Pharmacogenomics of Thiazolidinediones (PPAR)

The purpose of this study is to determine predictors of response to pioglitazone, an anti-diabetic medication. The investigators know from randomized clinical trials that some 30% of patients do not respond to this type of medication. There is presently no way to identify this group of patients leading to unnecessary drug exposure and medication costs.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes
• Intervention / Treatment: Drug: Pioglitazone

Detailed Description

In phase I, subjects who are eligible based on height and weight and general health information will sign informed consent. In phase II, subjects will be screened to ensure that they fit the inclusion/exclusion criteria, including an oral glucose tolerance test. Other blood tests will be performed to check complete blood count, lipids, liver functions and electrolytes.

Qualifying volunteers will enter phase III, which will consist of outpatient radioimaging and body composition, metabolic testing (intravenous glucose tolerance test), and tissue biopsies. Blood will also be drawn for genetic testing and for microarray studies of leukocytes. Written medication information and instructions for pioglitazone, discharge instructions and satisfaction surveys following the tissue biopsy procedures will be given to subjects during the study. During phase IV, subjects will begin pioglitazone therapy. Every 4 weeks throughout the drug intervention, glycemic control, lipoprotein profile, and weight will be monitored. After 12 weeks of pioglitazone therapy, the X-ray and magnetic resonance (MR) measurements of body composition, the biopsies and the metabolic tests performed during phase III will be repeated (phase V), and blood will be drawn for microarray studies of leukocytes.

Thereafter, subjects will have the option to be enrolled in a 10 week, behavioral weight loss program (phase VI). Following the 10-week weight loss program, a few outcome measurements will be repeated (phase VII).

Throughout the study, Women of Child Bearing Potential (WCBP) will have human human chorionic gonadotrophin (HCG) urine pregnancy tests. Pregnancy tests will only be performed on Women of childbearing potential, meaning women who are pre-menopausal and who have not had surgical sterilization. Women who have not had a hysterectomy or tubal ligation at least six months prior to signing informed consent or have been postmenopausal for at least one year, will be instructed to practice one of the following methods of birth control throughout the study: oral, transdermal, or implantable hormonal contraceptives, intrauterine device, diaphragm plus spermicide, condom plus spermicide, or abstinence. Pioglitazone may reduce the effectiveness of some hormonal types of contraceptives. Women using hormonal methods of birth control will be advised to use a barrier method as well. Female subjects are informed to notify the investigators immediately if they think they might have become pregnant during the study.

Participants who are eligible have 10 visits over an approximate 15-week period. Participants can choose to participate in an optional weight management program for an additional 10 weeks after treatment and before their final visit.

• Study Type: Interventional
• Enrollment (Actual): 114
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 35 years to 64 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Age 35-64
• BMI: ≥ 25 and ≤ 40

Exclusion Criteria:

• Pregnancy as determined by urine pregnancy test Breast-feeding, or planning to become pregnant during the study
• Physical dimensions exceeding the limits of any equipment used
• Stage III or greater congestive heart failure
• Symptomatic peripheral vascular disease
• Stroke
• Severe hypertension (>170/100 mmHg)
• Anemia (Hgb and Hct < normal reference range)
• Receiving treatment for thyroid, pituitary, kidney or liver disease (except controlled thyroid hormone replacement)
• History of diabetes (as told by doctor, or taking diabetic medications Fasting glucose value diagnostic for diabetes 2-h oral glucose tolerance test diagnostic for diabetes
• Rheumatoid arthritis
• History of wrist, hip or leg fracture after the age of 45
• History of kidney stones
• Medications that the investigator judges will make interpretation of the results difficult or increase the risk of participation (e.g. anticoagulants)
• Any disease or condition that the investigator judges will affect bone metabolism or make interpretation of the results difficult or increase the risk of participation (e.g. anemia, cardiac decompensation, intolerance to pioglitazone, lidocaine, or other agents used)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Pioglitazone (Actos); Participants will have metabolism studies to consist of outpatient X-ray and MR measurements of bone density and body composition, metabolic testing (intravenous glucose tolerance test), and muscle and adipose tissue biopsies. Blood will also be drawn for genetic testing and for microarray studies of leukocytes. Upon completion of the above studies, the participant will begin pioglitazone therapy. Every 4 weeks throughout the drug intervention, glycemic control, lipoprotein profile, and weight will be monitored. After 12 weeks of pioglitazone therapy, the X-ray and MR measurements of body composition, the biopsies, microarray studies for leukocytes and the metabolic tests will be repeated.

Drug: Pioglitazone; 30 mg tablet once daily for 4 weeks, then increased to 45 mg once daily for an additional 8 weeks. Total dosage period is 12 weeks.; Other Names: Actos

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Insulin Resistance	Change in insulin resistance was calculated as change (end of treatment minus baseline) in HOMA-IR index (glucose (mg/dL) x insulin (μU/mL)/405)	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Genes Determined to be Correlated With Change in Insulin Sensitivity	Number of genes determined to be correlated with change in insulin sensitivity as determined by HOMA-IR with a p-value below 0.000001	12 weeks

Collaborators and Investigators

• Sponsor: University of Maryland, Baltimore
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Principal Investigator: Soren Snitker, MD, PhD, University of Maryland, Baltimore

Study record dates

Study Major Dates

• Study Start: March 1, 2009
• Primary Completion (Actual): May 31, 2018
• Study Completion (Actual): May 31, 2018

Study Registration Dates

• First Submitted: June 1, 2010
• First Submitted That Met QC Criteria: June 1, 2010
• First Posted (Estimated): June 2, 2010

Study Record Updates

• Last Update Posted (Actual): March 15, 2024
• Last Update Submitted That Met QC Criteria: March 13, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Type 2 diabetes; Pharmacogenetics; Insulin sensitivity; Healthy adults; Thiazolidinediones; Pioglitazone
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Pioglitazone
• Other Study ID Numbers: HP-00043497; R01DK074828 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO