Direct Effects of PPARα Agonists on Retinal Inflammation and Angiogenesis May Explain How Fenofibrate Lowers Risk of Severe Proliferative Diabetic Retinopathy

In this issue of Diabetes, Chen et al. (1) used rodent models of type 1 diabetes and ischemia-induced retinal neovascularization to examine how the lipidlowering drug fenofibrate may prevent progression of diabetic retinopathy. Diabetic retinopathy is the sightthreatening complication of diabetes that causes retinal microvascular dysfunction, which in turn leads to diabetic macular edema (DME), formation of exudate deposits, and microhemorrhages. In the advanced proliferative stage of diabetic retinopathy, neovascularization can result in retinal detachment and blindness. Therapeutic options for diabetic retinopathy have been limited. Until recently, intensive glycemic control, with its risks of hypoglycemic events and increased mortality, was the only known means of reducing the progression of diabetic retinopathy (2,3). Laser photocoagulation of the peripheral retinal tissue, intravitreal injection of steroids or vascular endothelial growth factor (VEGF) inhibitors, and vitrectomy can each stabilize or improve vision, but they are all invasive and are associated with various complications. Additional treatment options are needed. An orally available drug that reduces the risk of diabetic retinopathy progression without intensive glycemic control, retinal destruction, or repeated intravitreal injections would be ideal. Type 2 diabetes is often associated with dyslipidemia characterized by elevated triglycerides, reduced HDL cholesterol, and variable LDL cholesterol. Although statins are clearly beneficial, a residual atherogenic dyslipidemia often remains (4). Fibric acid derivatives, such as fenofibrate, stimulate the peroxisome proliferator–activated receptor type a (PPARa) and lead to increased fatty acid b-oxidation, thus decreasing plasma triglyceride and LDL cholesterol levels and increasing HDL cholesterol levels (5). This makes fibrates, in combination with statins, a logical treatment for diabetic dyslipidemia. Recent large-scale clinical studies, including the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) and Action to Control Cardiovascular Risk in Diabetes (ACCORD) studies, examined the effects of fenofibrate on cardiovascular risk and diabetes complications in type 2 diabetes. Although fenofibrate failed to affect visual acuity measures, both studies showed that the drug reduced the risk of developing severe diabetic retinopathy by approximately one-third (6,7). These findings have resulted in recommendations that fenofibrate be used as an adjunct treatment for type 2 diabetic patients with nonproliferative diabetic retinopathy (8,9). Further evaluation of fenofibrate’s impact on diabetic retinopathy progression and its mechanism of action are needed. Fenofibrate may affect diabetic retinopathy either indirectly by lowering plasma free fatty acid and triglyceride levels or directly by activating retinal PPARa (Fig. 1). PPARa agonists influence cellular physiology in many ways that might prove beneficial in diabetes complication–prone tissues (for a recent review, see ref. 10). In particular, fenofibrate provokes direct PPARa-dependent actions on inflammatory gene expression by inhibiting proinflammatory transcription factors, including nuclear factor-kB (NF-kB) (10). Relevant to the reduced risk of macular edema in diabetic retinopathy is the observation that fenofibrate inhibits endothelial cell layer permeability caused by oxygen-glucose deprivation in a PPARa-dependent manner (11). Chen et al. (1) examined the effects of fenofibrate on vascular leakiness in type 1 diabetic rat and mouse models. They found that orally administered fenofibrate abrogated diabetes-induced vascular permeability. Supplemental data suggest that the effect of fenofibrate was not accompanied by significant changes in plasma triglyceride levels. To determine whether fenofibrate acted directly on the retina, they administered the drug by intravitreal injection and found similar effects on vascular permeability. The ability to inhibit permeability coincided with the inhibition of diabetes-induced vascular adherence of leukocytes (leukostasis), as well as decreased expression of NF-kB, monocyte chemoattractant protein (MCP)-1, and intracellular adhesion molecule (ICAM)-1 in the diabetic retina. These results support earlier studies showing that fenofibrate inhibits cytokineinduced NF-kB activity, MCP-1, and ICAM-1 expression, as well as monocyte adhesion in endothelial cultures (12–15). Although there is no conclusive evidence for leukostasis as the direct cause of increased retinal vascular permeability in diabetic retinopathy, the results suggest that antiinflammatory effects of fenofibrate diminish monocyte attraction and adherence to the retinal endothelium, thus preventing vascular damage and leakiness. There is precedent to suggest that fenofibrate could also inhibit neovascularization in proliferative diabetic retinopathy by acting directly on endothelial cells. In previous studies, fenofibrate reduced endothelial cell expression of VEGF receptor 2 and hindered the migration of endothelial From the Department of Ophthalmology and Visual Sciences, University of Michigan College of Medicine, Kellogg Eye Center, Ann Arbor, Michigan. Corresponding author: Steven F. Abcouwer, [email protected]. DOI: 10.2337/db12-1223 2013 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by -nc-nd/3.0/ for details. See accompanying original article, p. 261.