http://informahealthcare.com/erc ISSN: 0743-5800 (print), 1532-4206 (electronic) Endocr Res, Early Online: 1–6 ! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/07435800.2014.966385
ORIGINAL ARTICLE
Short-term intervention with liraglutide improved eating behavior in obese women with polycystic ovary syndrome Mojca Jensterle, Tomaz Kocjan, Nika Aleksandra Kravos, Marija Pfeifer, and Andrej Janez
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Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre Ljubljana, Ljubljana, Slovenia
Abstract
Keywords
Aim: Glucagon-like peptide 1 receptor agonists (GLP-1 RA) stimulate satiety leading to reductions in food intake and body weight. The effects of long- acting GLP-1 RA liraglutide on eating behavior of women with PCOS have not been investigated yet. Methods: Thirty-six obese women with PCOS (mean ± SD, aged 31.2 ± 7.8 years, with BMI 38.7 ± 0.1 kg/m2), pretreated with metformin (1000 mg BID) were switched to liraglutide 1.2 mg QD sc for 12 weeks. Adiposity parameters and eating behavior as assessed by Three-Factor Eating Questionnaire (TFEQ-R18) were examined at baseline and after 12 weeks. Results: Subjects treated with liraglutide lost on average 3.8 ± 0.1 kg (p50.001). Significant reductions of waist circumference and visceral adipose tissue (VAT) mass, volume and area were demonstrated from liraglutide induction to the end of the study. TFEQ-R18 scores were significantly different pre- and postliraglutide intervention. After treatment with liraglutide the uncontrolled eating (UE) score decreased from 36.8 ± 24.5 to 19.6 ± 18.4 (p50.001) and emotional eating (EE) score decreased from 49.9 ± 33.3 to 28.5 ± 26.9 (p50.001). Scores for cognitive restraint (CR) were not changed. Conclusions: Short-term liraglutide treatment was associated with weight loss and significantly improved eating behavior in obese women with PCOS.
Eating behavior, liraglutide, obesity, PCOS, TFEQ-R18
Introduction Eating behavior is a complex pattern regulated by cognitive functions and emotional inputs. An inability to control this behavior is the main culprit for eating beyond metabolic needs that result in obesity. Obesity is frequently associated with polycystic ovary syndrome (PCOS), the most common endocrine disorder in premenopausal women (1–5).There is some evidence that unique abnormalities in eating behavior contribute to difficulties in weight reduction this population (6,7). Effective anti-obesity treatment should target regulation of eating behavior. Glucagon-like peptide-1 (GLP-1) based therapy was recently introduced as a new treatment for patients with type 2 diabetes mellitus. GLP-1 receptor agonists (GLP-1 RA) enhance the endogenous secretion of insulin induced by meal ingestion and inhibit glucagon secretion, thereby improving glucose homeostasis. In addition, they also inhibit appetite what often results in weight loss linked to changed eating behavior in obese patients with type 2 diabetes mellitus. Such improvement in eating behavior has not been reported for other glucose-lowering agents (8,9). These agents are only approved for the management of type 2
Correspondence: Mojca Jensterle, Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre Ljubljana, Zaloska 7, SI-1525 Ljubljana, Slovenia. E-mail: [email protected]
History Received 30 April 2014 Revised 11 July 2014 Accepted 8 September 2014 Published online 20 October 2014
diabetes. Experiences with the use of GLP-1 RA in patients with PCOS are very limited. We have previously shown that obese women with PCOS who had not responded to standard weight loss strategies and metformin treatment might benefit from short-term intervention with long-acting GLP-1 RA liraglutide as an add-on therapy to metformin regarding weight loss (10). Another study of PCOS women provided evidence that combined treatment with short-acting GLP-1 RA exenatide and metformin was superior to exenatide and metformin monotherapies in improving their weight loss (11). In the present study we investigated the effects of shortterm 12-week liraglutide intervention on eating behavior of obese women with PCOS who had lost less than 5% body weight during 6-month pre-treatment with metformin. For the assessment of eating behavior before and after the intervention we used a simple questionnaire applicable in clinical practice.
Subjects and methods Thirty-six women previously diagnosed to have PCOS by the National Institute of Child Health and Human Development (NICHD) criteria (12) were recruited from the outpatients Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre Ljubljana. Before recruitment they were treated with metformin because they had metabolic disturbances and/or anovulation. They were eligible for enrolment if they had lost less than 5% of body
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weight in the last 6 months, were more than 18 years old, premenopausal, obese (body mass index (BMI) 30 kg/m2), had been taking metformin 2000 mg for at least 6 months. Exclusion criteria were known type 1 or type 2 diabetes mellitus, history of carcinoma, personal or family history of MEN 2, significant cardiovascular, kidney or liver disease and the use of medications other than metformin known or suspected to affect reproductive or metabolic functions, or statins, within 90 days prior to study entry. All subjects were informed of the study aims and provided written consent before entering the study, which was conducted in accordance with the Declaration of Helsinki and approved by the National Ethical Committee. The study is registered with clinicaltrials.gov No/NCT01911468.
