Myocardial Dysfunction in Type 2 Diabetes Mellitus (T2DM)

Myocardial Dysfunction in Type 2 Diabetes Mellitus (T2DM) - Role of Intramyocellular Lipid Content and Mitochondrial Dysfunction in Myocardial Insulin Resistance and Their Correction With Pioglitazone

The purpose of this study is to examine the existence of heart abnormalities in patients with diabetes and the effect of pioglitazone in correcting these abnormalities.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes; Coronary Heart Disease
• Intervention / Treatment: Drug: pioglitazone

Detailed Description

PRIMARY OBJECTIVES

1. To quantitate myocardial insulin sensitivity using positron emission tomography (PET) with 18F-deoxyglucose in type 2 diabetes mellitus (T2DM) and control subjects.
2. To quantitate pericardial fat using magnetic resonance spectroscopy in T2DM and control subjects.
3. To quantitate cardiac function using magnetic resonance imaging and echocardiography in T2DM and control subjects.
4. To examine the effect of pioglitazone on myocardial insulin sensitivity, pericardial fat content, and cardiac function.

SECONDARY OBJECTIVES To examine the relationships between myocardial insulin sensitivity, pericardial fat content, and cardiac function.

• Study Type: Interventional
• Enrollment (Actual): 130
• Phase: Phase 4

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients must be able to communicate meaningfully with the investigator and must be legally competent to provide written informed consent.
• Patients may be of either sex. Female patients must be non-lactating and must either be at least one year post-menopausal, or be using adequate contraceptive precautions (i.e. oral contraceptives, approved hormonal implant, intrauterine device, diaphragm with spermicide, condom with spermicide), or be surgically sterilized (i.e. bilateral tubal ligation, bilateral oophorectomy). Female patients who have undergone a hysterectomy are eligible for participation in the study. Female patients (except for those patients who have undergone a hysterectomy or a bilateral oophorectomy) are eligible only if they have a negative pregnancy test throughout the study period
• Patients must range in age from 18 to 75 years, inclusive.
• Patients with type 2 diabetes must be drug naïve, receiving monotherapy with metformin or with a sulfonylurea, or combination therapy with both: metformin & sulfonylurea.

• Patients must have the following laboratory values:

  • Hematocrit ≥ 34 vol%
  • Serum creatinine ≤ 1.8 mg/dl
  • AST (SGOT) ≤ 2.5 times upper limit of normal
  • ALT (SGPT) ≤ 2.5 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.
• Only subjects whose body weight has been stable (±3-4 pounds) over the three months prior to study will be included.

Exclusion Criteria:

• Patients must not have type 1 diabetes.
• Patients must not be receiving any medications with known adverse effects on glucose tolerance (except metformin or a sulfonylurea) unless the patient has been on stable doses of such agents for the past three months before entry into the study. Patients may be taking stable doses of estrogens or other hormonal replacement therapy, if the patient has been on these agents for the prior three months. Patients taking systemic glucocorticoids are excluded.
• Patients with a history of clinically significant heart disease (New York Heart Classification greater than class 2; more than non-specific ST-T wave changes on the EKG), peripheral vascular disease (history of claudication), or pulmonary disease (dyspnea on exertion of one flight or less; abnormal breath sounds on auscultation) will not be studied.
• Patients with hematocrit < 34% will be excluded.
• Patient who were exposed to any procedure involves radiation exposure and his total radiation dose equivalent exceeds 5 rem during the past year will be excluded from the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• 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; Only subjects with T2DM or non-diabetic subjects with coronary heart disease will receive Pioglitazone	Drug: pioglitazone; 45 mg per day for 6 months; Other Names: Actos

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in E to A Ratio	The E to A ratio is a marker of the function of the left ventricle of the heart. It represents the ratio of peak velocity flow in early diastole (the E wave) to peak velocity flow in late diastole caused by the atrial contraction (the A wave) This is measured using ultrasound-based cardiac imaging. In a healthy heart the E velocity is greater than the A velocity.	Baseline and 6-months Post Treatment
Myocardial Glucose Uptake	Measurement of change in myocardial glucose uptake from baseline to 6 months of treatment with pitoglitazone	Baseline and 6-months Post Treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Hemoglobin A1c	Change in hemoglobin A1c levels measured at 6 months	Baseline and 6-months Post Treatment

Collaborators and Investigators

• Sponsor: The University of Texas Health Science Center at San Antonio
• Collaborators: Takeda Pharmaceuticals North America, Inc.
• Investigators: Principal Investigator: Ralph A DeFronzo, MD, University of Texas

Publications and helpful links

General Publications

• Clarke GD, Solis-Herrera C, Molina-Wilkins M, Martinez S, Merovci A, Cersosimo E, Chilton RJ, Iozzo P, Gastaldelli A, Abdul-Ghani M, DeFronzo RA. Pioglitazone Improves Left Ventricular Diastolic Function in Subjects With Diabetes. Diabetes Care. 2017 Nov;40(11):1530-1536. doi: 10.2337/dc17-0078. Epub 2017 Aug 28.

Study record dates

Study Major Dates

• Study Start: June 1, 2006
• Primary Completion (Actual): December 1, 2011
• Study Completion (Actual): December 1, 2011

Study Registration Dates

• First Submitted: March 19, 2012
• First Submitted That Met QC Criteria: April 30, 2012
• First Posted (Estimate): May 1, 2012

Study Record Updates

• Last Update Posted (Actual): December 6, 2017
• Last Update Submitted That Met QC Criteria: October 31, 2017
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Keywords: mitochondria; pioglitazone; diastolic function; pericardial fat
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Endocrine System Diseases; Heart Diseases; Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Pioglitazone
• Other Study ID Numbers: MM20060280; T001 (Other Grant/Funding Number: Takeda)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: IPD data will not be available for other researchers. However, a manuscript describing the study results is under review for publication in the medical literature