Effect of Pioglitazone and Exenatide on Body Weight and Beta Cell Function

Study Overview
=================
Brief Summary
-----------------
Pioglitazone, a drug used in treatment of type 2 diabetes has been shown to improve insulin sensitivity in skeletal muscle, liver, and fat cells. Despite the beneficial effects of pioglitazone to improve insulin sensitivity and reduce cardiovascular disease in high risk type 2 diabetic patients, weight gain has been a limiting factor. Exenatide, another agent used for treatment of T2DM, improves glycemic control and promotes moderate weight loss. In this proposal we will examine the effect of combination therapy with pioglitazone plus exenatide on body weight, fat topography, beta cell function, glycemic control, and plasma lipid levels in subjects with type 2 diabetes mellitus compared to treatment with each drug separately. Assessment of beta cell function will be performed by measuring the maximal insulin secretory capacity using a maximal hyperglycemic stimulus combined with an intravenous arginine stimulus.

Detailed Description
-----------------
The thiazolidinedione (TZD) class of drugs has been shown to improve insulin sensitivity in skeletal muscle, liver, and adipocytes and to have anti-inflammatory and cardioprotective effects. The beta cell function, measured by the insulin secretion/insulin resistance index during the OGTT, improves significantly. In the present study, we will perform a more definitive assessment of beta cell function in TZD-treated diabetic patients by measuring the maximal insulin secretory capacity using a maximal hyperglycemic stimulus combined with an intravenous arginine stimulus. Despite the beneficial effects of pioglitazone to improve insulin sensitivity and reduce cardiovascular events in high risk type 2 diabetic patients, weight gain has been a limiting factor for primary care physicians even though pioglitazone treatment leads to a redistribution of fat out of muscle/liver/visceral area to subcutaneous fat. Exenatide (Byetta) is 39 amino acid peptide which exhibits biological actions similar to GLP-1. In clinical trials exenatide reduces HbA1c by 1-1.2% in subjects with type 2 diabetes and promotes moderate weight loss which is sustained for up to 2 years. In this proposal we will examine the effect of combination therapy with pioglitazone plus exenatide on body weight, fat topography, beta cell function, glycemic control, and plasma lipid levels in subjects with type 2 diabetes mellitus compared to monotherapy with each agent separately. We postulate that combination therapy will result in significant weight loss (in contrast to the weight gain which accompanies pioglitazone treatment) and have an additive, or even synergistic, effect to improve beta cell function and glycemic control in type 2 diabetic patients who are inadequately controlled on oral agent therapy with metformin alone, a sulfonylurea alone, or combination of metformin plus a sulfonylurea. We will also compare the insulin secretion in healthy control subjects (NGT, n=15) and subjects with impaired glucose tolerance (IGT, n=15) to evaluate the relative decline in beta cell function in T2DM compared to NGT and IGT subjects. NGT and IGT subjects will participate only in a OGTT and a Hyperglycemic clamp- they will not receive any medication.

Official Title
-----------------
Effect of Pioglitazone With and Without Exenatide on Body Weight, Fat Topography, Beta Cell Function, and Glycemic Control in Type 2 Diabetic Patients

Conditions
-----------------
Type 2 Diabetes, Healthy, Impaired Glucose Tolerance

Intervention / Treatment
-----------------
* Drug: Pioglitazone
* Drug: Exenatide
* Drug: Pioglitazone and Exenatide


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Diabetic patients must be on diet therapy alone or diet plus a sulfonylurea, or diet plus metformin, or diet plus sulfonylurea/metformin and have a HbA1c ≥ 7.0%. Patients must have the following laboratory values: Hematocrit ≥ 34 vol% Serum creatinine ≤ 1.8 mg/dl AST (SGOT) ≤ 2 times upper limit of normal ALT (SGPT) ≤ 2 times upper limit of normal Alkaline phosphatase ≤ 2 times upper limit of normal Patients must have been on a stable dose of allowed chronic medications for 30 days prior to entering the study. Body weight must be stable (± 3-4 pounds) over the three months prior to study The normal healthy control group will be age, weight (BMI), and gender matched with the diabetic group and must have a normal OGTT according to ADA criteria. Subjects with IFG/IGT will have a FPG (100-125mg/dl) and/or 2-h plasma glucose (140-199mg/dl) according to ADA criteria. Exclusion Criteria: Patients must not have type 1 diabetes. Patients must not have a fasting plasma glucose of greater than 270 mg/dl or HbA1c > 10.0%. Patients must not have received a thiazolidinedione or insulin for more than one week during the year prior to randomization. Patients with a history of clinically significant heart disease (New York Heart Classification greater than class 2.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

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: Pioglitazone<br>Pioglitazone: 15 Patients will be randomized to Pioglitazone only arm | Drug: Pioglitazone<br>* Pioglitazone 15 mg/day for 1 month and then 45 mg/day for 5 months<br>* Other names: ACTOS;|
| Experimental: Exenatide<br>Exenatide: 15 subjects will be randomized to receive Exenatide | Drug: Exenatide<br>* Exenatide 5mcg twice daily for 1 month, then 10mcg twice daily for 5 months<br>* Other names: BYETTA;|
| Experimental: Drug Pioglitazone and Drug Exentatide<br>Pioglitazone and Exenatide: 15 subjects will be randomized to Pioglitazone and Exenatide | Drug: Pioglitazone and Exenatide<br>* Pioglitazone 30mg daily for 1 month and then 45mg daily for 5 months and Exenatide 5mcg twice daily for one month then 10mcg twice daily for 5 months<br>* Other names: BYETTA;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect of Pioglitazone, Exenatide and Combined Pioglitazone and Exenatide on Body Weight | Effect of Pioglitazone, Exenatide and combined Pioglitazone and Exenatide on body weight and beta cell function | baseline and 6 months | 
| HbA1c | change in HbA1c was measured before and after treatment in three groups | baseline and 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect Pioglitazone, Exenatide, and Pioglitazone Plus Exenatide • Insulin Sensitivity • Inflammatory Cytokines • Glucagon and Free Fatty Acids • Plasma Lipids | Effect pioglitazone, exenatide, and pioglitazone plus exenatide on Insulin sensitivity Inflammatory cytokines glucagon and free fatty acids plasma lipids measured over a 6 month period | 6 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Type 2 diabetes pathogenesis, thiazolidinediones, impaired glucose tolerance, Incretins, Insulin secretion