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Experimental protocol In 36 obese women with PCOS metformin was discontinued and they were switched to liraglutide at a dose of 0.6 mg injected sc once per day and increased to 1.2 mg/day after 1 week. They were taking liraglutide for 12 weeks. The primary outcome was change in eating behavior. Prespecified secondary outcomes were changes in anthropometric measures of obesity. At baseline and at study endpoint an eating behavior was assessed in all patients. They underwent standard anthropometric measurements: height, weight, waist circumference and blood pressure. Waist circumference was measured in a standing position midway between the lower costal margin and the iliac crest. BMI was calculated as the weight in kilograms divided by square of height in meters. Moreover, measurement of whole-body composition by a Hologic Dualenergy X-ray Absorptiometry (DXA) was performed in all subjects at baseline and at study endpoint as described previously (13). We assumed that different phases of the menstrual cycle had little or no effect on body weight and body composition (14). A fasting blood was drawn for determination of glucose, insulin, luteinizing hormone (LH), follicle stimulating hormone (FSH), androstenedione, dehydroepiandrosterone sulphate (DHEAS), total and free testosterone followed by a standard 75 g oral glucose tolerance test (OGTT). Safety parameters (complete blood count, markers of hepatic and renal function and serum electrolytes) were assessed before and after 12 weeks of study treatment. All blood samples were centrifuged and the separated serum was kept frozen at 80 C until the time of the assay. Since many of the patients were oligoamenorrhoic during the previous year, the assessment of the subjects was not based on any specific stage of the menstrual cycle. Pregnancy was excluded by measuring b-human chorionic gonadotropin. Women were advised to strictly use barrier contraception. All patients were provided with glucose-monitoring devices, medication supplies and educated on their use. They were instructed to measure blood glucose levels at any signs and symptoms suggesting low blood glucose. Hypoglycemia was defined according to American Diabetes Association criteria as symptoms suggestive of low blood glucose confirmed by self-monitored blood glucose measurement below 3.9 mmol/l (15). They were also instructed to report any side effects during the treatment. An energy restricted diet
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(500–800 kcal/day reduction made up of 50% carbohydrates, 20% proteins and 30% of fat with increased consumption of fiber, whole grain breads, cereals, fruits and vegetables) along with at least 30 min of moderate intensity physical activity daily had been recommended to all women when the diagnosis of PCOS had been confirmed and metformin had been initially prescribed. At the beginning of the study lifestyle intervention was not again actively promoted or intensified. Assessment of eating behavior Eating behavior was assessed by using a Slovenian translation of Three-Factor Eating Questionnaire TFEQ-R18 (16). The instrument is a shortened and revised version of the original 51-item TFEQ (17). The translation of the Slovenian version had been back-translated by a native English speaker and evaluated as required. The questionnaire measures three different aspects of eating behavior: cognitive restraint (CR) referring to conscious restriction of food intake in order to control body weight or to promote weight loss, uncontrolled eating (UE) referring to tendency to eat more than usual due to a loss of control over intake accompanied by subjective feelings of hunger, and emotional eating (EE) referring to inability to resist emotional cues. The TFEQ-R18 consists of 18 items on a 4-point response scale (definitely true/mostly true/mostly false/definitely false). Responses to each of the 18 items are given a score between 1 and 4 and item scores are summed up into scale scores for CR, UE, and EE (16,17). The raw scale scores are transformed to a 0–100 scale [raw score lowest possible raw score)/possible raw score range 100] and the commonly used ‘‘half-scale’’ method is utilized to compensate for missing data on some items. Higher scores in the respective scales are indicative of greater CR, UE, or EE. Assays Glucose levels were determined using a standard glucose oxidase method (Beckman Coulter Glucose Analyzer, Beckman Coulter Inc., Brea, CA). LH and FSH were determined using an immunometric assay (Diagnostic Products Corporation, Los Angeles, CA). Androstenedione and DHEAS were measured by specific double antibody RIA using 125 I-labeled hormones (Diagnostic Systems Laboratories, Webster, TX). Total and free testosterone levels were measured by coated tube RIA (DiaSorin, S. p. A, Salluggia, Italy and Diagnostic Products Corporation, Los Angeles, CA, respectively). Insulin was determined by immunoradiometric assay (Biosource Europe S.A., Nivelles, Belgium). Intraassay variations ranged from 1.6 to 6.3%, and interassay variations ranged from 5.8 to 9.6% for the applied methods. Pre- and post-treatment samples from each patient were assayed in the same assay run. Determination of insulin resistance (IR) Homeostasis model assessment (HOMAIR) score calculation was applied as a measure for IR. The estimate of IR by HOMAIR score was calculated with the following formula: fasting serum insulin (mU/L) fasting plasma glucose (mmol/L)/22.5 (18).
Liraglutide and eating behavior in PCOS
DOI: 10.3109/07435800.2014.966385
Assessment of human body composition by Dual Energy X-ray Absorptiometry Whole-body composition was assessed by a DXA (Discovery A; Hologic, Waltham, MA) with the software provided by the manufacturer (QDR for Windows Version 12.5). The instrument generates values for whole-body fat mass, lean body mass and bone mineral content and all these parameters separately for different body parts.
