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

Sponsor
Emory University (Other)
Overall Status
Completed
CT.gov ID
NCT00122447
Collaborator
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH), Daiichi Sankyo, Inc. (Industry), National Center for Research Resources (NCRR) (NIH)
84
2
4
72
42
0.6

Study Details

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
N/A

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
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 1, 2005
Actual Primary Completion Date :
May 1, 2011
Actual Study Completion Date :
May 1, 2011

Arms and Interventions

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

    Outcome Measures

    Primary Outcome Measures

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

      Inflammatory marker

    Other Outcome Measures

    1. AIM 2: Difference in FMD (Measure of Endothelial Function) [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

    Criteria

    Ages Eligible for Study:
    18 Years to 75 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    Yes
    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

    Site City State Country Postal Code
    1 Grady Health System Atlanta Georgia United States 30303
    2 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

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Dr. Mary Rhee, Assistant Professor, Emory University
    ClinicalTrials.gov Identifier:
    NCT00122447
    Other Study ID Numbers:
    • IRB00000749
    • UL1RR025008
    • Sankyo CS-866
    • 1K23DK070715-01A1
    First Posted:
    Jul 22, 2005
    Last Update Posted:
    Dec 5, 2013
    Last Verified:
    Nov 1, 2013
    Keywords provided by Dr. Mary Rhee, Assistant Professor, Emory University
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details 266 subjects with IGT were contacted: 121 refused, 63 ineligible, 84 screened/enrolled. Among the 84 enrolled subjects: 1 was withdrawn, 13 dropped out before randomization, 70 were randomized (17 alpha lipoic acid, 18 aspirin, 18 olmesartan, 17 placebo). After randomization, 10 dropped out, and 3 were withdrawn.
    Pre-assignment Detail
    Arm/Group Title Aspirin (ASA) 325 mg PO Once Daily Olmesartan (ARB) 40 mg PO Once Daily Alpha Lipoic Acid (ALA) 600 mg PO Twice Daily Placebo
    Arm/Group Description Anti-inflammatory agent Angiotensin receptor blocker (ARB) Antioxidant Aspirin placebo PO once a day Olmesartan placebo PO once a day Alpha lipoic acid placebo PO twice a day
    Period Title: Overall Study
    STARTED 18 18 17 17
    COMPLETED 17 13 16 14
    NOT COMPLETED 1 5 1 3

    Baseline Characteristics

    Arm/Group Title Aspirin (ASA) 325 mg PO Once Daily Olmesartan (ARB) 40 mg PO Once Daily Alpha Lipoic Acid (ALA) 600 mg PO Twice Daily Placebo Total
    Arm/Group Description Anti-inflammatory agent Angiotensin receptor blocker (ARB) Antioxidant Aspirin placebo PO once a day Olmesartan placebo PO once a day Alpha lipoic acid placebo PO twice a day Total of all reporting groups
    Overall Participants 18 18 17 17 70
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    51.4
    (12.8)
    55.2
    (8.5)
    52.4
    (7.0)
    51.3
    (11.7)
    52.6
    (10.2)
    Sex: Female, Male (Count of Participants)
    Female
    13
    72.2%
    10
    55.6%
    10
    58.8%
    6
    35.3%
    39
    55.7%
    Male
    5
    27.8%
    8
    44.4%
    7
    41.2%
    11
    64.7%
    31
    44.3%
    Race/Ethnicity, Customized (participants) [Number]
    Black or African American
    13
    72.2%
    12
    66.7%
    10
    58.8%
    14
    82.4%
    49
    70%
    White
    5
    27.8%
    6
    33.3%
    7
    41.2%
    3
    17.6%
    21
    30%

    Outcome Measures

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

    Outcome Measure Data

    Analysis Population Description
    Based on the number of subjects who completed 12 months of intervention and testing
    Arm/Group Title Aspirin (ASA) 325 mg PO Once Daily Olmesartan (ARB) 40 mg PO Once Daily Alpha Lipoic Acid (ALA) 600 mg PO Twice Daily Placebo
    Arm/Group Description Anti-inflammatory agent Angiotensin receptor blocker (ARB) Antioxidant Aspirin placebo PO once a day Olmesartan placebo PO once a day Alpha lipoic acid placebo PO twice a day
    Measure Participants 11 11 11 10
    Mean (Standard Error) [mg/L]
    -1.27
    (0.86)
    -2.34
    (1.1)
    0.23
    (0.70)
    0.32
    (0.56)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Aspirin (ASA) 325 mg PO Once Daily, Placebo
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.449
    Comments Association between treatment arm, compared to placebo, on change in hsCRP from baseline to 12 months of intervention, adjusted for age, sex, and race.
    Method Regression, Linear
    Comments
    Method of Estimation Estimation Parameter Slope
    Estimated Value -0.941
    Confidence Interval (2-Sided) 95%
    -3.435 to 1.552
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.229
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Olmesartan (ARB) 40 mg PO Once Daily, Placebo
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.034
    Comments Association between treatment arm, compared to placebo, on change in hsCRP from baseline to 12 months of intervention, adjusted for age, sex, and race.
    Method Regression, Linear
    Comments
    Method of Estimation Estimation Parameter Slope
    Estimated Value -2.677
    Confidence Interval (2-Sided) 95%
    -5.133 to -0.221
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.211
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Alpha Lipoic Acid (ALA) 600 mg PO Twice Daily, Placebo
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.943
    Comments Association between treatment arm, compared to placebo, on change in hsCRP from baseline to 12 months of intervention, adjusted for age, sex, and race.
    Method Regression, Linear
    Comments
    Method of Estimation Estimation Parameter Slope
    Estimated Value 0.088
    Confidence Interval (2-Sided) 95%
    -2.367 to 2.542
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.210
    Estimation Comments
    2. Primary Outcome
    Title AIM 1: Change in Flow Mediated Dilation (FMD) (%)
    Description 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
    Time Frame 12 months of intervention

