Fenofibrate: A new treatment for diabetic retinopathy. molecular mechanisms and future perspectives

Current Medicinal Chemistry

Volumn 20, Issue 26, 2013, Pages 3258-3266

  Simó, Rafael ^a   Roy, Sayon ^b   Behar Cohen, Francine ^c   Keech, Anthony ^d   Mitchell, Paul ^e   Wong, Tien Yin ^f  

^a UNIVERSITAT AUTÒNOMA DE BARCELONA   (Spain)

^b BOSTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

^c UNIVERSITÉ PARIS DESCARTES   (France)

^d UNIVERSITY OF SYDNEY   (Australia)

^e WESTMEAD HOSPITAL   (Australia)

^f NATIONAL UNIVERSITY OF SINGAPORE   (Singapore)

Author keywords

Diabetic retinopathy; Fenofibrate; Mode of action; Pathogenesis; Type 2 diabetes

Indexed keywords

1 ALKYL 2 ACETYLGLYCEROPHOSPHOCHOLINE ESTERASE; FENOFIBRATE; FENOFIBRIC ACID; HIGH DENSITY LIPOPROTEIN CHOLESTEROL; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; LOW DENSITY LIPOPROTEIN CHOLESTEROL; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA; REACTIVE OXYGEN METABOLITE;

ANTIANGIOGENIC ACTIVITY; ANTIINFLAMMATORY ACTIVITY; ANTIOXIDANT ACTIVITY; ARTICLE; BLOOD PRESSURE REGULATION; BLOOD RETINA BARRIER; CARDIOVASCULAR RISK; CONTRAST SENSITIVITY; CREATININE BLOOD LEVEL; DIABETIC RETINOPATHY; EARLY INTERVENTION; GLIA CELL; GLYCEMIC CONTROL; HUMAN; IMMUNOCOMPETENT CELL; INSULIN DEPENDENT DIABETES MELLITUS; LASER COAGULATION; LIPID TRANSPORT; LUNG EMBOLISM; MICROANGIOPATHY; MICROGLIA; NEUROPROTECTION; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; OPHTHALMOLOGY; OXYGEN CONSUMPTION; RENIN ANGIOTENSIN ALDOSTERONE SYSTEM; RETINA NEOVASCULARIZATION; RHABDOMYOLYSIS; SYSTEMIC THERAPY; VISUAL IMPAIRMENT;

ANIMALS; DIABETES MELLITUS, TYPE 2; DIABETIC RETINOPATHY; DISEASE PROGRESSION; FENOFIBRATE; HUMANS; HYPOLIPIDEMIC AGENTS;

EID: 84883218141     PISSN: 09298673     EISSN: 1875533X     Source Type: Journal    
DOI: 10.2174/0929867311320260009     Document Type: Article

References (61)

