EQW, DAPA, EQW/DAPA, DAPA/MET ER and PHEN/TPM ER in Obese Women With PolycysticOvary Syndrome (PCOS)
Condition: Polycystic Ovary Syndrome; Obesity
MeSH terms: Polycystic Ovary Syndrome; Syndrome
Study type: Interventional
Phase: Phase 3

Summary: 
      This is a randomized, single-blind, parallel 5 treatment group 24-week trial designed to
      directly compare the therapeutic effects of exenatide once weekly (EQW), dapagliflozin
      (DAPA), EQW plus DAPA, combined DAPA/metformin extended release (XR) and the weight loss
      medication, phentermine/topiramate extended release (PHEN/TPM ER) on metabolic and
      endocrinological parameters in overweight/obese non-diabetic women with PCOS. In this study,
      we will examine the efficacy of these therapies on metabolic parameters, body weight and body
      composition, anthropometric measurements, and reproductive function in a well-defined group
      of pre-menopausal overweight/obese, non-diabetic women with PCOS, focusing on their
      relationship to insulin resistance and obesity. We hope to determine which treatment(s)
      addressing the multifaceted disturbances of individual subgroups emerge as the preferable
      therapy.
    

Detailed description: 
      Polycystic ovary syndrome is a heterogeneous condition characterized by disordered
      reproductive and metabolic function which accounts for the myriad of clinical features
      including androgen excess, chronic anovulation, insulin resistance adiposity, and
      dyslipidemia. This syndrome is highly prevalent, affecting between 8 and 18% of the female
      population, depending on the diagnostic criteria used. Hyperandrogenism, ovarian dysfunction
      and metabolic abnormalities - the main determinants of PCOS - all appear to be involved in a
      synergistic way in the pathophysiology of PCOS. Women with PCOS are more likely to be obese:
      between 38 and 88% of women with PCOS are overweight or obese, although PCOS can also
      manifest in lean women. Obesity, particularly abdominal obesity, plays a central role in the
      development of PCOS, and exacerbates the reproductive and metabolic dysfunction. Rather than
      absolute body weight, it is the distribution of fat that is important with central (visceral)
      adiposity being a risk factor. Visceral adipose tissue is more metabolically active than
      subcutaneous fat and the amount of visceral fat correlates with insulin resistance and
      hyperinsulinemia. Weight gain is also often an important pathogenic factor, with PCOS usually
      becoming clinically manifest in women with a presumable genetic predisposition for PCOS who
      subsequently gain weight. Therefore, environmental (particularly dietary) factors are
      important. However, BMI is also influenced by genetic factors such as the fat mass and
      obesity-associated protein, and obesity is a highly heritable condition. Therefore, the
      weight gain responsible for the manifestation of PCOS in many women with this condition is
      itself influenced by genetic factors. Ethnicity, genetic background, personal and family
      history, degree of obesity must all be taken into account because they might aggravate or
      even trigger metabolic disturbances women with PCOS. Moreover, the incidence of glucose
      intolerance, dyslipidemia, gestational diabetes, and type 2 diabetes (DM2) is increased in
      women with PCOS at all weight levels and at a young age. PCOS may be a more important risk
      factor than ethnicity or race for glucose intolerance in young women. The exact factors
      responsible for this excess risk in women with PCOS have not been identified; family history
      of DM 2, obesity, insulin resistance, beta cell (ß-cell) secretory dysfunction, and
      hyperandrogenism are possible candidates. With better understanding of its pathophysiology,
      the metabolic consequences of the syndrome are now evident. Therefore, these patients need to
      be followed up even after their presenting complaint has been adequately resolved.

