Fenofibrate and Diabetic Retinopathy

Two independent placebo controlled randomised trials; the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) [1] and Action to Control Cardiovascular Risk in Diabetes (ACCORD) Eye[2] Study, have demonstrated that oral therapy with the triglyceride-lowering / HDL-elevating drug fenofibrate significantly retards the rate of diabetic retinopathy (DR) progression in adults with Type 2 diabetes (T2D) and extant diabetic retinopathy, including macular oedema. This benefit is independent of conventional plasma lipid levels, glycaemia, and blood pressure.

Prevention and treatment of diabetic retinopathy

As discussed in other sections of Diapedia, optimal control of glycaemia, blood pressure, and plasma lipids, and refraining from smoking are recommended measures to prevent and retard DR and the other vascular complications of diabetes. In the STENO-2 trial of the combination of more intensive glycaemic control, antihypertensive therapy, a statin (which predominantly lowers LDL) and aspirin, the intervention moderately reduced DR progression [3]. Unfortunately, treatment targets are often difficult to achieve in clinical practice.

In addition to control of these systemic vascular risk factors, ocular secondary prevention therapies for sight-threatening DR are laser treatment, intra-ocular anti-vascular endothelial growth factor (VEGF) injections and intraocular corticosteroid injections. Unfortunately, these valuable therapies, which require specialist ophthalmologists to deliver them, are not always effective, are costly, and as with all other treatments, can have side-effects. Intra-ocular injections can be complicated by infection and can promote glaucoma and/or cataract progression. Laser surgery destroys some retinal tissue, resulting in some loss of visual fields and night-vision. As detailed below, there is now evidence of clinical benefit of oral fenofibrate in the secondary prevention of DR in adults with T2D.

Lipid Drugs and Diabetic Retinopathy Trials

The HMG CoA reductase inhibitors, ‘statins’, which predominantly lower LDL-cholesterol levels, are very effective for the primary and secondary prevention of cardiovascular disease (CVD) in diabetes[4], but have not demonstrated any substantial protective effects against DR. In contrast, fenofibrate, a peroxisome proliferator-activated receptor α (PPARα) agonist has proven effective for retarding DR progression in adults with T2D[1][2].

Figure 1 legend. Cumulative risk curves of time to event of any first laser treatment, by treatment group. Panel A: Macular oedema indicates laser treatment where the macula was involved; Panel B: Proliferative retinopathy shows cases without macular involvement; Panel C: All retinopathy includes all first instances of laser treatment for any diabetic retinopathy.  Reprinted from The Lancet, Vol 370, Keech AC, Mitchell P, Summanen PA, et al. Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial, page 1691, Copyright 2007, with permission from Elsevier.
Figure 1 legend. Cumulative risk curves of time to event of any first laser treatment, by treatment group. Panel A: Macular oedema indicates laser treatment where the macula was involved; Panel B: Proliferative retinopathy shows cases without macular involvement; Panel C: All retinopathy includes all first instances of laser treatment for any diabetic retinopathy. Reprinted from The Lancet, Vol 370, Keech AC, Mitchell P, Summanen PA, et al. Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial, page 1691, Copyright 2007, with permission from Elsevier.
The FIELD study of 9,795 T2D patients in Australia, New Zealand and Finland compared the effects of 5-years of oral fenofibrate vs. placebo treatment. Whilst the primary study end-point of CVD event reduction was not reached[5], the FIELD study demonstrated significant benefit for DR[1], as well as for nephropathy[6][7] and amputations, in particular amputations resulting from microvascular injury[8]. Relative to placebo, randomisation to five years of oral fenofibrate was associated with a 37% reduction in need for laser therapy for any DR, comprising a 36% reduction for maculopathy and 38% reduction for proliferative DR (see Figure 1)[1]. The ‘number needed to treat’ (NNT) with fenofibrate to prevent laser treatment in a person with existing DR at study-entry was 17.

In the ACCORD EYE sub-study, 1,593 of 5,518 T2D patients in North America were treated with simvastatin and either fenofibrate or matching placebo for four years. Randomisation to oral fenofibrate vs. placebo was associated with 40% less DR progression, or laser therapy or vitrectomy[2]. In both the FIELD and ACCORD EYE trials DR benefit was seen only in patients with pre-existing DR. Based on these findings some countries (including Australia) have approved oral fenofibrate use for actual DR in T2D patients, regardless of plasma lipid profiles.

