Effect of Pioglitazone and Exenatide on Body Weight and Beta Cell Function (PIO-EX)

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

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.

Study Overview

• Status: Completed
• Conditions: Healthy; Type 2 Diabetes; Impaired Glucose Tolerance
• Intervention / Treatment: Drug: Pioglitazone; Drug: Exenatide; Drug: Pioglitazone and Exenatide

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.

• Study Type: Interventional
• Enrollment (Actual): 43
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Texas
    • San Antonio, Texas, United States, 78229
      • Barter Research Center, ALM VA Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. 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%.

2. 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

3. Patients must have been on a stable dose of allowed chronic medications for 30 days prior to entering the study.
4. Body weight must be stable (± 3-4 pounds) over the three months prior to study
5. 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.
6. 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:

1. Patients must not have type 1 diabetes.
2. Patients must not have a fasting plasma glucose of greater than 270 mg/dl or HbA1c > 10.0%.
3. Patients must not have received a thiazolidinedione or insulin for more than one week during the year prior to randomization.
4. Patients with a history of clinically significant heart disease (New York Heart Classification greater than class 2.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Pioglitazone; Pioglitazone: 15 Patients will be randomized to Pioglitazone only arm	Drug: Pioglitazone; Pioglitazone 15 mg/day for 1 month and then 45 mg/day for 5 months; Other Names: ACTOS
Experimental: Exenatide; Exenatide: 15 subjects will be randomized to receive Exenatide	Drug: Exenatide; Exenatide 5mcg twice daily for 1 month, then 10mcg twice daily for 5 months; Other Names: BYETTA
Experimental: Drug Pioglitazone and Drug Exentatide; Pioglitazone and Exenatide: 15 subjects will be randomized to Pioglitazone and Exenatide	Drug: Pioglitazone and Exenatide; 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; Other Names: BYETTA; ACTOS

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

Collaborators and Investigators

• Sponsor: The University of Texas Health Science Center at San Antonio

Publications and helpful links

General Publications

• Guardado-Mendoza R, Chavez AO, Jimenez-Ceja LM, Hansis-Diarte A, DeFronzo RA, Folli F, Tripathy D. Islet amyloid polypeptide response to maximal hyperglycemia and arginine is altered in impaired glucose tolerance and type 2 diabetes mellitus. Acta Diabetol. 2017 Jan;54(1):53-61. doi: 10.1007/s00592-016-0904-7. Epub 2016 Sep 13.

Study record dates

Study Major Dates

• Study Start: June 1, 2007
• Primary Completion (Actual): July 1, 2010
• Study Completion (Actual): July 1, 2010

Study Registration Dates

• First Submitted: February 17, 2009
• First Submitted That Met QC Criteria: February 17, 2009
• First Posted (Estimate): February 18, 2009

Study Record Updates

• Last Update Posted (Actual): January 18, 2018
• Last Update Submitted That Met QC Criteria: December 18, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Keywords: Incretins; Insulin secretion; impaired glucose tolerance; Type 2 diabetes pathogenesis, thiazolidinediones
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Hyperglycemia; Diabetes Mellitus, Type 2; Glucose Intolerance; Body Weight; Hypoglycemic Agents; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Anti-Obesity Agents; Incretins; Pioglitazone; Exenatide
• Other Study ID Numbers: HSC2007243H