Lessons Learned From the ACCORD Eye Study

Better glycemic control and therapy of dyslipidemia can forestall progression of diabetic retinopathy in patients with type 2 diabetes.

EMILY Y. CHEW, MD ∙ THE ACCORD STUDY GROUP

Diabetic retinopathy, an important microvascular complication of diabetes, is a leading cause of blindness among working-age adults in the United States.¹ Timely administration of laser photocoagulation has resulted in durable prevention of severe vision loss in eyes with diabetic retinopathy.² However, laser treatment does destroy retinal tissue, and approaches to prevent the development and progression of diabetic retinopathy by reducing the associated risk factors would be desirable.

Randomized, controlled clinical trials in cohorts with type 1 and type 2 diabetes have demonstrated the beneficial effects of intensive therapy of glycemic control on both the incidence and progression of diabetic retinopathy.^3-6 Intensive treatment of elevated blood pressure, a known important contributing factor to the progression of diabetic retinopathy, also reduced the progression of diabetic retinopathy.⁷ Elevated serum cholesterol and triglyceride levels have been implicated in both population-based studies and prospective studies as a risk factor for the development of diabetic retinopathy, as well as visual loss.^8-11

However, there are limited randomized controlled intervention trials with sufficient sample size and duration to evaluate the role of dyslipidemia (Figure 1) in diabetic retinopathy.^12-15 The Fenofibrate Inter ven tion and Event Lowering in Diabetes (FIELD) study in patients (n=9,795 participants with 1,012 subjects in the FIELD Eye Study) with type 2 diabetes showed a beneficial effect of daily fenofibrate 200 mg on diabetic retinopathy progression.¹⁶

Figure 1. In hyperlipidemia, a variety of dyslipidemia, abnormally high lipid levels can separate to the top of blood samples.

THE ACCORD STUDY

The Action to Control Cardiovascular Risk in Diabetes (ACCORD) study was a randomized, controlled clinical trial (n=10,251) that evaluated the effects of the medical treatment strategies of lowering blood glucose, lipid lowering, and intensive blood pressure control on cardiovascular disease (CVD) in patients with type 2 diabetes who had either established CVD or additional risk factors.¹⁷ The intensive glycemic control targeted A1C levels of 6% in the intensive group and 7% to 7.9% in the standard group. These participants were then enrolled into a lipid-lowering or blood-pressure lowering study.

The lowering of serum triglycerides was done in combination with raising serum high-density lipoprotein cholesterol levels (comparing simvastatin alone with simvastatin plus 160 mg fenofibrate) and a lowering blood pressure study targeted at 120 mm Hg in the intensive group vs 140 mm Hg in the standard group. ACCORD provided an opportunity to evaluate the effects of these medical strategies on diabetic retinopathy progression. Progression of diabetic retinopathy was evaluated in a subset of the ACCORD study population (n=2,856) and was ACCORD's primary microvascular endpoint.¹⁸

THE ACCORD EYE STUDY

The ACCORD Eye Study was designed to evaluate the effects of these medical therapies on the progression of diabetic retinopathy (Figure 2). At baseline and year 4, the subset of participants received comprehensive eye exams consisting of visual acuity evaluation and color fundus photographs of the seven stereoscopic fields. The fundus photos were graded centrally by masked and trained personnel at the Fundus Photograph Reading Center at the University of Wisconsin-Madison. Progression of diabetic retinopathy was defined as worsening of diabetic retinopathy by three or more steps on the Early Treatment Diabetic Retinopathy Study (ETDRS) severity scale (person scale), photocoagulation, or vitrectomy for the treatment of diabetic retinopathy.

Figure 2. This eye shows evidence of nonproliferative diabetic retinopathy with increased hemorrhages and microaneurysms and mild venous abnormalities.

