Study will assess effect of statins on AMD

As the drugs lower blood cholesterol, the body may draw fatty retinal deposits back into the bloodstream.

MELBOURNE – Taking cholesterol-lowering drugs could slow the progression of age-related macular degeneration, some studies have suggested. Now a randomized controlled clinical trial will investigate whether the cholesterol-lowering drug simvastatin can slow the progression of AMD in patients at considerable risk of severe visual loss.

Data collected from a previous population-based study of eye diseases, the Melbourne Visual Impairment Project, indicated that progression of AMD may be delayed in people taking cholesterol-lowering medications, including statins. A nonsignificant trend toward slower progression was also found in the Vitamin E and Cataract Trial.

It is hoped the controlled trial now enrolling patients will build on the associations suggested by these studies.

“We are particularly keen to use the statin family, as their tremendous efficacy in atherosclerosis may be not only due to their cholesterol-lowering effect, but also their anti-inflammatory action. Both these mechanisms may be important in AMD. Our trial will assess the effect of simvastatin in reducing the progression of AMD in people with early, yet high-risk stages of the disease,” said Robyn H. Guymer, PhD, FRACO, FRACS, a senior research fellow at the Centre for Eye Research Australia, department of ophthalmology at Royal Victorian Eye and Ear Hospital.

Novel theory

Fatty deposits build up behind the retina as people age. But in people with AMD, these fat deposits are thicker, preventing nutrients from crossing the blood-retina barrier, causing retinal cell death, Dr. Guymer said.

In theory, cholesterol-lowering drugs might be effective in halting the condition because once the drugs lower cholesterol levels in the bloodstream, the body needs to establish equilibrium. Some of the fatty deposits behind the retina might move into the bloodstream to strike this balance, she said.

A 10-year study of 580 Australians diagnosed with early AMD showed that in all but one case, taking cholesterol-lowering drugs slowed the disease process. Patients taking cholesterol-lowering medications were nearly four times less likely to have progression of macular degeneration than people not on the drugs.

Clarifying the role of some of these cardiovascular risk factors is the subject of Australia’s Cardiovascular Health in Age-Related Maculopathy study (CHARM).

Recent genetic evidence has further implicated lipids in AMD pathogenesis, Dr. Guymer said. The cholesterol pathway gene, apolipoprotein E (APOE), plays a role in the degradation of particles rich in cholesterol and triglycerides that have been linked to AMD. The polymorphic nature of the gene affects various diseases, depending upon which allele is present.

This gene has been implicated in coronary heart disease, Alzheimer’s disease, diabetes and longevity, where the 2 allele is protective and the 4 allele is a risk factor. In AMD, APOE has an opposite effect. The 4 allele is protective while the 2 allele is associated with an increased risk of the disease.

The overlap between risk factors for cardiovascular disease and AMD implies that the two conditions may have common pathogenic mechanisms. Postulated mechanisms include reduction of outer retinal nutrition either by reduced blood flow in the choroid or reduced surface area of the choriocapillaris, as a result of atherosclerotic vessels.

The same mechanisms that cause lipids to be deposited in the walls of systemic arteries may also be involved in the deposition of lipids in Bruch’s membrane. Bruch’s membrane in the central macula has on average seven times the accumulation of cholesterol compared to the peripheral retina. Esterified cholesterol in Bruch’s membrane is enriched compared to plasma, thus resembling the plaques found in atherosclerotic disease.

“It is possible that Bruch’s membrane ages like the intimae of large atherosclerosis-prone arteries. In support of this concept, hypercholesterolemic mice have been shown to accumulate debris in Bruch’s membrane that resembles AMD,” Dr. Guymer said.

Leading cause of blindness

“Age-related macular degeneration is the leading cause of blindness in our community,” Dr. Guymer said. “There is no prevention for AMD or proven treatment for early forms of this disease. Treatment options for late AMD are limited and have had little impact on the rates of blindness. Until prevention and more effective treatments are available, intervention to slow the progression of this disease to the late, visually devastating stage is essential.”