    Outcome Measure Data

    Analysis Population Description
    Based on the number of subjects who completed 12 months of intervention and testing
    Arm/Group Title Aspirin (ASA) 325 mg PO Once Daily Olmesartan (ARB) 40 mg PO Once Daily Alpha Lipoic Acid (ALA) 600 mg PO Twice Daily Placebo
    Arm/Group Description Anti-inflammatory agent Angiotensin receptor blocker (ARB) Antioxidant Aspirin placebo PO once a day Olmesartan placebo PO once a day Alpha lipoic acid placebo PO twice a day
    Measure Participants 17 13 15 13
    Mean (Standard Deviation) [percentage of arterial dilation change]
    -0.0012
    (0.030)
    0.018
    (0.032)
    0.014
    (0.034)
    0.0053
    (0.030)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Aspirin (ASA) 325 mg PO Once Daily, Placebo
    Comments Null hypothesis: no difference between active treatment group compared to placebo.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.943
    Comments Association between treatment arm, compared to placebo, on change in FMD from baseline to 12 months of intervention, adjusted for age, sex, race, and LDL-cholesterol.
    Method Regression, Linear
    Comments
    Method of Estimation Estimation Parameter Slope
    Estimated Value -0.001
    Confidence Interval (2-Sided) 95%
    -0.025 to 0.023
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.012
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Olmesartan (ARB) 40 mg PO Once Daily, Placebo
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.280
    Comments Association between treatment arm, compared to placebo, on change in FMD from baseline to 12 months of intervention, adjusted for age, sex, race, and LDL-cholesterol.
    Method Regression, Linear
    Comments
    Method of Estimation Estimation Parameter Slope
    Estimated Value 0.014
    Confidence Interval (2-Sided) 95%
    -0.012 to 0.039
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.013
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Alpha Lipoic Acid (ALA) 600 mg PO Twice Daily, Placebo
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.313
    Comments Association between treatment arm, compared to placebo, on change in FMD from baseline to 12 months of intervention, adjusted for age, sex, race, and LDL-cholesterol.
    Method Regression, Linear
    Comments
    Method of Estimation Estimation Parameter Slope
    Estimated Value 0.012
    Confidence Interval (2-Sided) 95%
    -0.012 to 0.037
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.012
    Estimation Comments
    3. Other Pre-specified Outcome
    Title AIM 2: Difference in FMD (Measure of Endothelial Function)
    Description 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.
    Time Frame Cross-sectional

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Normal Glucose Tolerance (NGT) Impaired Glucose Tolerance (IGT) Diabetes
    Arm/Group Description Normal fasting glucose (<100 mg/dl) and normal 2-hr glucose level (<140 mg/dl) after 75g OGTT After 75g OGTT: Fasting glucose <126 mg/dl and 2-hr glucose level 140-199 mg/dl After 75g OGTT: Fasting glucose >=126 mg/dl and 2-hr glucose level >=200 mg/dl
    Measure Participants 0 0 0

    Adverse Events

    Time Frame 12 months
    Adverse Event Reporting Description
    Arm/Group Title Aspirin Olmesartan Alpha Lipoic Acid Placebo Enrolled, But Not Yet Randomized
    Arm/Group Description Anti-inflammatory agent Angiotensin receptor blocker (ARB) Antioxidant Aspirin placebo once a day Olmesartan placebo once a day Alpha lipoic acid placebo twice a day Enrolled into study, but not yet randomized to study medication
    All Cause Mortality
    Aspirin Olmesartan Alpha Lipoic Acid Placebo Enrolled, But Not Yet Randomized
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN) / (NaN) / (NaN) / (NaN)
    Serious Adverse Events
    Aspirin Olmesartan Alpha Lipoic Acid Placebo Enrolled, But Not Yet Randomized
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/18 (0%) 0/18 (0%) 0/17 (0%) 0/17 (0%) 1/14 (7.1%)
    Gastrointestinal disorders
    Cancer 0/18 (0%) 0 0/18 (0%) 0 0/17 (0%) 0 0/17 (0%) 0 1/14 (7.1%) 1
    Other (Not Including Serious) Adverse Events
    Aspirin Olmesartan Alpha Lipoic Acid Placebo Enrolled, But Not Yet Randomized
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/18 (0%) 1/18 (5.6%) 0/17 (0%) 0/17 (0%) 0/14 (0%)
    Cardiac disorders
    Reaction to nitroglycerin during FMD test 0/18 (0%) 0 1/18 (5.6%) 1 0/17 (0%) 0 0/17 (0%) 0 0/14 (0%) 0

    Limitations/Caveats

    Not fully powered due to under-enrollment and high drop-out rate. Higher than anticipated precision error of FMD measures. Possible Hawthorne effect with lifestyle changes. Short treatment period relative to long-term CVD risk in prediabetes.

    More Information

    Certain Agreements

    All Principal Investigators ARE employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Mary Rhee, M.D.
    Organization Emory University School of Medicine
    Phone 404-778-1660
    Email mrhee@emory.edu
    Responsible Party:
    Dr. Mary Rhee, Assistant Professor, Emory University
    ClinicalTrials.gov Identifier:
    NCT00122447
    Other Study ID Numbers:
    • IRB00000749
    • UL1RR025008
    • Sankyo CS-866
    • 1K23DK070715-01A1
    First Posted:
    Jul 22, 2005
    Last Update Posted:
    Dec 5, 2013
    Last Verified:
    Nov 1, 2013