**3. Conclusion**

in combination with metformin [88, 89]. Nevertheless, the mere fact that DPP4 inhibition is not associated with the weight gain that typically accompanies improved glycemic control in patients with T2DM suggests that DPP4 inhibitors may not be completely neutral in this respect [90]. Slowing of gastric emptying that might reinforce the sustained change of eating

The first study addressing the preservation of beta cell function in PCOS with DPP4 inhibitor reported an increase of insulin sensitivity and significant decrease of insulin resistance when alogliptin was added to metformin. Even greater improvement of these parameters was seen when triplet therapy with alogliptin, pioglitazone and metformin was used [92]. Beneficial effects of another DPP4 inhibitor sitagliptin were recently reported in metformin intolerant women with PCOS and high metabolic risk. After metformin withdrawal, a 12-week treatment with sitagliptin leads to significant improvement in beta cell function and prevented conversion rate from normal to impaired glucose tolerance and type 2 diabetes when compared to placebo [93]. Preliminary data suggest that DPP4 inhibitors seem to be a promising alternative in PCOS women with high metabolic risk who have failed with lifestyle intervention and are metformin intolerant. Future larger designs of longer duration should be powered.

A small single blind, randomized study on prediabetic PCOS women reported beneficial effect of DPP4 inhibitor saxagliptin on glucose homeostasis, metabolic parameters and clinical status. A 16-week intervention with saxagliptin/metformin (5 mg/2000 mg), monotherapy with saxagliptin (5 mg) and monotherapy with metformin (2000 mg) lead to normalization in glucose homeostasis in 91, 55 and 25% of patients, respectively. Improvement of metabolic

In a recent randomized study, another potential use of DPP4 inhibitors was demonstrated. Enhancement of endogenous GLP-1 signaling by sitagliptin prevented the expected weight regain after liraglutide 3.0 mg cessation in women with PCOS. During a 12-week follow-up period, sitagliptin in adjunct to metformin resulted in weight maintenance, whereas a switch to metformin alone resulted in a significant weight regain after liraglutide discontinuation. It was also demonstrated that the ability to resist emotional eating was greater in combined treatment than in monotherapy with metformin [95]. The observation provides first clinical findings suggesting that DPP4 inhibition may prevent weight regain after liraglutide cessation. This sequential treatment concept is particularly useful in patients who became intolerant, develop treatment resistance or decide to stop the antiobesity treatment with liraglutide. Further research is necessary to fully understand the cross talks between effects of peripheral signals of endogenous GLP-1 and central areas of satiety and reward in obese subjects.

Bariatric surgery is a well-established and effective method for the treatment of extreme obesity for

bidity related to obesity and who have been previously unsuccessful with medical treatment for obesity [96]. The mechanism of weight loss induced by bariatric surgery is multifactorial. Beside reduced gastric volume [97, 98], weight reduction could be possibly explained with the changes in gut-brain axis. Gastrointestinal bypass surgery results in a quick delivery of nutrients to the small intestine associated with large increase in postprandial levels of GLP1 and PYY hormones

or >35 kg/m<sup>2</sup>

, with at least one comor-

parameters and clinical status was reported in all groups [94].

well-informed and motivated patients with a BMI > 40 kg/m<sup>2</sup>

*2.4.6. Bariatric surgery in PCOS*

66 Debatable Topics in PCOS Patients

behavior was also demonstrated with treatment with DPP4 inhibitor sitagliptin [91].

Agents mediating through GLP-1 effects in combination with lifestyle intervention and metformin could potentially improve treatment outcomes in obese PCOS via co-targeting multifactorial origin of obesity and concomitant abnormalities intrinsically related to PCOS. Based on the limited available data, GLP-1RAs, in particular liraglutide, should be considered in obese PCOS. Enhanced understanding of the direct impact on GLP-1 beyond weight reducing and metabolic effects at the levels of pituitary and ovary are expected within the next 5 years [51]. Larger and longer randomized studies are needed to establish metabolic, reproductive and cardiovascular risk reduction and assess sustainability and safety profile of the benefits achieved by these potential new treatment strategies.
