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

• ClinicalTrials.gov Identifier: NCT00122447
• Recruitment Status: Completed
• First Posted: July 22, 2005
• Results First Posted: June 20, 2012
• Last Update Posted: December 5, 2013
• Sponsor: Emory University
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); Daiichi Sankyo, Inc.; National Center for Research Resources (NCRR)
• Information provided by (Responsible Party): Dr. Mary Rhee, Emory University

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Impaired Glucose Tolerance; Prediabetic State	Drug: Aspirin; Drug: Alpha lipoic acid; Drug: Olmesartan; Drug: Placebo	Not Applicable

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 84 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: CVD Risk and Prevention in Early Glucose Intolerance
• Study Start Date: May 2005
• Actual Primary Completion Date: May 2011
• Actual Study Completion Date: May 2011

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Anti-inflammatory agent; Aspirin (ASA)	Drug: Aspirin; 325 mg PO QD; Other Name: Bayer aspirin
Active Comparator: Angiotensin receptor blocker (ARB); Olmesartan (ARB)	Drug: Olmesartan; 40 mg PO QD; Other Name: 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

Outcome Measures

Primary Outcome Measures :

1. AIM 1: Change in Flow Mediated Dilation (FMD) (%) [ Time Frame: 12 months of intervention ]
   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

Secondary Outcome Measures :

1. AIM 1: Change in hsCRP (High Sensitivity C-reactive Peptide) Level [ Time Frame: 12 months of intervention ]
   Inflammatory marker

Other Outcome Measures:

1. AIM 2: Difference in FMD (Measure of Endothelial Function) [ Time Frame: Cross-sectional ]

   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.

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

United States, Georgia

Grady Health System

Atlanta, Georgia, United States, 30303

Emory University Hospital

Atlanta, Georgia, United States, 30322

Sponsors and Collaborators

Emory University

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

More Information

• Responsible Party: Dr. Mary Rhee, Assistant Professor, Emory University
• ClinicalTrials.gov Identifier: NCT00122447
• 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 )
• First Posted: July 22, 2005
• Results First Posted: June 20, 2012
• Last Update Posted: December 5, 2013
• Last Verified: November 2013

Keywords provided by Dr. Mary Rhee, Emory University:

Prediabetic state; Cardiovascular disease; Diabetes; Glucose intolerance

Additional relevant MeSH terms:

Cardiovascular Diseases; Glucose Intolerance; Prediabetic State; Hyperglycemia; Glucose Metabolism Disorders; Metabolic Diseases; Diabetes Mellitus; Endocrine System Diseases; Aspirin; Thioctic Acid; Olmesartan; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Molecular Mechanisms of Pharmacological Action; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Enzyme Inhibitors; Antipyretics; Antihypertensive Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Antioxidants