Fast track — ArticlesEffect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial
Introduction
Diabetic retinopathy has become the leading cause of vision loss and blindness in working-age adults in both developed and developing countries.1, 2 Visual loss results mainly from central macular oedema, and less frequently from proliferative diabetic retinopathy. The onset of diabetic retinopathy is characterised by vasodilation and hyperperfusion, followed by capillary loss and ischaemia. Leakage of protein and fluid from damaged capillaries leads to oedema at the macula, the focal centre of the retina, together with lipid and protein deposits termed hard exudates. The development of these pathological changes is strongly related to hyperglycaemia in type 2 diabetes.3, 4
Laser treatment to photocoagulate ischaemic retina and leaking microaneurysms has been proven in clinical trials to slow or prevent further vision loss from diabetic retinopathy.2, 5, 6 Although successful, laser treatment is frequently associated with visual field reduction and other ocular side-effects,7 and so any treatment that could reduce the need for the use of lasers would be an important advance. Medical management of risk factors associated with diabetic retinopathy is also important in slowing the progression of retinal disease.8, 9, 10 Although there is clear evidence of an association between diabetic retinopathy and glycaemia, duration of diabetes, raised blood pressure, and microalbuminuria, neither control of glycaemia nor blood pressure has fully prevented the progression of diabetic retinopathy, underscoring the importance of also assessing the management of other potential risk factors.
Raised serum cholesterol and triglyceride concentrations have been reported to be associated with both the development and severity of diabetic retinopathy.11, 12, 13 Increased lipid concentrations have also been linked in several studies to the development of macular oedema,14, 15, 16, 17 or to hard exudate deposition or proliferative retinopathy.17, 18, 19, 20 However, there is uncertainty regarding the beneficial effects of lipid lowering treatment for the management of diabetic retinopathy.21, 22
Nonetheless, the associations between raised lipid concentrations and the presence and severity of diabetic macular oedema and retinal hard exudate deposition highlight the potential for possible benefits from lipid-lowering drug therapy. Although statins have proven unsuccessful in preventing diabetic retinopathy,23 previous studies of peroxisome proliferator-activated receptor (PPAR)α agonists—also known as fibrates—in small numbers of patients have found beneficial effects on retinal24, 25, 26, 27 and macular hard exudates.28, 29
The aim of the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study was to assess whether long-term lipid-lowering therapy with fenofibrate could reduce macrovascular and microvascular outcomes in type 2 diabetes. Previously, we found that, in patients with type 2 diabetes and adequate glycaemic and blood pressure control, there was a significant relative reduction of almost a third in the rate of first laser treatment events for retinopathy after an average of 5 years treatment with fenofibrate 200 mg a day.30 Here, we report in detail on the effects of fenofibrate therapy on ophthalmic complications, and attempt to identify the underlying pathologies being treated in patients receiving laser treatment.
Section snippets
Patients
Participants in FIELD have been described in detail elsewhere.30, 31 Briefly, individuals were eligible for inclusion if they were aged between 50 and 75 years, had type 2 diabetes according to WHO criteria, and had an initial plasma total cholesterol concentration of 3·0–6·5 mmol/L and a total cholesterol/HDL-cholesterol ratio of 4·0 or more, or a plasma triglyceride concentration of 1·0–5·0 mmol/L, without requiring lipid-modifying treatment at study entry. Individuals with significant renal
Results
Of the 9795 participants randomised into the FIELD study, 4895 were assigned to receive fenofibrate and 4900 were assigned to receive matching placebo. 8·3% (412 participants in the placebo group and 402 in the fenofibrate group) of patients self-reported a history of diagnosed retinopathy before study entry, and 91·7% (4488 of those allocated placebo and 4493 allocated fenofibrate) reported no history of retinopathy. The fenofibrate and placebo treatment groups were well matched in terms of
Discussion
Our results show that treatment with micronised fenofibrate—in addition to therapies for hyperglycaemia and other risk factors for retinopathy—reduces the need for laser treatment for diabetic retinopathy in individuals with type 2 diabetes. This reduction was mainly associated with a lower prevalence of macular oedema as the underlying cause of diabetic retinopathy, although the need for treatment for proliferative retinopathy without macular involvement was also reduced by a similar amount.
References (58)
- et al.
Current approaches and perspectives in the medical treatment of diabetic retinopathy
Pharmacol Ther
(2004) Perspectives on diabetic retinopathy
Am J Ophthalmol
(2003)- et al.
The effects of lipid lowering on diabetic retinopathy
Am J Ophthalmol
(1991) - et al.
Lipid-lowering drug atorvastatin as an adjunct in the management of dibaetic macular edema
Am J Ophthalmol
(2004) Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial
Lancet
(2007)- et al.
Fenofibrate regulates retinal endothelial cell survival through the AMPK signal transduction pathway
Exp Eye Res
(2007) - et al.
Inhibition of TNF-alpha-induced RANTES expression in human hepatocyte-derived cells by fibrates, the hypolipidemic drugs
Int Immunopharmacol
(2003) - et al.
PPAR activators inhibit endothelial cell migration by targeting Akt
Biochem Biophys Res Comm
(2002) - et al.
Fenofibrate and pioglitazone improve endothelial function and reduce arterial stiffness in obese glucose tolerant men
Atherosclerosis
(2007) - et al.
Effect of simvastatin and fenofibrate on endothelium in type 2 diabetes
Eur J Pharmacol
(2004)
Lipid-lowering drugs and essential omega-6 and omega-3 fatty acids in patients with coronary heart disease
Nutr Metab Cardiovasc Dis
The metabolic syndrome: prevalence in worldwide populations
Endocrinol Metab Clin North Am
Laser treatment in diabetic retinopathy
Opthamologica
Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33)
Lancet
UKPDS 50: risk factors for incidence and progression of retinopathy in type II diabetes over 6 years from diagnosis
Diabetologia
Early photocoagulation for diabetic retinopathy. ETDRS report number 9
Ophthalmology
Photocoagulation for diabetic macular edema. ETDRS report number 1
Arch Ophthalmol
Diabetic retinopathy
Diabetes Care
The absence of a glycemic threshold for the development of long-term complications: the perspective of the Diabetic Control and Complications Trial
Diabetes
Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes
BMJ
Association of elevated serum lipid levels with retinal hard exudate in diabetic retinopathy. Early Treatment Diabetic Retinopathy Study (ETDRS) Report 22
Arch Ophthalmol
Risk factors for high-risk proliferative diabetic retinopathy and severe visual loss: Early Treatment Diabetic Retinopathy Study Report #18
Invest Ophthalmol Vis Sci
Serum lipids and diabetic retinopathy
Diabetes Care
The role of serum lipids in exudative diabetic maculopathy: is there a place for lipid lowering therapy?
Eye
Diabetic retinopathy and serum lipoprotein subclasses in the DCCT/EDIC cohort
Invest Ophthalmol Vis Sci
The importance of serum lipids in exudative diabetic macular edema in type 2 diabetic patients
Ann NY Acad Sci
A prospective study of serum lipids and risk of diabetic macular edema in type 1 diabetes
Diabetes
Low density lipoprotein cholesterol: an association with the severity of diabetic retinopathy
Diabetologia
Long-term follow-up of and underlying medical conditions in patients with diabetic exudative maculopathy
Eye
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