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Statistical analysis Results are presented as mean ± standard deviation (SD). Normal data distribution was checked with the Shapiro–Wilk test. The differences between treatment groups were checked and confirmed using paired samples t-test and Wilcoxon signed-rank test. p value of less than 0.05 was considered statistically significant. All statistical analyses were performed using the SPSS 17.0 statistical software package (International Business Machines Corporation, Armonk, NY).
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and emotional eating score (EE) decreased from 49.9 ± 33.3 to 28.5 ± 26.9 (p50.001). Scores for cognitive restraint (CR) did not change (52.8 ± 18.3 before intervention versus 52.5 ± 22.0; p ¼ 0.939; Figure 1). EE was significantly correlated with weight loss (r ¼ 0.344, p ¼ 0.040). Weight change Liraglutide administration was associated with significant decrease in body mass, BMI and waist circumference (p50.001 for the treatment/time effect). In addition, significant reductions of total body % fat and visceral adipose tissue (VAT) mass, volume and area as assessed by DXA were demonstrated from liraglutide induction to the end of the study (p50.001 and p ¼ 0.003, p ¼ 0.003 and p ¼ 0.003, respectively). At 3 months an average visceral adipose tissue
Results We recruited 36 obese women with PCOS aged 31.2 ± 7.8 years with BMI 38.7 ± 0.1 kg/m2. Baseline and post-treatment characteristics are presented in Table 1. Assessment of eating behavior After treatment with liraglutide the uncontrolled eating score (UE) decreased from 36.8 ± 24.5 to19.6 ± 18.4 (p50.001) Table 1. Baseline and 12-week post-treatment measures of obesity, metabolic and endocrine parameters in 36 obese women with PCOS.
Body weight Waist circumference BMI LH FSH DHEAS Androstenedione Total testosterone Free testosterone SHBG Fasting glucose Glucose during OGTT – 1200 Fasting insulin Insulin during OGTT – 1200 HOMA index Total body % fat VAT mass (g) by DXA VAT volume (cm3) by DXA VAT area (cm2) by DXA
Baseline Mean ± standard deviation
Post-treatment Mean ± standard deviation
Statistical significance
107.5 ± 17.7 123.2 ± 13.1 38.7 ± 5 7.1 ± 7.9 4.7 ± 2.4 5.1 ± 2.9 8.6 ± 4 1.8 ± 1.2 6.7 ± 3.6 28.6 ± 24.7 5.3 ± 0.6 7.4 ± 1.7
103.7 ± 17.8 119.8 ± 13.6 37.3 ± 5.2 7.4 ± 5.8 5.1 ± 2.1 5.1 ± 3 8.7 ± 4.6 1.7 ± 1.1 5.7 ± 3.5 27.6 ± 11.8 4.8 ± 0.5 5.5 ± 1.1
0.000 0.000 0.000 0.082 0.322 0.678 0.914 0.606 0.056 0.133 0.000 0.000
12 ± 8.4 102.2 ± 81.3
12.5 ± 7.1 92.9 ± 84
0.242 0.029
2.9 ± 2.4 45.7 ± 3.3 781.1 ± 278
2.7 ± 1.7 44.4 ± 3.6 731.9 ± 253.8
0.893 0.000 0.003
844.5 ± 300.6
791.1 ± 274.3
0.003
162.1 ± 57.7
151.8 ± 52.6
0.003
Legend: BMI-body mass index, LH- luteinizing hormone, FSH- follicle stimulating hormone, DHEAS- dehydroepiandrosterone sulphate, SHBG-sex hormone binding globulin, OGTT- oral glucose tolerance test, HOMA- Homeostasis model assessment, VAT- visceral adipose tissue, DXA-Dual-energy X-ray Absorptiometry.
Figure 1. Changes in the scores of eating behavior induced by liraglutide as assessed by Three-Factor Eating Questionnaire TFEQ-R18: uncontrolled (A), emotional (B) and restraint (C) eating.
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(VAT) area decreased below 160 cm2 threshold that is associated with high risk for cardiovascular disease in women (19). The results are shown in Table 1. Metabolic changes HOMAIR score values tended to be reduced after intervention, but did not significantly decrease. Fasting glucose and glucose values after 120 min during OGTT were significantly reduced by liraglutide (p50.001). A significant decrease in insulin levels at 120 min of OGTT was also observed (p ¼ 0.003). Endocrine changes
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No statistically significant change in hormonal profile was found (Table 1). Adverse events Adverse events associated with liraglutide were nausea (9/36), diarrhea (11/36), headache (3/36) and insomnia (2/36). Four patients reported hypoglycemic events. Gradual dose titration reduced the gastrointestinal side effects associated with liraglutide.
