Liraglutide and Metformin Combination on Weight Loss, Metabolic - Endocrine Parameters and Pregnancy Rate in Women With PCOS, Obesity and Infertility

Study Overview
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Brief Summary
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Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age and one of the leading causes of infertility. PCOS and obesity affect up to 12.5% - 48.3% Asian women, increase incidence of impaired glucose tolerance, type 2 diabetes and aggravate insulin resistance, cause ovulatory dysfunction and menstrual disorders, and negatively impact outcomes of Assited Reproductive Technology (ART), with higher miscarriage rate when receiving ART. Weight loss decrease insulin resistance and hyperandrogenism, improve ovulation rate and menstrual cycle, significantly higher conception and live birth rates. Weight loss prior to IVF procedures has been associated with significantly improved pregnancy rates (PR) and live birth rates. Furthermore, a decreased number of IVF cycles required to achieve a pregnancy has also been reported after weight loss interventions. Based on the principles of fetal programming, improving a lifestyle before conception might lead to improved longterm health of the offspring. Studies on the effect of anti-obesity medication combined with lifestyle changes on body weight and composition and metabolic - endocrine parameters and pregnancy rate in obese women diagnosed with PCOS are lacking. There is a growing need to develop pharmacologic interventions to improve metabolic function in women with polycystic ovary syndrome (PCOS).

Detailed Description
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The drug, liraglutide 3.0 mg was approved for chronic weight management in management in obese adults with an initial BMI of 30 kg/m2 or greater or in overweight adults BMI of 27 kg/m2 or greater with at least one weight-related co-morbid condition as an adjunct to a reduced-calorie diet and increased physical activity. Liraglutide is an acylated human glucagon-like peptide -1 (GLP-1) analog that binds to and activates the GLP-1 receptor. It lowers body weight through decreased caloric intake while stimulating insulin secretion and reducing glucagon via a glucose-dependent mechanism. For obesity management, patients may lose weight with GLP-1 receptor agonists due to other unique actions. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) can slow gastric emptying and increase satiety. While predictors of weight loss success for the general population are available (protein intake, weight loss medications), predictors of weight loss success may differ between normal and hyperandrogenic women. Glucagon-like peptide 1 agonists are linked with dose dependent weight lowering potential in different obesity related populations. The weight loss effects of GLP-1RAs previously demonstrated in diabetic and obese non-diabetic patients, offer a unique opportunity to expand the medical options available to patients with PCOS. Metformin was recommended for women with PCOS and obesity (BMI ≥ 25 kg/m2) or at metabolic risks and shown beneficial effects on menstrual disorders, anovulation, hyperandrogenism, and cardiovascular abnormalities. The aim of this study was to evaluate the impact of liraglutide in combination with metformin compared to metformin alone on weight reduction, the multifaceted metabolic - endocrine disturbances, and oocyte and embryo quality, IVF PRs and cumulative PRs (IVF and spontaneous pregnancies) in infertile obese women with PCOS who had been previously poor responders to weight reduction with lifestyle modification.

Official Title
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Effectiveness of the Combination Liraglutide and Metformin on Weight Loss, Metabolic - Endocrine Parameters and Pregnancy Rate in Women With Polycystic Ovarian Syndrome, Obesity and Infertility

Conditions
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Polycystic Ovary Syndrome, Obesity, Infertility, Female

