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|Objective:||To evaluate the effects of specific strategies for managing blood glucose levels, serum lipid levels, and blood pressure on the development and progression of diabetic retinopathy in participants with type 2 diabetes and additional cardiovascular risk factors.|
|Main inclusion criteria||
|Main exclusion criteria||
|Study design||Randomized multicentre study, incorporating two 2 x 2 factorial treatment arms.|
|Follow up duration:||
4.7 years for the primary outcome and 5 years for all deaths.
Glycemic control arm
Blood pressure arm
|Author's conclusion:||Intensive glycemic control and intensive combination treatment of dyslipidemia, but not intensive blood pressure control, reduced the rate of progression of diabetic retinopathy.|
ACCORD Eye1 was a substudy of the main ACCORD trial,2 in which 3 interventions were evaluated in patients with type 2 diabetes and additional cardiovascular risk factors according to a factorial design. Intensive vs. standard glycemic control was compared in all patients, whereas intensive vs. standard blood pressure control, and simvastatin-fenofibrate combination vs. simvastatin plus placebo were compared in two subsets of these patients. The ACCORD Eye substudy evaluated the effect of the 3 interventions on progression of diabetic retinopathy.
In ACCORD Eye, intensive glycemic control significantly reduced by 33% (p=0.03) progression of diabetic retinopathy.1 This was, however, associated with an unexpected and major drawback: an excess of all-cause deaths in the intensive glycemic control group led to the premature termination of the ACCORD glycemic arm.3 Subsequently, standard glycemic control was adopted for all ACCORD participants. The reasons for this excess mortality are not clear. A comparison with the ADVANCE trial,4 in which intensive glycemic control using a fixed combination of an ACE (perindopril) with a diuretic (indapamide) was not associated with an increased rate of deaths suggests that this adverse outcome might be treatment-dependent. Another difference between these two trials is that no reduction in diabetic retinopathy was seen in the ADVANCE trial.4
Another and rather unexpected result of ACCORD Eye was the lack of beneficial effect of intensive blood pressure control aiming at blood pressure normalization on diabetic retinopathy progression. In the United Kingdom Prospective Diabetes Study (UKPDS),5 conducted in patients with newly-diagnosed type 2 diabetes, tight blood pressure control slowed progression of retinopathy after 6 years of treatment. 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. It is also noteworthy that both baseline and achieved blood pressure levels were much higher in the UKPDS trial.
Finally, progression of diabetic retinopathy was significantly reduced by 40% (P=0.006) in patients treated with a simvastatin-fenofibrate combination compared with those treated with simvastatin plus placebo. Such a beneficial effect was achieved on top of well-controlled LDL-C, glycemia and systolic blood pressure. The simvastatin-fenofibrate combination was well tolerated. In particular, muscle toxicity was rare and not more frequent in patients treated with the combination than in those treated with simvastatin alone.
There were no significant interactions between the effect of fenofibrate and any of the prespecified characteristics in subgroup analyses. In particular, fenofibrate reduced diabetic retinopathy independently of LDL-C, HDL-C and TG levels. This contrasts with another publication stemming from the ACCORD trial: in ACCORD Lipid,6 fenofibrate reduced macrovascular events only in those patients with diabetes who had baseline atherogenic dyslipidemia (defined as TG>204 and HDL<42 mg/dL); in ACCORD Eye, a prespecified subgroup analysis showed no significant interaction between the presence or absence of atherogenic dyslipidemia on the changes in progression of diabetic retinopathy in patients treated with fenofibrate.1
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. The apparent interaction between treatment and presence or diabetic retinopathy at baseline (P=0.03) did not remain significant after multivariate analysis.
ACCORD Eye results confirm the benefit of fenofibrate on diabetic eye disease seen in the FIELD study.7 In a FIELD sub-analysis, fenofibrate reduced the rate of laser treatment by 37%. In ACCORD Eye, fenofibrate reduced the rate of progression of diabetic retinopathy by 40%.
ACCORD Eye had an appropriate design for a residual vascular risk reduction trial. Indeed, the treatments used in ACCORD Eye targeted three major modifiable macrovascular risk factors in patients with diabetes. The reduction of diabetic retinopathy by fenofibrate was seen in patients with LDL-C, blood glucose, and blood pressure at or near goal according to current clinical practice guidelines. Furthermore, the residual risk of diabetic retinopathy was safely and effectively addressed by fenofibrate in patients with a broad range of triglycerides and HDL-C levels. In ACCORD Eye, fenofibrate appeared effective in preventing progression of diabetic retinopathy irrespective of baseline non-LDL lipids, and with a lower number-needed-to-treat figure than intensive glycemic control, the latter otherwise associated with significant higher all-cause mortality.
* 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).8
|Key words||Type 2 Diabetes – Microvascular Residual Risk – Diabetic retinopathy – Atherogenic dyslipidemia – Fenofibrate – Simvastatin|