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

  1. Steven F. Abcouwer
  1. Department of Ophthalmology and Visual Sciences, University of Michigan College of Medicine, Kellogg Eye Center, Ann Arbor, Michigan
  1. Corresponding author: Steven F. Abcouwer, sabcouwe{at}umich.edu.

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 lipid-lowering drug fenofibrate may prevent progression of diabetic retinopathy. Diabetic retinopathy is the sight-threatening 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 α (PPARα) and lead to increased fatty acid β-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 …

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