Saxagliptin + Metformin Compared to Saxagliptin or Metformin Monotherapy in PCOS Women With Impaired Glucose Homeostasis
Condition: Polycystic Ovary Syndrome; Disorder of Glucose Regulation
MeSH terms: Polycystic Ovary Syndrome
Study type: Interventional
Phase: Phase 3

Summary: 
      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).
      Saxagliptin is an oral dipeptidyl peptidase IV (DPP-4) inhibitor whose mechanism of action is
      to prolong the duration of blood glucagon-like peptide (GLP-1) and glucose-dependent
      insulinotropic polypeptide (GIP) levels by inhibiting their degradation and thereby
      augmenting insulin secretion. This study will serve as a pilot investigation to open
      perspectives for future studies to explore the potential of combining anti-diabetic drugs
      with different mechanisms of action in in patients with PCOS and impaired glucose regulation
      (IGR), especially ones for whom standard treatment with metformin is less effective.
    

Detailed description: 
      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 gestational diabetes (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
    

Intervention name(s): Metformin XR; Saxagliptin; Saxagliptin-Metformin XR
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Start 2 pills (2 pills of 500 mg =1000mg XR) for 3 weeks
Increase to 4 pills as tolerated (4 pills of 500 mg XR =2000 mg XR) for remainder of study; Start 1 pill (5 mg)) for 3 weeks
Remain at 1 pill (5mg dose) for remainder of study; Start 1 pill (2.5 mg/ 1000mg XR) for 3 weeks
Increase to 2 pills as tolerated (5mg/2000 mg XR) for remainder of study
Other intervention name(s): Glucophage XR; Biguanide-insulin sensitizer; Onglyza; DPP-4 inhibitor; Kombiglyze XR; Combination DPP-4 inhibitor and Glucophage XR
Intervention MeSH terms: Metformin; Saxagliptin; Biguanides; Dipeptidyl-Peptidase IV Inhibitors
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Investigator)
Primary purpose: Treatment
Keywords: PCOS; IGT; DPP-4 inhibitor