Polycystic trials investigated the use of liraglutide and metformin

Polycystic ovary syndrome (PCOS) is characterized as a
heterogeneous 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.2
PCOS is known to be the most common endocrine/metabolic disorder in women.1
Those who are at high risk and are likely to get the syndrome are women
that are obese, diagnosed with diabetes, who have first-degree relatives with
PCOS, or use anti-epileptic drugs such as valproic acid. 1 The
current perspective of the cause of PCOS is thought to be a complex genetic
trait in which different variants of the trait, as well as environmental
factors that promote further development of the syndrome. 1 Variance
in genes that regulate androgen biosynthesis/action, gonadotropin
secretion/action, ovarian folliculogenesis, insulin secretion/action, and
weight/energy regulation are the main influences of PCOS. 1 Insulin
resistance is often highlighted in PCOS however the etiology for increased
insulin resistance is uncertain.1 The main environmental culprit
that can worsen the manifestations of PCOS is the presence of obesity. 1
Overall, obesity will worsen the insulin resistance, increase the severity of
menstrual dysfunction, and increase the risk of cardiovascular events in
patients with PCOS. 1

                  Current
treatment for PCOS focuses on weight loss and life-style changes which can
reestablish ovulatory cycles and improve metabolic function. 3 Calorie
restriction and exercise is suggested for women with PCOS and obesity. 3
Drugs such as metformin can reduce insulin levels as well as reduce androgen
production, however currently this methodology is no longer supported by
clinical data. 3 Recent clinical trials investigated the use of liraglutide
and metformin in patients with PCOS and its effect on weight loss. 4

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                  A
pilot prospective, randomized, open-label designed clinical trial was conducted
for 12 weeks to assess the effectiveness of low dose liraglutide in combination
with metformin versus high dose liraglutide alone in treatment of patients with
obese PCOS.4 Thirty women that were obese with PCOS were recruited
into the study. 4 The participants were randomized to a COMBO or
LIRA3 group. In the COMBO group the participants received metformin up to 1000
mg twice a day and liraglutide 1.2 mg injected subcutaneously once every day. 4
In the LIRA3 group, the participants received up to 3 mg of liraglutide
subcutaneously once every day.4 Anthropometric measurements such as
height, weight, and waist circumference were taken initially at baseline and at
the end of the study. 4

                  Patients
that were included in the study were women that had the type A phenotype of
PCOS which was diagnosed by the ASRM-ESHRE Rotterdam criteria. As well as
anyone who had the presence of hyperandrogenemia, menses abnormalities, aged 18
years to menopause, or obese. 4 Patients that were excluded in the
study were those with a history of carcinoma, as well as those with
cardiovascular, kidney, or hepatic disease. Any patients that were using
medications that affected reproductive or metabolic functions were also
excluded from the study. 4

                  The
primary outcome of this clinical trial was assessing the mean change in
measures of obesity in both groups by calculating the body mass index. 4
The secondary outcome was assessing metabolic and hormonal changes using
various methods, assays, and analyzers. 4

                  Statistical
analyses were completed using IBM SPSS Statistics version 19.0. 4
Logistic regressions were performed to compare the amount of patients losing
about 5% of weight. 4 A p-value of <0.05 was determined to be statistically significant. 4 Each group had to have had at least 14 patients to detect a statistically significant difference between the groups of 2.5 kg in weight loss with 80% power. 4 The non-parametric Wilcoxon signed-rank test was used to compare pre-treatment and post-treatment values within the groups. 4 The non-parametric Mann-Whitney test was used to compare pre-treatment values and change in clinical parameters between the two groups. 4                   Two patients violated protocol and were discontinued from the study. 4 Twenty-eight patients completed the study with an equal amount of 14 patients in the COMBO group and 14 in the LIRA3 group. 4 In reference to the primary outcome, there were statistically significant differences (all p-values < 0.05) in weight, waist circumference, and BMI decrease within both groups at the end of the study. 4 In comparison of absolute change between both treatment groups, only BMI (p = 0.05) and waist circumference (p <0.05) were statistically significant. 4 35.7% of patients in the COMBO group and 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. 4 In reference to the secondary outcomes only the absolute mean change LDL cholesterol was statistically significant (p <0.05).4 The common side effects that occurred in the LIRA3 group were nausea and diarrhea. One patient experienced vomiting and two experienced a mild headache. 4 The side effects occurred during the first four weeks of the treatment. The common side effects that occurred in the COMBO group were nausea and mild diarrhea, as well as one patient who experienced insomnia. The side effects subsided within the first four weeks. 4 One hypoglycemic event occurred in the LIRA3 group.4 All participants stayed in the study regardless of the side effects they experienced. 4 All things considered, the study concluded that treatment with liraglutide 3 mg monotherapy and liraglutide 1.2 mg with metformin resulted in a great amount of within treatment weight loss and BMI decrease in obese patients with PCOS. 4 LIRA3 group results was also associated with waist circumference reduction.4 Within 12 weeks, women in the LIRA3 group not only attained weight loss >5% but also
may have improved their cardiovascular risk profile. Two strengths in this
clinical study are: assessing multiple clinical parameters and use of
combination therapy.4 Two weaknesses in this clinical study are:
short duration of therapy and a small sample size. 4 The study was
also open label so the women in each of the groups would know they were given a
drug that has been stated in the media as weight loss drug.4