1. International Diabetes Federation. Diabetes Atlas (5th Edition). http://www.idf.org/diabetesatlas (Accessed March 31, 2012).
2. Cheung, N.; Mitchell, P.; Wong, T.Y. Diabetic retinopathy. Lancet, 2010, 376(9735), 124-136.
3. Yau, J.W.; Rogers, S.L.; Kawasaki, R.; Lamoureux, E.L.; Kowalski, J.W.; Bek, T.; Chen, S.J.; Dekker, J.M.; Fletcher, A.; Grauslund, J.; Haffner, S.; Hamman, R.F.; Ikram, M.K.; Kayama, T.; Klein, B.E.; Klein, R.; Krishnaiah, S.; Mayurasakorn, K.; O'Hare, J.P.; Orchard, T.J.; Porta, M.; Rema, M.; Roy, M.S.; Sharma, T.; Shaw, J.; Taylor, H.; Tielsch, J.M.; Varma, R.; Wang, J.J.; Wang, N.; West, S.; Xu,L.; Yasuda, M.; Zhang, X.; Mitchell, P.; Wong, T.Y.; Meta-Analysis for Eye Disease (META-EYE) Study Group. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care, 2012, 35(3), 556-564.
4. Pelletier, E.M.; Shim, B.; Ben-Joseph, R.; Caro, J.J. Economic outcomes associated with microvascular complications of type 2 diabetes mellitus: results from a US claims data analysis. Pharmacoeconomics, 2009, 27(6), 479-490.
5. Mohamed, Q.; Gillies, M.C.; Wong, T.Y. Management of diabetic retinopathy: a systematic review. JAMA., 2007, 298(8), 902-916.
6. Gaede, P.; Lund-Andersen, H.; Parving, H.H.; Pedersen, O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N. Engl. J. Med., 2008, 358(6), 580-591.
7. ACCORD Study Group; ACCORD Eye Study Group, Chew, E.Y.; Ambrosius, W.T.; Davis, M.D.; Danis, R.P.; Gangaputra, S.; Greven, C.M.; Hubbard, L,; Esser, B.A.; Lovato, J.F.; Perdue, L.H.; Goff, D.C.Jr.; Cushman, W.C.; Ginsberg, H.N.; Elam, M.B.; Genuth, S.; Gerstein, H.C.; Schubart, U.; Fine, L.J. Effects of medical therapies on retinopathy progression in type 2 diabetes. N. Engl. J. Med., 2010, 363(3), 233-244.
8. Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein, H.C.; Miller, M.E.; Byington, R.P.; Goff, D.C.Jr.; Bigger, J.T.; Buse, J.B.; Cushman, W.C.; Genuth, S.; Ismail-Beigi, F.; Grimm, R.H.Jr.; Probstfield, J.L.; Simons-Morton, D.G.; Friedewald, W.T. Effects of intensive glucose lowering in type 2 diabetes. N. Engl. J. Med., 2008, 358(24), 2545-2559.
9. Patel. A.; ADVANCE Collaborative Group, MacMahon, S.; Chalmers, J.; Neal, B.; Woodward, M.; Billot, L.; Harrap, S.; Poulter, N.; Marre, M.; Cooper, M.; Glasziou, P.; Grobbee, D.E.; Hamet, P.; Heller, S.; Liu, L.S.; Mancia, G.; Mogensen, C.E.; Pan, C.Y.; Rodgers, A.; Williams, B. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet, 2007, 370(9590), 829-840.
10. United Kingdom Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ.,1998, 317(7160), 703-713.
11. Lim, L.S.; Wong, T.Y. Lipids and diabetic retinopathy. Expert Opin.Biol.Ther., 2012, 12(1), 93-105.
12. Bloomgarden, Z.T. Diabetic retinopathy and diabetic neuropathy. Diabetes Care, 2007, 30(3), 760-765.
13. Huang, O.S.; Lamoureux, E.L.; Tay, W.T.; Tai, E.S.; Wang, J.J.; Wong, T.Y. Glycemic and blood pressure control in an asian malay population with diabetes and diabetic retinopathy. Arch. Ophthalmol., 2010, 128(9), 1185-1190.
14. Mauer, M.; Zinman, B.; Gardiner, R.; Suissa, S.; Sinaiko, A.; Strand, T.; Drummond, K.; Donnelly, S.; Goodyer, P.; Gubler, M.C.; Klein, R. Renal and retinal effects of enalapril and losartan in type 1 diabetes. N. Engl. J. Med., 2009, 361(1), 40-51.
15. Chaturvedi, N.; Porta, M.; Klein, R.; Orchard, T.; Fuller, J.; Parving, H.H.; Bilous, R.; Sjølie, A.K.; DIRECT Programme Study Group. Effect of candesartan on prevention (DIRECT-Prevent1) and progression (DIRECT-Protect1) of retinopathy in type 1 diabetes: randomised, placebo-controlled trials. Lancet, 2008, 372(9647), 1394-1402.
