Proof of concept, randomized, placebo-controlled study of the effect of simvastatin on the course of age-related macular degeneration

Robyn Heather Guymer; Paul N Baird; Mary Varsamidis; Lucy Busija; Peter Dimitrov; Khin Zaw Aung; Galina A Makeyeva; Andrea J Richardson; Lyndell L P Lim; Liubov Robman

doi:10.1371/journal.pone.0083759

Proof of concept, randomized, placebo-controlled study of the effect of simvastatin on the course of age-related macular degeneration

Robyn Heather Guymer, Paul N Baird, Mary Varsamidis, Lucy Busija, Peter Dimitrov, Khin Zaw Aung, Galina A Makeyeva, Andrea J Richardson, Lyndell L P Lim, Liubov Robman

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Research output: Contribution to journal › Article › Research › peer-review

29 Citations (Scopus)

Abstract

Background: HMG Co-A reductase inhibitors are ubiquitous in our community yet their potential role in age-related macular degeneration (AMD) remains to be determined. Methodology/Principal Findings: Objectives: To evaluate the effect of simvastatin on AMD progression and the effect modification by polymorphism in apolipoprotein E (ApoE) and complement factor H (CFH ) genes. Design: A proof of concept double-masked randomized controlled study. Participants: 114 participants aged 53 to 91 years, with either bilateral intermediate AMD or unilateral non-advanced AMD (with advanced AMD in fellow eye), BCVA=20/60 in at least one eye, and a normal lipid profile. Intervention: Simvastatin 40 mg/day or placebo, allocated 1:1. Main outcome measures: Progression of AMD either to advanced AMD or in severity of non-advanced AMD. Results. The cumulative AMD progression rates were 70 in the placebo and 54 in the simvastatin group. Intent to treat multivariable logistic regression analysis, adjusted for age, sex, smoking and baseline AMD severity, showed a significant 2-fold decrease in the risk of progression in the simvastatin group: OR 0.43 (0.18-0.99), p = 0.047. Post-hoc analysis stratified by baseline AMD severity showed no benefit from treatment in those who had advanced AMD in the fellow eye before enrolment: OR 0.97 (0.27-3.52), p = 0.96, after adjusting for age, sex and smoking. However, there was a significant reduction in the risk of progression in the bilateral intermediate AMD group compared to placebo [adjusted OR 0.23 (0.07-0.75), p = 0.015]. The most prominent effect was observed amongst those who had the CC (Y402H) at risk genotype of the CFH gene [OR 0.08 (0.02-0.45), p = 0.004]. No evidence of harm from simvastatin intervention was detected. Conclusion/Significance: Simvastatin may slow progression of non-advanced AMD, especially for those with the at risk CFH genotype CC ( Y402H). Further exploration of the potential use of statins for AMD, with emphasis on genetic subgroups, is warranted. Trial Registration: Australian New Zealand Clinical Trial Registry (ANZCTR) ACTRN1260500032065

Original language	English
Article number	e83759
Number of pages	10
Journal	PLoS ONE
Volume	8
Issue number	12
DOIs	https://doi.org/10.1371/journal.pone.0083759
Publication status	Published - 2013

Cite this

Guymer, R. H., Baird, P. N., Varsamidis, M., Busija, L., Dimitrov, P., Aung, K. Z., Makeyeva, G. A., Richardson, A. J., Lim, L. L. P., & Robman, L. (2013). Proof of concept, randomized, placebo-controlled study of the effect of simvastatin on the course of age-related macular degeneration. PLoS ONE, 8(12), [e83759]. https://doi.org/10.1371/journal.pone.0083759

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title = "Proof of concept, randomized, placebo-controlled study of the effect of simvastatin on the course of age-related macular degeneration",

abstract = "Background: HMG Co-A reductase inhibitors are ubiquitous in our community yet their potential role in age-related macular degeneration (AMD) remains to be determined. Methodology/Principal Findings: Objectives: To evaluate the effect of simvastatin on AMD progression and the effect modification by polymorphism in apolipoprotein E (ApoE) and complement factor H (CFH ) genes. Design: A proof of concept double-masked randomized controlled study. Participants: 114 participants aged 53 to 91 years, with either bilateral intermediate AMD or unilateral non-advanced AMD (with advanced AMD in fellow eye), BCVA=20/60 in at least one eye, and a normal lipid profile. Intervention: Simvastatin 40 mg/day or placebo, allocated 1:1. Main outcome measures: Progression of AMD either to advanced AMD or in severity of non-advanced AMD. Results. The cumulative AMD progression rates were 70 in the placebo and 54 in the simvastatin group. Intent to treat multivariable logistic regression analysis, adjusted for age, sex, smoking and baseline AMD severity, showed a significant 2-fold decrease in the risk of progression in the simvastatin group: OR 0.43 (0.18-0.99), p = 0.047. Post-hoc analysis stratified by baseline AMD severity showed no benefit from treatment in those who had advanced AMD in the fellow eye before enrolment: OR 0.97 (0.27-3.52), p = 0.96, after adjusting for age, sex and smoking. However, there was a significant reduction in the risk of progression in the bilateral intermediate AMD group compared to placebo [adjusted OR 0.23 (0.07-0.75), p = 0.015]. The most prominent effect was observed amongst those who had the CC (Y402H) at risk genotype of the CFH gene [OR 0.08 (0.02-0.45), p = 0.004]. No evidence of harm from simvastatin intervention was detected. Conclusion/Significance: Simvastatin may slow progression of non-advanced AMD, especially for those with the at risk CFH genotype CC ( Y402H). Further exploration of the potential use of statins for AMD, with emphasis on genetic subgroups, is warranted. Trial Registration: Australian New Zealand Clinical Trial Registry (ANZCTR) ACTRN1260500032065",

author = "Guymer, {Robyn Heather} and Baird, {Paul N} and Mary Varsamidis and Lucy Busija and Peter Dimitrov and Aung, {Khin Zaw} and Makeyeva, {Galina A} and Richardson, {Andrea J} and Lim, {Lyndell L P} and Liubov Robman",

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Proof of concept, randomized, placebo-controlled study of the effect of simvastatin on the course of age-related macular degeneration. / Guymer, Robyn Heather; Baird, Paul N; Varsamidis, Mary; Busija, Lucy; Dimitrov, Peter; Aung, Khin Zaw; Makeyeva, Galina A; Richardson, Andrea J; Lim, Lyndell L P; Robman, Liubov.

