Polycystic trials investigated the use of liraglutide and metformin

Polycystic ovary syndrome (PCOS) is characterized as aheterogeneous genetic trait that causes menstrual irregularity, infertility,and insulin resistance in women of reproductive age.

1 In addition,PCOS includes an excess of androgen, and appearances of acne and obesity.2PCOS is known to be the most common endocrine/metabolic disorder in women.1Those who are at high risk and are likely to get the syndrome are womenthat are obese, diagnosed with diabetes, who have first-degree relatives withPCOS, or use anti-epileptic drugs such as valproic acid. 1 Thecurrent perspective of the cause of PCOS is thought to be a complex genetictrait in which different variants of the trait, as well as environmentalfactors that promote further development of the syndrome.

1 Variancein genes that regulate androgen biosynthesis/action, gonadotropinsecretion/action, ovarian folliculogenesis, insulin secretion/action, andweight/energy regulation are the main influences of PCOS. 1 Insulinresistance is often highlighted in PCOS however the etiology for increasedinsulin resistance is uncertain.1 The main environmental culpritthat can worsen the manifestations of PCOS is the presence of obesity. 1Overall, obesity will worsen the insulin resistance, increase the severity ofmenstrual dysfunction, and increase the risk of cardiovascular events inpatients with PCOS. 1                  Currenttreatment for PCOS focuses on weight loss and life-style changes which canreestablish ovulatory cycles and improve metabolic function.

3 Calorierestriction and exercise is suggested for women with PCOS and obesity. 3Drugs such as metformin can reduce insulin levels as well as reduce androgenproduction, however currently this methodology is no longer supported byclinical data. 3 Recent clinical trials investigated the use of liraglutideand metformin in patients with PCOS and its effect on weight loss. 4                  Apilot prospective, randomized, open-label designed clinical trial was conductedfor 12 weeks to assess the effectiveness of low dose liraglutide in combinationwith metformin versus high dose liraglutide alone in treatment of patients withobese PCOS.4 Thirty women that were obese with PCOS were recruitedinto the study. 4 The participants were randomized to a COMBO orLIRA3 group. In the COMBO group the participants received metformin up to 1000mg twice a day and liraglutide 1.

2 mg injected subcutaneously once every day. 4In the LIRA3 group, the participants received up to 3 mg of liraglutidesubcutaneously once every day.4 Anthropometric measurements such asheight, weight, and waist circumference were taken initially at baseline and atthe end of the study. 4                  Patientsthat were included in the study were women that had the type A phenotype ofPCOS which was diagnosed by the ASRM-ESHRE Rotterdam criteria. As well asanyone who had the presence of hyperandrogenemia, menses abnormalities, aged 18years to menopause, or obese. 4 Patients that were excluded in thestudy were those with a history of carcinoma, as well as those withcardiovascular, kidney, or hepatic disease. Any patients that were usingmedications that affected reproductive or metabolic functions were alsoexcluded from the study. 4                   Theprimary outcome of this clinical trial was assessing the mean change inmeasures of obesity in both groups by calculating the body mass index.

4The secondary outcome was assessing metabolic and hormonal changes usingvarious methods, assays, and analyzers. 4                  Statisticalanalyses were completed using IBM SPSS Statistics version 19.0. 4Logistic regressions were performed to compare the amount of patients losingabout 5% of weight. 4 A p-value of <0.05 was determined to bestatistically significant. 4 Each group had to have had at least 14patients to detect a statistically significant difference between the groups of2.5 kg in weight loss with 80% power.

4 The non-parametric Wilcoxonsigned-rank test was used to compare pre-treatment and post-treatment valueswithin the groups. 4 The non-parametric Mann-Whitney test was usedto compare pre-treatment values and change in clinical parameters between thetwo groups. 4                  Twopatients violated protocol and were discontinued from the study. 4 Twenty-eightpatients completed the study with an equal amount of 14 patients in the COMBOgroup and 14 in the LIRA3 group. 4 In reference to the primaryoutcome, there were statistically significant differences (all p-values <0.05) in weight, waist circumference, and BMI decrease within both groups atthe end of the study.

4 In comparison of absolute change betweenboth treatment groups, only BMI (p = 0.05) and waist circumference (p <0.05)were statistically significant. 4 35.7% of patients in the COMBO groupand 57.1% of patients in the LIRA3 group attained more than 5% weight decrease,yet the results between the two groups was not statistically significant. 4In reference to the secondary outcomes only the absolute mean change LDLcholesterol was statistically significant (p <0.

05).4 The common side effects that occurredin the LIRA3 group were nausea and diarrhea. One patient experienced vomitingand two experienced a mild headache. 4 The side effects occurredduring the first four weeks of the treatment. The common side effects thatoccurred in the COMBO group were nausea and mild diarrhea, as well as onepatient who experienced insomnia. The side effects subsided within the first fourweeks. 4 One hypoglycemic event occurred in the LIRA3 group.4 Allparticipants stayed in the study regardless of the side effects theyexperienced.