16. Sjølie, A.K.; Klein, R.; Porta, M.; Orchard, T.; Fuller, J.; Parving, H.H.; Bilous, R.; Chaturvedi, N.; DIRECT Programme Study Group. Effect of candesartan on progression and regression of retinopathy in type 2 diabetes (DIRECT-Protect2): a randomised placebo-controlled trial. Lancet, 2008, 372(9647), 1385-1393.
17. Keech, A.; Simes, R.J.; Barter, P.; Best, J.; Scott, R.; Taskinen, M.R.; Forder, P.; Pillai, A.; Davis, T.; Glasziou, P.; Drury, P.; Kesäniemi, Y.A.; Sullivan, D.; Hunt, D.; Colman, P.; d'Emden, M.; Whiting, M.; Ehnholm, C.; Laakso, M.; FIELD study investigators. Effect 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), 1849-1861.
18. Keech, A.C.; Mitchell, P.; Summanen, P.A.; O'Day, J.; Davis, T.M.; Moffitt, M.S.; Taskinen, M.R.; Simes, R.J.; Tse, D.; Williamson, E.; Merrifield, A.; Laatikainen, L.T.; d'Emden, M.C.; Crimet, D.C.; O'Connell, R.L.; Colman, P.G.; FIELD study investigators. Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial. Lancet, 2007, 370(9600), 1687-1697.
19. Antonetti, D.A.; Klein, R.; Gardner, T.W. Diabetic retinopathy. N. Engl. J. Med., 2012, 366(13), 1227-1239.
20. Giacco, F.; Brownlee, M. Oxidative stress and diabetic complications. Circ. Res., 2010, 107(9), 1058-1070.
21. Simó, R.; Carrasco, E.; García-Ramírez, M.; Hernández, C. Angiogenic and antiangiogenic factors in proliferative diabetic retinopathy. Curr. Diabetes. Rev., 2006, 2(1), 71-98.
22. Barber, A.J.; Gardner, T.W.; Abcouwer, S.F. The significance of vascular and neural apoptosis to the pathology of diabetic retinopathy. Invest. Ophthalmol. Vis. Sci., 2011, 52(2), 1156-1163.
23. Simó, R.; Hernández, C. European Consortium for the Early Treatment of Diabetic Retinopathy (EUROCONDOR). Neurodegeneration is an early event in diabetic retinopathy: therapeutic implications. Br. J. Ophthalmol., 2012, 96(10), 1285-1290.
24. Shirao, Y.; Kawasaki, K. Electrical responses from diabetic retina. Prog.Retin. Eye. Res., 1998, 17(1), 59-76.
25. Park, H.Y.; Kim, I.T.; Park, C.K. Early diabetic changes in the nerve fiber layer at the macula detected by spectral domain optical coherence tomography. Br. J. Ophthalmol., 2011, 95(9), 1223-1228.
26. Zeng, H.Y.; Green, W.R.; Tso, M.O. Microglial activation in human diabetic retinopathy. Arch. Ophthalmol., 2008, 126(2), 227-232.
27. Omri, S.; Behar-Cohen, F.; de Kozak, Y.; Sennlaub, F.; Verissimo, L.M.; Jonet, L.; Savoldelli, M.; Omri, B.; Crisanti, P. Microglia/ macrophages migrate through retinal epithelium barrier by a transcellular route in diabetic retinopathy: role of PKC in the GotoKakizaki rat model. Am. J. Pathol., 2011, 179(2), 942-953.
28. Feng, Y.; Wang, Y.; Stock, O.; Pfister, F.; Tanimoto, N.; Seeliger, M.W.; Hillebrands, J.L.; Hoffmann, S.; Wolburg, H.; Gretz, N.; Hammes, H.P. Vasoregression linked to neuronal damage in the rat with defect of polycystin-2. PLoS One, 2009, 4(10), e7328. Reference available from: http://www.plosone.org/ article/info%3Adoi%2F10.1371%2Fjourna l.pone.0007328. (Accessed December 1, 2012).
29. Bringmann, A.; Wiedemann, P. Müller glial cells in retinal disease. Ophthalmologica, 2012, 227(1), 1-19.
30. Ballantyne, C.M.; Davidson, M.H. Possible differences between fibrates in pharmacokinetic interactions with statins. Arch. Intern. Med., 2003, 163(19), 2394-2395.
31. ACCORD Study Group, Ginsberg, H.N.; Elam, M.B.; Lovato, L.C.; Crouse, J.R.3rd.; Leiter, L.A.; Linz, P.; Friedewald, W.T.; Buse, J.B.; Gerstein, H.C.; Probstfield, J.; Grimm, R.H.; Ismail-Beigi, F.; Bigger, J.T.; Goff, D.C.Jr.; Cushman, W.C.; Simons-Morton, D.G.; Byington, R.P. Effects of combination lipid therapy in type 2 diabetes. N. Engl. J. Med., 2010, 362(17), 1563-1574.
