*2.4.3.1. Liraglutide in PCOS*

Liraglutide is a long-acting GLP-1 RA analogue that is 97% homologous to human GLP-1. Its dose-dependent effect on weight loss was first observed in overweight patients with type 2 diabetes and later also in overweight subjects without diabetes. In dose of 3 mg, it was recently approved for weight management in many countries [62–65].


**Table 1.** Reported effects of GLP-1 agonist treatment in women with PCOS.

The efficacy of 3 mg liraglutide on weight loss was studied in a Satiety and Clinical Adiposity-Liraglutide Evidence (SCALE) series of four trials involving 5358 patients who were divided in different patient categories. SCALE-prediabetes involved 3731 adult patients with prediabetes and BMI ≥ 30 kg/m<sup>2</sup> or BMI ≥ 27 kg/m<sup>2</sup> and associated hypertension or dyslipidemia [66]. SCALEdiabetes involved 846 adult patients with type 2 diabetes and BMI kg/m<sup>2</sup> ≥ 27 who were on peroral hypoglycemic therapy [63]. In SCALE Maintenance trial, the ability of high-dose liraglutide to maintain weight lost following a low-calorie diet and exercise intervention was observed on 422 obese nondiabetic patients [67]. SCALE OSA involved 359 nondiabetic obese adults with moderate or severe obstructive sleep apnea, who were unable to use CPAP [68]. In composite data analysis of the SCALE clinical trials, liraglutide 3.0 mg led to 7.5% weight loss over 1 year.

liraglutide 1.2 mg alone in reducing weight after 12 weeks in treatment naïve obese women with PCOS. Participants on combined treatment achieved clinically meaningful ≥5% weight loss in almost 60% compared to about 40% of good responders with low dose liraglutide monotherapy. Androgens were lower in all patients at study completion, yet only androstenedione was significantly decreased in the combination group. Systolic blood pressure was significantly lowered in the liraglutide arm. All subjects demonstrated a significant improvement in insulin resistance and fasting and 2-hour post-load glucose level [57]. The observed benefits of GLP-1 RAs in combination with metformin are mechanistically well supported. In animal models and in humans with or without type 2 diabetes, administration of metformin led to increase in GLP-1 concentration [74, 75]. It directly stimulated GLP-1 production and secretion from L cells through crosstalk between the insulin and Wnt signaling pathways. In addition, its impact on alteration in bile acid absorption may result in increased GLP-1 secretion. Furthermore, it was demonstrated that metformin enhances expression of GLP1 receptors through a mechanism requiring PPAR-alpha [72]. It also has a small impact on the inhibition of DPP4 activity [76].

Incretin System: New Pharmacological Target in Obese Women with Polycystic Ovary Syndrome

http://dx.doi.org/10.5772/intechopen.70648

63

Another interesting avenue was opened with a study conducted with 57 women with PCOS received liraglutide for 12 weeks. Recognizing that the weight reducing effects of GLP-1 RAs are mediated through GLP-1 receptor, it was hypothesized that inter-individual difference in weight loss potential of liraglutide might be linked with genetic variability of GLP-1 receptor. It was demonstrated that a difference in a liraglutide-induced weight loss potential in phenotypically and metabolically homogeneous group of obese women with PCOS was based on

The majority of available studies with liraglutide in PCOS did not focus on the cardiometabolic endpoints. In a small study, the potential impact of liraglutide on markers of liver fibrosis in PCOS was primarily investigated. Liraglutide was found to reduce procollagen type 3 amino terminal peptide, a predictor of liver cirrhosis. An average weight reduction of 3.0 kg achieved with larger dosage of 1.8 mg sc QD in monotherapy was observed over 24 weeks [78]. In another study, 6-month intervention with liraglutide was associated with significant reduction in atherothrombosis markers, including inflammation, endothelial function and clotting. The positive effect equally affected young obese women with PCOS and controls [58]. Few studies suggested an increase in menstrual frequencies when taking GLP-1 RAs [59–61]. The most recent study reported that liraglutide improved bleeding ratio and decreased ovarian volume with liraglutide when compared to placebo [61]. Moreover, after liraglutide discontinuation, one small 12-week study conducted with 40 infertile PCOS reported an increase of fertility potential. Women were randomized into three groups: MET group was treated with metformin 1000 mg BID, COMBI group was on combined treatment with metformin 1000 mg BID and liraglutide 1.2 mg QD and CON group were controls. CON directly proceeded with ovarian stimulation protocol, whereas MET and COMBI started with stimulation after 4-week washout period. More than 5% of weight reduction was achieved in over 75% in COMBI and about 45% of patients in metformin arm. In high responders who lost more than 5% of body weight, numbers of blastocysts/patient were greater in both treatment arms than in CON. High responders in COMBI had the highest number of oocytes/patient and of mature oocyte. In COMBI 3, patients became spontaneously pregnant before IVF in medication-free

some GLP1-R genotype [77].

