- ICH GCP
- Registro de ensayos clínicos de EE. UU.
- Ensayo clínico NCT00252525
Correlation of Plasma Endothelial Cell Activity With Cardiovascular Events in Patients With Diabetes Mellitus Type 2
CSP #465B - Correlation of Plasma Endothelial Cell (Basic Fibroblast Growth Factor) Activity With Cardiovascular Events In Patients With Diabetes Mellitus Type 2
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.
Descripción general del estudio
Estado
Condiciones
Descripción detallada
Primary Hypothesis: 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.
Secondary Hypotheses:
Primary Outcomes: cardiovascular morbidity and mortality
Study Abstract:
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.
Results: One hundred and five first cardiovascular events occurred in these 399 subjects.
The best fit model of risk factors associated with the time to first CVD occurrence (in the study) over a seven and one-half year period had as significant predictors: prior cardiovascular event [hazard ratio (HR) 3.378; 95% confidence intervals (CI) 3.079-3.807; P <0.0001), baseline plasma bFGF (HR 1.008; 95% CI 1.002-1.014; P D0.01), age (HR 1.027; 95% CI 1.004-1.051; P D0.019), baseline plasma triglycerides (HR 1.001; 95% CI 1.000-1.002; P D0.02), and diabetes duration-treatment interaction (P D0.03). Intensive glucose-lowering was associated with significantly decreased hazard ratios for CVD occurrence (0.38-0.63) in patients with known diabetes duration of 0-10 years, and nonsignificantly increased hazard ratios for CVD occurrence (0.82-1.78) in patients with longer diabetes duration. Conclusion: High level of plasma bFGF is a predictive biomarker of future CVD occurrence in this population of adult type 2 diabetes.
In conclusion, the present findings suggest that baseline plasma bFGF may be a marker of CVD risk in adult male veterans with type2 diabetes. These results suggest that increased plasma bFGF drive cell proliferation and be involved in the mechanism for increased CVD occurrence in older adults with advanced type2 diabetes mellitus.
Main Manuscript: Basic fibroblast growth factor predicts cardiovascular disease occurrence in participants from the veterans affairs diabetes trial.
Tipo de estudio
Inscripción (Actual)
Contactos y Ubicaciones
Ubicaciones de estudio
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Arizona
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Phoenix, Arizona, Estados Unidos, 85012
- Carl T. Hayden VA Medical Center
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California
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Long Beach, California, Estados Unidos, 90822
- VA Medical Center, Long Beach
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Florida
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Miami, Florida, Estados Unidos, 33125
- Miami VA Healthcare System, Miami, FL
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Nebraska
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Omaha, Nebraska, Estados Unidos, 68105-1873
- VA Medical Center, Omaha
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New Jersey
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East Orange, New Jersey, Estados Unidos, 07018
- VA New Jersey Health Care System, East Orange
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Texas
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San Antonio, Texas, Estados Unidos, 78229
- VA South Texas Health Care System, San Antonio
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Virginia
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Richmond, Virginia, Estados Unidos, 23249
- Hunter Holmes McGuire VA Medical Center
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Criterios de participación
Criterio de elegibilidad
Edades elegibles para estudiar
Acepta Voluntarios Saludables
Géneros elegibles para el estudio
Método de muestreo
Población de estudio
Descripción
Inclusion Criteria:
- Patients with type 2 DM who are no longer responsive to maximum dose of one or more oral agents.
Exclusion Criteria:
- Not a part of the VADT.
Plan de estudios
¿Cómo está diseñado el estudio?
Detalles de diseño
Cohortes e Intervenciones
Grupo / Cohorte |
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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@.
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¿Qué mide el estudio?
Medidas de resultado primarias
Medida de resultado |
Periodo de tiempo |
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The primary outcome measures are cardiovascular morbidity and mortality.
Periodo de tiempo: End of study.
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End of study.
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Colaboradores e Investigadores
Patrocinador
Colaboradores
Investigadores
- Silla de estudio: Carlos Abraira, MD, Miami VA Healthcare System, Miami, FL
Publicaciones y enlaces útiles
Publicaciones Generales
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
Fechas de registro del estudio
Fechas importantes del estudio
Inicio del estudio
Finalización primaria (Actual)
Finalización del estudio (Actual)
Fechas de registro del estudio
Enviado por primera vez
Primero enviado que cumplió con los criterios de control de calidad
Publicado por primera vez (Estimar)
Actualizaciones de registros de estudio
Última actualización publicada (Estimar)
Última actualización enviada que cumplió con los criterios de control de calidad
Última verificación
Más información
Términos relacionados con este estudio
Términos MeSH relevantes adicionales
Otros números de identificación del estudio
- 465B
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