Intervention / Treatment
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* Drug: Liraglutide + Metformin
* Drug: Metformin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female gender 18-65 years of age Diagnosis of polycystic ovary syndrome according to the revised Rotterdam criteria (2003) BMI ≥ 27 kg/m2 Infertility Agree to participate in the study Exclusion Criteria: Type 1 or type 2 diabetes. History of acute or chronic pancreatitis. Family or individual history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2 Known hypersensitivity or contraindication to the use of GLP-1 receptor agonists. Used of hormonal drugs, drugs causing clinically significant weight changes and drugs affecting glucose tolerance for at least 8 weeks. Used a anti-androgen drugs for at least 4 weeks. History of malignancy requiring chemotherapy. History of taking antidiabetic drugs other than gestational diabetes or weight-loss drugs discontinued for at least 4 weeks. History of gastrectomy or device-based intervention to manage obesity Eating disorders (anorexia or bulimia) or digestive disorders. Substance abuse (Tobacco or alcohol) History of major depression or other serious mental disorder. Inability or refusal to adhere treatment regimens.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LIME 3mg/1500mg<br>Metformin XR (extended-release) was initiated with a dose of 750 mg once per day for 2 week and increased to 1500 mg once per day for up to 12 weeks. Start injection liraglutide 0.6 mg subcutaneously (SC) 1week daily (QD), then titrated in increments of 0.6 mg once daily every 1 to 3 weeks to a final dose of 3.0 mg liraglutide SC daily for up to 12 weeks. | Drug: Liraglutide + Metformin<br>* Metformin XR (extended-release) was initiated at 750 mg once daily and increased to 1500 mg once daily after 2 week. Concomitantly, Liraglutide was initiated at a subcutaneous dose of 0.6 mg once daily for 1 week, then titrated in increments of 0.6 mg once daily every 1 to 3 weeks to a maintenance dose of 3.0 mg once daily for up to 12 weeks<br>* Other names: LIME;|
| Active Comparator: MET 1500mg<br>Metformin XR (extended-release) was initiated with a dose of 750 mg once per day for 2 week and increased to 1500 mg once per day for up to 12 weeks | Drug: Metformin<br>* Metformin XR (extended-release) was initiated at 750 mg once daily and increased to 1500 mg once daily after 2 week<br>* Other names: MET;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute Body Weight (BW) | Treatment impact on change in body weight after 12 weeks of treatment. | 12 weeks of treatment | 
| Change in Percent Body Weight | Treatment effect on reducing body weight expressed as percent body weight loss from baseline | 12 weeks of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Body Mass Index (BMI) | Treatment effect in reducing body mass | 12 weeks of treatment | 
| Abdominal Adiposity (Waist Circumference [WC]) | Treatment effect on loss of waist circumference (abdominal adiposity) with drug treatment | 12 weeks of treatment | 
| Waist-to-Hip Ratio (WHR) | Change in central adiposity with treatment as measured by waist-to-hip ratio. A reduction in ratio indicates a decrease in truncal fat. | 12 weeks of treatment | 
| Waist-to Height Ratio [WHtR] | Treatment effect on loss of central adiposity as determined by Waist-to Height Ratio. The lower the ratio indicates less abdominal adiposity. | 12 weeks of treatment | 
| Total Fat Mass Evaluated by BIA | Treatment effect on reduction of fat mass (kg) | 12 weeks of treatment | 
| Total Body Fat (%) by BIA (Bioelectrical Impedance Analysis) machine | Treatment effect on reduction of percent body fat by BIA | 12 weeks of treatment | 
| Visceral Fat Level (VFL) | Treatment effect on reduction of visceral fat level by BIA | 12 weeks of treatment | 
| Total lean body mass | Treatment impact on total lean body mass | 12 weeks of treatment | 
| Glucose OGTT 0 min | Treatment effect on fasting glucose prior to an oral glucose tolerance test (OGTT) | 12 weeks of treatment | 
| Glucose OGTT 120 min | Treatment effect on glucose measured at 120 minutes of an oral glucose tolerance test (OGTT) | 12 weeks of treatment | 
| Insulin OGTT 0 min | Treatment effect on fasting insulin prior to an oral glucose tolerance test (OGTT) | 12 weeks of treatment | 
| Insulin OGTT 120 min | Treatment effect on insulin measured at 120 minutes of an oral glucose tolerance test (OGTT) | 12 weeks of treatment | 
| Fasting Insulin Sensitivity (HOMA-IR) | Treatment effect on the HOMA-IR which is an insulin resistance measured derived from fasting blood glucose and insulin . The higher the number the more insulin resistant. | 12 weeks of treatment | 
| Matsuda Insulin Sensitivity Index Derived From the OGTT (SI OGTT) | The SI OGTT is a measure of peripheral insulin sensitivity derived from the insulin and glucoses measured during an OGTT. A increase in SI OGTTindicates greater insulin sensitivity | 12 weeks of treatment | 
| Total Cholesterol Levels | Treatment impact on improving total cholesterol levels | 12 weeks of treatment | 
