Regression of Some High-risk Features of Age-related Macular Degeneration (AMD) in Patients Receiving Intensive Statin Treatment

Demetrios G Vavvas, Anthony B Daniels, Zoi G Kapsala, Jeremy W Goldfarb, Emmanuel Ganotakis, John I Loewenstein, Lucy H Young, Evangelos S Gragoudas, Dean Eliott, Ivana K Kim, Miltiadis K Tsilimbaris, Joan W Miller, Demetrios G Vavvas, Anthony B Daniels, Zoi G Kapsala, Jeremy W Goldfarb, Emmanuel Ganotakis, John I Loewenstein, Lucy H Young, Evangelos S Gragoudas, Dean Eliott, Ivana K Kim, Miltiadis K Tsilimbaris, Joan W Miller

Abstract

Importance: Age-related macular degeneration (AMD) remains the leading cause of blindness in developed countries, and affects more than 150 million worldwide. Despite effective anti-angiogenic therapies for the less prevalent neovascular form of AMD, treatments are lacking for the more prevalent dry form. Similarities in risk factors and pathogenesis between AMD and atherosclerosis have led investigators to study the effects of statins on AMD incidence and progression with mixed results. A limitation of these studies has been the heterogeneity of AMD disease and the lack of standardization in statin dosage.

Objective: We were interested in studying the effects of high-dose statins, similar to those showing regression of atherosclerotic plaques, in AMD.

Design: Pilot multicenter open-label prospective clinical study of 26 patients with diagnosis of AMD and the presence of many large, soft drusenoid deposits. Patients received 80 mg of atorvastatin daily and were monitored at baseline and every 3 months with complete ophthalmologic exam, best corrected visual acuity (VA), fundus photographs, optical coherence tomography (OCT), and blood work (AST, ALT, CPK, total cholesterol, TSH, creatinine, as well as a pregnancy test for premenopausal women).

Results: Twenty-three subjects completed a minimum follow-up of 12 months. High-dose atorvastatin resulted in regression of drusen deposits associated with vision gain (+ 3.3 letters, p = 0.06) in 10 patients. No subjects progressed to advanced neovascular AMD.

Conclusions: High-dose statins may result in resolution of drusenoid pigment epithelial detachments (PEDs) and improvement in VA, without atrophy or neovascularization in a high-risk subgroup of AMD patients. Confirmation from larger studies is warranted.

Keywords: AMD; High-dose; Reversal; Soft-drusen; Statins; Vision gain.

Figures

Fig. 1
Fig. 1
Color fundus images of a 63-year-old man with AMD and large soft drusen and drusneoid pigment epithelial detachments. Upper panel at presentation, middle panels one year later at start of atorvastatin and lower panels a year after atorvastatin treatment.
Fig. 2
Fig. 2
High resolution optical coherence tomography of patient in Fig. 1. Upper panel prior to initiation of atorvastatin treatment and lower panels a year after atorvastatin treatment. Intraretinal hyperreflective foci remained at the end of treatment.

