Non-Traditional Cardiovascular Risk Factors and Atherosclerosis in Type 2 Diabetes
Information source: Department of Veterans Affairs
Information obtained from ClinicalTrials.gov on June 20, 2008
Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Type 2 Diabetes Mellitus
Intervention: Insulin (Drug); Glimepiride (Drug); Rosiglitazone (Drug); Metformin (Drug)
Phase: Phase 3
Status: Active, not recruiting
Sponsored by: Department of Veterans Affairs Official(s) and/or principal investigator(s):
Peter Reaven, MD, Principal Investigator, Affiliation: Phoenix VAMC
Carlos Abraira, MD, Study Chair, Affiliation: Miami VAMC
William Duckworth, MD, Study Chair, Affiliation: Phoenix VAMC
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 activation/injury 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.
Clinical Details
Official title: CSP #465-A - NON-TRADITIONAL CARDIOVASCULAR RISK FACTORS AND ATHEROSCLEROSIS IN TYPE 2 DIABETES
Study design: Treatment, Randomized, Open Label, Dose Comparison, Parallel Assignment, Safety/Efficacy Study
Detailed description:
Primary Hypothesis: Hypothesis 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.
2. Intensive 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 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, i. e., 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 activation/injury 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.
Main Manuscript:
Eligibility
Minimum age: N/A.
Maximum age: N/A.
Gender(s): Both.
Criteria:
Patients with type 2 DM who are no longer responsive to maximum dose of one or more oral
agents.
Locations and Contacts
Vamc - Tucson, Az, Tucson, Arizona 85723, United States
Vamc - Phoenix, Phoenix, Arizona 85012, United States
Vamc - San Diego, Ca, San Diego, California 92161, United States
Vamc - Long Beach, Ca, Long Beach, California 90822, United States
Vamc - Miami, Fl, Miami, Florida 33125, United States
Vamc - Hines, Il, Hines, Illinois 60141, United States
Vamc - Pittsburgh, Pa, Pittsburgh, Pennsylvania 15261, United States
Additional Information
Ending date: November 2007
Last updated: June 5, 2007
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