In: PLoS ONE, Vol. 8, No. 12, e83759, 2013.

Research output: Contribution to journal › Article › Research › peer-review

TY - JOUR

T1 - Proof of concept, randomized, placebo-controlled study of the effect of simvastatin on the course of age-related macular degeneration

AU - Guymer, Robyn Heather

AU - Baird, Paul N

AU - Varsamidis, Mary

AU - Busija, Lucy

AU - Dimitrov, Peter

AU - Aung, Khin Zaw

AU - Makeyeva, Galina A

AU - Richardson, Andrea J

AU - Lim, Lyndell L P

AU - Robman, Liubov

PY - 2013

Y1 - 2013

N2 - Background: HMG Co-A reductase inhibitors are ubiquitous in our community yet their potential role in age-related macular degeneration (AMD) remains to be determined. Methodology/Principal Findings: Objectives: To evaluate the effect of simvastatin on AMD progression and the effect modification by polymorphism in apolipoprotein E (ApoE) and complement factor H (CFH ) genes. Design: A proof of concept double-masked randomized controlled study. Participants: 114 participants aged 53 to 91 years, with either bilateral intermediate AMD or unilateral non-advanced AMD (with advanced AMD in fellow eye), BCVA=20/60 in at least one eye, and a normal lipid profile. Intervention: Simvastatin 40 mg/day or placebo, allocated 1:1. Main outcome measures: Progression of AMD either to advanced AMD or in severity of non-advanced AMD. Results. The cumulative AMD progression rates were 70 in the placebo and 54 in the simvastatin group. Intent to treat multivariable logistic regression analysis, adjusted for age, sex, smoking and baseline AMD severity, showed a significant 2-fold decrease in the risk of progression in the simvastatin group: OR 0.43 (0.18-0.99), p = 0.047. Post-hoc analysis stratified by baseline AMD severity showed no benefit from treatment in those who had advanced AMD in the fellow eye before enrolment: OR 0.97 (0.27-3.52), p = 0.96, after adjusting for age, sex and smoking. However, there was a significant reduction in the risk of progression in the bilateral intermediate AMD group compared to placebo [adjusted OR 0.23 (0.07-0.75), p = 0.015]. The most prominent effect was observed amongst those who had the CC (Y402H) at risk genotype of the CFH gene [OR 0.08 (0.02-0.45), p = 0.004]. No evidence of harm from simvastatin intervention was detected. Conclusion/Significance: Simvastatin may slow progression of non-advanced AMD, especially for those with the at risk CFH genotype CC ( Y402H). Further exploration of the potential use of statins for AMD, with emphasis on genetic subgroups, is warranted. Trial Registration: Australian New Zealand Clinical Trial Registry (ANZCTR) ACTRN1260500032065

AB - Background: HMG Co-A reductase inhibitors are ubiquitous in our community yet their potential role in age-related macular degeneration (AMD) remains to be determined. Methodology/Principal Findings: Objectives: To evaluate the effect of simvastatin on AMD progression and the effect modification by polymorphism in apolipoprotein E (ApoE) and complement factor H (CFH ) genes. Design: A proof of concept double-masked randomized controlled study. Participants: 114 participants aged 53 to 91 years, with either bilateral intermediate AMD or unilateral non-advanced AMD (with advanced AMD in fellow eye), BCVA=20/60 in at least one eye, and a normal lipid profile. Intervention: Simvastatin 40 mg/day or placebo, allocated 1:1. Main outcome measures: Progression of AMD either to advanced AMD or in severity of non-advanced AMD. Results. The cumulative AMD progression rates were 70 in the placebo and 54 in the simvastatin group. Intent to treat multivariable logistic regression analysis, adjusted for age, sex, smoking and baseline AMD severity, showed a significant 2-fold decrease in the risk of progression in the simvastatin group: OR 0.43 (0.18-0.99), p = 0.047. Post-hoc analysis stratified by baseline AMD severity showed no benefit from treatment in those who had advanced AMD in the fellow eye before enrolment: OR 0.97 (0.27-3.52), p = 0.96, after adjusting for age, sex and smoking. However, there was a significant reduction in the risk of progression in the bilateral intermediate AMD group compared to placebo [adjusted OR 0.23 (0.07-0.75), p = 0.015]. The most prominent effect was observed amongst those who had the CC (Y402H) at risk genotype of the CFH gene [OR 0.08 (0.02-0.45), p = 0.004]. No evidence of harm from simvastatin intervention was detected. Conclusion/Significance: Simvastatin may slow progression of non-advanced AMD, especially for those with the at risk CFH genotype CC ( Y402H). Further exploration of the potential use of statins for AMD, with emphasis on genetic subgroups, is warranted. Trial Registration: Australian New Zealand Clinical Trial Registry (ANZCTR) ACTRN1260500032065

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