Fenofibrate

Fenofibrate is a relatively low-cost drug, now off-patent in many countries, so that it can be prescribed and monitored by any medical practitioner. Given orally once a day, it is metabolised to the active moiety, fenofibric acid, and is eliminated mainly via the kidneys. The usual oral dose of fenofibrate in people with normal renal function is 145 mg once daily, reducing to 48 mg once daily if eGFR<30ml/min/1.73m[2]. Monitoring of fenofibrate therapy is the same as for statins. Contra-indications to fenofibrate include severe renal or liver disease, gallbladder disease, a past history of pancreatitis or pulmonary embolus, and allergy to fenofibrate.

Fenofibrate has low rates (<5%) of side-effects, that include (usually) reversible elevations of liver function tests, myalgia, and elevated creatinine kinase (CK) levels [9]. It induces a reversible small increase in serum creatinine levels and a decrease in the calculated (but not real) glomerular filtration rate (GFR) [6][7][10][11]. In fact, in the FIELD Study fenofibrate was renoprotective [6][7]. In FIELD, but not in ACCORD-LIPID, there was a small but statistically significant increase in acute pancreatitis and pulmonary emboli[1]. As demonstrated by ACCORD LIPID (of fenofibrate vs. placebo on simvastatin background) and in the statin-drop-in subset of the FIELD Study, a fenofibrate-statin combination is usually well-tolerated. Fenofibrate is the only fibrate currently recommended for use with a statin due to high risk of severe myositis with other fibrates when combined with a statin[12][13].

Fenofibrate should not be seen as a replacement for other treatments for late-stage DR, such as laser therapy, or intraocular anti-VEGF or corticosteroids. Regular DR screening visits should be continued.

Mechanisms of fenofibrate action in DR

Fenofibrate may retard DR by affecting several pathways related to lipid, lipoprotein and prostaglandin metabolism, inflammation, apoptosis and angiogenesis[14][15][16][17]. As discussed elsewhere in Diapedia, VEGF, which induces inflammation, vascular leakage and neovascularization, is central to the development of DR[18]. Fenofibrate or fenofibric acid can reduce VEGF and VEGF-receptor 2 expression[14][15][17] and oral fenofibrate increases circulating levels of pigment epithelium-derived factor (PEDF), a potent endogenous inhibitor of VEGF,[19]. As well as being a PPARα agonist, fenofibrate also modulates NF-κB, NOS, AMP-kinase and the Wnt signaling pathways[14][15][17]. Detailed knowledge of fenofibrate’s protective pathways for DR may also guide the development of other new therapeutic interventions for DR.

Future Directions

It is unknown whether oral fenofibrate can also protect against DR in people with Type 1 diabetes (T1D). A study to address this question, the Fenofibrate and Microvascular Complications of T1D-EYE (FAME-1 EYE) will soon commence in Australia. Effects in adolescents and young adults with T2D, who are at particularly high risk of vascular complications[20], are also untested. Clinical studies are also merited to discern if and how fenofibrate can be used in advanced DR in combination with anti-VEGF injections. Jian-Xing Ma’s team (Oklahoma University Health Sciences Centre, Oklahoma, USA) has promising animal studies of ocular fenofibrate (by injection or eye drops) protecting against DR15, [21], and this is an interesting area to follow.

Conflict of Interest statements:

AJ has received honoraria for lectures for Abbott Pharmaceuticals during the last 3 years.

DO’N No conflicts of interest.

AK has received funding from Abbott Pharmaceuticals for research using fenofibrate, and reimbursement of lecturing honoraria and travel costs and/or advisory committees during the last 5 years.

References

  1. ^ Keech AC, Mitchell P, Summanen PA, et al. Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomized controlled trial. Lancet 2007;370(9600):1687-97.

  2. ^ ACCORD Study Group; ACCORD Eye Study Group, Chew EY et al. Effects of medical therapies on retinopathy progression in type 2 diabetes. N Engl J Med 2010;363(3):233-44.

