Treating PCOS With Semaglutide vs Active Lifestyle Intervention

Study Overview
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Brief Summary
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Girls with obesity and polycystic ovarian syndrome will receive either glucagon like peptide-1 receptor agonist therapy or a dietary intervention for 12 weeks to decrease the metabolic syndrome, in particular to lower hepatic fat and improve insulin sensitivity.

Detailed Description
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In obese girls with polycystic ovarian syndrome, testosterone and obesity combine to create unique pathology to increase metabolic disease including fatty liver and insulin resistance, which may be mediated by altered glucagon like peptide-1 activity. The investigators will treat girls with obesity and polycystic ovarian syndrome for 4 months with a glucagon like peptide-1 receptor agonist compared to dietary intervention to primarily lower hepatic fat and secondarily improve whole body and adipose insulin sensitivity. Mechanisms of hepatic metabolism, including rates of de novo lipogenesis and relative mitochondrial flux will also be assessed.

Official Title
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Treating PCOS With Semaglutide vs Active Lifestyle Intervention

Conditions
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PCOS, Adolescent Obesity, NAFLD

Intervention / Treatment
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* Drug: Semaglutide 3mg and 7mg [Rybelsus]
* Other: Weight loss diet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Sedentary- less than 2 hours of moderate (jogging, swimming etc) exercise a week. BMI equal or greater than the 90th percentile for age and gender PCOS per the most stringent NIH criteria adapted for adolescents (irregular menses >12 months post-menarche and clinical or biochemical hypertestosteronemia Participants cannot be on hormonal contraception, so participants should remain abstinent or use reliable non-hormonal contraception (e.g. copper IUD) for the entire study period. For participants who receive semaglutide, they should avoid pregnancy for at least 2 months after stopping medication to avoid fetal exposure to the medication. Exclusion Criteria: Diagnosed with or have a family history of medullary thyroid carcinoma (MTC) or Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Family history of medullary thyroid cancer or thyroid nodule palpated by endocrinologist at screening. Use of medications known to affect insulin sensitivity: metformin (cannot have been used in the 3 months prior to screening), oral glucocorticoids within 10 days, atypical antipsychotics, immunosuppressant agents, HIV medications, hormonal contraception (cannot have been used in the 6 months prior to screening). Dermal patch or vaginal ring contraception methods.Weight loss medications or stimulants. Use of other products containing other GLP-1 agonists. Currently pregnant or breastfeeding women. Development of pregnancy during the study period will necessitate withdrawal from the study. Severe illness requiring hospitalization within 60 days. Diabetes, defined as Hemoglobin A1C > 6.4% BMI percentile less than the 90th percentile for age and sex. Weight >325 lbs. or <84 lbs. Anemia, defined as Hemoglobin < 11 mg/dL Diagnosed major psychiatric or developmental disorder limiting informed consent. Implanted metal devices that are not compatible with MRI Use of blood pressure medications. Known liver disease other than NAFLD or AST or ALT >100 IU/L. Personal history of pancreatitis Known renal disease of any severity or an eGFR at screening of <45ml/min/1.73m2 History of severe GI disease (e.g. gastroparesis) History of gallstones Untreated thyroid disease History of hypersensitivity to semaglutide Other causes of hyperandrogenism (example: tumor, CAH) or amenorrhea (untreated thyroid disease, tumor, primary ovarian failure, prolactinoma). Active symptoms or undergoing treatment for anorexia nervosa or binging/purging disorder

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 21 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 |
| --- | --- |
| Active Comparator: Diet Intervention<br>Weight loss with dietary intervention | Other: Weight loss diet<br>* Prescribed weight loss diet to match weight loss in Drug arm<br>|
| Experimental: GLP-1 Intervention<br>Participants will take a daily oral tablet of semaglutide for 4 months. | Drug: Semaglutide 3mg and 7mg [Rybelsus]<br>* Once daily oral tablet of semaglutide for 4 months<br>* Other names: GLP-1 receptor agonist;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Hepatic Fat Fraction | Change from baseline in presence/severity of hepatic fat fraction will be measured with MRI, and calculated via the Dixon method as the proton density hepatic fat fraction, which ranges from 0-75%. | Baseline and 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Rate of De Novo Lipogenesis | Change from baseline of the rate of overnight de novo lipogenesis will be measured utilizing stable isotope methods with deuterated water, and expressed as the rate of newly synthesized lipids in the serum triglyceride fraction. | Baseline and 12 weeks | 
| Change in Whole Body Insulin Sensitivity | Participants will undergo a 75 gram oral glucose tolerance test, and the change from baseline in whole body insulin sensitivity will be expressed as Si, calculated via the oral minimal model. | Baseline and 12 weeks | 
| Change in Adipose Insulin Sensitivity | Change from baseline of adipose insulin sensitivity will be calculated as the percent suppression of free fatty acids, and the nadir of free fatty acids during the oral glucose tolerance test. | Baseline and 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Insulin Resistance