Effects of Pioglitazone on High-density Lipoprotein (HDL) Function in Persons With Diabetes

This study has been completed.
Sponsor:
Collaborator:
Takeda Pharmaceuticals North America, Inc.
Information provided by (Responsible Party):
Armando J Mendez, University of Miami
ClinicalTrials.gov Identifier:
NCT01156597
First received: July 2, 2010
Last updated: November 11, 2014
Last verified: November 2014
  Purpose

Metabolic defects contributing to the development of type 2 diabetes (T2D) are relative insulin insufficiency and insulin resistance that are associated with a cluster of abnormalities that increase the risk for cardiovascular disease including dyslipidemia, inflammation, hemodynamic changes and endothelial dysfunction. The dyslipidemia associated with T2D is characterized by elevated triglycerides and decreased high-density lipoprotein-cholesterol (HDL). The ability of the insulin sensitizing agent pioglitazone (ACTOS®) , to improve hyperglycemia in subjects with T2D is now well established. Pioglitazone functions as a PPAR-γ (peroxisome proliferator-activated receptor gamma) agonists and this class of drugs have demonstrated several other potential benefits, beyond glucose homeostasis. Specifically pioglitazone can improve diabetic dyslipidemia by increasing HDL cholesterol and lowing triglycerides. A potential beneficial effect on reverse cholesterol transport may be mediated by the increased HDL levels. This proposal aims to examine the effect of PPAR-γ activation by PIO on various aspects of reverse cholesterol transport by testing the hypothesis that PIO treatment affects key steps in the reverse cholesterol transport pathway either directly, through induction of protein expression, or indirectly, by altering HDL structure and composition leading to increase cholesterol flux through this pathway.


Condition Intervention Phase
Type 2 Diabetes Mellitus
Drug: pioglitazone
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Basic Science
Official Title: Effects of Pioglitazone on Reverse Cholesterol Transport and HDL Function in Persons With Diabetes

Resource links provided by NLM:


Further study details as provided by University of Miami:

Primary Outcome Measures:
  • Increased HDL-Cholesterol and Decreased Triglycerides [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]

    The primary endpoint will be increased high density lipoprotein cholesterol and decreased triglycerides measured as the difference after 12 or 24 weeks of treatment from baseline levels. The data are expressed as the percent change from the baseline value and calculated using he equation:

    • Change=[100%*(Endpoint value - Baseline Value)/Baseline Value]


Secondary Outcome Measures:
  • HDL Apolipoprotein Levels at Study End-point [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
    Lipoproteins will be isolated and analyzed using the gradient ultracentrifugation-high pressure liquid chromatography technique to isolate very low-density lipoprotein (VLDL), intermediate density lipoprotein (IDL), LDL, and high density lipoprotein (HDL) subfractions. Protein and lipid compositions of HDL is determined

  • Cholesterol Efflux Capacity of HDL [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
    The ability of serum HDL to remove cholesterol from cultured cells will be assessed as an in vitro method to evaluate a functional changes in HDL mediated by changes due to pioglitazone treatment. Cells were incubated with 2% serum from each study subject diluted in culture medium and incubations were performed for a total of 4 hours. Cholesterol efflux was calculated as the percent of cholesterol removed from the cells and appearing in the culture medium normalized to a reference serum pool as described in detail by de la Llera-Moya et al (de la Llera-Moya M, Drazul-Schrader D, Asztalos BF, Cuchel M, Rader DJ, Rothblat GH. The ability to promote efflux via ABCA1 determines the capacity of serum specimens with similar high-density lipoprotein cholesterol to remove cholesterol from macrophages. Arterioscler Thromb Vasc Biol. 2010 Apr;30(4):796-801. doi: 10.1161/ATVBAHA.109.199158. PMID: 20075420).


Enrollment: 30
Study Start Date: April 2008
Study Completion Date: September 2010
Primary Completion Date: September 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Pioglitazone Group
This is a baseline versus treatment study comparing subjects on pioglitazone to a matched group of subjects treated with either metformin or sulfonylurea with the intent of controlling blood sugar to a comparable level
Drug: pioglitazone
30 mg daily for three weeks increase to 45 mg daily for 21 more weeks
Other Name: ACTOS
No Intervention: Comparator Group
This group of subjects will be maintained on standard treatment with either metformin or sulfonylurea with the intent of controlling blood sugar to a comparable level as group treated with pioglitazone.

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   35 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Type 2 diabetes, men and women, WHO criteria, aged 35-70 years
  • HbA1c 7.5-10.0%
  • BMI 26-39 Kg/m2
  • Either receiving dietary therapy only or monotherapy with either sulfonylurea or metformin
  • Already on statin therapy

Exclusion Criteria:

  • Cardiovascular disease
  • Renal disease
  • Other systemic disease
  • Abnormal liver function tests (ALT or AST>1.5 X ULN)
  • Uncontrolled hypertension (BP >160/110)
  • Triglyceride levels >400 mg/dl
  • Lipid modifying drugs; fibrates, ezetimibe, niacin, bile sequestrants, but not statins (see below),
  • Estrogen treatment or thyroid disease
  • Psychiatric condition or substance abuse
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01156597

Locations
United States, Florida
Diabetes Research Institute
Miami, Florida, United States, 33136
Sponsors and Collaborators
University of Miami
Takeda Pharmaceuticals North America, Inc.
Investigators
Principal Investigator: Armando J Mendez, PhD University of Miami
Principal Investigator: Ronald Goldberg, MD University of Miami
  More Information

Publications:
Responsible Party: Armando J Mendez, Research Associate Professor, University of Miami
ClinicalTrials.gov Identifier: NCT01156597     History of Changes
Other Study ID Numbers: 06-009A
Study First Received: July 2, 2010
Results First Received: April 18, 2014
Last Updated: November 11, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by University of Miami:
diabetes
dyslipidemia
pioglitazone
HDL-Cholesterol
Reverse cholesterol transport

Additional relevant MeSH terms:
Diabetes Mellitus, Type 2
Diabetes Mellitus
Endocrine System Diseases
Glucose Metabolism Disorders
Metabolic Diseases
Pioglitazone
Hypoglycemic Agents
Pharmacologic Actions
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on May 21, 2015