Effect of Exenatide, Sitagliptin or Glimepiride on Functional ß -Cell Mass

Study Overview
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Brief Summary
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This study evaluates exenatide, sitagliptin, and glimepiride for the treatment of high blood sugar in patients with impaired fasting glucose or early type 2 diabetes. The purpose of this study is to determine if exenatide and sitagliptin increase the amount of insulin made by the pancreas compared to glimepiride. It is hypothesized that exenatide or sitagliptin will sustain or increase the amount of insulin made by the pancreas in comparison to glimepiride.

Detailed Description
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The incidence of type 2 diabetes (T2D) has reached epidemic proportions throughout the world. In the United States more than 1.5 million new cases of diabetes were diagnosed in 2005, and the estimated prevalence of the disease was over 20 million. Another 54 million Americans are believed to have impaired fasting glucose, which represents a pre-diabetic state at increased risk for progression to overt diabetes. T2D ultimately results from an inadequate mass of functional beta-cells, where insufficient beta-cell compensation for insulin resistance leads to the development of impaired glucose tolerance and eventually diabetes. Autopsy studies have demonstrated a decreased beta-cell mass occurring with fasting glucose > 110 mg/dl, consistent with functional studies that demonstrate decreased beta-cell (insulin) secretory capacity beginning in the range of impaired fasting glucose. Strategies that might preserve or expand functional beta-cell mass in vivo would be expected to reverse the progressive deterioration in blood glucose control seen with diabetes. One such strategy involves the incretin hormone glucagon-like peptide-1 (GLP-1), which is trophic for islet beta-cells, having both pro-proliferative and anti-apoptotic effects. However, it is not known whether increasing GLP-1 effects can preserve or enhance functional beta-cell mass in humans. This proposal will determine the effect of increasing GLP-1 levels on functional beta-cell mass in human subjects with impaired fasting glucose (fasting glucose 110 - 126 mg/dl) or early T2D (fasting glucose 127 - 149 mg/dl) where a critical window exists for reversing further beta-cell deterioration. GLP-1 effects will be promoted by administration of either the GLP-1 analog, exenatide, or by increasing endogenous GLP-1 levels through administration of the oral dipeptidyl peptidase 4 (DPP4) inhibitor sitagliptin for a 6-month period. To control for the effect of exenatide and sitagliptin on normalization of blood glucose, subjects will be randomized to receive exenatide, sitagliptin or the sulfonylurea glimepiride, the latter being a first-line anti-diabetogenic agent that will serve as an active comparator.

Official Title
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A Randomized, Controlled Trial Comparing the Effect of Exenatide, Sitagliptin or Glimepiride on Functional ß -Cell Mass in Patients With Impaired Fasting Glucose or Early Type 2 Diabetes

Conditions
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Pre-diabetes, Type 2 Diabetes

Intervention / Treatment
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* Drug: Exenatide
* Drug: Sitagliptin
* Drug: Glimepiride


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female patients age 18 to 70 years. Ability to provide written informed consent Mentally stable and able to comply with the procedures of the study protocol Clinical history compatible with impaired fasting glucose or early T2D as defined by a plasma glucose concentration between 110-159 mg/dl following a 12 hour overnight fast performed off any anti-diabetogenic agent for at least 2 weeks (6 weeks for thiazolidinediones) Stable body weight (+ 5%) for at least 2 weeks Female Patients: Agree to use adequate contraception if reproductively capable. Adequate contraception includes either a hormonal or barrier method, or surgical sterilization. Exclusion Criteria: Diagnosis of type 1 diabetes Receiving insulin, exenatide (Byetta®), or sitagliptin (Januvia®) treatment or taking > 2 oral anti-diabetogenic agents for the treatment of diabetes BMI > 44 kg/m2 Allergy to any sulfa-containing compounds Uncontrolled hypertension (Systolic Blood Pressure >160 or Diastolic Blood Pressure > 100 mmHg) Uncontrolled hyperlipidemia (triglycerides > 500 or LDL > 160 mg/dl) Elevation of liver function tests > 2 times the upper limit of normal Estimated Glomerular Filtration Rate (GFR) < 55 ml/min/1.73m2 (46) Hyperkalemia (serum potassium > 5.5 mmol/L) Moderate anemia (hemoglobin concentration < 12 g/dl in men and < 11 g/dl in women) Female patients: pregnant or lactating Hepatic cirrhosis Known active alcohol or substance abuse Active cardiovascular disease Use of any investigational agent within 6 weeks of the baseline visit Any medical condition that, in the opinion of the investigator, will interfere with the safe completion of the trial

