable and nonsustainable in

Metformin as an established treatment in PCOS with many potential roles, including attenuating IR and direct blocking ovarian androgen production, has inconsistently demonstrated weight reduction. The absolute weight loss that was best documented in obese rather in lean women with PCOS had been about 2.7 kg, representing less than 5% of weight reduction

**2.4. Therapeutic interventions targeting incretin system in obese PCOS**

trols [20].

60 Debatable Topics in PCOS Patients

[20, 35] GIP levels after OGTT.

in this population [39–41].

everyday life.

*2.4.2. Metformin in PCOS*

*2.4.1. Lifestyle intervention in PCOS*

The available recent data offer new opportunity to include an adjunct management in obese PCOS patients who have not responded to lifestyle modification with or without metformin [51, 52].

GLP-1 receptor agonists (GLP-1 RA) are class of antidiabetes medications, which are incretin mimetics. There are six GLP-1 RAs approved and available, of which only liraglutide and exenatide have been studied in PCOS [53–61]. Studies have been of short duration and have all shown the expected effective weight reduction with GLP-1Ras alone or in combination with metformin and improvement in glucose parameters with variable results on gynecological abnormalities and hyperandrogenism (**Table 1**).