Discussion We demonstrated that short-term liraglutide treatment significantly improved eating behavior in obese patients with PCOS and that this improvement correlated with weight loss in these patients. It hasn’t been established whether eating behavior is different in obese women with PCOS when compared to weight matched non-PCOS controls. The reports are few and the results are not conclusive. There is evidence that disturbed regulation of satiety peptides is intrinsic to PCOS (6,7,20,21). Furthermore, an increased frequency of PCOS was found in bulimic women, suggesting that androgens have appetitestimulating effects and could impair the impulse control of eating behavior (21). Disturbed appetite was also associated with altered opioid function demonstrated in PCOS linked to the stimulation of food intake and appetite for high fat/high glucose food through amygdala and nucleus accumbens reward circuits (22). In addition, there are few conflicting reports on the impaired secretion of endogenous GLP-1 in PCOS patients (23,24). Recognizing the important role of endogenous GLP-1 in promoting satiety and suppression of energy intake in animals (25,26) and humans (27–30), the impaired secretion pattern of GLP-1 might contribute to the pathogenesis of PCOS. GLP-1 RA are unique in their ability to regulate metabolism and eating behavior. Relevant effects of their action are widely distributed. They act in the hypothalamus, hindbrain and in the mesolimbic reward system, resulting in altering many components of eating behavior. Stimulation of mesolimbic GLP-1R is sufficient to reduce hunger-driven feeding, the hedonic value of food and food-motivation (31). In two studies liraglutide produced significant improvements in all major scores of eating behavior questionnaire that was similar to ours in obese patients with type 2 diabetes mellitus. The effect was maintained throughout the 6 months after
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discontinuation of liraglutide. It significantly reduced the urge for fat intake (8,9). Such improvement in eating behavior induced by liraglutide has not been reported for other glucoselowering agents. The influence of GLP-1 RA on eating behavior has never been investigated in PCOS. In the present study we demonstrated significantly improved eating behavior as assessed by TFEQ-R18 after short-term intervention with liraglutide in obese women with PCOS pretreated with metformin. Uncontrolled and emotional eating significantly decreased whereas restrained eating remained unchanged. Emotional eating score was significantly correlated with weight loss. Previously, TFEQ-R18 questionnaire had been shown to be able to distinguish among different eating patterns in a general population. Higher scores on restrained eating had been associated with a lower energy intake. Energy intake increased with uncontrolled eating scores. Higher cognitive restraint was positively associated with consuming healthy food groups and negatively associated with consumption of French fries and sugar. Energy-dense foods, such as fat, were positively associated with uncontrolled eating scores. Finally, emotional eaters had a higher snacking food intake (16). Similarly to observations in our study, liraglutide was associated with dose-escalation nausea and other gastrointestinal adverse effects in trials of liraglutide for type 2 diabetes. Nausea and other gastrointestinal side effects are reported by up to 40% of individuals on liraglutide 1.2 mg per day, but are mostly mild and transient and generally tolerable. The contribution of these adverse events to reductions in appetite and energy intake is less clear, but is definitely not considered as the main mechanism behind liraglutide induced weight loss. Weight loss in diabetic population was significantly greater for individuals on liraglutide than for those on placebo whether they did or did not reported nausea or diarrhea or vomiting (32). In addition to improved eating behavior correlated with weight reduction, we observed a significant beneficial reduction of waist circumference (WC) and visceral fat adiposity (VFA) as assessed by DXA. The weight reduction is in agreement with the well-known evidence that treatment with GLP-1 RA results in clinically relevant progressive and sustained weight loss when given to obese patients with or without diabetes (9,33,34). The exact interrelationship between the relevant amounts of visceral and subcutaneous adipose tissue loss in patients treated with GLP-1 RA is not fully clarified (35). The LEAD-2 trial showed that liraglutide significantly decreased WC and VFA compared to glimepiride, while there was no significant difference in the reduction of WC and VFA between liraglutide and placebo (34). In another study WC and VFA did not change while obese patients with type 2 diabetes mellitus were treated with insulin and/or oral glucose-lowering agents but reduced significantly after introduction of liraglutide (9). Liraglutide administration and weight loss were not associated with statistically significant improvement of androgen profile and IR in our patients. The failure to significantly influence the androgen levels may be due to a relatively small number of patients and generally-known methodological problem for assessment of androgens in PCOS. Similarly, the lack of statistically significant difference
DOI: 10.3109/07435800.2014.966385
in IR as assessed by HOMAIR score may be due to small sample size and short duration. In addition, large variability in IR calculated using HOMAIR score in women with PCOS and relatively low sensitivity of HOMAIR score method in detecting specific form of IR that characterizes PCOS were reported in other trails (36,37). The present study has some limitations. It was not designed as a randomized clinical trial (RCT) or a crossover study and was performed in a small population. Longer term larger RCT are warranted to more thoroughly elucidate the effect of GLP-1 RA in PCOS population. However, the main strength of our study is the implication of simple tool applicable in routine clinical practice that is able to assess a neglected and undiscovered impact on eating behavior in weight reduction approaches.
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Conclusion Our study is the first to imply that obese women with PCOS who have not responded to standard weight-loss strategies and metformin treatment might benefit from short-term intervention with a long acting GLP-1 agonist liraglutide. We provide preliminary data that 12-week treatment with liraglutide was associated with the improved eating behavior and that significantly decreased emotional eating tended to correlate with a substantial weight loss. A short-term safety profile was acceptable. We underscore that the assessment of eating behavior by an appropriate questionnaire should become an integral part of anti-obesity management in PCOS representing a simple and useful tool in estimation of treatment efficacy.
Acknowledgements The authors would like to thank Franci Cucek and Ziga Krizaj for statistical analysis. We appreciate the assistance of Mirela Ozura and Elizabeta Stepanovic, RNs.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of paper. The study was supported by grant Number 20120047 of the University Medical Centre Ljubljana, Slovenia. The study is registered with clinicaltrials.gov No/NCT01911468.
