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

• Sponsor: The University of Texas Health Science Center at San Antonio (Other)
• Overall Status: Completed
• CT.gov ID: NCT00845182
• Collaborator: (none)
• Enrollment: 43
• Location: 1
• Arms: 3
• Duration (Months): 37
• Patients Per Site Per Month: 1.2

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Type 2 Diabetes; Healthy; Impaired Glucose Tolerance	Drug: Pioglitazone; Drug: Exenatide; Drug: Pioglitazone and Exenatide	Phase 4

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 Design

• Study Type: Interventional
• Actual Enrollment: 43 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Participant)
• Primary Purpose: Treatment
• 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
• Study Start Date: Jun 1, 2007
• Actual Primary Completion Date: Jul 1, 2010
• Actual Study Completion Date: Jul 1, 2010

Arms and Interventions

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: ACTOS BYETTA

Outcome Measures

Primary Outcome Measures

1. Effect of Pioglitazone, Exenatide and Combined Pioglitazone and Exenatide on Body Weight [baseline and 6 months]

   Effect of Pioglitazone, Exenatide and combined Pioglitazone and Exenatide on body weight and beta cell function

2. HbA1c [baseline and 6 months]

   change in HbA1c was measured before and after treatment in three groups

Secondary Outcome Measures

1. Effect Pioglitazone, Exenatide, and Pioglitazone Plus Exenatide • Insulin Sensitivity • Inflammatory Cytokines • Glucagon and Free Fatty Acids • Plasma Lipids [6 months]

   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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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

1. Patients must have been on a stable dose of allowed chronic medications for 30 days prior to entering the study.

2. Body weight must be stable (± 3-4 pounds) over the three months prior to study

3. 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.

4. 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Barter Research Center, ALM VA Hospital	San Antonio	Texas	United States	78229

Sponsors and Collaborators

• The University of Texas Health Science Center at San Antonio

Investigators

• Principal Investigator: Devjit Tripathy, MD, The University of Texas Health Science Center at San Antonio

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: The University of Texas Health Science Center at San Antonio
• ClinicalTrials.gov Identifier: NCT00845182
• Other Study ID Numbers: HSC2007243H
• First Posted: Feb 18, 2009
• Last Update Posted: Jan 18, 2018
• Last Verified: May 1, 2017

• Keywords provided by The University of Texas Health Science Center at San Antonio: Type 2 diabetes pathogenesis, thiazolidinediones; impaired glucose tolerance; Incretins; Insulin secretion
• Additional relevant MeSH terms: Diabetes Mellitus, Type 2; Glucose Intolerance; Body Weight; Pioglitazone; Exenatide

Study Results

Participant Flow

Arm/Group Title	Pioglitazone	Exenatide	Pioglitazone and Exentatide
Arm/Group Description	Pioglitazone: 15 Patients will be randomized to Pioglitazone only arm	Exenatide: 15 subjects will be randomized to receive Exenatide	Pioglitazone and Exenatide: 15 subjects will be randomized to Pioglitazone and Exenatide
Period Title: Overall Study
STARTED	13	15	15
COMPLETED	10	11	9
NOT COMPLETED	3	4	6

Baseline Characteristics

Arm/Group Title	Pioglitazone	Exenatide	Pioglitazone and Exentatide	Total
Arm/Group Description	Pioglitazone: 15 Patients will be randomized to Pioglitazone only arm	Exenatide: 15 subjects will be randomized to receive Exenatide	Pioglitazone and Exenatide: 15 subjects will be randomized to Pioglitazone and Exenatide	Total of all reporting groups
Overall Participants	13	15	15	43
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	13 100%	14 93.3%	15 100%	42 97.7%
>=65 years	0 0%	1 6.7%	0 0%	1 2.3%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	54.6 (5.7)	54.3 (8.5)	53.8 (9.8)	54.2 (8.02)
Sex: Female, Male (Count of Participants)
Female	4 30.8%	4 26.7%	5 33.3%	13 30.2%
Male	9 69.2%	11 73.3%	10 66.7%	30 69.8%
Region of Enrollment (participants) [Number]
United States	13 100%	15 100%	15 100%	43 100%