The results of the ACCORD Eye Study were recently published in the New England Journal of Medicine.¹⁹ Compared with standard glycemic control, intensive control decreased the progression of diabetic retinopathy from 10.4% to 7.3% over four years. Participants in the intensive control group had a median hemoglobin A1C of 6.4%, and the standard glycemic control group maintained a median level of 7.5%. In addition, compared with simvastatin treatment alone, combination lipid therapy with fenofibrate plus simvastatin also reduced disease progression from 10.2% to 6.5% over four years.

No prior clinical trial has shown that the combination of fenofibrate and simvastatin reduces diabetic retinopathy progression among participants randomized to an intensive blood pressure therapy that achieved a median systolic blood pressure of 117 mm Hg, compared with a median of 133 mm Hg in the standard group.

In the main ACCORD Study, none of the three treatment strategies resulted in a significant decrease in the combined rates of heart attack, stroke or cardiovascular death, compared with standard treatments. However, over about 3.5 years of follow-up, participants in the intensive glycemic group had a 22% higher risk of death (5.0% vs 4.0%) and a three times higher risk of hypoglycemic episodes requiring medical intervention (10.5% vs 3.5%), compared with participants in the standard glycemic control group. The Data and Safety Monitoring Committee stopped the glycemic control study arm prior to its scheduled completion.

The results of the ACCORD Eye Study may reflect similar findings from previous studies, such as the Diabetes Control and Complications Trial, in which microvascular complications showed early benefits from intensive glycemic control. Two smaller trials of glycemic control also reported nonsignificant results in the direction of benefit.^20-22 The message for ophthalmologists treating diabetic retinopathy includes the importance of maintaining good glycemic and lipid control. Furthermore, the treatment strategy will need to be individualized for the patient, taking into account the patient's medical history and the specific health goals that he or she wishes to achieve. There are no major adverse effects in the treatment of dyslipidemia with fenofibrate and simvastatin in the ACCORD Study.

Although no treatment effect on progression of diabetic retinopathy was seen in the intensive therapy arm of the blood pressure control compared with the standard arm, it is important to consider the differences between the ACCORD Eye Study population and the participants in the United Kingdom Prospective Diabetes Study (UKPDS), in which the intensive arm targeted systolic blood pressure of 140 mm Hg (similar to our standard group in the ACCORD Eye Study), while the standard group targeted 180 mm Hg. The UKPDS participants were newly diagnosed with diabetes, and they had not yet developed lipid abnormalities, hypertension or established cardiovascular disease,⁴ while the ACCORD study population was older and at greater cardiovascular risk.

Perhaps the effect of intensive blood pressure control in the ACCORD Eye Study may only be evident with longer follow-up, as demonstrated in the UKPDS data. It is also possible that the intensive blood pressure treatment beyond a systolic pressure of 140 mm Hg may not be necessary, and controlling the systolic blood pressure less than 120 mm Hg has no effect on the microvascular system. However, there was a decrease in strokes in the ACCORD Study in participants enrolled in the intensive blood pressure control.

CONCLUSION

In summary, the ACCORD Eye Study provides evidence that the beneficial effect of intensive glycemic therapy on retinopathy progression, previously demonstrated in type 1 diabetes ^2,3 and type 2 diabetes that was newly diagnosed⁵ or not yet accompanied by hypertension, lipid abnormalities or established cardiovascular disease,⁴ applies also to patients with type 2 diabetes, like those enrolled in ACCORD, who were older and at greater cardiovascular risk. Our study also demonstrates that fenofibrate, when added to statin therapy, slows the progression of diabetic retinopathy in patients with type 2 diabetes. We did not find a significant difference in progression of diabetic retinopathy between our standard and intensive hypertension treatment protocols. For application to clinical practice, these results should be taken in context with results of the main ACCORD study.

As with all treatments, the balance between risks and benefits must be considered, as well as each patient's current health status and individual needs and expectations. We will continue to assess the risk and benefits of the treatment strategies as the ACCORD study participants are followed for an additional five years, following the cessation of the randomized trial. RP

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