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ORIGINAL ARTICLE
Short-term intervention with liraglutide improved eating behavior in obese women with polycystic ovary syndrome Mojca Jensterle, Tomaz Kocjan, Nika Aleksandra Kravos, Marija Pfeifer, and Andrej Janez
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Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre Ljubljana, Ljubljana, Slovenia
Abstract
Keywords
Aim: Glucagon-like peptide 1 receptor agonists (GLP-1 RA) stimulate satiety leading to reductions in food intake and body weight. The effects of long- acting GLP-1 RA liraglutide on eating behavior of women with PCOS have not been investigated yet. Methods: Thirty-six obese women with PCOS (mean ± SD, aged 31.2 ± 7.8 years, with BMI 38.7 ± 0.1 kg/m2), pretreated with metformin (1000 mg BID) were switched to liraglutide 1.2 mg QD sc for 12 weeks. Adiposity parameters and eating behavior as assessed by Three-Factor Eating Questionnaire (TFEQ-R18) were examined at baseline and after 12 weeks. Results: Subjects treated with liraglutide lost on average 3.8 ± 0.1 kg (p50.001). Significant reductions of waist circumference and visceral adipose tissue (VAT) mass, volume and area were demonstrated from liraglutide induction to the end of the study. TFEQ-R18 scores were significantly different pre- and postliraglutide intervention. After treatment with liraglutide the uncontrolled eating (UE) score decreased from 36.8 ± 24.5 to 19.6 ± 18.4 (p50.001) and emotional eating (EE) score decreased from 49.9 ± 33.3 to 28.5 ± 26.9 (p50.001). Scores for cognitive restraint (CR) were not changed. Conclusions: Short-term liraglutide treatment was associated with weight loss and significantly improved eating behavior in obese women with PCOS.
Eating behavior, liraglutide, obesity, PCOS, TFEQ-R18
Introduction Eating behavior is a complex pattern regulated by cognitive functions and emotional inputs. An inability to control this behavior is the main culprit for eating beyond metabolic needs that result in obesity. Obesity is frequently associated with polycystic ovary syndrome (PCOS), the most common endocrine disorder in premenopausal women (1–5).There is some evidence that unique abnormalities in eating behavior contribute to difficulties in weight reduction this population (6,7). Effective anti-obesity treatment should target regulation of eating behavior. Glucagon-like peptide-1 (GLP-1) based therapy was recently introduced as a new treatment for patients with type 2 diabetes mellitus. GLP-1 receptor agonists (GLP-1 RA) enhance the endogenous secretion of insulin induced by meal ingestion and inhibit glucagon secretion, thereby improving glucose homeostasis. In addition, they also inhibit appetite what often results in weight loss linked to changed eating behavior in obese patients with type 2 diabetes mellitus. Such improvement in eating behavior has not been reported for other glucose-lowering agents (8,9). These agents are only approved for the management of type 2
Correspondence: Mojca Jensterle, Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre Ljubljana, Zaloska 7, SI-1525 Ljubljana, Slovenia. E-mail: [email protected]
History Received 30 April 2014 Revised 11 July 2014 Accepted 8 September 2014 Published online 20 October 2014
diabetes. Experiences with the use of GLP-1 RA in patients with PCOS are very limited. We have previously shown that obese women with PCOS who had not responded to standard weight loss strategies and metformin treatment might benefit from short-term intervention with long-acting GLP-1 RA liraglutide as an add-on therapy to metformin regarding weight loss (10). Another study of PCOS women provided evidence that combined treatment with short-acting GLP-1 RA exenatide and metformin was superior to exenatide and metformin monotherapies in improving their weight loss (11). In the present study we investigated the effects of shortterm 12-week liraglutide intervention on eating behavior of obese women with PCOS who had lost less than 5% body weight during 6-month pre-treatment with metformin. For the assessment of eating behavior before and after the intervention we used a simple questionnaire applicable in clinical practice.
Subjects and methods Thirty-six women previously diagnosed to have PCOS by the National Institute of Child Health and Human Development (NICHD) criteria (12) were recruited from the outpatients Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre Ljubljana. Before recruitment they were treated with metformin because they had metabolic disturbances and/or anovulation. They were eligible for enrolment if they had lost less than 5% of body
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weight in the last 6 months, were more than 18 years old, premenopausal, obese (body mass index (BMI) 30 kg/m2), had been taking metformin 2000 mg for at least 6 months. Exclusion criteria were known type 1 or type 2 diabetes mellitus, history of carcinoma, personal or family history of MEN 2, significant cardiovascular, kidney or liver disease and the use of medications other than metformin known or suspected to affect reproductive or metabolic functions, or statins, within 90 days prior to study entry. All subjects were informed of the study aims and provided written consent before entering the study, which was conducted in accordance with the Declaration of Helsinki and approved by the National Ethical Committee. The study is registered with clinicaltrials.gov No/NCT01911468.