Its impact on weight loss appears to be due to reduction of appetite, mediated partly through incretin effect and consequent suppress of ghrelin release and partly through its influence on gastric emptying via the autonomous nervous system [69]. Liraglutide is the only known glucoselowering agent with proven ability to regulate eating behavior. It probably sufficiently activates mesolimbic GLP-1 receptor and suppresses hunger-driven feeding and reduces the hedonic value of food and food motivation [69]. It was demonstrated that liraglutide produces significant improvements in eating behavior in obese patients with T2DM and importantly reduces lust for fat intake. The effect was sustained 6 months after withdrawal of liraglutide [70, 71].

Current data about liraglutide use in obese patients with PCOS are very limited. In a 12-week study with 40 obese PCOS women who had been insufficiently treated with lifestyle modification and metformin regarding weight reduction, liraglutide 1.2 mg sc QD alone or in combination with metformin 1000 mg BID was associated with significantly greater weight loss when compared to metformin monotherapy. The mean weight loss in combined treatment was 6.5 kg. Liraglutide monotherapy resulted in 3.8 kg loss and metformin alone in 1.2 kg loss. The majority of patients who achieved at least 5% of weight reduction were on combination therapy. Two-hour post-load glucose level was significantly lower in the treatment groups with liraglutide. Menstrual frequency and androgen profile were not significantly changed in any group over the observed period [53]. Another study with newly diagnosed obese PCOS patients with high metabolic risk also showed significantly greater weight reduction with liraglutide therapy when compared to metformin and lifestyle intervention [54]. In both studies, liraglutide 1.2 mg QD was used before liraglutide in a dose of 3 mg was approved as an anti-obesity drug. In an observational study of 84 overweight and obese women with PCOS with mean duration of 27.8 weeks and with liraglutide doses ranging from 0.6 mg up to 1.8 mg per day, combined treatment with liraglutide and metformin was associated with significant weight reduction of 9 kg. More than 80% of patients lost at least 5% of baseline weight [55]. It was also reported that liraglutide treatment improved the impaired eating behavior of women with PCOS who were pre-treated with metformin and switched to liraglutide for 12 weeks. There was significant decrease in emotional eating that correlated with weight loss [56].

Adding metformin to liraglutide was proven as well-suited combination that enhances the therapeutic index of GLP-1RA and enables the use of lower liraglutide dose [57, 72– 75]. Metformin in combination with low dose liraglutide 1.2 mg was superior to low dose liraglutide 1.2 mg alone in reducing weight after 12 weeks in treatment naïve obese women with PCOS. Participants on combined treatment achieved clinically meaningful ≥5% weight loss in almost 60% compared to about 40% of good responders with low dose liraglutide monotherapy. Androgens were lower in all patients at study completion, yet only androstenedione was significantly decreased in the combination group. Systolic blood pressure was significantly lowered in the liraglutide arm. All subjects demonstrated a significant improvement in insulin resistance and fasting and 2-hour post-load glucose level [57]. The observed benefits of GLP-1 RAs in combination with metformin are mechanistically well supported. In animal models and in humans with or without type 2 diabetes, administration of metformin led to increase in GLP-1 concentration [74, 75]. It directly stimulated GLP-1 production and secretion from L cells through crosstalk between the insulin and Wnt signaling pathways. In addition, its impact on alteration in bile acid absorption may result in increased GLP-1 secretion. Furthermore, it was demonstrated that metformin enhances expression of GLP1 receptors through a mechanism requiring PPAR-alpha [72]. It also has a small impact on the inhibition of DPP4 activity [76].