      Lifestyle modification is a key component for the improvement of reproductive function for
      overweight, anovulatory women with PCOS. Even a modest weight loss 5% of total body weight
      can restore ovulation in overweight women with PCOS. Features of PCOS (e.g., hirsutism,
      testosterone levels, insulin resistance, menstrual cyclicity and ovulation) showed marked
      improvements, and PCOS frequently resolved after substantial weight loss induced by bariatric
      surgery. Recently a number of anti-diabetes medications have been approved which facilitate
      weight loss and improve the underlying insulin resistance. We reported that treatment with
      the glucagon like peptide -1 (GLP-1) agonist, exenatide for 24 weeks was superior to single
      agent metformin treatment in improving insulin action and reducing body weight and
      hyperandrogenism in obese women with PCOS. We further observed exenatide treatment
      significantly improved first-phase insulin responses to oral glucose administration. Since
      aberrant first-phase insulin secretion and impaired suppression of endogenous glucose
      production are major contributors to postprandial hyperglycemia and development of type 2
      diabetes, the effects of exenatide once weekly [EQW (2 mg)] to target these defects, and
      normalize glucose excursions are likely to be clinically significant in obese patients with
      PCOS. Sodium/glucose cotransporter 2 (SGLT-2) inhibitors are the newest class of medications
      for diabetes management that have not been investigated for use in the women with PCOS. The
      SGLT2 inhibitor, dapagliflozin [DAPA (10 mg/day)] has an insulin-independent action, promotes
      weight loss, has a low incidence of hypoglycemia, and complements the action of other
      antidiabetic agents. The loss of glucose with attendant caloric loss contributes to weight
      loss; in addition, improvements in β cell function have been seen. Because the SGLT2
      inhibitors have a distinct mechanism of action that is independent of insulin secretion, the
      efficacy of this class of drugs is not anticipated to decline in the presence of severe
      insulin resistance. The weight loss seen with SGLT2 inhibitors is similar to that seen with
      glucagon-like peptide 1 agonists, and may be more acceptable because they are oral agents.
      The resulting weight loss will further assist in decreasing insulin resistance, leading to
      increased glucose disposal thus contributing to an increased insulin secretion-insulin
      sensitivity (ISSI) index, the primary outcomes measure.

      The non-diabetic female with PCOS offers a unique model to study the relationship between
      insulin resistance and adiposity. Women with PCOS demonstrate abnormal body composition
      characterized by a greater percent body fat, body fat mass, and increased ratio of fat to
      lean mass (F/L ratio). Studies using dual-energy X-ray absorptiometry (DEXA) methodology
      report a higher degree of metabolic dysfunction in patients with PCOS which appears be
      directly associated with their higher F/L ratio. Given that monotherapy and combined therapy
      with exenatide once weekly (EQW),and dapagliflozin (DAPA) along with DAPA/ metformin XR
      therapy are associated with weight loss introduces a confounder to the current study since it
      prevents distinguishing direct effects of the compounds on β-cell function vs. effects due to
      reduced adiposity. To control for loss of body mass and provide appropriate intervention in
      the remaining study arm we propose the use of a comparator weight loss drug alone,
      combination phentermine (PHEN)/topiramate (TPM) extended release (ER). To avoid the
      confounding relationship of body fat and insulin resistance, we will enroll only obese
      non-diabetic women with PCOS. All patients will receive diet and lifestyle counselling,
      including advice on exercise, according to usual clinical routine commencing during the
      lead-in period and continuing throughout the study We propose a randomized, single-blind,
      parallel 5 treatment group 24-week trial designed to directly compare the therapeutic effects
      of exenatide once weekly (EQW), dapagliflozin (DAPA), EQW plus DAPA, combined DAPA/metformin
      ER and the weight loss medication, phentermine/topiramate extended release (PHEN/TPM ER) on
      metabolic and endocrinological parameters in obese non-diabetic women with PCOS.
    

Intervention name(s): Exenatide once weekly (EQW ); Dapagliflozin (DAPA); EQW plus DAPA; Dapagliflozin plus Glucophage (MET ER); Phentermine /Topiramate (PHEN/ TPM) ER
Intervention type(s): Drug; Drug; Drug; Drug; Drug
Intervention description(s): 2 mg SC injection every 7 days; One pill (10 mg) by mouth daily (QD) in am; 2 mg SC injection every 7 days One pill (10 mg) by mouth QD in am; DAPA/MET ER-5 mg /1000 mg - 1 pill by mouth in am with food for 4 weeks DAPA/MET ER-10 mg /2000 mg - 2 pills in am by mouth with food -final dose; PHEN 3.75/TPM ER 23mg - 1 pill by mouth once daily in am for 2 weeks. After 2 weeks, PHEN 7.5mg/TPM ER 46mg- 1 pill by mouth once daily in am
Other intervention name(s): • Bydureon; • Long acting glucagon like peptide 1 (GLP1) agonist; • Farxiga; • SGLT2 inhibitor; Bydureon plus Farxiga; Long acting GLP1 agonist plus SGLT2 inhibitor; Xigduo; •Combination SGLT2 inhibitor and metformin ER; Qsymia
Intervention MeSH terms: Metformin; Dapagliflozin; Exenatide; Topiramate; Sodium-Glucose Transporter 2 Inhibitors; Phentermine; Glucagon; Glucagon-Like Peptide 1
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Investigator)
Primary purpose: Treatment
Keywords: PCOS; GLP1 agonists; SGLT2 inhibitors