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      Benefits of Renin-Angiotensin Blockade on Retinopathy in Type 1 Diabetes Vary With Glycemic Control

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      , MD 1 , , MD 1 , 2 , , MD, MPH 3 , , MD 4 , , MD 2 , , MD, PHD 1 , 2 , for the Renin Angiotensin System Study (RASS) group
      Diabetes Care
      American Diabetes Association

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          Abstract

          OBJECTIVE

          Optimal glycemic control slows diabetic retinopathy (DR) development and progression and is the standard of care for type 1 diabetes. However, these glycemic goals are difficult to achieve and sustain in clinical practice. The Renin Angiotensin System Study (RASS) showed that renin-angiotensin system (RAS) blockade can slow DR progression. In the current study, we evaluate whether glycemic control influenced the benefit of RAS blockade on DR progression in type 1 diabetic patients.

          RESEARCH DESIGN AND METHODS

          We used RASS data to analyze the relationships between two-steps or more DR progression and baseline glycemic levels in 223 normotensive, normoalbuminuric type 1 diabetic patients randomized to receive 5 years of enalapril or losartan compared with placebo.

          RESULTS

          A total of 147 of 223 patients (65.9%) had DR at baseline (47 of 74 patients [63.5%] in placebo and 100 of 149 patients [67.1%] in the combined treatment groups [ P = 0.67]). Patients with two-steps or more DR progression had higher baseline A1C than those without progression (9.4 vs. 8.2%, P < 0.001). There was no beneficial effect of RAS blockade ( P = 0.92) in patients with baseline A1C ≤7.5%. In contrast, 30 of 112 (27%) patients on the active treatment arms with A1C >7.5% had two-steps or more DR progression compared with 26 of 56 patients (46%) in the placebo group ( P = 0.03).

          CONCLUSIONS

          RAS blockade reduces DR progression in normotensive, normoalbuminuric type 1 diabetic patients with A1C >7.5%. Whether this therapy could benefit patients with A1C ≤7.5% will require long-term studies of much larger cohorts.

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          Most cited references20

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          Grading diabetic retinopathy from stereoscopic color fundus photographs--an extension of the modified Airlie House classification. ETDRS report number 10. Early Treatment Diabetic Retinopathy Study Research Group.

          (1991)
          The modified Airlie House classification of diabetic retinopathy has been extended for use in the Early Treatment Diabetic Retinopathy Study (ETDRS). The revised classification provides additional steps in the grading scale for some characteristics, separates other characteristics previously combined, expands the section on macular edema, and adds several characteristics not previously graded. The classification is described and illustrated and its reproducibility between graders is assessed by calculating percentages of agreement and kappa statistics for duplicate gradings of baseline color nonsimultaneous stereoscopic fundus photographs. For retinal hemorrhages and/or microaneurysms, hard exudates, new vessels, fibrous proliferations, and macular edema, agreement was substantial (weighted kappa, 0.61 to 0.80). For soft exudates, intraretinal microvascular abnormalities, and venous beading, agreement was moderate (weighted kappa, 0.41 to 0.60). A double grading system, with adjudication of disagreements of two or more steps between duplicate gradings, led to some improvement in reproducibility for most characteristics.
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            Modern-day clinical course of type 1 diabetes mellitus after 30 years' duration: the diabetes control and complications trial/epidemiology of diabetes interventions and complications and Pittsburgh epidemiology of diabetes complications experience (1983-2005).

            Clinical treatment goals of type 1 diabetes mellitus (T1DM) have changed since the Diabetes Control and Complications Trial (DCCT) demonstrated reduced long-term complications with intensive diabetes therapy. There have been few longitudinal studies to describe the clinical course of T1DM in the age of intensive therapy. Our objective was to describe the current-day clinical course of T1DM. An analysis of the cumulative incidence of long-term complications was performed. The DCCT (1983-1993) assigned patients to conventional or intensive therapy. Since 1993, the DCCT has been observational, and intensive therapy was recommended for all patients. The Pittsburgh Epidemiology of Diabetes Complications (EDC) study is an observational study of patients with T1DM from Allegheny County, Pennsylvania. The study population comprised the DCCT T1DM cohort (N = 1441) and a subset of the EDC cohort (n = 161) selected to match DCCT entry criteria. In the DCCT, intensive therapy aimed for a near-normal glycemic level with 3 or more daily insulin injections or an insulin pump. Conventional therapy, with 1 to 2 daily insulin injections, was not designed to achieve specific glycemic targets. Main outcome measures included the incidences of proliferative retinopathy, nephropathy (albumin excretion rate >300 mg/24 h, creatinine level >or=2 mg/dL [to convert to micromoles per liter, multiply by 88.4], or renal replacement), and cardiovascular disease. After 30 years of diabetes, the cumulative incidences of proliferative retinopathy, nephropathy, and cardiovascular disease were 50%, 25%, and 14%, respectively, in the DCCT conventional treatment group, and 47%, 17%, and 14%, respectively, in the EDC cohort. The DCCT intensive therapy group had substantially lower cumulative incidences (21%, 9%, and 9%) and fewer than 1% became blind, required kidney replacement, or had an amputation because of diabetes during that time. The frequencies of serious complications in patients with T1DM, especially when treated intensively, are lower than that reported historically.
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              Fundus photographic risk factors for progression of diabetic retinopathy. ETDRS report number 12. Early Treatment Diabetic Retinopathy Study Research Group.

              (1991)
              In the Early Treatment Diabetic Retinopathy Study, a randomized clinical trial sponsored by the National Eye Institute, one eye of each patient was assigned to early photocoagulation and the other to deferral of photocoagulation (i.e., careful follow-up and initiation of photocoagulation only if high-risk proliferative retinopathy developed). This design allowed observation of the natural course of diabetic retinopathy in the initially untreated eye. Gradings of baseline stereoscopic fundus photographs of eyes with nonproliferative retinopathy assigned to deferral of photocoagulation were used to examine the power of various abnormalities and combinations of abnormalities to predict progression to proliferative retinopathy in photographs taken at the 1-, 3-, and 5-year follow-up visits. Severity of intraretinal microvascular abnormalities, hemorrhages and/or microaneurysms, and venous beading were found to be the most important factors in predicting progression. On the basis of these analyses and other considerations, a retinopathy severity scale was developed. This scale, which divides diabetic retinopathy into 13 levels ranging from absence of retinopathy to severe vitreous hemorrhage, can be used to describe overall retinopathy severity and change in severity over time.
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                Author and article information

                Journal
                Diabetes Care
                diacare
                dcare
                Diabetes Care
                Diabetes Care
                American Diabetes Association
                0149-5992
                1935-5548
                August 2011
                16 July 2011
                : 34
                : 8
                : 1838-1842
                Affiliations
                [1] 1Department of Medicine, University of Minnesota, Minneapolis, Minnesota
                [2] 2Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota
                [3] 3Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, Wisconsin
                [4] 4Department of Medicine, University of Toronto, Toronto, Canada
                Author notes
                Corresponding author: Tasma Harindhanavudhi, hari0049@ 123456umn.edu .
                Article
                0476
                10.2337/dc11-0476
                3142059
                21715517
                c06324c6-7349-4f2d-a0e3-13db8eae9663
                © 2011 by the American Diabetes Association.

                Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

                History
                : 9 March 2011
                : 25 April 2011
                Categories
                Original Research
                Pathophysiology/Complications

                Endocrinology & Diabetes
                Endocrinology & Diabetes

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