The efficacy of 3 mg liraglutide on weight loss was studied in a Satiety and Clinical Adiposity-Liraglutide Evidence (SCALE) series of four trials involving 5358 patients who were divided in different patient categories. SCALE-prediabetes involved 3731 adult patients with prediabetes

diabetes involved 846 adult patients with type 2 diabetes and BMI kg/m<sup>2</sup> ≥ 27 who were on peroral hypoglycemic therapy [63]. In SCALE Maintenance trial, the ability of high-dose liraglutide to maintain weight lost following a low-calorie diet and exercise intervention was observed on 422 obese nondiabetic patients [67]. SCALE OSA involved 359 nondiabetic obese adults with moderate or severe obstructive sleep apnea, who were unable to use CPAP [68]. In composite data analysis of the SCALE clinical trials, liraglutide 3.0 mg led to 7.5% weight loss over 1 year. Its impact on weight loss appears to be due to reduction of appetite, mediated partly through incretin effect and consequent suppress of ghrelin release and partly through its influence on gastric emptying via the autonomous nervous system [69]. Liraglutide is the only known glucoselowering agent with proven ability to regulate eating behavior. It probably sufficiently activates mesolimbic GLP-1 receptor and suppresses hunger-driven feeding and reduces the hedonic value of food and food motivation [69]. It was demonstrated that liraglutide produces significant improvements in eating behavior in obese patients with T2DM and importantly reduces lust for

fat intake. The effect was sustained 6 months after withdrawal of liraglutide [70, 71].

Current data about liraglutide use in obese patients with PCOS are very limited. In a 12-week study with 40 obese PCOS women who had been insufficiently treated with lifestyle modification and metformin regarding weight reduction, liraglutide 1.2 mg sc QD alone or in combination with metformin 1000 mg BID was associated with significantly greater weight loss when compared to metformin monotherapy. The mean weight loss in combined treatment was 6.5 kg. Liraglutide monotherapy resulted in 3.8 kg loss and metformin alone in 1.2 kg loss. The majority of patients who achieved at least 5% of weight reduction were on combination therapy. Two-hour post-load glucose level was significantly lower in the treatment groups with liraglutide. Menstrual frequency and androgen profile were not significantly changed in any group over the observed period [53]. Another study with newly diagnosed obese PCOS patients with high metabolic risk also showed significantly greater weight reduction with liraglutide therapy when compared to metformin and lifestyle intervention [54]. In both studies, liraglutide 1.2 mg QD was used before liraglutide in a dose of 3 mg was approved as an anti-obesity drug. In an observational study of 84 overweight and obese women with PCOS with mean duration of 27.8 weeks and with liraglutide doses ranging from 0.6 mg up to 1.8 mg per day, combined treatment with liraglutide and metformin was associated with significant weight reduction of 9 kg. More than 80% of patients lost at least 5% of baseline weight [55]. It was also reported that liraglutide treatment improved the impaired eating behavior of women with PCOS who were pre-treated with metformin and switched to liraglutide for 12 weeks. There was significant decrease in emotional eating that correlated

Adding metformin to liraglutide was proven as well-suited combination that enhances the therapeutic index of GLP-1RA and enables the use of lower liraglutide dose [57, 72– 75]. Metformin in combination with low dose liraglutide 1.2 mg was superior to low dose

and associated hypertension or dyslipidemia [66]. SCALE-

and BMI ≥ 30 kg/m<sup>2</sup>

62 Debatable Topics in PCOS Patients

with weight loss [56].

or BMI ≥ 27 kg/m<sup>2</sup>

Another interesting avenue was opened with a study conducted with 57 women with PCOS received liraglutide for 12 weeks. Recognizing that the weight reducing effects of GLP-1 RAs are mediated through GLP-1 receptor, it was hypothesized that inter-individual difference in weight loss potential of liraglutide might be linked with genetic variability of GLP-1 receptor. It was demonstrated that a difference in a liraglutide-induced weight loss potential in phenotypically and metabolically homogeneous group of obese women with PCOS was based on some GLP1-R genotype [77].

The majority of available studies with liraglutide in PCOS did not focus on the cardiometabolic endpoints. In a small study, the potential impact of liraglutide on markers of liver fibrosis in PCOS was primarily investigated. Liraglutide was found to reduce procollagen type 3 amino terminal peptide, a predictor of liver cirrhosis. An average weight reduction of 3.0 kg achieved with larger dosage of 1.8 mg sc QD in monotherapy was observed over 24 weeks [78]. In another study, 6-month intervention with liraglutide was associated with significant reduction in atherothrombosis markers, including inflammation, endothelial function and clotting. The positive effect equally affected young obese women with PCOS and controls [58].

