Symptoms and General Pathology

All Conditions

Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Gland and Hormone Related Diseases

Syndrome

Polycystic Ovary Syndrome

Cysts

Ovarian Cysts

Ovarian Diseases

Adnexal Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Gonadal Disorders

Endocrine System Diseases

Hypoglycemic Agents

All Drugs and Chemicals

Anti-Infective Agents

Metformin

Insulin

Insulin, Globin Zinc

Dipeptidyl-Peptidase IV Inhibitors

Biguanides

Saxagliptin

Incretins

Hormones

Hormone Antagonists

HIV Protease Inhibitors

Protease Inhibitors

Enzyme Inhibitors

Metformin 2000 mg daily (QD) for 16 weeks

Saxagliptin-Metformin XR (combination pill)

5mg Saxagliptin/2000 mg Metformin XR QD for 16 weeks

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

Metformin XR

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

Saxagliptin-Metformin XR

Karen Elkind-Hirsch, Ph.D.

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.

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

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

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

The safety criteria will include laboratory values for liver enzymes and document the absence of pregnancy in all participants during the trial

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.

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

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.

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

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).

Height and weight measurements were used to calculate body mass index (BMI), defined as kg/m2.

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.

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.

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

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.

AstraZeneca

Woman's

Director of Research

Metformin 2000 mg QD for 16 weeks

Metformin XR: 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

Saxagliptin 5 mg QD for 16 weeks

Saxagliptin: Start 1 pill (5 mg)) for 3 weeks

Remain at 1 pill (5mg dose) for remainder of study

Saxagliptin-Metformin XR (combination pill)

5mg Saxagliptin/2000 mg Metformin XR QD for 16 weeks

Saxagliptin-Metformin XR: 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

Total

All participants had to be 18 to 42 years to participate

Age, Categorical

All participants had to be female to qualify

Sex: Female, Male

Our patient population is approximately 64% Caucasian and 35% African -American. The remaining ethnicities comprise about 1%.

Race (NIH/OMB)

United States

All participants were from Baton Rouge and surrounding parishes

Region of Enrollment

All participants had PCOS and were glucose impaired

Study limitations were the small number of patients and the short interval (16 weeks) of drug treatment.

Surrogate measures derived from the OGTT were used to estimate insulin sensitivity and secretion. .

Dr Karen Elkind-Hirsch

Study change from dysglycemia to normal glucose state

Change from impaired to normal was evaluated. No patients were diabetic at the start or completion of the study

Glucose Metabolism

This was a Subjects (SS)/Groups repeated measures design

Oral Disposition Index

Pretreatment fasting glucose levels were compared with post-treatment levels

Spots Global Cancer Trial Database for saxagliptin

Every month we try and update this database with for saxagliptin cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for saxagliptin

Every month we try and update this database with for saxagliptin cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for saxagliptin cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.