In Australia, 15% of the population more than 40 years old has signs of AMD. This increases to two of three in those more than 90 years old. The prevalence of late AMD and vision loss also increases dramatically with age, affecting less than 1% of those younger than 65 years, but 25% of those more than 90.

“This disease has enormous personal costs and places a massive burden on health resources,” Dr. Guymer said. “The high prevalence of AMD, the increase in the aging population and the limited treatment options highlight the urgency with which we need to implement preventative strategies to retard the progression of this debilitating disease.”

New research begins

Dr. Guymer’s research focuses on the study of affected families to identify the genes responsible for AMD, and the clinical trials to investigate the prophylactic role of cholesterol-lowering drugs in patients with high-risk AMD.

She and her research team have begun a randomized, double-masked, controlled study to document progression of AMD in a group of subjects at high risk of progressing to end-stage disease. Progression will be determined after grading of macular photographs by a reading center according to the internationally recognized Wisconsin grading system. Progression will be defined as worsening to a higher stage of AMD. Participants will be randomized in a 1:1 ratio to receive either simvastatin 20 mg orally or the placebo for 3 years.

The APOE gene allele status of each individual will be determined to investigate whether the allele type influences the effect of this medication, as may be the case in cardiovascular disease. It has been shown that the allelic status of APOE affects the plasma lipid and lipoprotein response of the statin.

The main outcome will be the rates of progression of AMD or the reduced performance on psychophysical testing of macular function. These changes will be assessed in relation to the APOE genotype to determine if particular alleles correlate with better response to treatment, as has been found in cardiovascular diseases.

Enrollment begins

Currently, the study population includes men and women over the age of 50. Inclusion criteria include people at high risk of developing complications during the course of the clinical trial. They also include end stage AMD in one eye, bilateral high-risk drusen in both eyes and cholesterol level below guidelines for recommending treatment. Patients may not currently take any cholesterol-lowering medication.

Progression of AMD is determined by macular photo grading. Worsening of AMD is determined by side-by-side grading of baseline and follow-up photos.

Researchers have already identified 100 eligible patients. They now hope to recruit 15 patients per week for 60 weeks. The end goal is to recruit 477 patients in the treatment group and the same number for the placebo group. An interim analysis will occur each 12 months, primarily to document adverse events.

Study protocol

Statins are well-tolerated in most individuals, with most side effects being mild. Simvastatin has been used in clinical studies with mild side effects. At each visit, adverse reactions will be documented and referred to an independent safety monitoring committee. The committee will review all adverse events and conduct a yearly review of the primary end point data.

Participants will be reviewed at 4 weeks with a fasting blood sample to assess lipid levels and liver function. Compliance will also be measured by noting the number of capsules returned at each visit and by quarterly phone calls.

At 6 months all tests will be repeated to determine if the treatment is having an early effect as is dramatically seen in cardiovascular disease. Follow-up is then every 12 months.

Colored slides will be graded by the reading center according to the Wisconsin Grading System by two independent graders. Inter- and intragrader agreement on retinal features will be regularly assessed. Stages of AMD will be stratified according to most severe drusen type, largest drusen size, area involved by drusen, drusen confluence, increased retinal pigmentation or depigmentation or presence of an end stage lesion.

Next, subjects will be categorized by their worse eye and progression will be determined by a worsening to the next or further stages of AMD. Analysis will be conducted on the basis of worst eye that has not reach end stage. All comparisons will be made on an intent-to-treat basis.

For Your Information:

• Robyn H. Guymer, PhD, FRACO, FRACS, is a senior research fellow at the Centre for Eye Research Australia, department of ophthalmology, Royal Victorian Eye and Ear Hospital, Faculty of Medicine, Dentistry and Health Sciences University of Melbourne. She can be reached at C.E.R.A., Locked Bag 8, East Melbourne, Victoria 8002, Australia; +(61) 3-9929-8360; fax: +(61) 3-9662-3859; e-mail: rhg@unimelb.edu.au.