32. Davis, T.M.; Ting, R.; Best, J.D.; Donoghoe, M.W.; Drury, P.L.; Sullivan, D.R.; Jenkins, A.J.; O'Connell, R.L.; Whiting, M.J.; Glasziou, P.P.; Simes, R.J.; Kesäniemi, Y.A.; Gebski, V.J.; Scott, R.S.; Keech, A.C.; Fenofibrate Intervention and Event Lowering in Diabetes Study Investigators. 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), 280-290.
33. Mychaleckyj, J.C.; Craven, T.; Nayak, U.; Buse, J.; Crouse, J.R.; Elam, M.; Kirchner, K.; Lorber, D.; Marcovina, S.;Sivitz, W.; Sperl-Hillen, J.; Bonds, D.E.; Ginsberg. H. Reversibility of fenofibrate therapy-induced renal function impairment in ACCORD type 2 diabetes participants. Diabetes Care, 2012, 35(5), 1008-1014.
34. Leung, H.; Wang, J.J.; Rochtchina, E.; Wong, T.Y.; Klein, R.; Mitchell, P. Dyslipidaemia and microvascular disease in the retina. Eye, 2005, 19(8), 861-868.
35. Colhoun, H.M.; Betteridge, D.J.; Durrington, P.N.; Hitman, G.A.; Neil, H.A.; Livingstone, S.J.; Thomason, M.J.; Mackness, M.I.; Charlton-Menys, V.; Fuller, J.H.; CARDS investigators. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet, 2004, 364(9435), 685-696.
36. Sasongko, M.B.; Wong, T.Y.; Nguyen, T.T.; Shaw, J.E.; Jenkins, A.J.; Wang,J.J. Novel versus traditional risk markers for diabetic retinopathy. Diabetologia, 2012, 55(3), 666-670.
37. Piro, S.; Spampinato, D.; Spadaro, L.; Oliveri, C.E.; Purrello, F.; Rabuazzo, A.M. Direct apoptotic effects of free fatty acids on human endothelial cells. Nutr. Metab. Cardiovasc. Dis., 2008, 18(2), 96-104.
38. Simó, R.; Hernández, C. Fenofibrate for diabetic retinopathy. Lancet, 2007, 370(9600), 1667-1668.
39. Simó, R.; Higuera, M.; García-Ramírez, M.; Canals, F.; García-Arumí, J.; Hernández, C. Elevation of apolipoprotein A-I and apolipoprotein H levels in the vitreous fluid and overexpression in the retina of diabetic patients. Arch. Ophthalmol., 2008, 126(8), 1076-1081.
40. Simó, R.; García-Ramírez, M.; Higuera, M.; Hernández, C. Apolipoprotein A1 is overexpressed in the retina of diabetic patients. Am. J. Ophthalmol., 2009, 147(2), 319-325.e1.
41. Rosenson, R.S. Fenofibrate reduces lipoprotein associated phospholipase A2 mass and oxidative lipids in hypertriglyceridemic subjects with the metabolic syndrome. Am. Heart. J., 2008, 155(3), 499.e9-e16.
42. Carlquist, J.F.; Muhlestein, J.B.; Anderson, J.L. Lipoproteinassociated phospholipase A2: a new biomarker for cardiovascular risk assessment and potential therapeutic target. Expert. Rev. Mol. Diagn., 2007, 7(5), 511-517.
43. Van Themsche, C.; Jacob, M.; Salesse, C. Human retinal epithelium secretes phospholipase A2 and contains two novel intracellular phospholipases A2. Biochem. Cell. Biol., 2001, 79(1), 1-10.
44. Barnett, J.M.; McCollum, G.W.; Penn, J.S. Role of cytosolic phospholipase A(2) in retinal neovascularisation. Invest. Ophthalmol. Vis. Sci., 2010, 51(2), 1136-1142.
45. Simó, R.; Hernández, C. Advances in the medical treatment of diabetic retinopathy. Diabetes Care, 2009, 32(8), 1556-1562.
46. Miranda, S.; González-Rodríguez, Á.; García-Ramírez, M.; Revuelta-Cervantes, J.; Hernández, C.; Simó, R.; Valverde, Á.M. Beneficial effects of fenofibrate in retinal pigment epithelium by the modulation of stress and survival signaling under diabetic conditions. J. Cell. Physiol., 2012, 227(6), 2352-2362.
47. Bordet, R.; Ouk, T.; Petrault, O.; Gelé, P.; Gautier, S.; Laprais, M.; Deplanque, D.; Duriez. P.; Staels, B.; Fruchart, J.C.; Bastide, M. PPAR: a new pharmacological target for neuroprotection in stroke and neurodegenerative diseases. Biochem. Soc. Trans., 2006, 34(Pt 6), 1341-1346.
