Ignite Creation Date:
2024-05-05 @ 12:09 PM
Last Modification Date:
2024-10-26 @ 9:21 AM
Study NCT ID:
NCT00256607
Status:
COMPLETED
Last Update Posted:
2014-06-27
First Post:
2005-11-17
Brief Title:
Non-traditional Cardiovascular Risk Factors and Atherosclerosis in Type 2 Diabetes
Sponsor:
US Department of Veterans Affairs
Organization:
VA Office of Research and Development
Study Overview
Official Title:
CSP 465A - Non-Traditional Cardiovascular Risk Factors And Atherosclerosis In Type 2 Diabetes
Status:
COMPLETED
Status Verified Date:
2014-06
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
A predominant consequence of diabetes mellitus DM type 2 is accelerated development of atherosclerosis related conditions Conventional cardiovascular risk factors only explain a portion of the excess risk for atherosclerosis in this population In vitro animal and epidemiologic studies have suggested that a variety of novel cardiovascular risk factors CVRF including triglyceride-rich lipoproteins TGRL small dense low density lipoprotein D-LDL subfractions oxidative stress and advanced glycation endproduct AGE formation may contribute to the development of atherosclerosis These risk factors may also induce endothelial cell activationinjury or local or systemic inflammation that cause elevations in plasma levels of additional novel risk factors such as soluble adhesion molecules plasminogen activator inhibitor-1 PAI-1 fibrinogen and C-reactive protein CRP Many of these risk factors are increased in DM type 2 presumably as a consequence of hyperglycemia and insulin resistance However no studies have evaluated the singular or synergistic relationship of these novel CVRF to measures of atherosclerosis as well as to the development of clinical macrovascular events in individuals with diabetes If as we suspect these novel CVRF are related to development of atherosclerosis and macrovascular disease it will be critical for the future design of prevention strategies to know whether intensive glucose lowering significantly reduces the levels of these novel CVRF Furthermore it would be important to explore whether the relationship of the above novel risk factors to atherosclerosis and development of clinical events is attenuated in those individuals receiving glucose lowering therapy Alternatively if glucose lowering has no effect or a negative effect on relevant novel CVRF this could potentially explain the limited success of intensive glucose lowering to reduce macrovascular events in several prior trials
The investigator proposes to take advantage of the study population and framework of the recently approved VA Cooperative Study of Glycemic Control and Complications in Diabetes Mellitus Type 2 to address these issues in an efficient and cost-effective manner
The investigator proposes to take advantage of the study population and framework of the recently approved VA Cooperative Study of Glycemic Control and Complications in Diabetes Mellitus Type 2 to address these issues in an efficient and cost-effective manner
Detailed Description:
Primary HypothesisHypothesis The novel CVRF including the selected indicators of artery wall injury and local or systemic inflammation are related to the presence and development of atherosclerosis and macrovascular events in DM type 2
2Intensive glucose lowering therapy will reduce the levels of several if not all of the novel CVRF
Secondary Hypotheses
Primary Outcomes
1 MYOCARDIAL INFARCTION Myocardial infarctions MI will be determined based on the algorithm supplied at the end of this appendix All suspected MI will be evaluated in detail by the Endpoints Committee All supporting documentation ie ECGs hospital records laboratory values etc needed to confirm or rule out the presence or absence of an MI will be obtained by personnel at the ECG Laboratory
2 CONGESTIVE HEART FAILURE Diagnosis of new congestive heart failure CHF can be made in the presence of at least two minor manifestations or new onset of pulmonary congestion requiring treatment Treatment with diuretic digitalis glycoside ACE inhibitor or hospitalization for management of symptoms of CHF would be appropriate
Study Abstract