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Experimental protocol In 36 obese women with PCOS metformin was discontinued and they were switched to liraglutide at a dose of 0.6 mg injected sc once per day and increased to 1.2 mg/day after 1 week. They were taking liraglutide for 12 weeks. The primary outcome was change in eating behavior. Prespecified secondary outcomes were changes in anthropometric measures of obesity. At baseline and at study endpoint an eating behavior was assessed in all patients. They underwent standard anthropometric measurements: height, weight, waist circumference and blood pressure. Waist circumference was measured in a standing position midway between the lower costal margin and the iliac crest. BMI was calculated as the weight in kilograms divided by square of height in meters. Moreover, measurement of whole-body composition by a Hologic Dualenergy X-ray Absorptiometry (DXA) was performed in all subjects at baseline and at study endpoint as described previously (13). We assumed that different phases of the menstrual cycle had little or no effect on body weight and body composition (14). A fasting blood was drawn for determination of glucose, insulin, luteinizing hormone (LH), follicle stimulating hormone (FSH), androstenedione, dehydroepiandrosterone sulphate (DHEAS), total and free testosterone followed by a standard 75 g oral glucose tolerance test (OGTT). Safety parameters (complete blood count, markers of hepatic and renal function and serum electrolytes) were assessed before and after 12 weeks of study treatment. All blood samples were centrifuged and the separated serum was kept frozen at 80 C until the time of the assay. Since many of the patients were oligoamenorrhoic during the previous year, the assessment of the subjects was not based on any specific stage of the menstrual cycle. Pregnancy was excluded by measuring b-human chorionic gonadotropin. Women were advised to strictly use barrier contraception. All patients were provided with glucose-monitoring devices, medication supplies and educated on their use. They were instructed to measure blood glucose levels at any signs and symptoms suggesting low blood glucose. Hypoglycemia was defined according to American Diabetes Association criteria as symptoms suggestive of low blood glucose confirmed by self-monitored blood glucose measurement below 3.9 mmol/l (15). They were also instructed to report any side effects during the treatment. An energy restricted diet
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(500–800 kcal/day reduction made up of 50% carbohydrates, 20% proteins and 30% of fat with increased consumption of fiber, whole grain breads, cereals, fruits and vegetables) along with at least 30 min of moderate intensity physical activity daily had been recommended to all women when the diagnosis of PCOS had been confirmed and metformin had been initially prescribed. At the beginning of the study lifestyle intervention was not again actively promoted or intensified. Assessment of eating behavior Eating behavior was assessed by using a Slovenian translation of Three-Factor Eating Questionnaire TFEQ-R18 (16). The instrument is a shortened and revised version of the original 51-item TFEQ (17). The translation of the Slovenian version had been back-translated by a native English speaker and evaluated as required. The questionnaire measures three different aspects of eating behavior: cognitive restraint (CR) referring to conscious restriction of food intake in order to control body weight or to promote weight loss, uncontrolled eating (UE) referring to tendency to eat more than usual due to a loss of control over intake accompanied by subjective feelings of hunger, and emotional eating (EE) referring to inability to resist emotional cues. The TFEQ-R18 consists of 18 items on a 4-point response scale (definitely true/mostly true/mostly false/definitely false). Responses to each of the 18 items are given a score between 1 and 4 and item scores are summed up into scale scores for CR, UE, and EE (16,17). The raw scale scores are transformed to a 0–100 scale [raw score lowest possible raw score)/possible raw score range 100] and the commonly used ‘‘half-scale’’ method is utilized to compensate for missing data on some items. Higher scores in the respective scales are indicative of greater CR, UE, or EE. Assays Glucose levels were determined using a standard glucose oxidase method (Beckman Coulter Glucose Analyzer, Beckman Coulter Inc., Brea, CA). LH and FSH were determined using an immunometric assay (Diagnostic Products Corporation, Los Angeles, CA). Androstenedione and DHEAS were measured by specific double antibody RIA using 125 I-labeled hormones (Diagnostic Systems Laboratories, Webster, TX). Total and free testosterone levels were measured by coated tube RIA (DiaSorin, S. p. A, Salluggia, Italy and Diagnostic Products Corporation, Los Angeles, CA, respectively). Insulin was determined by immunoradiometric assay (Biosource Europe S.A., Nivelles, Belgium). Intraassay variations ranged from 1.6 to 6.3%, and interassay variations ranged from 5.8 to 9.6% for the applied methods. Pre- and post-treatment samples from each patient were assayed in the same assay run. Determination of insulin resistance (IR) Homeostasis model assessment (HOMAIR) score calculation was applied as a measure for IR. The estimate of IR by HOMAIR score was calculated with the following formula: fasting serum insulin (mU/L) fasting plasma glucose (mmol/L)/22.5 (18).
Liraglutide and eating behavior in PCOS
DOI: 10.3109/07435800.2014.966385
Assessment of human body composition by Dual Energy X-ray Absorptiometry Whole-body composition was assessed by a DXA (Discovery A; Hologic, Waltham, MA) with the software provided by the manufacturer (QDR for Windows Version 12.5). The instrument generates values for whole-body fat mass, lean body mass and bone mineral content and all these parameters separately for different body parts.
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Statistical analysis Results are presented as mean ± standard deviation (SD). Normal data distribution was checked with the Shapiro–Wilk test. The differences between treatment groups were checked and confirmed using paired samples t-test and Wilcoxon signed-rank test. p value of less than 0.05 was considered statistically significant. All statistical analyses were performed using the SPSS 17.0 statistical software package (International Business Machines Corporation, Armonk, NY).
