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

Study Overview
=================
Brief 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

Official Title
-----------------
Metabolic and Endocrine Effects of Combination of Metformin and DPP-4 Inhibitor Saxagliptin Compared to Saxagliptin or Metformin XR Monotherapy in Patients With PCOS and Impaired Glucose Regulation: A Single-blinded Randomized Pilot Study

Conditions
-----------------
Polycystic Ovary Syndrome, Disorder of Glucose Regulation

Intervention / Treatment
-----------------
* Drug: Metformin XR
* Drug: Saxagliptin
* Drug: Saxagliptin-Metformin XR


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Females 18 years to 42 years of age with polycystic ovary syndrome(NIH PCOS 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, gonadotropin releasing hormone (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, glucagon-like peptide -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 pregnancy 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 42 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Metformin XR<br>Metformin 2000 mg daily (QD) for 16 weeks | Drug: Metformin XR<br>* 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<br>* Other names: Biguanide-insulin sensitizer;|
| Active Comparator: Saxagliptin<br>Saxagliptin 5 mg QD for 16 weeks | Drug: Saxagliptin<br>* Start 1 pill (5 mg)) for 3 weeks Remain at 1 pill (5mg dose) for remainder of study<br>* Other names: DPP-4 inhibitor;|
| Experimental: Saxagliptin-Metformin XR<br>Saxagliptin-Metformin XR (combination pill) 5mg Saxagliptin/2000 mg Metformin XR QD for 16 weeks | Drug: Saxagliptin-Metformin XR<br>* 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<br>* Other names: Combination DPP-4 inhibitor and Glucophage XR;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Glucose Metabolism | Glucose metabolic secretory status after drug treatment (normal, impaired or diabetic). We used the American Diabetes Association (ADA) definition of impairment which is fasting glucose greater than 100 mg/dL and/or 2 hour glucose greater than 140 mg/dL. | 16 weeks | 
| Oral Disposition Index | Post-treatment in insulin-sensitivity-secretion index . The insulin secretion-sensitivity index (IS-SI) provides an estimate of β-cell compensation relative to the prevailing insulin resistance, not absolute insulin secretion. It is derived by applying the concept of the disposition index (DI) to measurements obtained during the 2-h OGTT. The IS-SI, a surrogate measure of the DI derived from the OGTT (IGI multiplied by the SIOGTT], was calculated as the product of acute β-cell response [IGI] and Matsuda index (SIOGTT) based on the existence of the predicted hyperbolic relationship between these two measures | 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fasting Glucose | Post-treatment fasting glucose levels | 16 weeks | 
| Mean Blood Glucose During the OGTT | Post-treatment mean blood glucose levels. Mean blood glucose (MBG) concentrations were calculated by summing glucose values obtained at 0,30,60 and 120 minutes during the OGTT and dividing by 4. | 16 weeks | 
| Matsuda Index of Insulin-Sensitivity (SI OGTT) | Post-treatment insulin sensitivity index. The Matsuda index of whole-body insulin sensitivity is calculated from an oral glucose tolerance test (10,000/square root of [fasting glucose x fasting insulin] x [mean glucose x mean insulin during OGTT]), and is highly correlated with the rate of whole-body glucose disposal during the euglycemic insulin clamp | 16 weeks | 
| Pancreatic ß-cell Compensatory Function | Post-treatment corrected early phase insulin secretion index (IGI/HOMA-IR). . Early pancreatic β-cell response is estimated as the insulinogenic index (IGI) derived from the ratio of the increment of insulin to that of glucose 30 minutes after a glucose load (insulin 30 min - insulin 0 min/glucose 30 min - glucose 0 min) corrected for by the relative level of insulin resistance (IGI/HOMA-IR which is estimated by homeostasis model assessment of insulin resistance using fasting insulin and glucose levels). | 16 weeks | 
| Body Mass Index at 16 Weeks | Height and weight measurements were used to calculate body mass index (BMI), defined as kg/m2. | 16 weeks | 
| Waist Circumference at 16 Weeks | The circumference measurement was taken in the upright position using a 15-mm width flexible metric tape held close to the body but not tight enough to indent the skin. Waist circumference (WC) was measured in centimeters at the narrowest level midway between the lowest ribs and the iliac crest. | 16 weeks | 
| Menstrual Cycle Interval at 16 Weeks | The number of menstrual cycles during the previous year was recorded and the average menstrual interval calculated by dividing 365 by the number of menstrual cycles in the previous year . During the study period, the patients in a menstrual diary recorded vaginal bleeding over 16 weeks. The effects of treatment intervention on menstrual cycle interval was calculated evaluated by dividing 112 days by the number of menstrual cycles recorded in each patient's menstrual cycle diary. | 16 weeks | 
| Triglyceride (TRG) /HDL-cholesterol Ratio | The measure of TRG levels and HDL- cholesterol levels are used as an estimate of insulin sensitivity. A TRG/HDL-C ratio of greater than 3.0 is used as an indirect measure of insulin resistance | 16 weeks | 
| Free Androgen Index (FAI) | Hyperandrogenism is measured by a combination of total testosterone (T) and sex hormone binding globulin (SHBG). The FAI was calculated as the quotient 100 x T/SHBG; hyperandrogenism was defined by a FAI value >3.85. | 16 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
PCOS, IGT, DPP-4 inhibitor