References

    1. Arad Y., Ramakrishnan R., Ginsberg H.N. Lovastatin therapy reduces low density lipoprotein apoB levels in subjects with combined hyperlipidemia by reducing the production of apoB-containing lipoproteins: implications for the pathophysiology of apoB production. J. Lipid Res. 1990;31:567–582.
    1. Barathi V.A., Yeo S.W., Guymer R.H., Wong T.Y., Luu C.D. Effects of simvastatin on retinal structure and function of a high-fat atherogenic mouse model of thickened Bruch's membrane. Invest. Ophthalmol. Vis. Sci. 2014;55:460–468.
    1. Bilheimer D.W., Grundy S.M., Brown M.S., Goldstein J.L. Mevinolin and colestipol stimulate receptor-mediated clearance of low density lipoprotein from plasma in familial hypercholesterolemia heterozygotes. Proc. Natl. Acad. Sci. U. S. A. 1983;80:4124–4128.
    1. Brader H.S., Ying G.S., Martin E.R., Maguire M.G. Complications of age-related macular degeneration prevention trial research Group. Characteristics of incident geographic atrophy in the complications of age-related macular degeneration prevention trial. Ophthalmology. 2013;120:1871–1879.
    1. Cankova Z., Huang J.D., Kruth H.S., Johnson M. Passage of low-density lipoproteins through Bruch's membrane and choroid. Exp. Eye Res. 2011;93:947–955.
    1. Cannon C.P., Braunwald E., McCabe C.H. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N. Engl. J. Med. 2004;350:1495–1504.
    1. Chen W., Stambolian D., Edwards A.O. Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration. Proc. Natl. Acad. Sci. U. S. A. 2010;107:7401–7406.
    1. Cheng C.Y., Yamashiro K., Chen L.J. New loci and coding variants confer risk for age-related macular degeneration in East Asians. Nat. Commun. 2015;6:6063.
    1. Chitose T., Sugiyama S., Sakamoto K. Effect of a hydrophilic and a hydrophobic statin on cardiac salvage after ST-elevated acute myocardial infarction — a pilot study. Atherosclerosis. 2014;237:251–258.
    1. Cougnard-Gregoire A., Delyfer M.N., Korobelnik J.F. Elevated high-density lipoprotein cholesterol and age-related macular degeneration: the Alienor study. PLoS One. 2014;9:e90973.
    1. Crabb J.W. The proteomics of drusen. Cold Spring Harb. Perspect. Med. 2014;4:a017194.
    1. Crabb J.W., Miyagi M., Gu X. Drusen proteome analysis: an approach to the etiology of age-related macular degeneration. Proc. Natl. Acad. Sci. U. S. A. 2002;99:14682–14687.
    1. Curcio C.A., Millican C.L., Bailey T., Kruth H.S. Accumulation of cholesterol with age in human Bruch's membrane. Invest. Ophthalmol. Vis. Sci. 2001;42:265–274.
    1. Curcio C.A., Johnson M., Rudolf M., Huang J.D. The oil spill in ageing Bruch membrane. Br. J. Ophthalmol. 2011;95:1638–1645.
    1. Ethier C.R., Johnson M., Ruberti J. Ocular biomechanics and biotransport. Annu. Rev. Biomed. Eng. 2004;6:249–273.
    1. Fong C.W. Statins in therapy: understanding their hydrophilicity, lipophilicity, binding to 3-hydroxy-3-methylglutaryl-CoA reductase, ability to cross the blood brain barrier and metabolic stability based on electrostatic molecular orbital studies. Eur. J. Med. Chem. 2014;85:661–674.
    1. Friberg T.R., Musch D.C., Lim J.I. Prophylactic treatment of age-related macular degeneration report number 1: 810-nanometer laser to eyes with drusen. Unilaterally eligible patients. Ophthalmology. 2006;113:622 e1.
    1. Friedman E., Kopald H.H., Smith T.R. Retinal and choroidal blood flow determined with Krypton-85 anesthetized animals. Invest. Ophthalmol. 1964;3:539–547.
    1. Fritsche L.G., Chen W., Schu M. Seven new loci associated with age-related macular degeneration. Nat. Genet. 2013;45:433–439. (9e1–2)
    1. Fritsche L.G., Igl W., JN Bailey. A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants. Nat. Genet. 2015
    1. Garcia Filho C.A., Yehoshua Z., Gregori G. Change in drusen volume as a novel clinical trial endpoint for the study of complement inhibition in age-related macular degeneration. Ophthalmic Surg. Lasers Imaging Retina. 2014;45:18–31.
    1. Gehlbach P., Li T., Hatef E. Statins for age-related macular degeneration. Cochrane Database Syst. Rev. 2009:CD006927.
    1. Gehlbach P., Li T., Hatef E. Statins for age-related macular degeneration. Cochrane Database Syst. Rev. 2015;2:CD006927.
    1. Guymer R.H., Baird P.N., Varsamidis M. Proof of concept, randomized, placebo-controlled study of the effect of simvastatin on the course of age-related macular degeneration. PLoS One. 2013;8:e83759.
    1. Hall N.F., Gale C.R., Syddall H., Phillips D.I., Martyn C.N. Risk of macular degeneration in users of statins: cross sectional study. BMJ. 2001;323:375–376.
