Clinical trial NCT03480022: Liraglutide 3mg (Saxenda) on Weight, Body Composition, Hormonal and Metabolic Parameters in Obese Women With PCOS
Official title: A Randomized Placebo-controlled Double Blind Trial of Liraglutide 3 mg [Saxenda] on Weight, Body Composition, Hormonal and Metabolic Parameters in Obese Women With Polycystic Ovary Syndrome (PCOS)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Pre Diabetes
Polycystic Ovary Syndrome
Obesity Android
Keywords: prediabetes
PCOS
GLP-1 agonist
weight loss
Lead sponsor: Woman's
Sponsor class: OTHER
Collaborators: name: Novo Nordisk A/S
First posted: 2018-03-27
Enrollment: 88
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Absolute Body Weight (BW)
timeFrame: 32 weeks of treatment
measure: Free Androgen Index (FAI)
timeFrame: 32 weeks of treatment
Secondary outcomes:
measure: Body Mass Index (BMI)
timeFrame: 32 weeks of treatment
measure: Change in Percent Body Weight
timeFrame: Change from baseline (time 0) to study end (32 weeks)
measure: 5% Weight Loss From Baseline
timeFrame: 32 weeks of treatment
measure: 10% Body Weight Loss From Baseline
timeFrame: 32 weeks of treatment
measure: Abdominal Adiposity (Waist Circumference [WC]
timeFrame: 32 weeks of treatment
measure: Waist-to-Hip Ratio
timeFrame: 32 weeks of treatment
measure: Waist-to Height Ratio [WHtR])
timeFrame: 32 weeks of treatment
measure: Total Fat Mass Evaluated by DEXA
timeFrame: 32 weeks of treatment
measure: Total Body Fat (%) by DXA
timeFrame: 32 weeks of treatment
measure: Android-Gynoid Ratio (AGR) by DXA
timeFrame: 32 weeks of treatment
measure: Trunk/Leg Fat Ratio (TLR) by DXA
timeFrame: 32 weeks of treatment
measure: Menstrual Cycle Frequency
timeFrame: 32 weeks of treatment
measure: Total Testosterone Concentrations (T)
timeFrame: 32 weeks of treatment
measure: Adrenal Dehydroepiandrosterone Sulfate (DHEAS)
timeFrame: 32 weeks of treatment
measure: Fasting Blood Glucose (FG)
timeFrame: 32 weeks of treatment
measure: OGTT Mean Blood Glucose (MBG)
timeFrame: 32 weeks of treatment
measure: Fasting Insulin Sensitivity (HOMA-IR)
timeFrame: 32 weeks of treatment
measure: Matsuda Insulin Sensitivity Index Derived From the OGTT (SI OGTT)
timeFrame: 32 weeks of treatment
measure: Corrected First Phase Insulin Secretion (IGI/HOMA-IR)
timeFrame: 32 weeks of treatment
measure: Insulin Secretion- Insulin Sensitivity Index (Oral Disposition Index-IS-SI)
timeFrame: 32 weeks of treatment
measure: Total Cholesterol Levels
timeFrame: 32 weeks of treatment
measure: High Density Lipoprotein Cholesterol (HDL-C)
timeFrame: 32 weeks of treatment
measure: Triglyceride Levels (TRG)
timeFrame: 32 weeks of treatment
measure: Triglyceride to HDL-Cholesterol Ratio (TRG/HDL-C)
timeFrame: 32 weeks of treatment
measure: Triglyceride and Glucose Index (TyG)
timeFrame: 32 weeks of treatment
measure: Systolic Blood Pressure
timeFrame: 32 weeks of treatment
measure: Diastolic Blood Pressure (BP)
timeFrame: 32 weeks of treatment
Other outcomes:
Locations:
city: Baton Rouge
country: United States
facility: Woman's Hospital
state: Louisiana
Study officials:
affiliation: Woman's Hospital Foundation IRB
name: Peggy Dean, PharmD
role: STUDY_CHAIR
References:
citation: Elkind-Hirsch KE, Chappell N, Shaler D, Storment J, Bellanger D. Liraglutide 3 mg on weight, body composition, and hormonal and metabolic parameters in women with obesity and polycystic ovary syndrome: a randomized placebo-controlled-phase 3 study. Fertil Steril. 2022 Aug;118(2):371-381. doi: 10.1016/j.fertnstert.2022.04.027. Epub 2022 Jun 13.