Outcome Measures

1. Primary Outcome

Title	Effect of Pioglitazone, Exenatide and Combined Pioglitazone and Exenatide on Body Weight
Description	Effect of Pioglitazone, Exenatide and combined Pioglitazone and Exenatide on body weight and beta cell function
Time Frame	baseline and 6 months

Outcome Measure Data

Analysis Population Description

we analyzed the weight at the end of study completion

Arm/Group Title	PIOGLITAZONE	EXENATIDE	PIOGLITAZONE and EXNATIDE
Arm/Group Description	PIO therapy led to a weigh gain of 5.5 kg	PIO therapy led to a weigh loss of 2.4 kg	Combinatiton of PIoglitazone and Exenatide led to weight gain of 2.7 kg
Measure Participants	10	11	9
Mean (Standard Deviation) [kg]	5.5 (7.3)	2.4 (2.8)	2.7 (4.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	PIOGLITAZONE, EXENATIDE, PIOGLITAZONE and EXNATIDE
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	PIOGLITAZONE, EXENATIDE, PIOGLITAZONE and EXNATIDE
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	ANOVA
	Comments

2. Primary Outcome

Title	HbA1c
Description	change in HbA1c was measured before and after treatment in three groups
Time Frame	baseline and 6 months

Outcome Measure Data

Analysis Population Description

There was a greater improvement in HbA1c from baseline after combined treatment with Pioglitazone and Exenatide when compared with either therapy alone.

Arm/Group Title	Pioglitazone	Exenatide	Drug Pioglitazone and Drug Exentatide
Arm/Group Description	Pioglitazone: 15 Patients will be randomized to Pioglitazone only arm Pioglitazone: Pioglitazone 15 mg/day for 1 month and then 45 mg/day for 5 months	Exenatide: 15 subjects will be randomized to receive Exenatide Exenatide: Exenatide 5mcg twice daily for 1 month, then 10mcg twice daily for 5 months	Pioglitazone and Exenatide: 15 subjects will be randomized to Pioglitazone and Exenatide 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
Measure Participants	10	11	9
Mean (Standard Deviation) [percent point decrease from baseline]	1.37 (0.68)	1.09 (0.68)	1.91 (1.20)

3. Secondary Outcome

Title	Effect Pioglitazone, Exenatide, and Pioglitazone Plus Exenatide • Insulin Sensitivity • Inflammatory Cytokines • Glucagon and Free Fatty Acids • Plasma Lipids
Description	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
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

Data were not collected for this analysis

Arm/Group Title	Effect Pioglitazone, Exenatide, and Pioglitazone Plus Exenatid
Arm/Group Description	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
Measure Participants	0

Adverse Events

Time Frame	Patients were followed for 6 months.
Arm/Group Title	Pioglitazone		Exenatide		Pioglitazone and Exentatide
Arm/Group Description	Pioglitazone: 15 Patients will be randomized to Pioglitazone only arm		Exenatide: 15 subjects will be randomized to receive Exenatide		Pioglitazone and Exenatide: 15 subjects will be randomized to Pioglitazone and Exenatide
All Cause Mortality
	Pioglitazone		Exenatide		Pioglitazone and Exentatide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Pioglitazone		Exenatide		Pioglitazone and Exentatide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0%)		0/15 (0%)		0/15 (0%)
Other (Not Including Serious) Adverse Events
	Pioglitazone		Exenatide		Pioglitazone and Exentatide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/12 (16.7%)		1/15 (6.7%)		1/15 (6.7%)
General disorders
weight gain	2/12 (16.7%)	2	0/15 (0%)	0	1/15 (6.7%)	1
nausea	0/12 (0%)	0	1/15 (6.7%)	1	0/15 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.