    1. Hollyfield J.G. Age-related macular degeneration: the molecular link between oxidative damage, tissue-specific inflammation and outer retinal disease: the proctor lecture. Invest. Ophthalmol. Vis. Sci. 2010;51:1275–1281.
    1. Hussain A.A., Starita C., Hodgetts A., Marshall J. Macromolecular diffusion characteristics of ageing human Bruch's membrane: implications for age-related macular degeneration (AMD) Exp. Eye Res. 2010;90:703–710.
    1. Ito T., Ikeda U., Shimpo M. HMG-CoA reductase inhibitors reduce interleukin-6 synthesis in human vascular smooth muscle cells. Cardiovasc. Drugs Ther. 2002;16:121–126.
    1. Johnson L.V., Forest D.L., Banna C.D. Cell culture model that mimics drusen formation and triggers complement activation associated with age-related macular degeneration. Proc. Natl. Acad. Sci. U. S. A. 2011;108:18277–18282.
    1. Khush K.K., Waters D. Lessons from the PROVE-IT trial. higher dose of potent statin better for high-risk patients. Cleve. Clin. J. Med. 2004;71:609–616.
    1. Kim K.J., Kim K.S., Kim N.R., Chin H.S. Effects of simvastatin on the expression of heme oxygenase-1 in human RPE cells. Invest. Ophthalmol. Vis. Sci. 2012;53:6456–6464.
    1. Kino T., Kozasa T., Chrousos G.P. Statin-induced blockade of prenylation alters nucleocytoplasmic shuttling of GTP-binding proteins gamma2 and beta2 and enhances their suppressive effect on glucocorticoid receptor transcriptional activity. Eur. J. Clin. Invest. 2005;35:508–513.
    1. Klein R., Peto T., Bird A., Vannewkirk M.R. The epidemiology of age-related macular degeneration. Am. J. Ophthalmol. 2004;137:486–495.
    1. Klein R., Deng Y., Klein B.E. Cardiovascular disease, its risk factors and treatment, and age-related macular degeneration: women's health initiative sight exam ancillary study. Am. J. Ophthalmol. 2007;143:473–483.
    1. Klein R., Myers C.E., Buitendijk G.H. Lipids, lipid genes, and incident age-related macular degeneration: the three continent age-related macular degeneration consortium. Am. J. Ophthalmol. 2014;158:513–524. e3.
    1. Klein R., Myers C.E., Cruickshanks K.J. Markers of inflammation, oxidative stress, and endothelial dysfunction and the 20-year cumulative incidence of early age-related macular degeneration: the Beaver Dam eye study. JAMA Ophthalmol. 2014;132:446–455.
    1. Kramer C.M., Mani V., Fayad Z.A. MR imaging-verified plaque delipidation with lipid-lowering therapy important questions remain. JACC Cardiovasc. Imaging. 2011;4:987–989.
    1. Linsenmeier R.A., Braun R.D. Oxygen distribution and consumption in the cat retina during normoxia and hypoxemia. J. Gen. Physiol. 1992;99:177–197.
    1. Luibl V., Isas J.M., Kayed R., Glabe C.G., Langen R., Chen J. Drusen deposits associated with aging and age-related macular degeneration contain nonfibrillar amyloid oligomers. J. Clin. Invest. 2006;116:378–385.
    1. Miller J.W. Age-related macular degeneration revisited—piecing the puzzle: the LXIX Edward Jackson memorial lecture. Am. J. Ophthalmol. 2013;155:1–35 e13.
    1. Moore D.J., Hussain A.A., Marshall J. Age-related variation in the hydraulic conductivity of Bruch's membrane. Invest. Ophthalmol. Vis. Sci. 1995;36:1290–1297.
    1. Mullins R.F., Russell S.R., Anderson D.H., Hageman G.S. Drusen associated with aging and age-related macular degeneration contain proteins common to extracellular deposits associated with atherosclerosis, elastosis, amyloidosis, and dense deposit disease. FASEB J. 2000;14:835–846.
    1. Neale B.M., Fagerness J., Reynolds R. Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene (LIPC) Proc. Natl. Acad. Sci. U. S. A. 2010;107:7395–7400.
    1. Nicholls S.J., Ballantyne C.M., Barter P.J. Effect of two intensive statin regimens on progression of coronary disease. N. Engl. J. Med. 2011;365:2078–2087.
    1. Nissen S.E. Effect of intensive lipid lowering on progression of coronary atherosclerosis: evidence for an early benefit from the reversal of atherosclerosis with aggressive lipid lowering (REVERSAL) trial. Am. J. Cardiol. 2005;96:61F–68F.
    1. Nissen S.E., Tuzcu E.M., Schoenhagen P. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA. 2004;291:1071–1080.
    1. Nissen S.E., Nicholls S.J., Sipahi I. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA. 2006;295:1556–1565.
    1. Pauleikhoff D., Harper C.A., Marshall J., Bird A.C. Aging changes in Bruch's membrane. A histochemical and morphologic study. Ophthalmology. 1990;97:171–178.
    1. Pikuleva I.A., Curcio C.A. Cholesterol in the retina: the best is yet to come. Prog. Retin. Eye Res. 2014;41:64–89.
