Cardiovascular Disease (CVD) Risk and Prevention in Early Glucose Intolerance

CVD Risk and Prevention in Early Glucose Intolerance

The purpose of this study is to determine whether cardiovascular disease (CVD) risk markers, β-cell function, and insulin sensitivity can be improved by targeting mechanisms of both diabetes and CVD - using an antioxidant, an angiotensin II receptor blocker (ARB), or an anti-inflammatory agent - in patients with impaired glucose tolerance (IGT) in a randomized, controlled trial.

Study Overview

• Status: Completed
• Conditions: Prediabetic State; Impaired Glucose Tolerance
• Intervention / Treatment: Drug: Aspirin; Drug: Olmesartan; Drug: Alpha lipoic acid; Drug: Placebo

Detailed Description

Diabetes is a common, major health problem in the United States, and it significantly increases the risk of developing heart disease, which is the leading cause of death. Research studies have shown that the risk of heart disease is increased, even in the "pre-diabetes" or impaired glucose tolerance (IGT) stage, before the onset of true diabetes. While many studies have shown that aggressive management of diabetes lowers the risk of heart disease, at the present time, it is not known how best to treat patients with impaired glucose tolerance (pre-diabetes) to prevent the development of heart disease. It is also not known where in the range of blood sugar levels risk begins to increase. The purpose of this study is to determine:

• whether medications, which target pathways involved in the development of heart disease, can decrease the risk of heart disease in individuals with impaired glucose tolerance; and
• whether a "high" blood sugar level measured one hour after drinking a standard high-sugar drink is associated with an increased risk of heart disease even in individuals who have no evidence of diabetes or pre-diabetes.

The purpose of Aim 1 of this study is to determine whether medications, which target pathways involved in the development of heart disease, can decrease the risk of heart disease in individuals with impaired glucose tolerance. One hundred-twenty volunteers with impaired glucose tolerance and 30 volunteers with normal glucose tolerance (normal blood sugars after ingesting a standard high-sugar drink) will be recruited from the "Screening for Impaired Glucose Tolerance" (SIGT) study. The 30 volunteers with normal glucose tolerance will not take any study medication, but will undergo medical testing to determine their risk of heart disease at the beginning of the study, after which their participation in the study will be complete. The 120 volunteers with impaired glucose tolerance will be randomly assigned to one of four medications to be taken over a one-year period:

• alpha lipoic acid (an antioxidant, dietary supplement);
• olmesartan (a drug used to treat high blood pressure);
• aspirin (an anti-inflammatory drug); and
• placebo (an inactive, "dummy" pill).

Subjects with impaired glucose tolerance will undergo medical testing to determine their risk of heart disease at the beginning of the study (before beginning study medications), after 3 months of intervention, and again at the end of the study (12 months after enrollment). Test results will be compared between the subjects taking each of the active medications and those taking placebo, to determine if the medications lead to a significant reduction in the risk for the development of heart disease. The medical tests used in this study are currently used in medical practice, and include blood and urine specimens, ultrasound testing of the artery at the arm, and an insulin sensitivity test (test of how effectively the body uses sugar). All visits and tests will be conducted in the General Clinical Research Centers of Emory University Hospital and Grady Memorial Hospital.

The purpose of Aim 2 of this study is to determine whether a "high" blood sugar level measured one hour after drinking a standard high-sugar drink (1-hour blood sugar level) is associated with an increased risk of heart disease even in individuals who have no evidence of diabetes or pre-diabetes. Seventy-five volunteers with normal glucose tolerance (normal blood sugars after ingesting a standard high-sugar drink) will be recruited from the SIGT study, as well as 15 subjects with impaired glucose tolerance and 15 with diabetes. The subjects with normal glucose tolerance will be grouped into those with "low", "middle", and "high" 1-hour blood sugar levels. All subjects will undergo medical testing (as in Aim 1 above) to determine their risk of heart disease. Test results of subjects with "low", "middle", and "high" 1-hour blood sugar levels will be compared against one another, as well as against those of subjects with IGT and diabetes. If subjects with normal glucose tolerance but "high" 1-hour blood sugar levels are found to have increased risk for heart disease compared to those with "low" 1-hour blood sugar levels, then the 1-hour blood sugar levels may provide important information regarding an increased risk of heart disease even in individuals with normal glucose tolerance but "high" 1-hour blood sugar levels - a population which otherwise would not be identified with the current standard tests used for the diagnosis of diabetes and pre-diabetes.