48. Chinetti, G.; Griglio, S.; Antonucci, M.; Torra, I.P.; Delerive, P.; Majd, Z.; Fruchart, J.C.; Chapman, J.; Najib, J.; Staels, B. Activation of proliferator-activated receptors alphaand gammainduces apoptosis of human monocyte derived macrophages. J. Biol.Chem., 1998, 273(40), 25573-25580.
49. Israelian-Konaraki, Z.; Reaven, P.D. Peroxisome proliferatoractivated receptor-alpha and atherosclerosis: from basic mechanisms to clinical implications. Cardiol. Rev., 2005, 13(5), 240-246.
50. Chen, Y.; Hu, Y.; Zhou, T.; Zhou, K.K.; Mott, R.; Wu, M.; Boulton, M.; Lyons, T.J.; Gao, G.; Ma, J.X. Activation of the Wnt pathway plays a pathogenic role in diabetic retinopathy in humans and animal models. Am. J. Pathol., 2009, 175(6), 2676-2685.
51. Krysiak, R.; Labuzek, K.; Okopien, B. Effect of atorvastatin and fenofibric acid on adipokine release from visceral and subcutaneous adipose tissue of patients with mixed dyslipidemia and normolipidemic subjects. Pharmacol.Rep., 2009, 61(6), 1134-1145.
52. Koh, K.K.; Quon, M.J.; Lim, S.; Lee, Y.; Sakuma, I.; Lee, Y.H.; Han, S.H.; Shin, E.K. Effects of fenofibratetherapy on circulating adipocytokines in patients with primary hypertriglyceridemia. Atherosclerosis, 2011, 214(1), 144-147.
53. Higuchi, A.; Ohashi, K.; Kihara, S.; Walsh, K.; Ouchi, N. Adiponectin suppresses pathological microvessel formation in retina through modulation of tumor necrosis factor-alpha expression. Circ. Res., 2009, 104(9), 1058-1065.
54. Villarroel, M.; Garcia-Ramírez, M.; Corraliza, L.; Hernández, C.; Simó, R. Fenofibric acid prevents retinal pigment epithelium disruption induced by interleukin-1- by suppressing AMP-activated protein kinase (AMPK) activation. Diabetologia, 2011, 54(6), 1543-1553.
55. Scharl, M.; Paul, G.; Barrett, K.E.; McCole, D.F. AMPK-activated protein kinase mediates the interferon-gamma-induced decrease in intestinal epithelial barrier function. J. Biol.Chem., 2009, 284(41), 27952-27963.
56. Zheng, B.; Cantley, L.C. Regulation of epithelial tight junction assembly and disassembly by AMP-activated protein kinase.Proc.Natl.Acad.Sci. USA., 2007, 104(3), 819-822.
57. Mysiorek, C.; Culot, M.; Dehouck, L.; Derudas, B.; Staels, B.; Bordet, R.; Cecchelli, R.; Fenart, L.; Berezowski, V. Peroxisomeproliferator-activated receptor-alpha activation protects brain capillary endothelial cells from oxygen-glucose deprivation-induced hyperpermeability in the blood-retinal barrier. Curr. Neurovasc. Res., 2009, 6(3), 181-193.
58. Trudeau, K.; Roy, S.; Guo, W.; Hernández, C.; Villarroel, M.; Simó, R.; Roy, S. Fenofibric acid reduces fibronectin and collagen type IV overexpression in human retinal pigment epithelial cells grown in conditions mimicking the diabetic milieu: functional implications in retinal permeability. Invest. Ophthalmol. Vis. Sci., 2011, 52(9), 6348-6354.
59. Arai, K.; Ikegaya, Y.; Nakatani, Y.; Kudo, I.; Nishiyama, N.; Matsuki, N. Phospholipase A2 mediates ischemic injury in the hippocampus: a regional difference of neural vulnerability. Eur. J. Neurosci., 2001, 13(12), 2319-2323.
60. Chen, Y.; Hu, Y.; Lin, M.; Jenkins, A.J.; Keech, A.C.; Mott, R.; Lyons, T.J.; Ma, J.X. Therapeutic effects of PPARalpha agonists on diabetic retinopathy in type 1 diabetes dodels. Diabetes, 2013, 62(1), 261-272.
61. Wong, T.Y.; Simó, R.; Mitchell, P. Fenofibrate-A potential systemic treatment for diabetic retinopathy? Am. J. Ophthalmol., 2012, 154(1), 6-12.