Saxagliptin + Metformin Compared to Saxagliptin or Metformin Monotherapy in PCOS Women With Impaired Glucose Homeostasis

A major change in the treatment of polycystic ovary syndrome (PCOS) was initiated by the
understanding that many women with this disorder compensate insulin resistance with a period
of hypersecretion of insulin by the pancreatic ß-cell. In addition, women with PCOS have
significantly higher basal insulin secretory rates, reduced insulin clearance rates, and
attenuated secretory responses to meals. The decreased postprandial response in these
patients resembles the ß-cell dysfunction of type 2 diabetes (DM2) and may account for the
increased incidence of impaired glucose tolerance in this population. Current research has
shown that the use of diabetes management practices aimed at reducing insulin resistance and
hyperinsulinemia (such as weight reduction and the administration of oral antidiabetic
drugs) in women with PCOS can not only improve glucose and lipid metabolism but can also
reverse testosterone abnormalities and restore menstrual cycles.

The optimal modality for long-term treatment of PCOS should positively influence androgen
synthesis, sex hormone binding globulin (SHBG) production, the lipid profile, insulin
sensitivity, and clinical symptoms including hirsutism and irregular menstrual cycles.
Improvement of insulin sensitivity may reverse some of the demand on the ß-cell and promote
improvement in glucose tolerance. However, while insulin resistance plays a key role in the
predisposition to diabetes in PCOS; defects in insulin secretion also appear to contribute
to its development. Preferably therapy for women with PCOS should also produce no weight
gain, hypoglycemia, or other limiting or unmanageable side effects as well as preserve or
enhance ß-cell function.

Presently, in the literature, there are described new, more efficient methods of diabetes
prevention in groups with a high risk of this disorder, which involve both, lifestyle
modification and pharmacological therapies. Lifestyle intervention was found to reduce the
incidence of type 2 diabetes by 58% and metformin by 31% as compared with placebo. The use
of rosiglitazone in subjects with prediabetes resulted in a 60% reduction of the diabetes
incidence rate. Whether pharmacological therapy should be prescribed for diabetes prevention
is an open question given that waiting to add drug therapy until diabetes develops can
arrest β-cell decline, albeit at a lower level of β-cell function than when medications are
used for prevention. Studies are needed for optimal postpartum and long-term health of women
who have had GDM. Considerable recent evidence suggests that incretin-based therapies may be
useful for the prevention of DM2. Whereas native GLP-1 has a very short half-life,
continuous infusion of GLP-1 improves first and second-phase insulin secretion suggesting
that early GLP-1 therapy may preserve ß-cell function in subjects with IGT or mild DM2.
Incretin mimetics and inhibitors of the protease dipeptidyl peptidase (DPP)-4 use the
anti-diabetic properties of the incretin hormone, glucagon-like peptide (GLP)-1 hormone to
augment glucose-induced insulin secretion in a highly glucose-dependent manner, thus
preventing GLP-1 alone from provoking hypoglycemia. Additional beneficial effects of GLP-1
on endocrine pancreatic islets are that it 1) supports the synthesis of proinsulin to
replenish insulin stores in β-cells; 2) reduces the rate of β-cell apoptosis when islets are
incubated in a toxic environment (glucotoxicity, lipotoxicity, cytotoxic cytokines); and 3)
promotes differentiation of precursor cells with the ability to develop into β-cells and
proliferation of β-cell lines, and in whole animals (rodent studies), this leads to an
increased β-cell mass within a few days or weeks. Furthermore, GLP-1 can lower glucagon
concentrations, i.e., induce α-cells to respond again to the inhibitory action of
hyperglycemia, while leaving the counterregulatory glucagon responses undisturbed, as in the
case of hypoglycemia. Additional activities of GLP-1 are the deceleration of gastric
emptying, which slows the entry of nutrients into the circulation after meals, a reduction
in appetite, and earlier induction of satiety, leading to weight reduction with chronic
exposure. Inhibition of DPP-4 increases the concentration of GLP-1 and may potentially delay
disease progression in prediabetes considering the β-cell function improvement in DM2 and
β-cell mass shown to increase in animal models. The objective of the present proposal is to
compare the clinical, endocrine and metabolic effects of therapy with combination
saxagliptin and metformin to saxagliptin and metformin monotherapy in women with PCOS and
prediabetic hyperglycemia (IFG, IGT or IFG/IGT). Since aberrant first-phase insulin
secretion and impaired suppression of endogenous glucose production are major contributors
to postprandial hyperglycemia and development of DM2, the effects of saxagliptin to target
these defects, and normalize glucose excursions are likely to be clinically significant in
patients with PCOS and impaired glucose regulation. This study will evaluate the impact of
treatment with combination of metformin and saxagliptin (Kombiglyze XR) compared to
saxagliptin (Onglyza) or metformin XR (Glucophage XR) monotherapy over a 16-week period on
glycemia and insulin action (fasting, 2 hour, and mean stimulated glucose levels, insulin
sensitivity and secretion), hyperandrogenism (total T, DHEAS, SHBG and calculated free
androgen index [FAI]), cardiometabolic markers (lipid profile, blood pressure), and
anthropometric measurements (BMI, waist: hip ratio, absolute weight) in patients with PCOS
and prediabetic hyperglycemia

