R3i Editorial

Reducing the large residual risk of diabetic retinopathy persisting despite provision of current evidence-based standards of care is one of the key priorities defined by the R3i Foundation. Thus, diabetic retinopathy remains one of the most devastating microvascular complications of hyperglycemia and a leading cause of blindness in populations of working age in industrialized countries.(1)

The ACCORD Eye results(2) confirm similar results in the FIELD study and raise the level of evidence for the beneficial effects of fenofibrate on diabetic retinopathy as suggested from the FIELD trial.(3)

As in the main ACCORD trial, (4) the ACCORD Eye substudy tested 3 interventions (intensive vs. standard glycemic control, intensive vs. standard blood pressure control, and simvastatin-fenofibrate combination vs. simvastatin alone) using a 2x2 factorial design. The primary microvascular clinical endpoint was progression of diabetic retinopathy ≥3 stages on the ETDRS scale* (5) or photocoagulation or vitrectomy for diabetic retinopathy.

When intensive glycemic control was compared to standard glycemic control, there was a significant 33% reduction of progression of diabetic retinopathy in the intensive treatment group (p=0.003). The novelty here is that tight glycemic control, already shown to slow progression of diabetic retinopathy in patients with newly diagnosed type 2 diabetes, remains effective in patients with a longer known duration of type 2 diabetes (about 10 years) and additional cardiovascular risk factors.

More disturbing was the excess of all-cause deaths in patients receiving the intensive glycemic treatment, that led to the premature termination of the ACCORD glycemic arm.(7) The reasons for the excess mortality remain at present unclear and might be treatment-dependent, since no excess mortality was reported in ADVANCE, (8) another clinical trial in which patients with type 2 diabetes were treated in order to achieve intensive glycemic control. In the latter study, in type 2 diabetes patients with similar characteristics as those included in ACCORD, no reduction in diabetic retinopathy was reported.

In ACCORD Eye, there was an apparent lack of beneficial effect of intensive blood pressure control on progression of retinopathy. This contrasts with previous results of the landmark United Kingdom Prospective Diabetes Study (UKPDS),(9) in which tight blood pressure control slowed progression of retinopathy in patients with newly-diagnosed type 2 diabetes. However, it took up to a 6-year follow-up in the UKPDS trial to achieve a meaningful difference in cumulative retinopathic events between treatment groups. Whether a longer duration of intensive blood pressure therapy might have resulted in a significant impact on progression of diabetic retinopathy in the ACCORD Eye study remains speculative.

The results of the glycemic control and blood pressure arms of ACCORD Eye underline the difficulty of demonstrating additional improvements in the management of diabetic eye disease. This makes the results observed in the lipid arm of ACCORD Eye all the more clinically relevant for patients with type 2 diabetes.

Progression of diabetic retinopathy reduced by 40% in patients treated with a simvastatin-fenofibrate combination

The primary endpoint of ACCORD Eye was significantly reduced by 40% after 4 years in patients treated with a simvastatin + fenofibrate combination compared to patients treated with simvastatin alone (adjusted odds ratio, 0.60; 95% CI, 0.42 to 0.87; p=0.006). The rates of progression of diabetic retinopathy were 6.5% with the combination, versus 10.2% with simvastatin monotherapy, giving a 3.7% absolute risk reduction (ARR). Consequently, the number of patients needed to treat (NNT=1/ARR) with the combination over 4 years to avoid progression of diabetic retinopathy in one was 27.


It must be emphasized that about 50% of participants in the ACCORD Eye lipid arm had already signs or symptoms of diabetic retinopathy at baseline, and were therefore in secondary microvascular prevention. Also, other modifiable vascular risk factors were at or near goal according to current clinical practice guidelines. In particular, mean LDL-C at baseline was 97 mg/dL, and mean blood pressure was 131/74 mmHg. Thus, the ACCORD Eye lipid arm may be viewed as the embodiment of appropriate design for a residual vascular risk reduction trial.

In ACCORD Eye, a pharmacological intervention (fenofibrate) that improves dyslipidemia reduced the progression of diabetic retinopathy in patients with type 2 diabetes. Earlier trials with small samples had suggested an association between diabetic retinopathy and elevated levels of TGs or low levels of HDL-C. (10-13) However, the subgroup analysis of ACCORD Eye did not show any difference in outcome between patients with and without low baseline HDL-C levels, those with and without elevated TG levels, and those with both abnormalities, i.e. atherogenic dyslipidemia, at baseline. This contrasts with the results of ACCORD Lipid regarding macrovascular outcomes published earlier,(14) in which only those patients who had both type 2 diabetes and atherogenic dyslipidemia seemed to benefit from the simvastatin-fenofibrate combination.

In brief, ACCORD Eye demonstrates that the residual microvascular risk of diabetic retinopathy can be safely and effectively addressed by fenofibrate in patients with type 2 diabetes and a broad range of triglycerides and HDL-C. In contrast, the ACCORD Lipid main results showed that fenofibrate reduced macrovascular events only in those patients who had atherogenic dyslipidemia, i.e. TG>204 and HDL<42 mg/dL.

The R3i Foundation regards these results of the ACCORD Eye trial as a milestone in prevention of diabetic retinopathy. The R3i Foundation is keen to actively participate to ongoing and future debates focusing on the major clinical implications of this landmark trial.


* The Early Treatment Diabetic Retinopathy Study (ETDRS) classification comprises six categories of increasing diabetic retinopathy severity: (1) clinically absent diabetic retinopathy, (2) mild to moderate nonproliferative diabetic retinopathy (NPDR), (3) moderate to severe NPDR, (4) severe NPDR, (5) very severe NPDR, and (6) proliferative diabetic retinopathy (PDR).


References

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