    1. Pitt B., Waters D., Brown W.V. Aggressive lipid-lowering therapy compared with angioplasty in stable coronary artery disease. Atorvastatin versus revascularization treatment investigators. N. Engl. J. Med. 1999;341:70–76.
    1. Profumo E., Buttari B., Saso L., Rigano R. Pleiotropic effects of statins in atherosclerotic disease: focus on the antioxidant activity of atorvastatin. Curr. Top. Med. Chem. 2014;14:2542–2551.
    1. Qian J., Keyes K.T., Long B., Chen G., Ye Y. Impact of HMG-CoA reductase inhibition on oxidant-induced injury in human retinal pigment epithelium cells. J. Cell. Biochem. 2011;112:2480–2489.
    1. Reynolds R., Rosner B., Seddon J.M. Serum lipid biomarkers and hepatic lipase gene associations with age-related macular degeneration. Ophthalmology. 2010;117:1989–1995.
    1. Robinson R., Ho C.E., Tan Q.S. Fluvastatin downregulates VEGF-A expression in TNF-alpha-induced retinal vessel tortuosity. Invest. Ophthalmol. Vis. Sci. 2011;52:7423–7431.
    1. Rodriguez I.R., Clark M.E., Lee J.W., Curcio C.A. 7-Ketocholesterol accumulates in ocular tissues as a consequence of aging and is present in high levels in drusen. Exp. Eye Res. 2014;128:151–155.
    1. Sarks J.P., Sarks S.H., Killingsworth M.C. Evolution of soft drusen in age-related macular degeneration. Eye (Lond.) 1994;8(Pt 3):269–283.
    1. Sene A., Apte R.S. Eyeballing cholesterol efflux and macrophage function in disease pathogenesis. Trends Endocrinol. Metab. 2014;25:107–114.
    1. Sene A., Khan A.A., Cox D. Impaired cholesterol efflux in senescent macrophages promotes age-related macular degeneration. Cell Metab. 2013;17:549–561.
    1. Sene A., Chin-Yee D., Apte R.S. Seeing through VEGF: innate and adaptive immunity in pathological angiogenesis in the eye. Trends Mol. Med. 2015;21:43–51.
    1. Sivaprasad S., Bailey T.A., Chong V.N. Bruch's membrane and the vascular intima: is there a common basis for age-related changes and disease? Clin. Experiment. Ophthalmol. 2005;33:518–523.
    1. Suzuki M., Kamei M., Itabe H. Oxidized phospholipids in the macula increase with age and in eyes with age-related macular degeneration. Mol. Vis. 2007;13:772–778.
    1. Suzuki M., Tsujikawa M., Itabe H. Chronic photo-oxidative stress and subsequent MCP-1 activation as causative factors for age-related macular degeneration. J. Cell Sci. 2012;125:2407–2415.
    1. Tan J.S., Mitchell P., Rochtchina E., Wang J.J. Statins and the long-term risk of incident age-related macular degeneration: the Blue Mountains eye study. Am. J. Ophthalmol. 2007;143:685–687.
    1. Tomany S.C., Wang J.J., Van Leeuwen R. Risk factors for incident age-related macular degeneration: pooled findings from 3 continents. Ophthalmology. 2004;111:1280–1287.
    1. VanderBeek B.L., Zacks D.N., Talwar N., Nan B., Stein J.D. Role of statins in the development and progression of age-related macular degeneration. Retina. 2013;33:414–422.
    1. Wang L., Li C.M., Rudolf M. Lipoprotein particles of intraocular origin in human Bruch membrane: an unusual lipid profile. Invest. Ophthalmol. Vis. Sci. 2009;50:870–877.
    1. Winkler B.S., Boulton M.E., Gottsch J.D., Sternberg P. Oxidative damage and age-related macular degeneration. Mol. Vis. 1999;5:32.
    1. Wong W.L., Su X., Li X. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob. Health. 2014;2:e106–e116.
    1. Wu T., Fujihara M., Tian J. Apolipoprotein B100 secretion by cultured ARPE-19 cells is modulated by alteration of cholesterol levels. J. Neurochem. 2010;114:1734–1744.
    1. Yamada K., Sakurai E., Itaya M., Yamasaki S., Ogura Y. Inhibition of laser-induced choroidal neovascularization by atorvastatin by downregulation of monocyte chemotactic protein-1 synthesis in mice. Invest. Ophthalmol. Vis. Sci. 2007;48:1839–1843.
    1. Yehoshua Z., Wang F., Rosenfeld P.J., Penha F.M., Feuer W.J., Gregori G. Natural history of drusen morphology in age-related macular degeneration using spectral domain optical coherence tomography. Ophthalmology. 2011;118:2434–2441.
    1. Yip J.L., Khawaja A.P., Chan M.P. Cross sectional and longitudinal associations between cardiovascular risk factors and age related macular degeneration in the EPIC-Norfolk eye study. PLoS One. 2015;10:e0132565.
    1. Yu C.M., Zhang Q., Lam L. Comparison of intensive and low-dose atorvastatin therapy in the reduction of carotid intimal-medial thickness in patients with coronary heart disease. Heart. 2007;93:933–939.
    1. Zhao X.Q., Dong L., Hatsukami T. MR imaging of carotid plaque composition during lipid-lowering therapy a prospective assessment of effect and time course. JACC Cardiovasc. Imaging. 2011;4:977–986.

Source: PubMed

Sponsorer och medarbetare

Medicinska tillstånd

Läkemedelsinterventioner

3
Prenumerera