Symptoms and General Pathology

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Nutritional and Metabolic Diseases

Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Gland and Hormone Related Diseases

Syndrome

Obesity

Polycystic Ovary Syndrome

Cysts

Ovarian Cysts

Ovarian Diseases

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Genital Diseases, Female

Genital Diseases

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Female Urogenital Diseases

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Female Urogenital Diseases and Pregnancy Complications

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Hypoglycemic Agents

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Gastrointestinal Agents

Metformin

Semaglutide

Glucagon

Glucagon-Like Peptide-1 Receptor Agonists

Glucagon-Like Peptide 1

Participants in this group will be given metformin

Participants in this group with receive Semaglutide

Participants in this group will receive injectable Semaglutide

Semaglutide Injectable Product

Chair in Academic Diabetes, Endocrinology and Metabolism

Thozhukat Sathyapalan, MD FRCP

Harshal Deshmukh, MBBS PhD

Thozhukat Sathyapalan, MD, FRCP

The goal of this clinical trial is to compare the effect of Semaglutide and metformin on weight loss in obese women with Polycystic Ovarian Syndrome (PCOS) over a 28-week treatment period.

The main question it aims to answer is:

• Which of the 2 drugs, metformin or Semaglutide causes more weight loss when used over a 28 week treatment period in obese women with PCOS?

Participants will be divided into 2 groups by chance. In the first group, participants will be asked to take metformin orally. In the second group, participants will take Semaglutide by injection under the skin weekly.

The maximum duration of participation for the patients in the trial is 32 weeks.

Researchers will compare the weight reduction, quality of life and individuals' wellbeing between the two groups.

Background:

Polycystic ovary syndrome (PCOS) is one of the most common metabolic disorders that affects 6-20% of reproductive-aged women and has an increased risk for type 2 diabetes mellitus (T2DM) and cardiovascular disease. Obesity affects more than 50% of women with PCOS and has been demonstrated to play a vital role in the establishment of symptoms in these patients. Bariatric surgery has been shown to improve metabolic parameters but reports of dietary intervention studies have been variable. PCOS is associated with an increased risk of depressive symptoms and a low quality of life (QOL) with weight being a major contributor. Even modest weight loss of 5% of initial body weight has been shown to improve menstrual disturbance, testosterone levels, hyperlipidaemia, and insulin resistance in women with PCOS. Metformin, most commonly used medication for PCOS works by improving insulin sensitivity in peripheral tissues, inhibit hepatic glucose production and increase glucose disposal by the peripheral tissues.

It has been used for decades in treatment of PCOS with improvement in menstrual irregularities and possible reduction of androgen levels. However, the effect of metformin on body weight (a major contributor of pathophysiology and symptoms in PCOS) remained highly variable between these patients. The first observational study of metformin in PCOS reported weight loss during metformin therapy. In a randomised controlled trial (RCT) designed to investigate the effect of metformin in body weight reported a significant decrease in BMI in obese women independent of their lifestyle. The recent meta-analysis assessed the effectiveness of metformin in PCOS reported a significant effect on body mass index (BMI) in women with PCOS. It is clear, however, that metformin does not increase body weight and might help to limit weight gain. Along with wide variation in response metformin is not tolerated by 10-20% of women with PCOS mainly due to its gastrointestinal side effects. Therefore, it is imperative that investigators look beyond metformin in obese women with PCOS, as this has shown to improve metabolic and hormonal parameters.

In a pilot study, another glucagon like peptide - 1 receptor agonist (GLP-1RA), liraglutide 1.8mg daily for 6 months reduced weight in obese women with PCOS and age and body mass index matched control women. They also demonstrated that liraglutide 1.8mg daily for 6 months in young obese women with PCOS showed significant improvement in physical health, social health, psychological and hence quality of life in this group.

Semaglutide a new GLP-1RA approved as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes and is associated with significant weight loss. In patients with type 2 diabetes, there was ≥5% weight loss in 63% of patients treated with Semaglutide. On the other hand, liraglutide has shown around 5-7 kg of weight reduction from the baseline in patient with T2DM. However, it has been previously reported in the SUSTAIN trials, Semaglutide-treated subjects have achieved a significant weight loss of \>10% compared to placebo. The effect of Semaglutide on weight loss and resultant improvement in the metabolic parameters and QOL in women with PCOS is unknown. In a recent double-blind randomized trial, compared Semaglutide to liraglutide in obese patients with no diabetes has shown a significant weight loss compared to placebo. Liraglutide is administered as a daily subcutaneous injection whereas Semaglutide is administered as a weekly subcutaneous injection. Therefore, investigators are conducting this trial to assess the feasibility and trying to replicate the greater weight loss with Semaglutide that has already been shown in other trial, in obese women with PCOS.

Overall hypothesis:

Treatment with Semaglutide will result in significant weight loss compared to metformin and that will be associated with significant improvements in hormonal and metabolic parameters, quality of life and cardiovascular risk factors as secondary endpoints in obese women with PCOS.

This is a randomized controlled trial

The trial consists of 7 visits and 3 telephone calls. Patients will be randomized on a 1:1 ratio to receive either:

Semaglutide 0.25mg subcutaneous weekly for 4 weeks followed by semaglutide 0.5 mg weekly for 4 weeks, then escalating to semaglutide 1 mg/ week for 4 weeks, followed by semaglutide 1.7 mg/week for 4 weeks before titrated up to maximum dose of 2.4 mg a week for 12 weeks if tolerated.

Or Metformin 500 mg/ day for 1 week followed by 500mg/twice a day for 1 week titrated up to 500 mg / day with breakfast and 1000 mg/ day with evening meals for 26 weeks if tolerated.

Semaglutide vs Metformin in Polycystic Ovary Syndrome (PCOS)

The Effect of Semaglutide Compared to Metformin in Obese Women With Polycystic Ovary Syndrome (PCOS): a Randomised Controlled Study (Semaglutide-PCOS Trial).

Changes in body fat percentage (%) measured using TANITA

Changes in Free androgen index (%) calculated from testosterone and sex hormone binding globulin; FAI= (Total Testosterone/Sex Hormone binding globulin)X100%

Changes in glucose reading (mmol/l) at 2 hours following 75g of oral glucose

University of Hull

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