Objectives A predominant consequence of diabetes mellitus DM type 2 is accelerated development of atherosclerosis related conditions Conventional cardiovascular risk factors only explain a portion of the excess risk for atherosclerosis in this population In vitro animal and epidemiologic studies have suggested that a variety of novel cardiovascular risk factors CVRF including triglyceride-rich lipoproteins TGRL small dense low density lipoprotein D-LDL subfractions oxidative stress and advanced glycation endproduct AGE formation may contribute to the development of atherosclerosis These risk factors may also induce endothelial cell activationinjury or local or systemic inflammation that cause elevations in plasma levels of additional novel risk factors such as soluble adhesion molecules plasminogen activator inhibitor-1 PAI-1 fibrinogen and C-reactive protein CRP Many of these risk factors are increased in DM type 2 presumably as a consequence of hyperglycemia and insulin resistance However no studies have evaluated the singular or synergistic relationship of these novel CVRF to measures of atherosclerosis as well as to the development of clinical macrovascular events in individuals with diabetes If as we suspect these novel CVRF are related to development of atherosclerosis and macrovascular disease it will be critical for the future design of prevention strategies to know whether intensive glucose lowering significantly reduces the levels of these novel CVRF Furthermore it would be important to explore whether the relationship of the above novel risk factors to atherosclerosis and development of clinical events is attenuated in those individuals receiving glucose lowering therapy Alternatively if glucose lowering has no effect or a negative effect on relevant novel CVRF this could potentially explain the limited success of intensive glucose lowering to reduce macrovascular events in several prior trials
The investigator proposes to take advantage of the study population and framework of the recently approved VA Cooperative Study of Glycemic Control and Complications in Diabetes Mellitus Type 2 to address these issues in an efficient and cost-effective manner
Hypothesis
1 The above novel CVRF outlined in Table 1 including the selected indicators of artery wall injury and local or systemic inflammation are related to the presence and development of atherosclerosis and macrovascular events in DM type 2
2 Intensive glucose lowering therapy will reduce the levels of several if not all of the novel CVRF
Research Plan Specific objectives 1 2 Cross-sectional observational objectives
1 Determine the cross-sectional relationship between baseline levels of novel CVRF and the presence of atherosclerosis as assessed by electron beam computed tomography measurement EBCT of coronary artery calcium CAC and abdominal aortic calcium AAC
2 Determine the cross-sectional relationship between baseline levels of novel CVRF and prevalence of clinical macrovascular disease
Specific objective 3 Prospective interventional objective Determine whether intensive glucose lowering reduces levels of novel CVRF
Future long-term specific objectives Prospective observational objectives
1 Determine the ability of baseline levels on trial levels and change in levels of novel CVRF to predict progression of atherosclerosis
2 Determine the ability of baseline levels on trial levels and change in levels of novel CVRF to predict clinical macrovascular events
Results 89 cardiovascular events occurred during a median follow-up duration of 52 years Although intensive glucose lowering therapy did not significantly reduce cardiovascular events in the substudy cohort as a whole there was evidence that the response was modified by baseline CAC as indicated by significant p-values for treatment by log CAC1 interaction terms in unadjusted and multivariable adjusted models 001 and 003 respectively Multivariable adjusted hazard ratios HR for the effect of treatment indicated a progressive diminution of benefit with increasing CAC Subgroup analyses were also conducted for clinically relevant CAC categories those above and below a Coronary Calcium score Agatston score of 100 For the subgroup with CAC 100 11 of 62 individuals had events while only 1 of 52 individuals with CAC 100 suffered an event The multivariable HR for intensive treatment for those with CAC 100 was 074 046-120 p021 while for the subgroup with CAC 100 the corresponding HR was 008 0008- 077 p003 with event rates of 39 and 4 per 1000 person-years respectively
Main ManuscriptIntensive Glucose Lowering Therapy Reduces Cardiovascular Disease Events in Veterans Affairs Diabetes Trial VADT Participants with Lower Calcified Coronary Atherosclerosis
2Intensive glucose lowering therapy will reduce the levels of several if not all of the novel CVRF
Secondary Hypotheses
Primary Outcomes
1 MYOCARDIAL INFARCTION Myocardial infarctions MI will be determined based on the algorithm supplied at the end of this appendix All suspected MI will be evaluated in detail by the Endpoints Committee All supporting documentation ie ECGs hospital records laboratory values etc needed to confirm or rule out the presence or absence of an MI will be obtained by personnel at the ECG Laboratory
2 CONGESTIVE HEART FAILURE Diagnosis of new congestive heart failure CHF can be made in the presence of at least two minor manifestations or new onset of pulmonary congestion requiring treatment Treatment with diuretic digitalis glycoside ACE inhibitor or hospitalization for management of symptoms of CHF would be appropriate
