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      Persistent Effects of Intensive Glycemic Control on Retinopathy in Type 2 Diabetes in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Follow-On Study


      The Action to Control Cardiovascular Risk in Diabetes Follow-On (ACCORDION) Eye Study Group and the Action to Control Cardiovascular Risk in Diabetes Follow-On (ACCORDION) Study Group *

      Diabetes Care

      American Diabetes Association

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          This study investigated whether the beneficial effects of intensive glycemic control and fenofibrate treatment of dyslipidemia in reducing retinopathy progression demonstrated in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Eye Study persisted beyond the clinical trial.


          The ACCORD Study (2003–2009) randomized participants with type 2 diabetes to intensive or standard treatment for glycemia (A1C level at <6.0% [42 mmol/mol] vs. 7.0–7.9% [53–63 mmol/mol]), systolic blood pressure (<120 vs. 140 mmHg), and dyslipidemia (fenofibrate [160 mg] plus simvastatin or placebo plus simvastatin). ACCORD Eye Study participants, who had baseline and year 4 eye examinations and fundus photographs, were reexamined in the ACCORD Follow-On (ACCORDION) Eye Study (2010–2014) 4 years after the ACCORD trial closeout. The outcome measure was diabetic retinopathy progression of three or more steps on the Early Treatment Diabetic Retinopathy Study scale.


          Diabetic retinopathy progressed in 5.8% with intensive glycemic treatment versus 12.7% with standard (adjusted odds ratio [aOR] 0.42, 95% CI 0.28–0.63, P < 0.0001), 7.5% with intensive blood pressure treatment versus 6.0% for standard (aOR 1.21, 95% CI 0.61–2.40, P = 0.59), and 11.8% with fenofibrate versus 10.2% with placebo (aOR 1.13, 95% CI 0.71–1.79, P = 0.60) in ACCORDION Eye participants ( n = 1,310).


          Prior intensive glycemic control continued to reduce diabetic retinopathy progression, despite similar A1C levels, when the ACCORD Study ended. This is the first study in people with type 2 diabetes of 10 years’ duration and established cardiovascular disease, unlike the newly diagnosed participants of the UK Prospective Diabetes Study, to demonstrate this effect. The benefit of fenofibrate, however, did not persist. Intensive blood pressure control had no effect.

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          Most cited references 13

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          Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial.

          Laser treatment for diabetic retinopathy is often associated with visual field reduction and other ocular side-effects. Our aim was to assess whether long-term lipid-lowering therapy with fenofibrate could reduce the progression of retinopathy and the need for laser treatment in patients with type 2 diabetes mellitus. The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study was a multinational randomised trial of 9795 patients aged 50-75 years with type 2 diabetes mellitus. Eligible patients were randomly assigned to receive fenofibrate 200 mg/day (n=4895) or matching placebo (n=4900). At each clinic visit, information concerning laser treatment for diabetic retinopathy-a prespecified tertiary endpoint of the main study-was gathered. Adjudication by ophthalmologists masked to treatment allocation defined instances of laser treatment for macular oedema, proliferative retinopathy, or other eye conditions. In a substudy of 1012 patients, standardised retinal photography was done and photographs graded with Early Treatment Diabetic Retinopathy Study (ETDRS) criteria to determine the cumulative incidence of diabetic retinopathy and its component lesions. Analyses were by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN64783481. Laser treatment was needed more frequently in participants with poorer glycaemic or blood pressure control than in those with good control of these factors, and in those with a greater burden of clinical microvascular disease, but the need for such treatment was not affected by plasma lipid concentrations. The requirement for first laser treatment for all retinopathy was significantly lower in the fenofibrate group than in the placebo group (164 [3.4%] patients on fenofibrate vs 238 [4.9%] on placebo; hazard ratio [HR] 0.69, 95% CI 0.56-0.84; p=0.0002; absolute risk reduction 1.5% [0.7-2.3]). In the ophthalmology substudy, the primary endpoint of 2-step progression of retinopathy grade did not differ significantly between the two groups overall (46 [9.6%] patients on fenofibrate vs 57 [12.3%] on placebo; p=0.19) or in the subset of patients without pre-existing retinopathy (43 [11.4%] vs 43 [11.7%]; p=0.87). By contrast, in patients with pre-existing retinopathy, significantly fewer patients on fenofibrate had a 2-step progression than did those on placebo (three [3.1%] patients vs 14 [14.6%]; p=0.004). An exploratory composite endpoint of 2-step progression of retinopathy grade, macular oedema, or laser treatments was significantly lower in the fenofibrate group than in the placebo group (HR 0.66, 95% CI 0.47-0.94; p=0.022). Treatment with fenofibrate in individuals with type 2 diabetes mellitus reduces the need for laser treatment for diabetic retinopathy, although the mechanism of this effect does not seem to be related to plasma concentrations of lipids.
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            A Proportional Hazards Model for the Subdistribution of a Competing Risk

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              Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group.

              Among patients with type 1 diabetes mellitus, intensive therapy (with the aim of achieving near-normal blood glucose and glycosylated hemoglobin concentrations [hemoglobin A1c]) markedly reduces the risk of microvascular complications as compared with conventional therapy. To assess whether these benefits persist, we compared the effects of former and intensive conventional therapy on the recurrence and severity of retinopathy and nephropathy for four years after the end of the Diabetes Control and Complications Trial (DCCT). At the end of the DCCT, the patients in the conventional-therapy group were offered intensive therapy, and the care of all patients was transferred to their own physicians. Retinopathy was evaluated on the basis of centrally graded fundus photographs in 1208 patients during the fourth year after the DCCT ended, and nephropathy was evaluated on the basis of urine specimens obtained from 1302 patients during the third or fourth year, approximately half of whom were from each treatment group. The difference in the median glycosylated hemoglobin values between the conventional-therapy and intensive-therapy groups during the 6.5 years of the DCCT (average, 9.1 percent and 7.2 percent, respectively) narrowed during follow-up (median during 4 years, 8.2 percent and 7.9 percent, respectively, P<0.001). Nevertheless, the proportion of patients who had worsening retinopathy, including proliferative retinopathy, macular edema, and the need for laser therapy, was lower in the intensive-therapy group than in the conventional-therapy group (odds reduction, 72 percent to 87 percent, P<0.001). The proportion of patients with an increase in urinary albumin excretion was significantly lower in the intensive-therapy group. The reduction in the risk of progressive retinopathy and nephropathy resulting from intensive therapy in patients with type 1 diabetes persists for at least four years, despite increasing hyperglycemia.

                Author and article information

                Diabetes Care
                Diabetes Care
                Diabetes Care
                Diabetes Care
                American Diabetes Association
                July 2016
                11 June 2016
                : 39
                : 7
                : 1089-1100
                Author notes
                Corresponding author: Emily Y. Chew, echew@ 123456nei.nih.gov .
                © 2016 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.
                Page count
                Figures: 5, Tables: 5, Equations: 0, References: 23, Pages: 12
                Funded by: National Heart Lung and Blood Institute http://dx.doi.org/10.13039/100000050
                Award ID: N01-HC-95178
                Award ID: N01-HC-95179
                Award ID: N01-HC-95180
                Award ID: N01-HC-95181
                Award ID: N01-HC-95182
                Award ID: N01-HC-95183
                Award ID: N01-HC-95184
                Award ID: IAA #Y1-HC-9035
                Award ID: IAA#Y1-HC-1010
                Diabetes Care Symposium

                Endocrinology & Diabetes


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