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

PLoS One. 2013 Dec 31;8(12):e83759. doi: 10.1371/journal.pone.0083759. eCollection 2013.


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.

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.

Publication types

  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Apolipoprotein E2 / genetics
  • Complement Factor H / genetics
  • Disease Progression
  • Double-Blind Method
  • Female
  • Follow-Up Studies
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use*
  • Macular Degeneration / drug therapy*
  • Macular Degeneration / genetics
  • Male
  • Middle Aged
  • Polymorphism, Genetic / genetics
  • Prognosis
  • Risk Factors
  • Simvastatin / therapeutic use*


  • Apolipoprotein E2
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Complement Factor H
  • Simvastatin

Grant support

This work was supported by grants from the Ian Potter Foundation, John Reid Charitable Trust and Royal Victorian Eye and Ear Hospital. Merck Sharp and Dohme supplied the active simvastatin and placebo medication. The National Health and Medical Research Council (NHMRC) supported the study through a Centre for Clinical Research Excellence award to CERA(#529923), a Practitioner Fellowship (#529905) to RHG and a Senior Research Fellowship (#1028444) to PNB. LDR was supported by the Wagstaff Fellowship. CERA receives operational infrastructure from the Victorian Government. CERA is a recepient of the NHMRC award "Centre for Clinical Research Excellence" # 529923. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.