| High Density Lipoprotein Cholesterol (HDL-C) | Impact of treatment on HDL levels after 12 weeks of treatment | 12 weeks of treatment | 
| Triglyceride Levels (TRG) | Drug effect of TRG levels after treatment | 12 weeks of treatment | 
| Low Density Lipoprotein Cholesterol (LDL-C) | Treatment impact on improving LDL-C after treatment | 12 weeks of treatment | 
| Systolic Blood Pressure | Treatment impact on systolic blood pressure | 12 weeks of treatment | 
| Diastolic Blood Pressure | Treatment impact on reducing diastolic blood pressure | 12 weeks of treatment | 
| Menstrual Cycle Frequency | Drug treatment impact on normalization of cycle frequency (cycle every 28-30 days). All cycle data is expressed as number of menses annualized to one year. | 12 weeks of treatment | 
| Free Androgen Index (FAI) | Drug treatment effect on free androgen levels as calculated as FAI= total testosterone (T) concentrations divided by sex hormone binding globulin (SHBG) levels. A higher score indicates a worse outcome (more androgenic). | 12 weeks of treatment | 
| Total Testosterone Concentrations (T) | Drug treatment effect on total testosterone concentrations | 12 weeks of treatment | 
| Sex Hormone Binding Globulin (SHBG) | Drug treatment effect on SHBG | 12 weeks of treatment | 
| Adrenal Dehydroepiandrosterone Sulfate (DHEAS) | Treatment efficacy in reducing adrenal hyperandrogenism | 12 weeks of treatment | 
| 17(OH)-progesterone | Treatment efficacy in reducing adrenal hyperandrogenism | 12 weeks of treatment | 
| Androstenedione | Drug treatment effect on androstenedione | 12 weeks of treatment | 
| Progesterone | Drug treatment effect on progesterone | 12 weeks of treatment | 
| Luteinizing Hormone (LH) | Drug treatment effect on LH | 12 weeks of treatment | 
| Follicle Stimulating Hormone (FSH) | Drug treatment effect on FSH | 12 weeks of treatment | 
| Ovary Volume | Treatment efficacy in reducing ovary volume | 12 weeks of treatment | 
| Spontaneous Pregnancy Rate | Treatment effect on spontaneous pregnancy rate | 12 months after treatment | 
| Assisted Reproductive Therapy Pregnancy Rate | Treatment effect on Assisted Reproductive Therapy Pregnancy Rate | 12 months after treatment | 
| Cumulative Pregnancy Rate | Treatment effect on Cumulative Pregnancy Rate | 12 months after treatment | 
| Total dosage gonadotropin (GNT) | Drug treatment impact on total dosage GNT | 12 weeks of treatment | 
| No. of retrieved oocytes/patient | Drug treatment impact on No. of retrieved oocytes/patient | 12 weeks of treatment | 
| No. of mature (MII) oocytes/patient | Drug treatment impact on No. of mature (MII) oocytes/patient | 12 weeks of treatment | 
| Fertilization rate | Drug treatment impact on fertilization rate | 12 weeks of treatment | 
| Oocyte degeneration rate | Drug treatment impact on oocyte degeneration rate | 12 weeks of treatment | 
| Immaturity rate | Drug treatment impact on immaturity rate | 12 weeks of treatment | 
| No. of embryos on day 5/patient | Drug treatment impact on No. of embryos on day 5/patient | 12 weeks of treatment | 
| No. of blastocysts/patient | Drug treatment impact on No. of blastocysts/patient | 12 weeks of treatment | 
| Blastulation rate | Drug treatment impact on blastulation rate | 12 weeks of treatment | 
| No. of transferred embryos | Drug treatment impact on No. of transferred embryos | 12 weeks of treatment | 
| Pregnancy rate per cycle | Drug treatment impact on pregnancy rate per cycle | 12 weeks of treatment | 
| Pregnancy rate per Embryo Transfer (ET) | Drug treatment impact on pregnancy rate per ET | 12 weeks of treatment | 
| Implantation rate | Drug treatment impact on implantation rate | 12 weeks of treatment | 
| No. of cancelled fresh Embryo Transfer (ET) because of hyperstimulation risk | Drug treatment impact on No. of cancelled fresh Embryo Transfer (ET because of hyperstimulation risk | 12 weeks of treatment | 
| Cryopreservation | Drug treatment impact on cryopreservation | 12 weeks of treatment | 
| No. of cryopreserved embryos/patient | Drug treatment impact on No. of cryopreserved embryos/patient | 12 weeks of treatment | 
| Ectopic Pregnancy Rate | Drug treatment impact on Ectopic Pregnancy Rate | 12 weeks of treatment | 
| Stillbirth Rate | Drug treatment impact on Stillbirth Rate | 24 months after treatment | 
| Abortion Rate | Drug treatment impact on Abortion Rate | 24 months after treatment | 
| Gestational Diabetes Mellitus Rate | Drug treatment impact on Gestational Diabetes Mellitus Rate | 24 months after treatment | 
| Gestational hypertensive disorder (GHD) Rate | Drug treatment impact on Gestational hypertensive disorder (GHD) Rate | 24 months after treatment | 
| Live Birth Rate | Drug treatment impact on Live Birth Rate | 24 months after treatment | 
| Gestational age at birth | Drug treatment impact on gestational age at birth | 24 months after treatment | 
| Type of Delivery Method | Drug treatment impact on Type of Delivery Method | 24 months after treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Polycystic Ovary Syndrome, GLP-1 agonist, Liraglutide, obesity, weight loss, insulin resistance, androgens, pregnancy rates, In Vitro Fertilization