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and emotional eating score (EE) decreased from 49.9 ± 33.3 to 28.5 ± 26.9 (p50.001). Scores for cognitive restraint (CR) did not change (52.8 ± 18.3 before intervention versus 52.5 ± 22.0; p ¼ 0.939; Figure 1). EE was significantly correlated with weight loss (r ¼ 0.344, p ¼ 0.040). Weight change Liraglutide administration was associated with significant decrease in body mass, BMI and waist circumference (p50.001 for the treatment/time effect). In addition, significant reductions of total body % fat and visceral adipose tissue (VAT) mass, volume and area as assessed by DXA were demonstrated from liraglutide induction to the end of the study (p50.001 and p ¼ 0.003, p ¼ 0.003 and p ¼ 0.003, respectively). At 3 months an average visceral adipose tissue
Results We recruited 36 obese women with PCOS aged 31.2 ± 7.8 years with BMI 38.7 ± 0.1 kg/m2. Baseline and post-treatment characteristics are presented in Table 1. Assessment of eating behavior After treatment with liraglutide the uncontrolled eating score (UE) decreased from 36.8 ± 24.5 to19.6 ± 18.4 (p50.001) Table 1. Baseline and 12-week post-treatment measures of obesity, metabolic and endocrine parameters in 36 obese women with PCOS.
Body weight Waist circumference BMI LH FSH DHEAS Androstenedione Total testosterone Free testosterone SHBG Fasting glucose Glucose during OGTT – 1200 Fasting insulin Insulin during OGTT – 1200 HOMA index Total body % fat VAT mass (g) by DXA VAT volume (cm3) by DXA VAT area (cm2) by DXA
Baseline Mean ± standard deviation
Post-treatment Mean ± standard deviation
Statistical significance
107.5 ± 17.7 123.2 ± 13.1 38.7 ± 5 7.1 ± 7.9 4.7 ± 2.4 5.1 ± 2.9 8.6 ± 4 1.8 ± 1.2 6.7 ± 3.6 28.6 ± 24.7 5.3 ± 0.6 7.4 ± 1.7
103.7 ± 17.8 119.8 ± 13.6 37.3 ± 5.2 7.4 ± 5.8 5.1 ± 2.1 5.1 ± 3 8.7 ± 4.6 1.7 ± 1.1 5.7 ± 3.5 27.6 ± 11.8 4.8 ± 0.5 5.5 ± 1.1
0.000 0.000 0.000 0.082 0.322 0.678 0.914 0.606 0.056 0.133 0.000 0.000
12 ± 8.4 102.2 ± 81.3
12.5 ± 7.1 92.9 ± 84
0.242 0.029
2.9 ± 2.4 45.7 ± 3.3 781.1 ± 278
2.7 ± 1.7 44.4 ± 3.6 731.9 ± 253.8
0.893 0.000 0.003
844.5 ± 300.6
791.1 ± 274.3
0.003
162.1 ± 57.7
151.8 ± 52.6
0.003
Legend: BMI-body mass index, LH- luteinizing hormone, FSH- follicle stimulating hormone, DHEAS- dehydroepiandrosterone sulphate, SHBG-sex hormone binding globulin, OGTT- oral glucose tolerance test, HOMA- Homeostasis model assessment, VAT- visceral adipose tissue, DXA-Dual-energy X-ray Absorptiometry.
Figure 1. Changes in the scores of eating behavior induced by liraglutide as assessed by Three-Factor Eating Questionnaire TFEQ-R18: uncontrolled (A), emotional (B) and restraint (C) eating.
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(VAT) area decreased below 160 cm2 threshold that is associated with high risk for cardiovascular disease in women (19). The results are shown in Table 1. Metabolic changes HOMAIR score values tended to be reduced after intervention, but did not significantly decrease. Fasting glucose and glucose values after 120 min during OGTT were significantly reduced by liraglutide (p50.001). A significant decrease in insulin levels at 120 min of OGTT was also observed (p ¼ 0.003). Endocrine changes
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No statistically significant change in hormonal profile was found (Table 1). Adverse events Adverse events associated with liraglutide were nausea (9/36), diarrhea (11/36), headache (3/36) and insomnia (2/36). Four patients reported hypoglycemic events. Gradual dose titration reduced the gastrointestinal side effects associated with liraglutide.