Study Abstract
Objectives A predominant consequence of diabetes mellitus DM type 2 is accelerated development of atherosclerosis related conditions Conventional cardiovascular risk factors only explain a portion of the excess risk for atherosclerosis in this population In vitro animal and epidemiologic studies have suggested that a variety of novel cardiovascular risk factors CVRF including triglyceride-rich lipoproteins TGRL small dense low density lipoprotein D-LDL subfractions oxidative stress and advanced glycation endproduct AGE formation may contribute to the development of atherosclerosis These risk factors may also induce endothelial cell activationinjury or local or systemic inflammation that cause elevations in plasma levels of additional novel risk factors such as soluble adhesion molecules plasminogen activator inhibitor-1 PAI-1 fibrinogen and C-reactive protein CRP Many of these risk factors are increased in DM type 2 presumably as a consequence of hyperglycemia and insulin resistance However no studies have evaluated the singular or synergistic relationship of these novel CVRF to measures of atherosclerosis as well as to the development of clinical macrovascular events in individuals with diabetes If as we suspect these novel CVRF are related to development of atherosclerosis and macrovascular disease it will be critical for the future design of prevention strategies to know whether intensive glucose lowering significantly reduces the levels of these novel CVRF Furthermore it would be important to explore whether the relationship of the above novel risk factors to atherosclerosis and development of clinical events is attenuated in those individuals receiving glucose lowering therapy Alternatively if glucose lowering has no effect or a negative effect on relevant novel CVRF this could potentially explain the limited success of intensive glucose lowering to reduce macrovascular events in several prior trials
The investigator proposes to take advantage of the study population and framework of the recently approved VA Cooperative Study of Glycemic Control and Complications in Diabetes Mellitus Type 2 to address these issues in an efficient and cost-effective manner
Hypothesis
1 The above novel CVRF outlined in Table 1 including the selected indicators of artery wall injury and local or systemic inflammation are related to the presence and development of atherosclerosis and macrovascular events in DM type 2
2 Intensive glucose lowering therapy will reduce the levels of several if not all of the novel CVRF
Research Plan Specific objectives 1 2 Cross-sectional observational objectives
1 Determine the cross-sectional relationship between baseline levels of novel CVRF and the presence of atherosclerosis as assessed by electron beam computed tomography measurement EBCT of coronary artery calcium CAC and abdominal aortic calcium AAC
2 Determine the cross-sectional relationship between baseline levels of novel CVRF and prevalence of clinical macrovascular disease
Specific objective 3 Prospective interventional objective Determine whether intensive glucose lowering reduces levels of novel CVRF
Future long-term specific objectives Prospective observational objectives
1 Determine the ability of baseline levels on trial levels and change in levels of novel CVRF to predict progression of atherosclerosis
2 Determine the ability of baseline levels on trial levels and change in levels of novel CVRF to predict clinical macrovascular events
Results 89 cardiovascular events occurred during a median follow-up duration of 52 years Although intensive glucose lowering therapy did not significantly reduce cardiovascular events in the substudy cohort as a whole there was evidence that the response was modified by baseline CAC as indicated by significant p-values for treatment by log CAC1 interaction terms in unadjusted and multivariable adjusted models 001 and 003 respectively Multivariable adjusted hazard ratios HR for the effect of treatment indicated a progressive diminution of benefit with increasing CAC Subgroup analyses were also conducted for clinically relevant CAC categories those above and below a Coronary Calcium score Agatston score of 100 For the subgroup with CAC 100 11 of 62 individuals had events while only 1 of 52 individuals with CAC 100 suffered an event The multivariable HR for intensive treatment for those with CAC 100 was 074 046-120 p021 while for the subgroup with CAC 100 the corresponding HR was 008 0008- 077 p003 with event rates of 39 and 4 per 1000 person-years respectively
Main ManuscriptIntensive Glucose Lowering Therapy Reduces Cardiovascular Disease Events in Veterans Affairs Diabetes Trial VADT Participants with Lower Calcified Coronary Atherosclerosis
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None