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Exenatide<br>Exenatide (Byetta®)-5 µg injected subcutaneously twice daily and increased after 1 month to 10 µg twice daily as tolerated by gastrointestinal effects | Drug: Exenatide<br>* Exenatide (Byetta®)-5 µg injected subcutaneously twice daily and increased after 1 month to 10 µg twice daily as tolerated by gastrointestinal effects<br>* Other names: Byetta®;|
| Experimental: Sitagliptin<br>Sitagliptin (Januvia®)-100 mg by mouth every morning | Drug: Sitagliptin<br>* Sitagliptin (Januvia®)100 mg by mouth every morning<br>* Other names: Januvia®;|
| Active Comparator: Glimepiride<br>Glimepiride (Amaryl®)-0.5 mg by mouth every morning and then increased by 0.5 - 1.0 mg at each monthly visit to achieve an average fasting glucose < 110mg/dl | Drug: Glimepiride<br>* Glimepiride (Amaryl®)-0.5 mg by mouth every morning and then increased by 0.5 - 1.0 mg at each monthly visit to achieve an average fasting glucose < 110mg/dl<br>* Other names: Amaryl®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect on Functional Beta-cell Mass as Determined by Change in ß-cell Secretory Capacity at 6 Months (μU/ml) | The acute insulin response to arginine (AIRarg) performed during the 340mg/dl glucose clamp allows for estimation of the the beta-cell secretory capacity (AIRmax) or functional beta-cell mass. Changes from baseline to 6 months of AIRmax were compared across groups | Baseline and 6 months | 
| Effect on Functional Beta-cell Mass as Determined by Change in ß-cell Secretory Capacity at 6 Months (pg/mL) | AGRmin is performed during the 340mg/dl glucose clamp allows for estimation of the minimum alpha-cell glucagon secretion. Changes from baseline to 6 months of AGRmin were compared across groups. | Baseline and 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Acute Insulin Response to Arginine. (AIRarg) | The changes in B-cell insulin secretion, Acute Insulin Response to arginine (AIRarg) after 6 months were compared to baseline AIRarg for each group. Listed below are AIRarg at baseline and 6 months for each group. | Baseline and 6 months | 
| Insulin Sensitivity at Baseline and 6 Months | Insulin sensitivity (M/I) was determined by dividing the mean glucose infusion rate required during the 230 mg/dL glucose clamp (M) by the mean prestimulus insulin level (I) between 40 and 45 min of the glucose infusion The mean difference after 6 months in insulin sensitivity (M/I) were compared | Baseline and 6 months | 
| PG 50 (the Plasma Glucose Level at Which Half-maximal Insulin Secretion is Achieved During the Glucose-potentiated Arginine Test) at Baseline and 6 Months | Between ∼60 and 250 mg/dL, the magnitude of AIRarg is a linear function of the plasma glucose level, so the difference in AIRarg at fasting and 230 mg/dL glucose levels divided by the difference in plasma glucose (ΔAIRarg/ΔPG) gives the glucose-potentiation slope (GPS) (8,24-26). Using the y-intercept (b) from the line created by these two points, the plasma glucose level at which half-maximal insulin secretion is achieved (PG50) is derived from solving the equation 1/2 (AIRmax) = (GPS · PG50) + b, and provides a measure of β-cell sensitivity to glucose The mean difference after 6 months in PG 50 were compared. Listed below are the PG50 values at baseline and 6 months. | Baseline and 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Exenatide, Sitagliptin, Glimepiride, Glucagon-Like Peptide-1, Impaired Fasting Glucose, Type 2 Diabetes, Beta-cell Function, Beta-cell Secretory Capacity, Glucose-potentiated arginine