Over 40 million Americans have pre-diabetes (impaired glucose tolerance), which is associated with an increased risk of the development of both diabetes and heart disease. Findings from these studies will provide important insights into the pathways that lead to the development of heart disease related to pre-diabetes, prevention of heart disease in the pre-diabetic population, and identification of individuals at high risk for heart disease earlier in their natural history - even before the onset of pre-diabetes.

• Study Type: Interventional
• Enrollment (Actual): 84
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University Hospital
    • Atlanta, Georgia, United States, 30303
      • Grady Health System

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 73 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Impaired glucose tolerance

Exclusion Criteria:

• Diagnosis of diabetes
• Taking an ACE inhibitor (ACE-I), angiotensin II receptor blocker (ARB), or aspirin
• Have systolic blood pressure >140 mm Hg
• Have a chronic inflammatory disorder (i.e. rheumatoid arthritis, inflammatory bowel disease, sinusitis)
• Vascular disease (cardiac, peripheral, cerebral)
• Renal insufficiency or hepatic abnormalities
• Gastrointestinal bleeding (defined as gastric or duodenal ulcer, hematemesis, and/or blood in the stool) or significant other upper gastrointestinal problems (i.e. gastritis) within the previous 6 months
• Anemia or a history of bleeding disorder
• Have a history of ARB or aspirin allergy
• Have the syndrome of asthma, rhinitis, and nasal polyps
• Have other medical problems which would preclude taking potential study medications for 12 months
• Are pregnant or have a positive pregnancy test
• Are breast feeding
• Are unable or unwilling to tolerate having one catheter in each arm for 4 hours
• Have health status such that the envisioned blood sampling would confer a physiologic risk
• Have other physical, social, or behavioral problems which would decrease the likelihood that they would remain in the study for 12 months
• Do not appear capable of giving informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Anti-inflammatory agent; Aspirin (ASA)	Drug: Aspirin; 325 mg PO QD; Other Names: Bayer aspirin
Active Comparator: Angiotensin receptor blocker (ARB); Olmesartan (ARB)	Drug: Olmesartan; 40 mg PO QD; Other Names: Benicar
Active Comparator: Antioxidant; Alpha lipoic acid (ALA)	Drug: Alpha lipoic acid; 600 mg PO BID
Placebo Comparator: Placebo; Aspirin placebo once a day Olmesartan placebo once a day Alpha lipoic acid placebo twice a day	Drug: Placebo; Identical placebo for each active comparator: placebo aspirin 325 mg PO QD; placebo for alpha lipoic acid 600 mg PO BID; placebo for olmesartan 40 mg PO QD

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AIM 1: Change in Flow Mediated Dilation (FMD) (%)	Surrogate measure of endothelial function defined as the percent change in dilation of the brachial artery after cuff compression of arm compared to before cuff compression	12 months of intervention

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AIM 1: Change in hsCRP (High Sensitivity C-reactive Peptide) Level	Inflammatory marker	12 months of intervention

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
AIM 2: Difference in FMD (Measure of Endothelial Function)	Comparison of FMD (measure of endothelial function) between NGT, IGT and diabetes at baseline. FMD is a surrogate measure of endothelial function defined as the percent change in dilation of the brachial artery after cuff compression of arm compared to before cuff compression. No analysis was conducted due to under-recruitment.	Cross-sectional

Collaborators and Investigators

• Sponsor: Emory University
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); Daiichi Sankyo, Inc.; National Center for Research Resources (NCRR)
• Investigators: Principal Investigator: Mary K Rhee, MD, MS, Emory University

Study record dates

Study Major Dates

• Study Start: May 1, 2005
• Primary Completion (Actual): May 1, 2011
• Study Completion (Actual): May 1, 2011

Study Registration Dates

• First Submitted: July 21, 2005
• First Submitted That Met QC Criteria: July 21, 2005
• First Posted (Estimate): July 22, 2005

Study Record Updates

• Last Update Posted (Estimate): December 5, 2013
• Last Update Submitted That Met QC Criteria: November 12, 2013
• Last Verified: November 1, 2013

More Information

Terms related to this study

• Keywords: Cardiovascular disease; Diabetes; Glucose intolerance; Prediabetic state
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Hyperglycemia; Cardiovascular Diseases; Prediabetic State; Glucose Intolerance; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Protective Agents; Micronutrients; Vitamins; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Antioxidants; Vitamin B Complex; Aspirin; Olmesartan; Thioctic Acid
• Other Study ID Numbers: IRB00000749; UL1RR025008 (U.S. NIH Grant/Contract); Sankyo CS-866 (Other Identifier: Daiichi Sankyo); 1K23DK070715-01A1 (U.S. NIH Grant/Contract)