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July/August 2005

Clinical Update: Retina
AMD and the Statin Promise: The Research
By Miriam Karmel, Contributing Writer

A growing body of literature suggests that the cholesterol-lowering drugs known as statins, long prescribed to prevent heart disease, may also hold benefits for the eyes. But despite encouraging results from a flurry of recent studies on statins and age-related macular degeneration, it’s too soon to say that ophthalmologists should be prescribing them.

“I think evidence is mounting to suggest there’s a relationship,” said Jacque L. Duncan, MD, assistant professor of ophthalmology at University of California, San Francisco, and an author of one of the studies. But the findings aren’t conclusive and there are too many unanswered questions, such as which groups will benefit and what the side effects are. “It might be premature to say, ‘Let’s take everybody who has AMD and put them on a statin.’”

Gerald McGwin Jr., PhD, agrees. “This is not something clinicians can get any traction from yet.” Dr. McGwin, an associate professor of epidemiology and ophthalmology at the University of Alabama at Birmingham, advocates a randomized clinical trial to test whether statins reduce the risk of AMD; he hopes that will shed more light on the nature of the disease. “This is a body of research that’s getting into etiology as much as it is identifying something for prevention. If statins, in fact, reduce the risk of AMD, it can tell us something about the cause of AMD. That’s important for understanding the natural history of the disease in and of itself.”

Why Statins?

Statins are a class of lipid-lowering drugs that reduce serum cholesterol levels by inhibiting a key enzyme involved in the biosynthesis of cholesterol. The FDA approved the first such drug, lovastatin, in 1987.

While cholesterol is critical to the normal functioning of cells, it is also the main component in plaques that block arteries, which can lead to angina, heart attack or stroke. It has also been theorized that inflammation in the walls of the arteries may be another contributing factor to cardiovascular disease, and newer research shows that statins reduce inflammation.

If statins work for even half the conditions with which they have been associated, they could assume the mantle of “wonder drug.” Aside from reducing cardiovascular mortality, they have been linked to benefits for diabetes, diabetic vitreous hemorrhage, Alzheimer’s, heart and lung transplant rejection, multiple sclerosis, arthritis and even prostate cancer. Now they are being touted for AMD and possibly even glaucoma (see sidebar, next page).

AMD Connection

A number of theories may explain the possible AMD-statin connection, including an association between serum cholesterol and choroidal neovascularization. Cholesterol accumulation in Bruch’s membrane may play a role in the pathogenesis of AMD. Inflammation might play a role as well, and statins may inhibit production of proteins involved in inflammation. Statins are also antioxidants, which have been shown to reduce risk of CNV in AMD patients.

The Research

The first report of a statin-AMD connection emerged in 2001.1 That same year, a cross-sectional study of 379 British men and women found signs of AMD in 22 percent of those who did not take the drugs, compared with 4 percent of those who did.2

Statins and CNV.
Then Dr. Duncan and colleagues reported an association between statin use and decreased rates of CNV in more than 300 elderly people with AMD.3 This retrospective consecutive case series included all patients with AMD aged 60 and older seen over a decade at the San Francisco Veterans Affairs Hospital eye clinic. It found that those patients already taking statins were half as likely to develop CNV, the advanced form of the disease, as those who didn’t take these drugs. Of those with CNV, 20 percent used statins, while 38 percent of patients with dry AMD used them. The authors concluded that a common disease mechanism might be responsible for both cardiovascular disease and advanced AMD.

Recent research.
Dr. McGwin and colleagues reported a statistically significant relationship between AMD and statin use.4 Their case-control study was based on a review of the Atherosclerosis Risk in Communities study, which involved 15,792 individuals enrolled from four communities between 1987 and 1989. Researchers looked for anyone using cholesterol-lowering medications at any time during the study and compared them with controls. They identified 871 AMD cases and 11,717 controls. Of the AMD cases, 11 percent used cholesterol- lowering medications, compared with 12.3 percent of controls.

Inconclusive evidence.
The studies showing a benefit from statins are at odds with the epidemiologic evidence from other population-based studies, according to Ronald Klein, MD, MPH. He was referring to three large prospective cohorts: the Rotterdam, Blue Mountains and Beaver Dam eye studies. “I don’t think we can say one way or the other that statins prevent AMD. The information is not consistent,” said Dr. Klein, professor of ophthalmology and visual science at the University of Wisconsin, Madison, and coprincipal investigator of the Beaver Dam study.

The Blue Mountains data show that people using statins at baseline had a 2.5 times increase in the odds of five-year incidence of CNV, compared with those who never used statins. And the 1993 to 1995 data on Beaver Dam participants show no significant cross- sectional associations between statin use and early or late AMD. In the Rotterdam Study, with 26,781 person years of follow-up in 457 participants, those using cholesterol-lowering drugs had an incidence of AMD similar to those not using drugs.

Prospective Study Needed?

Dr. Klein advocates holding off on a large-scale clinical trial until the next sets of data from the population-based studies are analyzed. Dr. Klein said that those studies might eventually reveal more about the true relationship between statins and AMD since the cohorts are older and statin use has increased over the years. “There finally may be the statistical power to assess whether statins have a protective effect for AMD,” he said. “For the interim, there should be careful follow-up of extant cohorts where information on the exposures and end points is collected by specific protocols.”

Dr. McGwin doesn’t see the need to wait. All of the existing studies have built-in limitations due to their reliance on secondary data, collected for other purposes, he noted. “So the state of the literature is that it’s as murky as anything else is in epidemiology.” He added that the recent studies may have problems, “but they have consistency in terms of results. We know the drug is safe. Why not do a trial?” In the meantime, he is planning a primary observational study designed to test the relationship between statins and AMD.

So where does all this leave ophthalmologists on the front line? “No place different than they were yesterday. Clinicians shouldn’t do anything,” Dr. McGwin said, noting that, given the average age of AMD patients, many are probably on statins already.

Dr. Duncan agrees. “Most people need a statin for other reasons,” she said. “If somebody is on a statin, that’s great. But the evidence isn’t strong enough to say, ‘Take a statin purely to reduce the risk of AMD.’”

1 McCarty, C. A. et al. Let Med J Aust 2001; 175:340.
2 Hall, N. F. et al. Br Med J 2001;323:375–376.
3 Wilson, H. L. et al. Am J Ophthalmol 2004; 137(4):615–624.
4 Ophthalmology 2005;112(3):488–494.

Drs. Duncan, Klein and McGwin have no related financial interests.

Statins Show Promise for Glaucoma

Now we can add glaucoma to the list of diseases that may benefit from treatment with statins. Researchers at Duke University and the University of Alabama at Birmingham found that statin use reduced the risk for the blinding eye disease. This pilot study has implications for treating glaucoma with this class of drugs.¹

The researchers reviewed a large patient database and compared patients with and without glaucoma, and their use of statins and other cholesterol-lowering drugs. They found a 40 percent decrease in primary open-angle glaucoma among long-term (24 months or more) statin users.

One possible explanation for the risk reduction is that statins enhance the outflow of fluid from inside the eye, said Paul P. Lee, MD, JD, professor of ophthalmology at Duke University. Many statins inhibit the activity of rho kinase, which could enhance aqueous outflow and thus presumably lower IOP.

Another explanation is that statins may enhance vascular flow because they may be able to inhibit vascular obstructions to the optic nerve. “So there are a couple of good reasons to suspect that statins might actually be protective for patients against developing glaucoma, or perhaps in the future against the worsening of glaucoma if someone has already developed it.”

1 Arch Ophthalmol 2004;122:822–826.