Association of PAI-1 and fibrinogen with diabetic retinopathy in the Veterans Affairs Diabetes Trial (VADT)

Nasrin Azad, Lily Agrawal, Nicholas V Emanuele, Ronald Klein, Gideon D Bahn, Madeline McCarren, Peter Reaven, Rodney Hayward, William Duckworth, VADT Study Group, Nasrin Azad, Lily Agrawal, Nicholas V Emanuele, Ronald Klein, Gideon D Bahn, Madeline McCarren, Peter Reaven, Rodney Hayward, William Duckworth, VADT Study Group

Abstract

Objective: To test the hypothesis that high levels of plasminogen-activating inhibitor (PAI)-1 and fibrinogen at baseline were associated with the onset or progression of diabetic retinopathy (DR) during the Veterans Affairs Diabetes Trial (VADT).

Research design and methods: The VADT was an open-label, prospective, randomized controlled trial to test the effect of standard glycemic control (STD) compared with intensive control (INT) on cardiovascular events in patients with advanced type 2 diabetes mellitus (T2DM). Diabetic retinopathy (DR) outcomes were also collected. Incidence and progression of DR were assessed by grading seven-field stereoscopic fundus photographs at baseline and 5 years later taken in 858 of a total of 1,791 participants who completed both eye examinations.

Results: Assignment to INT was not independently associated with decreased risk of onset of DR. However, after adjustment for multiple covariates, baseline level of PAI-1 was an independent risk factor for the onset of DR. The risk for incidence of DR increased by 12% for each 10 ng/dL increase in baseline PAI-1 concentration (odds ratio [OR] 1.012 [95% CI 1.00-1.024], P = 0.042). Assignment to INT was not independently associated with decreased risk of progression of DR. However, there was an interaction between glycemic treatment assignment and fibrinogen level at baseline. INT was associated with decreased progression of retinopathy in those with fibrinogen <296 mg/dL (OR 0.55 [95% CI 0.31-1.00], P = 0.03).

Conclusions: The results require confirmation but are consistent with greater hypercoagulabilty and inflammation, as measured by higher levels of PAI-1 and fibrinogen, being related to DR and responsiveness to INT.

Figures

Figure 1
Figure 1
The solid line represents the point estimate of the treatment ORs at various levels along the x-axis that ranges from the minimum to the maximum observed value, while the dotted lines represent the 95% CIs. INT was associated with decreased progression of retinopathy in those with fibrinogen <296 mg/dL (OR 0.55 [95% CI 0.31–1], P = 0.0347).

