Fenofibrate and Diabetic Retinopathy

Diabetic retinopathy (DR) is a preventable, frequent, and serious complication of diabetes, with a large impact on morbidity and disability. More than 125 million people worldwide suffer from DR. The pathogenesis of DR involves different pathways, many of them exacerbated by chronic hyperglycemia, but not necessarily a direct consequence of it. Fibrates are a well-known family of medications traditionally employed for the treatment of hypertriglyceridemia and low HDL cholesterol, which act through binding to the nuclear receptor peroxisome proliferator-activated receptors (PPAR)-alpha in several tissues. PPAR-alpha is expressed in the human retina. Animal and cellular models have demonstrated that PPAR activation by fibrates improves cellular phenomena involved in the genesis of DR, including chronic inflammation, oxidative damage, vascular hyperpermeability and microglial activation. Secondary analyses of fenofibrate trials originally designed to assess cardiovascular outcomes, systematically found an apparent benefit from fenofibrate treatment on diverse measures of DR appearance and severity. Finally, the LENS (Lowering Events in Non-Proliferative Retinopathy) study proved in a dedicated randomized trial that early fenofibrate use lowers the risk of DR progression in a statistically significant and clinically meaningful manner. These results have positioned fenofibrate as the first agent proven to specifically delay DR, without mediation by glycemic control. Future studies will test whether this effect extends to other microvascular diabetes complications.