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Fenofibrate Therapy in Diabetic Retinopathy

Studies suggest fenofibrate can prevent microvascular changes, decrease need for surgery.

Diabetic retinopathy is a one of the most common microvascular complications in patients with poorly controlled diabetes. The hypothesized mechanisms by which diabetic retinopathy occurs relies on oxidative stress, which can lead to neuronal accumulation, altered balance of neurotrophic factors, and loss of nuclear gene expressions. All of these mechanisms lead patients to experience clinical manifestations, such as electroretinography changes, perimeter vision change, dark adaption, contrast sensitivity, and changes in color vision. Hence, this is how improper glucose control has been linked to these pathophysiological mechanisms. The CDC estimates that 4.2 million adults have diabetic retinopathy and 655,000 suffer from life-threatening diabetic retinopathy. Thus, proper disease management is imperative to delay the progression of uncontrolled blood glucose to diabetic retinopathy or life-threatening diabetic retinopathy.

Consequently, with proper glucose control and proper blood pressure management, the retinal vasculature and neuronal tissue damage can be delayed in this patient population.

Various studies have focused on studying medications that can potentially help delay the progression of uncontrolled diabetes to retinopathy. The FIELD study and the ACCORD-eye studies have studied the use of fenofibrate in this patient population to understand its effect on diabetic retinopathy. Both studies saw a reduction in the need for laser surgery in those subjects receiving fenofibrate. Based on these studies, it was explained how activation of the nuclear transcription factor peroxisome proliferator-activated receptor alpha (PPARa) leads to anti-apoptosis signaling, inhibition of inflammatory factors and various antioxidant effects in the vasculature. It was also noted that these effects were independent of the lipid-lowering properties of fenofibrate.

In another study recently published, Marta Garcia-Ramirez and colleagues discovered other benefits of fenofibrate in retinopathy. In the retinal pigment epithelium of the eye, fenofibric acid, the active metabolite of fenofibrate, downregulates fibronectin and collagen in the basement membrane of the epithelium that leads to fluid accumulation, which impacts normal eye function. It also promotes downregulation of stress-mediated signaling pathways (i.e apoptosis, autophagy) and increases survival pathways. Inflammation in the eye vasculature is also reduced with the use of fenofibrate through downregulation of NF-kB. Thus, providing increased benefits in the management of diabetic retinopathy.

The profound effects of fenofibrate have not been evaluated in recent clinical studies. However, a study done in the Ukraine looked at the use of fenofibrate and statins in patients with type 2 diabetes patients. In this trial conducted by Yevgeniya Ilyina and colleagues, 47 patients with moderate non-proliferative diabetic retinopathy were enrolled to evaluate the effect of dual statin and fenofibrate therapy. Study subjects were separated into two groups, one control and with moderate non-proliferative diabetic retinopathy. All patients were followed for one year and changes in ophthalmological measurements were used as the primary endpoint of the study. Patients with moderate non-proliferative diabetic retinopathy were exposed to atorvastatin 20 mg daily and fibrates 250 mg daily (supplied as lipofen). All patients were assessed every 6 months for visual acuity, light sensitivity, and mean defect of the visual field. There was a significant difference in between mean defects visual fields, hence, those patients in the study group obtained a 22% reduction in mean defects of visual fields, whereas those patients in the control group obtained a 54% reduction (p<0.05). Meaning that the local defects in visual fields was progressively slower in the study population. The microvascular changes observed were more severe in the control group that in those patients exposed to the treatment regimen.

In conclusion, the use of fibrates and statins provided some visual field stabilization. This relationship has been observed independent of levels of A1c. This study further explores the potential of using fenofibrate and statin as a means of slowing the progression of diabetic retinopathy.  These findings support the findings obtained by the FIELD and ACCORD-eye studies. Therefore, with adequate glycemic control and use of other therapies, such as fenofibrate, microvascular complications like retinopathy, can be delayed. However, further studies are needed to translate these findings in patient populations with more advanced stages of diabetes.

Practice Pearls:

  • Fenofibrate therapy can decrease the need for eye surgery in patients with diabetic retinopathy.
  • The use of statins and fenofibrate can potentially slow local defects in visual field and prevent severe microvascular changes.
  • Fenofibrate can decrease inflammation through downregulation of cytokines.

Researched and prepared by Pablo A. Marrero-Núñez – USF College of Pharmacy Student Delegate –  Doctor of Pharmacy Candidate 2017 – University of South Florida – College of Pharmacy

References:

Garcia-Ramírez, Marta, Cristina Hernández, Xavier Palomer, Manuel Vázquez-Carrera, and Rafael Simó. “Fenofibrate Prevents the Disruption of the Outer Blood Retinal Barrier through Downregulation of NF-κB Activity.” Acta Diabetol Acta Diabetologica 53.1 (2015): 109-18. Web.

Ilyina, Yevgeniya, Pavlo Bezditko, Ajaj Samer Mohamed, Olesya Zavoloka, and Darya Zubkova. “Statins and Fibrates as the Treatment of Nonproliferative Diabetic Retinopathy in Type 2 Diabetes Mellitus.” Spektrum Augenheilkd. Spektrum Der Augenheilkunde 30.3 (2016): 111-16. Web.

Moraes, Gabriela De, and Christopher J. Layton. “Therapeutic Targeting of Diabetic Retinal Neuropathy as a Strategy in Preventing Diabetic Retinopathy.” Clinical & Experimental Ophthalmology (2016): n. pag. Web.

Knickelbein, Jared E., Akshar B. Abbott, and Emily Y. Chew. “Fenofibrate and Diabetic Retinopathy.” Curr Diab Rep Current Diabetes Reports 16.10 (2016): n. pag. Web.