Cardiovascular Disease (CVD) Risk and Prevention in Early Glucose Intolerance
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
Arms and Interventions
Arm | Intervention/Treatment |
---|---|
Active Comparator: Anti-inflammatory agent Aspirin (ASA) |
Drug: Aspirin
325 mg PO QD
Other Names:
|
Active Comparator: Angiotensin receptor blocker (ARB) Olmesartan (ARB) |
Drug: Olmesartan
40 mg PO QD
Other Names:
|
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
- 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
- AIM 1: Change in hsCRP (High Sensitivity C-reactive Peptide) Level [12 months of intervention]
Inflammatory marker
Other Outcome Measures
- 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
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.- IRB00000749
- UL1RR025008
- Sankyo CS-866
- 1K23DK070715-01A1
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
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 |
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 |
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
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 |
mrhee@emory.edu |
- IRB00000749
- UL1RR025008
- Sankyo CS-866
- 1K23DK070715-01A1