Few studies suggested an increase in menstrual frequencies when taking GLP-1 RAs [59–61]. The most recent study reported that liraglutide improved bleeding ratio and decreased ovarian volume with liraglutide when compared to placebo [61]. Moreover, after liraglutide discontinuation, one small 12-week study conducted with 40 infertile PCOS reported an increase of fertility potential. Women were randomized into three groups: MET group was treated with metformin 1000 mg BID, COMBI group was on combined treatment with metformin 1000 mg BID and liraglutide 1.2 mg QD and CON group were controls. CON directly proceeded with ovarian stimulation protocol, whereas MET and COMBI started with stimulation after 4-week washout period. More than 5% of weight reduction was achieved in over 75% in COMBI and about 45% of patients in metformin arm. In high responders who lost more than 5% of body weight, numbers of blastocysts/patient were greater in both treatment arms than in CON. High responders in COMBI had the highest number of oocytes/patient and of mature oocyte. In COMBI 3, patients became spontaneously pregnant before IVF in medication-free period. The high rate of spontaneous pregnancies in COMBI after liraglutide discontinuation implies the potential role of GLP-1 in reproduction in the pre-conception period [79]. In line with these preliminary results, new data support a role for GLP-1RAs in fertility beyond merely weight reduction [51]. In animal models, GLP-1 and GLP receptors have been identified directly in the hypothalamo-pituitary ovary axis [80].

is involved in regulation of signaling pathways linked to GLP-1 release [84]. In line with this consideration are data from experimental rodent model where a single treatment with roflumilast enhanced plasma GLP-1 levels up to 2.5-fold [84]. A direct comparison of short-term intervention with liraglutide and roflumilast addressing weight management was performed in PCOS-related obesity [60]. It was demonstrated that both monotherapy with liraglutide and roflumilast were associated with significant weight reduction in obese PCOS when compared to metformin mono-

Incretin System: New Pharmacological Target in Obese Women with Polycystic Ovary Syndrome

http://dx.doi.org/10.5772/intechopen.70648

65

The endogenous incretins are quickly degraded by DPP4 in serum. Degradation of endogenous incretins can be prevented by DPP4 inhibitors. DPP4 inhibitors are taken orally and are used as antidiabetic agents. They influence glucose homeostasis through the enhancement of endogenous incretion hormones. As incretin enhances insulin secretion in response to meal, DPP4 inhibitors do not cause hypoglycemia. They have been reported to cause a 0.5–1% HbA1c reduction [85, 86]. Five DPP4 inhibitors are approved in the treatment of type 2 diabetes: sitagliptin, alogliptin, saxagliptin, vildagliptin and linagliptin. The role of enhancement of endogenous GLP-1 with DPP4 inhibitors in the treatment of obese PCOS patient is yet to be established. So far, only sitagliptin, alogliptin and saxagliptin were studied in PCOS (**Table 2**). The present evidences suggest that DPP4 inhibitors preserve beta cell function [23, 87]. The fact that body weight gain and associated insulin resistance lead to increased load of beta cells and consequent beta cell dysfunction give rise to thoughts that the use of DPP4 inhibitors in

Another aspect is weight management. The enhancement of endogenous incretin hormones by DPP4 inhibitors is generally described as being weight neutral, although modest weight reduction has been seen in some clinical trials, particularly when DPP4 inhibitors are used

> **Insulin resistance**

Sitagliptin Improved Decreased Less weight gain

Saxagliptin Improved Increased Decreased Decreased Reduction

Sitagliptin In combination

**T2DM development** **Weight**

compared to lifestyle

with metformin less weight gain compared to metformin monotherapy

**Insulin sensitivity**

therapy. Reduction of weight with liraglutide was greater than with roflumilast [60].

treatment of PCOS with high metabolic risk is reasonable.

**function**

Alogliptin Improved Increased Decreased

**Table 2.** Reported effects of treatment with DPP4 inhibitors in women with PCOS.

*2.4.5. DPP4 inhibitors in PCOS*

**Study DPP4 inhibitor Beta cell** 

Jensterle et al. [92]

Ferjan et al. [93]

Elkind-Hirsch et al. [94]

Jensterle Sever et al. [95]