Inclusion Criteria:

- Females 18 years to 42 years of age with PCOS (NIH criteria) with prediabetic
hyperglycemia determined by an 75 gram oral glucose tolerance test (OGTT). Study
subjects will be inclusive of PCOS women with impaired fasting glucose (IFG),
impaired glucose tolerance (IGT), or both (IFG/IGT).

- Written consent for participation in the study

Exclusion Criteria:

- Presence of significant systemic disease, heart problems including congestive heart
failure, history of pancreatitis, or diabetes mellitus (Type 1 or 2)

- Any hepatic diseases in the past (viral hepatitis, toxic hepatic damage, jaundice of
unknown etiology), gallstones, abnormal liver function tests or renal impairment
(elevated serum creatinine levels or abnormal creatinine clearance)

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

- Significantly elevated triglyceride levels (fasting triglyceride > 400 mg %)

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

- Use of hormonal medications, drugs known to affect gastrointestinal motility,
lipid-lowering (statins, etc.) and/or anti-obesity drugs or medications that
interfere with carbohydrate metabolism (such as isotretinoin, hormonal
contraceptives, GnRH analogues, glucocorticoids, anabolic steroids, C-19 progestins)
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

- Known hypersensitivity or contraindications to use of insulin sensitizers such as
metformin or thiazolidinediones

- History of hypersensitivity reaction to saxagliptin or other DPP-4 inhibitors (e.g.
anaphylaxis, angioedema, exfoliative skin conditions)

- Current use of metformin, thiazolidinediones, GLP-1 receptor agonists, DPP-4
inhibitors, or weight loss medications (prescription or OTC) Patients must stop use
of insulin sensitizers or antidiabetic medicines such as metformin for at least 4
weeks or thiazolidinediones, GLP1 agonists or DPPIV inhibitors for 8 weeks.

- Prior use of medication to treat diabetes except gestational diabetes

- Use of drugs known to exacerbate glucose tolerance

- Eating disorders (anorexia, bulimia) or gastrointestinal disorders

- Suspected pregnancy (documented negative serum ßhCG test), desiring pregnancy during
the study treatment interval, breastfeeding, or known pregnancy in last 2 months

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

- Patient not willing to use adequate barrier contraception during study period (unless
sterilized or have an IUD).

- Debilitating psychiatric disorder such as psychosis or neurological condition that
might confound outcome variables

- Inability or refusal to comply with protocol

- Not currently participating or having participated in an experimental drug study in
previous three months