A similar clinical trial was
conducted with the sole purpose of investigating the change in eating behavior
of obese patients with PCOS upon using liraglutide.5 This study was a
short-term, 12-week intervention, assessed with a simple questionnaire and
anthropometric measurements of obesity.5 Thirty-six women were
recruited into the study.5 The patients that were included were
those: with a loss of less than 5% of body fat in the last 6 months, greater
than 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 The
patients that were excluded in the study were those with: type 1 or type 2
diabetes, a history of carcinoma, cardiovascular disease/kidney/liver disease,
and the use of medications that affect reproductive/metabolic functions as well
as statins within 90 days before the study.5  The 36 obese women were treated with
liraglutide 1.2 mg subcutaneously everyday for 12 weeks.5

The primary outcome for this study
was the change in the patient’s eating behavior through assessment by the Three-Factor
Eating Questionnaire (TFEQ-R18). The secondary outcome measures for this study
were the changes in the anthropometric measurements of obesity.5
Eating behavior was assessed at baseline and the end of the study.5 The
anthropometric measurements that were taken were height, weight, waist
circumference, and blood pressure.5 The patients were given glucose
monitoring devices to measure their blood glucose and were told to communicate
any 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 to
manage their body weight.5 Uncontrolled eating is the propensity to
eat more due to the not having control of hunger.5 Emotional eating
is the when the patient uses food to suppress negative emotions.5 The
TFEQ-R18 involved 18 questions with responses of either definitely true, mostly
true, mostly false, and definitely false.5 The responses were given
a score between 1 to 4 in each category (CR, UE, EE) and then added up.5
The scores are then converted to a scale of 0-100 in each category.5 The
higher the score signified greater CR, UU, or EE.5

Statistical analysis was executed
using the SPSS 17.0 statistical software package.5 The difference
between baseline and post-treatment was illustrated using paired samples t-test
and Wilcoxon signed-rank test.5 A p-value of less than 0.05
signified that the result was statistically significant.5

                  In
reference to the primary outcome of this study, there were statistically
significant differences in the uncontrolled eating (decrease from 36.8 ± 24.5
to 19.6 ± 18.4) and emotional eating score (49.9 ± 33.3 to 28.5 ± 26.9).5
There 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 were
statistical significance in body weight, waist circumference, and BMI (p < 0.001).5 Liraglutide administration resulted in a substantial decrease in these measures.5 Common side effects that occurred during the study were nausea, diarrhea, headache, and insomnia.5 There were four patients that experienced hypoglycemia.5                                     All things considered, this study illustrated that short-term intervention of liraglutide enhanced eating behavior which coincided with significant weight-loss in obese PCOS patients.5 Uncontrolled eating and emotional eating decreased and was correlated to decrease in weight, which decreased BMI, and was ultimately on the verge of decreasing obesity.5 Two strengths in this study are the use of different assessments: questionnaire and anthropometric measurements at baseline and at the end of the study.5 Two weaknesses in this clinical study is that trial was not randomized and the population was small.5                                     Ultimately, the two clinical trials that were studied had similar outcomes. Liraglutide either given by itself or in combination with metformin shows a significant amount of weight loss in obese patients with PCOS.4 The first study concluded that short-term monotherapy with liraglutide 3 mg or treatment with both liraglutide and metformin resulted in substantial weight loss and BMI decrease in obese patients with PCOS.4 The second study concluded that liraglutide given to obese women with PCOS benefit with better eating habits and significant weight loss.5 Given that liraglutide improved the eating habits, showed significant weight loss, decrease in waist circumference, and decrease in BMI in these patients, I would recommend liraglutide as a weight-loss adjunct in patients with polycystic ovary syndrome.