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).
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
188
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
Metformin XR (extended-release) was initiated at 750 mg once daily and increased to 1500 mg once daily after 2 week
Absolute Body Weight (BW)
Treatment impact on change in body weight after 12 weeks of treatment.
Time frame: 12 weeks of treatment
Change in Percent Body Weight
Treatment effect on reducing body weight expressed as percent body weight loss from baseline
Time frame: 12 weeks of treatment
Body Mass Index (BMI)
Treatment effect in reducing body mass
Time frame: 12 weeks of treatment
Abdominal Adiposity (Waist Circumference [WC])
Treatment effect on loss of waist circumference (abdominal adiposity) with drug treatment
Time frame: 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.
Time frame: 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.
Time frame: 12 weeks of treatment
Total Fat Mass Evaluated by BIA
Treatment effect on reduction of fat mass (kg)
Time frame: 12 weeks of treatment
Total Body Fat (%) by BIA (Bioelectrical Impedance Analysis) machine
Treatment effect on reduction of percent body fat by BIA
Time frame: 12 weeks of treatment
Visceral Fat Level (VFL)
Treatment effect on reduction of visceral fat level by BIA
Time frame: 12 weeks of treatment
Total lean body mass
Treatment impact on total lean body mass
Time frame: 12 weeks of treatment
Glucose OGTT 0 min
Treatment effect on fasting glucose prior to an oral glucose tolerance test (OGTT)
Time frame: 12 weeks of treatment
Glucose OGTT 120 min
Treatment effect on glucose measured at 120 minutes of an oral glucose tolerance test (OGTT)
Time frame: 12 weeks of treatment
Insulin OGTT 0 min
Treatment effect on fasting insulin prior to an oral glucose tolerance test (OGTT)
Time frame: 12 weeks of treatment
Insulin OGTT 120 min
Treatment effect on insulin measured at 120 minutes of an oral glucose tolerance test (OGTT)
Time frame: 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.
Time frame: 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
Time frame: 12 weeks of treatment
Total Cholesterol Levels
Treatment impact on improving total cholesterol levels
Time frame: 12 weeks of treatment
High Density Lipoprotein Cholesterol (HDL-C)
Impact of treatment on HDL levels after 12 weeks of treatment
Time frame: 12 weeks of treatment
Triglyceride Levels (TRG)
Drug effect of TRG levels after treatment
Time frame: 12 weeks of treatment
Low Density Lipoprotein Cholesterol (LDL-C)
Treatment impact on improving LDL-C after treatment
Time frame: 12 weeks of treatment
Systolic Blood Pressure
Treatment impact on systolic blood pressure
Time frame: 12 weeks of treatment
Diastolic Blood Pressure
Treatment impact on reducing diastolic blood pressure
Time frame: 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.
Time frame: 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).
Time frame: 12 weeks of treatment
Total Testosterone Concentrations (T)
Drug treatment effect on total testosterone concentrations
Time frame: 12 weeks of treatment
Sex Hormone Binding Globulin (SHBG)
Drug treatment effect on SHBG
Time frame: 12 weeks of treatment
Adrenal Dehydroepiandrosterone Sulfate (DHEAS)
Treatment efficacy in reducing adrenal hyperandrogenism
Time frame: 12 weeks of treatment
17(OH)-progesterone
Treatment efficacy in reducing adrenal hyperandrogenism
Time frame: 12 weeks of treatment
Androstenedione
Drug treatment effect on androstenedione
Time frame: 12 weeks of treatment
Progesterone
Drug treatment effect on progesterone
Time frame: 12 weeks of treatment
Luteinizing Hormone (LH)
Drug treatment effect on LH
Time frame: 12 weeks of treatment
Follicle Stimulating Hormone (FSH)
Drug treatment effect on FSH
Time frame: 12 weeks of treatment
Ovary Volume
Treatment efficacy in reducing ovary volume
Time frame: 12 weeks of treatment
Spontaneous Pregnancy Rate
Treatment effect on spontaneous pregnancy rate
Time frame: 12 months after treatment
Assisted Reproductive Therapy Pregnancy Rate
Treatment effect on Assisted Reproductive Therapy Pregnancy Rate
Time frame: 12 months after treatment
Cumulative Pregnancy Rate
Treatment effect on Cumulative Pregnancy Rate
Time frame: 12 months after treatment
Total dosage gonadotropin (GNT)
Drug treatment impact on total dosage GNT
Time frame: 12 weeks of treatment
No. of retrieved oocytes/patient
Drug treatment impact on No. of retrieved oocytes/patient
Time frame: 12 weeks of treatment
No. of mature (MII) oocytes/patient
Drug treatment impact on No. of mature (MII) oocytes/patient
Time frame: 12 weeks of treatment
Fertilization rate
Drug treatment impact on fertilization rate
Time frame: 12 weeks of treatment
Oocyte degeneration rate
Drug treatment impact on oocyte degeneration rate
Time frame: 12 weeks of treatment
Immaturity rate
Drug treatment impact on immaturity rate
Time frame: 12 weeks of treatment
No. of embryos on day 5/patient
Drug treatment impact on No. of embryos on day 5/patient
Time frame: 12 weeks of treatment
No. of blastocysts/patient
Drug treatment impact on No. of blastocysts/patient
Time frame: 12 weeks of treatment
Blastulation rate
Drug treatment impact on blastulation rate
Time frame: 12 weeks of treatment
No. of transferred embryos
Drug treatment impact on No. of transferred embryos
Time frame: 12 weeks of treatment
Pregnancy rate per cycle
Drug treatment impact on pregnancy rate per cycle
Time frame: 12 weeks of treatment
Pregnancy rate per Embryo Transfer (ET)
Drug treatment impact on pregnancy rate per ET
Time frame: 12 weeks of treatment
Implantation rate
Drug treatment impact on implantation rate
Time frame: 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
Time frame: 12 weeks of treatment
Cryopreservation
Drug treatment impact on cryopreservation
Time frame: 12 weeks of treatment
No. of cryopreserved embryos/patient
Drug treatment impact on No. of cryopreserved embryos/patient
Time frame: 12 weeks of treatment
Ectopic Pregnancy Rate
Drug treatment impact on Ectopic Pregnancy Rate
Time frame: 12 weeks of treatment
Stillbirth Rate
Drug treatment impact on Stillbirth Rate
Time frame: 24 months after treatment
Abortion Rate
Drug treatment impact on Abortion Rate
Time frame: 24 months after treatment
Gestational Diabetes Mellitus Rate
Drug treatment impact on Gestational Diabetes Mellitus Rate
Time frame: 24 months after treatment
Gestational hypertensive disorder (GHD) Rate
Drug treatment impact on Gestational hypertensive disorder (GHD) Rate
Time frame: 24 months after treatment
Live Birth Rate
Drug treatment impact on Live Birth Rate
Time frame: 24 months after treatment
Gestational age at birth
Drug treatment impact on gestational age at birth
Time frame: 24 months after treatment
Type of Delivery Method
Drug treatment impact on Type of Delivery Method
Time frame: 24 months after treatment
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