4 All things considered, the studyconcluded that treatment with liraglutide 3 mg monotherapy and liraglutide 1.2mg with metformin resulted in a great amount of within treatment weight lossand BMI decrease in obese patients with PCOS. 4 LIRA3 group resultswas also associated with waist circumference reduction.4 Within 12weeks, women in the LIRA3 group not only attained weight loss >5% but alsomay have improved their cardiovascular risk profile.

Two strengths in thisclinical study are: assessing multiple clinical parameters and use ofcombination therapy.4 Two weaknesses in this clinical study are:short duration of therapy and a small sample size. 4 The study wasalso open label so the women in each of the groups would know they were given adrug that has been stated in the media as weight loss drug.4 A similar clinical trial wasconducted with the sole purpose of investigating the change in eating behaviorof obese patients with PCOS upon using liraglutide.5 This study was ashort-term, 12-week intervention, assessed with a simple questionnaire andanthropometric measurements of obesity.5 Thirty-six women wererecruited into the study.

5 The patients that were included werethose: with a loss of less than 5% of body fat in the last 6 months, greaterthan 18 years of age, premenopausal, with a BMI greater then 30kg/m2,and who had been on metformin 2000 mg for about 6 months.5 Thepatients that were excluded in the study were those with: type 1 or type 2diabetes, a history of carcinoma, cardiovascular disease/kidney/liver disease,and the use of medications that affect reproductive/metabolic functions as wellas statins within 90 days before the study.5  The 36 obese women were treated withliraglutide 1.2 mg subcutaneously everyday for 12 weeks.

5The primary outcome for this studywas the change in the patient’s eating behavior through assessment by the Three-FactorEating Questionnaire (TFEQ-R18). The secondary outcome measures for this studywere the changes in the anthropometric measurements of obesity.5Eating behavior was assessed at baseline and the end of the study.5 Theanthropometric measurements that were taken were height, weight, waistcircumference, and blood pressure.5 The patients were given glucosemonitoring devices to measure their blood glucose and were told to communicateany side effects that occurred.5 In assessing the eating behavior,the TFEQ-R18 questionnaire measured three different components of the behavior:cognitive restraint (CR), uncontrolled eating (UE), and emotional eating (EE).Cognitive restraint is the ability to restrain oneself of eating in order tomanage their body weight.

5 Uncontrolled eating is the propensity toeat more due to the not having control of hunger.5 Emotional eatingis the when the patient uses food to suppress negative emotions.5 TheTFEQ-R18 involved 18 questions with responses of either definitely true, mostlytrue, mostly false, and definitely false.5 The responses were givena score between 1 to 4 in each category (CR, UE, EE) and then added up.

5The scores are then converted to a scale of 0-100 in each category.5 Thehigher the score signified greater CR, UU, or EE.5Statistical analysis was executedusing the SPSS 17.0 statistical software package.5 The differencebetween baseline and post-treatment was illustrated using paired samples t-testand Wilcoxon signed-rank test.5 A p-value of less than 0.05signified that the result was statistically significant.5                   Inreference to the primary outcome of this study, there were statisticallysignificant differences in the uncontrolled eating (decrease from 36.

8 ± 24.5to 19.6 ± 18.4) and emotional eating score (49.9 ± 33.3 to 28.5 ± 26.

9).5There were no changes in the cognitive restraint scores (52.8 ± 18.3 vs. 52.5 ±22.

0). In reference to the secondary outcomes of this study, there werestatistical significance in body weight, waist circumference, and BMI (p <0.001).5 Liraglutide administration resulted in a substantialdecrease in these measures.

5 Common side effects that occurredduring the study were nausea, diarrhea, headache, and insomnia.5There were four patients that experienced hypoglycemia.5                                    All things considered, this studyillustrated that short-term intervention of liraglutide enhanced eatingbehavior which coincided with significant weight-loss in obese PCOS patients.5Uncontrolled eating and emotional eating decreased and was correlated todecrease in weight, which decreased BMI, and was ultimately on the verge ofdecreasing obesity.5 Two strengths in this study are the use of differentassessments: questionnaire and anthropometric measurements at baseline and atthe end of the study.5 Two weaknesses in this clinical study is thattrial was not randomized and the population was small.5                                    Ultimately, the two clinical trialsthat were studied had similar outcomes.

Liraglutide either given by itself orin combination with metformin shows a significant amount of weight loss inobese patients with PCOS.4 The first study concluded that short-termmonotherapy with liraglutide 3 mg or treatment with both liraglutide andmetformin resulted in substantial weight loss and BMI decrease in obesepatients with PCOS.4 The second study concluded that liraglutidegiven to obese women with PCOS benefit with better eating habits andsignificant weight loss.5 Given that liraglutide improved the eatinghabits, showed significant weight loss, decrease in waist circumference, anddecrease in BMI in these patients, I would recommend liraglutide as aweight-loss adjunct in patients with polycystic ovary syndrome.