Liraglutide 3mg (Saxenda) on Weight, Body Composition, Hormonal and Metabolic Parameters in Obese Women With PCOS
Liraglutide 3mg (Saxenda) on Weight, Body Composition, Hormonal and Metabolic Parameters in Obese Women With PCOS
There is a growing need to develop pharmacologic interventions to improve metabolic function
 in women with polycystic ovary syndrome (PCOS). Given that PCOS is a frequent condition and
 weight loss is essential but difficult to achieve, it is important to study if the effect on
 body weight reported in other studies can be confirmed in a selected population of
 hyperandrogenic patients, especially with medications currently approved for weight
 reduction. High dose liraglutide alone results in significant weight reduction in obese women
 without PCOS. There is limited data on weight loss with high dose liraglutide in non-diabetic
 females with PCOS treated with this agent . Studies on the effect of anti-obesity medication
 combined with lifestyle changes on body weight and composition and androgen excess in obese
 women diagnosed with PCOS are lacking. The investigators aim to elucidate the most
 efficacious weight reduction regime in obese PCOS women. The investigators further hope to
 determine which treatment(s) addressing the multifaceted disturbances of this disorder in
 patients with PCOS and obesity emerges as the preferable therapy.
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.

 Given this lack of information, the aim of the present study was to investigate the effects
 of liraglutide 3mg vs. placebo on body composition as well as hormonal and metabolic features
 in non-diabetic obese women with PCOS.The non-diabetic obese female with PCOS offers a unique
 model to study the relationship between insulin resistance and adiposity. The investigators
 propose a double-blind, placebo-controlled 30-week trial designed to directly examine the
 therapeutic effects of liraglutide 3 mg (LIRA 3 mg) compared to placebo on body weight,
 hormonal and cardiometabolic parameters in obese non-diabetic women with PCOS. All patients
 will receive diet and lifestyle counseling, including advice on exercise commencing during
 the lead-in period and continuing throughout the study. In this study, the investigators will
 examine the efficacy of LIRA 3mg on body weight and body composition, reproductive function
 metabolic parameters and cardiovascular risk factors in a well-defined group of
 pre-menopausal obese non-diabetic women with hyperandrogenism, focusing on the relationship
 to obesity and insulin resistance.
Inclusion Criteria:

 -  Female gender

 -  18-45 years of age

 -  BMI ≥30 kg/m2 or BMI ≥27 kg/m2 with one or more obesity-associated co-morbid
 conditions (e.g. hypertension, and dyslipidemia)

 -  PCOS- NIH criteria hyperandrogenism and irregular menstrual cyclicity

 -  Non-diabetic as determined by a 75 gram oral glucose tolerance test (OGTT) and
 hemoglobin A1C. Non-diabetic is inclusive of women with impaired fasting glucose
 (IFG), impaired glucose tolerance (IGT), or both (IFG/IGT). Participants with diabetes
 will be excluded

 -  Willing to use effective contraception consistently during therapy which is defined
 as:

 -  an intrauterine device, tubal sterilization, or male partner vasectomy, or

 -  combination of two barrier methods with one being male condom.

 -  Written consent for participation in the study

 Exclusion Criteria:

 -  Presence of significant systemic disease, cerebrovascular disease, clinically
 significant cardiac abnormalities or heart problems including congestive heart
 failure, unstable angina or acute myocardial infarction, current infectious liver
 disease, acute stroke or transient ischemic attacks, history of pancreatitis, or
 diabetes mellitus (Type 1 or 2)

 -  Any hepatic diseases in the past (infectious liver disease, viral hepatitis, toxic
 hepatic damage, jaundice of unknown etiology) or severe hepatic insufficiency and/or
 significant abnormal liver function tests defined as aspartate aminotransferase (AST)
 >3x upper limit of normal (ULN) and/or alanine aminotransferase (ALT) >3x ULN

 -  Renal impairment (e.g., serum creatinine levels ≥1.4 mg/dL for women, or eGFR <60
 mL/min/1.73 m2) or history of unstable or rapidly progressing renal disease or end
 stage renal disease.

 -  Uncontrolled thyroid disease (documented normal TSH), Cushing's syndrome, congenital
 adrenal hyperplasia or clinically significant elevations in prolactin levels. The
 clinical significance of prolactin levels will be determined by the treating physician

 -  Significantly elevated triglyceride levels (fasting triglyceride > 400 mg %)

 -  Untreated or poorly controlled hypertension (sitting blood pressure > 160/95 mm Hg)

 -  Use of hormonal medications, the use of medications that cause clinically significant
 weight gain or loss (prescription or OTC) and medications known to exacerbate glucose
 tolerance (such as isotretinoin, hormonal contraceptives, GnRH analogues,
 glucocorticoids, anabolic steroids, C-19 progestins) including herbal medicines for at
 least 8 weeks. Use of anti-androgens that act peripherally to reduce hirsutism such as
 5-alpha reductase inhibitors (finasteride, spironolactone, flutamide) for at least 4
 weeks

 -  Prior history of a malignant disease requiring chemotherapy

 -  Family or personal history of familial medullary thyroid carcinoma or multiple
 endocrine neoplasia type 2

 -  Known hypersensitivity or contraindications to use GLP1 receptor agonists

 -  Use of metformin, thiazolidinediones, GLP-1 receptor agonists, dipeptidyl peptidase-4
 (DPP-4) inhibitors, sodium/glucose co-transporter 2 (SGLT2) inhibitors or weight loss
 medications (prescription or OTC) stopped for at least 4 weeks

 -  Prior use of medication to treat diabetes except gestational diabetes

 -  Eating disorders (anorexia, bulimia) or gastrointestinal disorders

 -  Suspected pregnancy (documented negative serum pregnancy test), desiring pregnancy in
 next 15 months, breastfeeding, or known pregnancy in last three months

 -  Active or prior history of substance abuse (smoke or tobacco use within past 6 months)
 or significant intake of alcohol

 -  Previous bariatric surgery or device intervention for obesity

 -  Patient not willing to use barrier contraception during study period (unless
 sterilized or have an IUD)

 -  History of major depressive or other severe psychiatric disorders

 -  Inability or refusal to comply with protocol

 -  Currently participating or having participated in an experimental drug study in
 previous three months