DAPA, EQW, DAPA/MET ER and PHEN/TPM ER in Obese Women With PolycysticOvary Syndrome (PCOS)

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.

Inclusion Criteria:

1. Non-diabetic women (18-45 years)

2. PCOS- NIH criteria hyperandrogenism and irregular menses

3. Obese class I, II, and III (BMI >30<45)

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

1. an intrauterine device, tubal sterilization, or male partner vasectomy, or

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

5. Written consent for participation in the study

Exclusion Criteria:

1. Presence of significant systemic disease, 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)

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

3. Renal impairment (e.g., serum creatinine levels ≥1.4 mg/dL for women, or estimated
glomerular filtration rate (eGFR) <60 mL/min/1.73 m2) or history of unstable or
rapidly progressing renal disease or end stage renal disease. Patients with a history
of nephrolithiasis are also excluded due to increased association with kidney stone
formation.

4. Uncontrolled thyroid disease (documented normal TSH), Cushing's syndrome, congenital
adrenal hyperplasia or hyperprolactinemia

5. Significantly elevated triglyceride levels (fasting triglyceride > 400 mg/dL)

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

7. Use of hormonal medications, lipid-lowering (statins, etc.), anti-obesity drugs or
weight loss medications (prescription or OTC) and medications known to exacerbate
glucose tolerance (such as isotretinoin, hormonal contraceptives,
gonadotropin-releasing hormone agonists, glucocorticoids, anabolic steroids, C-19
progestins) stopped for at least 8 weeks. Use of anti-androgens that act peripherally
to reduce hirsutism such as 5-alpha reductase inhibitors (finasteride, spironolactone,
flutamide) stopped for at least 4 weeks

8. Prior history of a malignant disease requiring chemotherapy

9. Patients at risk for volume depletion due to co-existing conditions or concomitant
medications, such as loop diuretics should have careful monitoring of their volume
status

10. History of unexplained microscopic or gross hematuria, or microscopic hematuria at
visit 1, confirmed by a follow-up sample at next scheduled visit.

11. Presence of hypersensitivity to dapagliflozin or other SGLT2 inhibitors (e.g.
anaphylaxis, angioedema, exfoliative skin conditions

12. Known hypersensitivity or contraindications to use GLP1 receptor agonists (exenatide,
liraglutide)

13. Use of metformin, thiazolidinediones, GLP-1 receptor agonists, dipeptidyl peptidase 4
(DPP-4) inhibitors, SGLT2 inhibitors stopped for at least 4 weeks.

14. Prior use of medication to treat diabetes except gestational diabetes

15. Eating disorders (anorexia, bulimia) or gastrointestinal disorders

16. Suspected pregnancy (documented negative serum pregnancy test), desiring pregnancy in
next 6 months, breastfeeding, or known pregnancy in last 2 months

17. Active or prior history of substance abuse (smoke or tobacco use within past 3 years)
or significant intake of alcohol

18. Having a history of bariatric surgery

19. Patient not willing to use two barrier method contraception during study period
(unless sterilized or have an IUD)

20. Patients with glaucoma or history of increased intraocular pressure, or use of any
medications to treat increased intraocular pressure

21. Debilitating psychiatric disorder such as psychosis or neurological condition that
might confound outcome variables. Patients with a history of bipolar disorder or
psychosis, greater than one lifetime, episode of major depression, current depression
of moderate or greater severity (PHQ-9score of 10 or more), presence or history of
suicidal behavior or ideation with some intent to act on it, or antidepressant use
that has not been stable for at least 3 months will also be excluded.

22. Inability or refusal to comply with protocol

23. Current participation or participation in an experimental drug study in previous three
months