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

Abstract

Objectives: 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.

Research design and methods: 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.

Results: 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).

Conclusions: 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.

Trial registration: ClinicalTrials.gov NCT00000620 NCT00542178.

Figure 1

Consolidated Standards of Reporting Trials chart shows ACCORD participants enrolled in the ACCORDION Eye Study. *ACCORD Eye Study participants who were not eligible for the ACCORDION Eye Study for the above reasons.

Figure 2

Mean levels for glycosylated hemoglobin A_1c (A), triglyceride (B), HDL cholesterol (C), and systolic BP (D) through ACCORD and ACCORDION. Exit, end of ACCORD trial; M, month; Post, postend of ACCORD trial.

Figure 3

Subgroup effects in the ACCORDION participants previously randomized in the glycemia trial. The estimated ORs for progression of diabetic retinopathy are indicated as squares (with the area proportional to the sample size). The vertical line is the overall treatment effect. Data were missing for some patients in some subgroups. The comparison between the subgroup enrolled in the ACCORDION lipid trial and the subgroup enrolled in the ACCORDION BP trial was not specified within the protocol. Race was self-reported. The BMI is the weight in kilograms divided by the square of the height in meters. A logarithmic scale is used on the x axis.

Figure 4

Subgroup effects in the ACCORDION participants previously randomized in the lipid trial. The estimated ORs for progression of diabetic retinopathy are indicated as squares (with the area proportional to the sample size). The vertical line is the overall treatment effect. Data were missing for some patients in some subgroups. Two comparisons were not specified within the protocol: the comparison between the subgroup with triglyceride levels of 204 mg/dL (2.3 mmol/L) or higher and HDL cholesterol levels of 34 mg/dL (0.9 mmol/L) or less and the subgroup with lower triglyceride levels or higher HDL cholesterol levels, and the comparison between the subgroup with some retinopathy and the subgroup with none. Race was self-reported. The BMI is the weight in kilograms divided by the square of the height in meters. To convert values for cholesterol to millimoles per liter, multiply by 0.02586. To convert values for triglycerides to millimoles per liter, multiply by 0.01129. A logarithmic scale is used on the x axis.

Figure 5

Subgroup effects in the ACCORDION participants previously randomized in the BP trial. The estimated ORs for progression of diabetic retinopathy are indicated as squares (with the area proportional to the sample size). The vertical line is the overall treatment effect. Data were missing for some patients in some subgroups. The last four comparisons shown in the figure were not specified in the protocol. Race was self-reported. The BMI is the weight in kilograms divided by the square of the height in meters. A logarithmic scale is used on the x axis.