  3. ^ Pedersen O, Gaede P. Intensified multifactorial intervention and cardiovascular outcome in type 2 diabetes: the Steno-2 study. Metabolism. 2003;52(8 Suppl 1):19-23.

  4. ^ Cholesterol Treatment Trialists' (CTT) Collaborators, Kearney PM, Blackwell L et al. Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet. 2008;371(9607):117-25.

  5. ^ Keech A, Simes RJ, Barter P, et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet. 2005;366(9500):1849-61. Erratum in: Lancet. 2006;368(9545):1415 and Lancet. 2006;368(9545):1420.

  6. ^ Ting RD, Keech AC, Drury PL, et al. Benefits and safety of long-term fenofibrate therapy in people with type 2 diabetes and renal impairment: the FIELD Study. Diabetes Care. 2012;35(2):218-25.

  7. ^ Davis TM, Ting R, Best JD, et al. Effects of fenofibrate on renal function in patients with type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study. Diabetologia. 2011;54(2):280-90.

  8. ^ Rajamani K, Colman PG, Li LP, et al. Effect of fenofibrate on amputation events in people with type 2 diabetes mellitus (FIELD study): a prespecified analysis of a andomized controlled trial. Lancet. 2009;373(9677):1780-8.

  9. ^ Ansquer JC, Foucher C, Aubonnet P, et al. Fibrates and microvascular complications in diabetes—insight from the FIELD study. Curr Pharm Des. 2009;15(5):537-52

  10. ^ Bonds DE, Craven TE, Buse J et al. Fenofibrate-associated changes in renal function and relationship to clinical outcomes among individuals with type 2 diabetes: the Action to Control Cardiovascular Risk in Diabetes (ACCORD) experience. Diabetologia. 2012;55(6):1641-50.

  11. ^ Mychaleckyj JC, Craven T, Nayak U et al. Reversibility of fenofibrate therapy-induced renal function impairment in ACCORD type 2 diabetic participants. Diabetes Care. 2012;35(5):1008-.

  12. ^ Jones PH, Davidson MH. Reporting rate of rhabdomyolysis with fenofibrate +statin versus gemfibrozil + any statin. Am J Cardiol. 2005;95(1):120-2.

  13. ^ Vasudevan AR, Jones PH. Effective use of combination lipid therapy. Curr

  14. ^ Noonan JE, Jenkins AJ, Ma JX, et al. An update on the molecular actions of fenofibrate and its clinical effects on diabetic retinopathy and other microvascular end points in patients with diabetes. Diabetes. 2013;62(12):3968-75.

  15. ^ Chen Y, Hu Y, Lin M, et al. Therapeutic effects of PPARα agonists on diabetic retinopathy in type 1 diabetes models. Diabetes. 2013;62(1):261-72.

  16. ^ Ding L, Cheng R, Hu Y et al. Peroxisome proliferator-activated receptor α protects capillary pericytes in the retina. Am J Pathol. 2014;184(10):2709-20.

  17. ^ Meissner M, Stein M, Urbich C, et al. PPARalpha activators inhibit vascular endothelial growth factor receptor-2 expression by repressing Sp1-dependent DNA binding and transactivation. Circ Res 2004 Feb 20;94(3):324–32.

  18. ^ Aiello LP, Avery RL, Arrigg PG, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med. 1994;331(22):1480-7.

  19. ^ A Jenkins, A Januszewski, D Calandro et al. Serum PEDF levels in type 2 diabetes: correlations, predictive power for vascular events and increases by fenofibrate in the FIELD Study. Moderated poster presented at the EASD, 2014. Vienna, Austria.

  20. ^ Constantino MI, Molyneaux L, Limacher-Gisler F et al. Long-term complications and mortality in young-onset diabetes: type 2 diabetes is more hazardous and lethal than type 1 diabetes. Diabetes Care. 2013;36(12):3863-9.

  21. ^ Chen Y, Lu B, Zhang Q, et al. Therapeutic effect of fenofibrate eyedrops on diabetic retinopathy. Paper presented at: The Association for Research in Vision and Ophthalmology (ARVO) 2012 Annual Meeting; 6-9 May 2012; Fort Lauderdale, Florida, USA. Abstract 453/D1130.

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