Correlation of Plasma Endothelial Cell Activity With Cardiovascular Events in Patients With Diabetes Mellitus Type 2

NCT00252525 | Completed DMC

• 1 other identifier: 465B
• Study Type: observational
• Target: 400
• Locations: 1 country
• Sites: 7

Brief Summary

CSP 465-B, Correlation of Plasma Endothelial Cell (Basic Fibroblast Growth Factor) Activity With Cardiovascular Events in Patients with Diabetes Mellitus, Type II. Mark Zimering M.D. Objectives: Endothelial cell dysfunction plays a role in the development of the atherosclerotic vascular lesion and it is also thought to provide a mechanism for increased urinary albumin excretion in type 2 diabetes mellitus. Micro- or macroalbuminuria are associated with increased cardiovascular (CV) morbidity and mortality in type 2 diabetes mellitus. In at least one longitudinal study in older-age onset patients, micro-or macroalbuminuria robustly predicted increased CV risk independent of other diabetes-related factors.1 The pathogenetic mechanisms underlying a significant association between micro- or macroalbuminuria and CV risk in diabetes mellitus are not known but may include: growth factors, clotting factors, lipids, or hemodynamic factors. The aim of the present study is to investigate whether an angiogenic growth factor, basic fibroblast growth factor (bFGF), plays a role in increased CV risk in type 2 diabetes mellitus. Research Plan: BFGF (FGF-2) is one of the most potent known angiogenesis factors. Increased bFGF was previously associated with both endothelial cell injury and micro- or macroalbuminuria. In a prior study of 73 older-age onset veterans with type 2 diabetes mellitus (JCEM, 1996), we found plasma endothelial cell (bFGF) activity was significantly associated with glycemic levels, and (in multiple regression analysis) independently associated with both microalbuminuria and retinopathy. We will test whether plasma endothelial cell (bFGF) activity is significantly, independently associated with a pooled endpoint of cardiovascular events that includes myocardial infarction (MI), coronary revascularization, congestive heart failure (CHF), or CV mortality. We expect that increased bFGF may itself be a robust marker for increased CV risk in diabetes mellitus for three reasons. First, because bFGF was independently associated with (micro)-albuminuria in type 2 diabetes mellitus. Second, because increased bFGF was associated with increased activity in the renin-angiotensin system in vascular smooth muscle cells (Dzau, et al. JCI, 1995). And third, because (as we reported) angiotensin converting enzyme inhibitor (ACEi) drugs substantially decreased plasma bFGF levels in (micro)- albuminuric diabetes mellitus type 2, and (as others reported) ACEi drugs substantially reduced the risk of development of CHF in patients with LVH 2, the risk of mortality after MI (8,9), and the risk of CV death in diabetic patients with proteinuria. Because plasma endothelial cell (bFGF) activity correlated significantly with glycemic levels in diabetes mellitus type 2, plasma bFGF may be one of the pathogenetic links between glycemic levels and an increased risk of cardiovascular events in diabetes mellitus, type 2. Methods: Blood (3 mL EDTA plasma) will be collected from each subject in Years 1, and 2 of the Study at each of 6 local participating VA substudy sites. Because plasma endothelial cell (bFGF-like) bioactivity and bFGFR-IR in vivo are stable for months and years based on our prior published studies (1-3), we anticipate that obtaining 2 specimens, 1 each in Years 1, 2 of the study, will provide sufficient data to model proportional risk.

Conditions

Type 2 Diabetes Mellitus

Outcome Measures

Primary Outcomes (1)

• The primary outcome measures are cardiovascular morbidity and mortality.

  End of study.

Study Arms (1)

Group 1

This is an observational study of patients who are enrolled in the ongoing randomized clinical trial AGlycemic Control and Complications in Diabetes Mellitus Type 2@.

Eligibility Criteria

• Age: 40 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

This is an observational study of patients who are enrolled in the ongoing randomized clinical trial AGlycemic Control and Complications in Diabetes Mellitus Type 2@.

You may qualify if:

• Patients with type 2 DM who are no longer responsive to maximum dose of one or more oral agents.

You may not qualify if:

• Not a part of the VADT.