References

    1. National Estimates and General Information on Diabetes and Prediabetes in the U.S., 2011 Atlanta, GA, U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, 2011
    1. Yau JW, Rogers SL, Kawasaki R, et al. Meta-Analysis for Eye Disease (META-EYE) Study Group Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care 2012;35:556–564
    1. Klein R, Klein BEK. Vision disorders in diabetes. In Diabetes in America Hamman R, Harris MWH, Eds. Bethesda, MD, U.S. Health Service NIH Publications, 1983, p. 1–36
    1. Fong DS, Aiello L, Gardner TW, et al. American Diabetes Association Diabetic retinopathy. Diabetes Care 2003;26:226–229
    1. The Diabetes Control and Complications Trial Research Group The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977–986
    1. UK Prospective Diabetes Study (UKPDS) Group Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837–853
    1. Klein RL, Hunter SJ, Jenkins AJ, et al. DCCT/ECIC STUDY GROUP Fibrinogen is a marker for nephropathy and peripheral vascular disease in type 1 diabetes: studies of plasma fibrinogen and fibrinogen gene polymorphism in the DCCT/EDIC cohort. Diabetes Care 2003;26:1439–1448
    1. Agirbasli M. Pivotal role of plasminogen-activator inhibitor 1 in vascular disease. Int J Clin Pract 2005;59:102–106
    1. Schneider DJ, Sobel BE. PAI-1 and diabetes: a journey from the bench to the bedside. Diabetes Care 2012;35:1961–1967
    1. Duckworth W, Abraira C, Moritz T, et al. VADT Investigators Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009;360:129–139
    1. Abraira C, Duckworth W, McCarren M, et al. VA Cooperative Study of Glycemic Control and Complications in Diabetes Mellitus Type 2 Design of the cooperative study on glycemic control and complications in diabetes mellitus type 2: Veterans Affairs Diabetes Trial. J Diabetes Complications 2003;17:314–322
    1. Swaim WR, Feders MB. Fibrinogen assay. Clin Chem 1967;13:1026–1028
    1. Declerck PJ, Alessi MC, Verstreken M, Kruithof EK, Juhan-Vague I, Collen D. Measurement of plasminogen activator inhibitor 1 in biologic fluids with a murine monoclonal antibody-based enzyme-linked immunosorbent assay. Blood 1988;71:220–225
    1. Emanuele N, Moritz T, Klein R, et al. Veterans Affairs Diabetes Trial Study Group Ethnicity, race, and clinically significant macular edema in the Veterans Affairs Diabetes Trial (VADT). Diabetes Res Clin Pract 2009;86:104–110
    1. Emanuele N, Klein R, Mortiz M. Comparison of dilated fundus examination by ophthalmologists, with 7-field stereo photographs in the VADT. J Diabetes Complications 2009;23:323–329
    1. Trost S, Pratley RE, Sobel BE. Impaired fibrinolysis and risk for cardiovascular disease in the metabolic syndrome and type 2 diabetes. Curr Diab Rep 2006;6:47–54
    1. Meigs JB, O’donnell CJ, Tofler GH, et al. Hemostatic markers of endothelial dysfunction and risk of incident type 2 diabetes: the Framingham Offspring Study. Diabetes 2006;55:530–537
    1. Stoney RM, O’Dea K, Herbert HE, et al. Insulin resistance as a major determinant of increased coronary heart disease risk in postmenopausal womwn with type 2 diabetes mellitus. Diabet Med 2001;18:476–482
    1. Brazionis L, Rowley K, Jenkins A, Itsiopoulos C, O’Dea K. Plasminogen activator inhibitor-1 activity in type 2 diabetes: a different relationship with coronary heart disease and diabetic retinopathy. Arterioscler Thromb Vasc Biol 2008;28:786–791
    1. Grant MB, Ellis EA, Caballero S, Mames RN. Plasminogen activator inhibitor-1 over expression in nonproliferative diabetic retinopathy. Exp Eye Res 1996;63:233–244
    1. Erem C, Hacihasanoğlu A, Celik S, et al. Coagulation and fibrinolysis parameters in type 2 diabetic patients with and without diabetic vascular complications. Med Princ Pract 2005;14:22–30
    1. Stec JJ, Silbershatz H, Tofler GH, et al. Association of fibrinogen with cardiovascular risk factors and cardiovascular disease in the Framingham Offspring Population. Circulation 2000;102:1634–1638
    1. Mendall MA, Patel P, Ballam L, Strachan D, Northfield TC. C reactive protein and its relation to cardiovascular risk factors: a population based cross sectional study. BMJ 1996;312:1061–1065
    1. Low GD, Rumley A. Fibrinogen and its degradation products as thrombotic risk factors. Ann N Y Acad Sci 1997;2:115–125
    1. Saito I, Folsom AR, Brancati FL, Duncan BB, Chambless LE, McGovern PG. Nontraditional risk factors for coronary heart disease incidence among persons with diabetes: the Atherosclerosis Risk in Communities (ARIC) Study. Ann Intern Med 2000;133:81–91
    1. Jager A, van Hinsbergh VW, Kostense PJ, et al. Increased levels of soluble vascular cell adhesion molecule 1 are associated with risk of cardiovascular mortality in type 2 diabetes: the Hoorn study. Diabetes 2000;49:485–491
    1. Fujisawa T, Ikegami H, Yamato E, et al. Association of plasma fibrinogen level and blood pressure with diabetic retinopathy, and renal complications associated with proliferative diabetic retinopathy, in Type 2 diabetes mellitus. Diabet Med 1999;16:522–526
    1. Nguyen TT, Alibrahim E, Islam FM, et al. Inflammatory, hemostatic, and other novel biomarkers for diabetic retinopathy: the multi-ethnic study of atherosclerosis. Diabetes Care 2009;32:1704–1709
    1. Soedamah-Muthu SS, Chaturvedi N, Pickup JC, Fuller JH, EURODIAB Prospective Complications Study Group. The EURODIAB Prospective Complications Study (PCS) Relationship between plasma sialic acid and fibrinogen concentration and incident micro- and macrovascular complications in type 1 diabetes. Diabetologia 2008;51:493–501

Source: PubMed

スポンサーと協力者

医学的状態

薬物療法

3
購読する