An update on the molecular actions of fenofibrate and its clinical effects on diabetic retinopathy and other microvascular end points in patients with diabetes

Abstract

The drug fenofibrate has received major attention as a novel medical treatment for diabetic retinopathy (DR) and other diabetes-induced microvascular complications. This interest stems from two recent large, well-designed clinical trials that demonstrated large reductions in the progression of DR and the need for laser intervention, in addition to a reduction in renal and neurological outcomes, in patients with type 2 diabetes. In both trials, the greatest benefit on DR progression was observed in those patients with DR at baseline. Originally considered a lipid-modifying drug, it now appears that multiple mechanisms may underpin the benefit of fenofibrate on diabetic microvascular end points. Fenofibrate regulates the expression of many different genes, with a range of beneficial effects on lipid control, inflammation, angiogenesis, and cell apoptosis. These factors are believed to be important in the development of DR regardless of the underlying diabetes etiology. Cell experiments have demonstrated improved survival of retinal endothelial and pigment epithelial cells in conjunction with reduced stress signaling under diabetic conditions. Further, fenofibrate improves retinal outcomes in rodent models of diabetes and retinal neovascularization. Given the results of these preclinical studies, further clinical trials are needed to establish the benefits of fenofibrate in other forms of diabetes, including type 1 diabetes. In DR management, fenofibrate could be a useful adjunctive treatment to modifiable risk factor control and regular ophthalmic review. Its incorporation into clinical practice should be continually revised as more information becomes available.

Figures

FIG. 1.

Chemical structure of fenofibrate. Lines indicate carbon bonds. O, oxygen; Cl, chlorine.

FIG. 2.

Identified lipid and nonlipid molecular actions of fenofibrate and its active metabolite, fenofibric acid. IGF1R, IGF-1 receptor; LRP-6, LDL receptor–related protein-6; NF-κB, nuclear factor-κB.

FIG. 3.

Classical fenofibrate signaling pathway. Fenofibrate is rapidly converted to fenofibric acid (FA) in vivo by tissue and plasma esterases before entering the cell. Fenofibric acid binds to PPARα and forms a heterodimer complex with retinoid X receptor (RXR). This complex then binds to specific peroxisome proliferator response elements (PPREs) to activate target gene transcription. RA, 9-cis retinoic acid.

FIG. 4.

Canonical Wnt signaling in an endothelial cell. A: Wnt ligand induces recruitment of dishevelled (Dsh) and Axin to the Frizzled receptor and LDL receptor–related protein (LRP) coreceptor, respectively, and inhibition of the β-catenin destruction complex. This allows β-catenin to accumulate in the cytoplasm and translocate to the nucleus, where it binds with T-cell factor (TCF) and activates transcription of proangiogenic genes. B: Fenofibrate (F) appears to inhibit Wnt signaling through inhibition of LRP6 phosphorylation. The mechanism is not completely understood but may involve upregulation of the VLDL receptor (VLDLR). APC, adenomatous polyposis coli; GSK3, glycogen synthase kinase-3; P, phosphate.