Sponsors & Collaborators

• US Department of Veterans Affairs: lead
• American Diabetes Association: collaborator

Study Sites (7)

Carl T. Hayden VA Medical Center

Phoenix, Arizona, 85012, United States

Location

VA Medical Center, Long Beach

Long Beach, California, 90822, United States

Location

Miami VA Healthcare System, Miami, FL

Miami, Florida, 33125, United States

Location

VA Medical Center, Omaha

Omaha, Nebraska, 68105-1873, United States

Location

VA New Jersey Health Care System, East Orange

East Orange, New Jersey, 07018, United States

Location

VA South Texas Health Care System, San Antonio

San Antonio, Texas, 78229, United States

Location

Hunter Holmes McGuire VA Medical Center

Richmond, Virginia, 23249, United States

Location

Related Publications (7)

• Zimering MB, Anderson RJ, Ge L, Moritz TE; Investigators for the VADT. Increased plasma basic fibroblast growth factor is associated with coronary heart disease in adult type 2 diabetes mellitus. Metabolism. 2011 Feb;60(2):284-91. doi: 10.1016/j.metabol.2010.02.003. Epub 2010 Mar 6.

  PMID: 20206949 RESULT

• Zimering MB, Anderson RJ, Moritz TE, Ge L; Investigators for the VADT. Endothelial cell inhibitory autoantibodies are associated with laser photocoagulation in adults from the Veterans Affairs Diabetes Trial. Metabolism. 2009 Jun;58(6):882-7. doi: 10.1016/j.metabol.2009.02.023.

  PMID: 19375761 RESULT

• Zimering MB, Anderson RJ, Moritz TE, Ge L; Investigators for the VADT. Low plasma basic fibroblast growth factor is associated with laser photocoagulation treatment in adult type 2 diabetes mellitus from the Veterans Affairs Diabetes Trial. Metabolism. 2009 Mar;58(3):393-400. doi: 10.1016/j.metabol.2008.10.014.

  PMID: 19217457 RESULT

• Zimering MB, Anderson RJ, Luo P, Moritz TE; Investigators for the Veterans Affairs Diabetes Trial. Plasma basic fibroblast growth factor is correlated with plasminogen activator inhibitor-1 concentration in adults from the Veterans Affairs Diabetes Trial. Metabolism. 2008 Nov;57(11):1563-9. doi: 10.1016/j.metabol.2008.06.012.

  PMID: 18940395 RESULT

• Zimering MB, Pan Z. Autoantibodies in type 2 diabetes induce stress fiber formation and apoptosis in endothelial cells. J Clin Endocrinol Metab. 2009 Jun;94(6):2171-7. doi: 10.1210/jc.2008-2354. Epub 2009 Mar 17.

  PMID: 19293267 RESULT

• Zimering MB, Moritz TE, Donnelly RJ. Anti-neurotrophic effects from autoantibodies in adult diabetes having primary open angle glaucoma or dementia. Front Endocrinol (Lausanne). 2013 May 15;4:58. doi: 10.3389/fendo.2013.00058. eCollection 2013.

  PMID: 23720653 RESULT

• Zimering MB, Anderson RJ, Ge L, Moritz TE, Duckworth WC; Investigators for the VADT. Basic fibroblast growth factor predicts cardiovascular disease occurrence in participants from the veterans affairs diabetes trial. Front Endocrinol (Lausanne). 2013 Nov 22;4:183. doi: 10.3389/fendo.2013.00183. eCollection 2013.

  PMID: 24319441 RESULT

Biospecimen

Retention: NONE RETAINED

The cohort consisted of patients that participated in the 465 main study.

MeSH Terms

Conditions

Diabetes Mellitus, Type 2

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Study Officials

• Carlos Abraira, MD

  Miami VA Healthcare System, Miami, FL

  STUDY CHAIR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Sponsor Type: FED
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 9, 2005
• First Posted: November 11, 2005
• Study Start: June 1, 2007
• Primary Completion: May 1, 2008
• Study Completion: May 1, 2008
• Last Updated: June 27, 2014

Record last verified: 2014-06

Locations

US (7)