Discussion We demonstrated that short-term liraglutide treatment significantly improved eating behavior in obese patients with PCOS and that this improvement correlated with weight loss in these patients. It hasn’t been established whether eating behavior is different in obese women with PCOS when compared to weight matched non-PCOS controls. The reports are few and the results are not conclusive. There is evidence that disturbed regulation of satiety peptides is intrinsic to PCOS (6,7,20,21). Furthermore, an increased frequency of PCOS was found in bulimic women, suggesting that androgens have appetitestimulating effects and could impair the impulse control of eating behavior (21). Disturbed appetite was also associated with altered opioid function demonstrated in PCOS linked to the stimulation of food intake and appetite for high fat/high glucose food through amygdala and nucleus accumbens reward circuits (22). In addition, there are few conflicting reports on the impaired secretion of endogenous GLP-1 in PCOS patients (23,24). Recognizing the important role of endogenous GLP-1 in promoting satiety and suppression of energy intake in animals (25,26) and humans (27–30), the impaired secretion pattern of GLP-1 might contribute to the pathogenesis of PCOS. GLP-1 RA are unique in their ability to regulate metabolism and eating behavior. Relevant effects of their action are widely distributed. They act in the hypothalamus, hindbrain and in the mesolimbic reward system, resulting in altering many components of eating behavior. Stimulation of mesolimbic GLP-1R is sufficient to reduce hunger-driven feeding, the hedonic value of food and food-motivation (31). In two studies liraglutide produced significant improvements in all major scores of eating behavior questionnaire that was similar to ours in obese patients with type 2 diabetes mellitus. The effect was maintained throughout the 6 months after
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discontinuation of liraglutide. It significantly reduced the urge for fat intake (8,9). Such improvement in eating behavior induced by liraglutide has not been reported for other glucoselowering agents. The influence of GLP-1 RA on eating behavior has never been investigated in PCOS. In the present study we demonstrated significantly improved eating behavior as assessed by TFEQ-R18 after short-term intervention with liraglutide in obese women with PCOS pretreated with metformin. Uncontrolled and emotional eating significantly decreased whereas restrained eating remained unchanged. Emotional eating score was significantly correlated with weight loss. Previously, TFEQ-R18 questionnaire had been shown to be able to distinguish among different eating patterns in a general population. Higher scores on restrained eating had been associated with a lower energy intake. Energy intake increased with uncontrolled eating scores. Higher cognitive restraint was positively associated with consuming healthy food groups and negatively associated with consumption of French fries and sugar. Energy-dense foods, such as fat, were positively associated with uncontrolled eating scores. Finally, emotional eaters had a higher snacking food intake (16). Similarly to observations in our study, liraglutide was associated with dose-escalation nausea and other gastrointestinal adverse effects in trials of liraglutide for type 2 diabetes. Nausea and other gastrointestinal side effects are reported by up to 40% of individuals on liraglutide 1.2 mg per day, but are mostly mild and transient and generally tolerable. The contribution of these adverse events to reductions in appetite and energy intake is less clear, but is definitely not considered as the main mechanism behind liraglutide induced weight loss. Weight loss in diabetic population was significantly greater for individuals on liraglutide than for those on placebo whether they did or did not reported nausea or diarrhea or vomiting (32). In addition to improved eating behavior correlated with weight reduction, we observed a significant beneficial reduction of waist circumference (WC) and visceral fat adiposity (VFA) as assessed by DXA. The weight reduction is in agreement with the well-known evidence that treatment with GLP-1 RA results in clinically relevant progressive and sustained weight loss when given to obese patients with or without diabetes (9,33,34). The exact interrelationship between the relevant amounts of visceral and subcutaneous adipose tissue loss in patients treated with GLP-1 RA is not fully clarified (35). The LEAD-2 trial showed that liraglutide significantly decreased WC and VFA compared to glimepiride, while there was no significant difference in the reduction of WC and VFA between liraglutide and placebo (34). In another study WC and VFA did not change while obese patients with type 2 diabetes mellitus were treated with insulin and/or oral glucose-lowering agents but reduced significantly after introduction of liraglutide (9). Liraglutide administration and weight loss were not associated with statistically significant improvement of androgen profile and IR in our patients. The failure to significantly influence the androgen levels may be due to a relatively small number of patients and generally-known methodological problem for assessment of androgens in PCOS. Similarly, the lack of statistically significant difference
DOI: 10.3109/07435800.2014.966385
in IR as assessed by HOMAIR score may be due to small sample size and short duration. In addition, large variability in IR calculated using HOMAIR score in women with PCOS and relatively low sensitivity of HOMAIR score method in detecting specific form of IR that characterizes PCOS were reported in other trails (36,37). The present study has some limitations. It was not designed as a randomized clinical trial (RCT) or a crossover study and was performed in a small population. Longer term larger RCT are warranted to more thoroughly elucidate the effect of GLP-1 RA in PCOS population. However, the main strength of our study is the implication of simple tool applicable in routine clinical practice that is able to assess a neglected and undiscovered impact on eating behavior in weight reduction approaches.
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Conclusion Our study is the first to imply that obese women with PCOS who have not responded to standard weight-loss strategies and metformin treatment might benefit from short-term intervention with a long acting GLP-1 agonist liraglutide. We provide preliminary data that 12-week treatment with liraglutide was associated with the improved eating behavior and that significantly decreased emotional eating tended to correlate with a substantial weight loss. A short-term safety profile was acceptable. We underscore that the assessment of eating behavior by an appropriate questionnaire should become an integral part of anti-obesity management in PCOS representing a simple and useful tool in estimation of treatment efficacy.
Acknowledgements The authors would like to thank Franci Cucek and Ziga Krizaj for statistical analysis. We appreciate the assistance of Mirela Ozura and Elizabeta Stepanovic, RNs.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of paper. The study was supported by grant Number 20120047 of the University Medical Centre Ljubljana, Slovenia. The study is registered with clinicaltrials.gov No/NCT01911468.
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