In this longitudinal analysis of a large group of older Americans with hyperlipidemia, after adjustment for a number of important confounding factors, we found that those who were prescribed statins experienced a decreased risk of developing OAG from no prior OAG diagnosis, a decreased risk of converting from a diagnosis of suspected glaucoma to one of OAG, and a decreased risk of receiving one or more prescriptions for intraocular pressure lowering medications. Furthermore, a dose response effect was observed, whereby the greater the number of months of exposure to statins over the past 2 year duration, the greater the reduction in risk of developing OAG or requiring medical treatment for glaucoma. Individuals who were prescribed statins for 1 year had a 5% decreased hazard of developing OAG while those who were prescribed statins for 2 years had a 9% decreased hazard of OAG relative to those who were not taking statins. For those taking non-statin cholesterol-lowering medications, we found a reduction in the use of medical therapy for glaucoma, but we did not find that these medications conferred a significant reduction in risk of receiving a diagnosis of OAG, of converting from a glaucoma suspect to OAG or requiring glaucoma surgery. While one of the mechanisms through which statins and non-statin cholesterol lowering medications may exert their protective effect is through lowering cholesterol, the fact that statins significantly attenuated the hazard of developing OAG and of converting from suspected OAG to OAG while other cholesterol-lowering medications did not suggests that statins may have an effect on the development of glaucoma that is independent of their cholesterol-lowering properties.
Several other population-based studies and studies using administrative claims data have investigated the relationship between statin use and glaucoma. In a case-control study of male patients at a Veterans Administration Medical Center (VAMC), McGwin and coworkers found that individuals prescribed statins for at least 24 months had a 40% reduced odds of developing OAG. This group also showed a protective effect against OAG among those prescribed other cholesterol-lowering agents.4
A prospective study by Leung and colleagues demonstrated that statin use was associated with visual field stabilization over three years in patients with normal tension glaucoma.5
DeCastro and coworkers showed that statin use slowed glaucomatous changes to the optic nerve and nerve fiber layer on confocal scanning laser ophthalmoscopy.6
While these studies, like ours, suggest that statins may be protective against OAG, not all do. A large case-control study by Owen and colleagues using information from a primary care database in the United Kingdom found no relationship between statin use and OAG.7
Using administrative data from Canada, Iskedjain and colleagues showed no difference in the need for additional pressure lowering medications among persons taking prostaglandin analogs with or without statins.8
Direct comparisons of these studies with one another and with the findings of the present analysis are challenging due to differences in study design, differences in the extent to which potential confounding factors were accounted for, and differences in the sociodemographic profiles of the study patients. Since hyperlipidemia is associated with other components of metabolic syndrome, including hypertension and diabetes mellitus, both of which have been found to be associated with OAG,15–27
when studying the relationship between statin use and OAG, it is important to adjust for these medical co-morbidities. Some of the prior studies did not consider these potential confounders unlike the current study which did.
There are several proposed mechanisms that could explain why individuals who are taking statins have a reduced risk of OAG. Statins have been shown to upregulate endothelial nitric oxide synthase. Nitric oxide synthase causes vasodilation and an increase in retinal and choroidal blood flow.28
Improved retinal and choroidal perfusion may be important in maintenance of the health of the optic nerve and retinal nerve fiber layer. Additionally, statins are known to exert a neuro-protective effect in the setting of ischemia and may protect retinal ganglion cells in a similar way, as was demonstrated in an ischemia-reperfusion model of the rat retina.29
Proposed mechanisms for the neuro-protective effect of statins include decreasing gluatamate-mediated cytotoxicity30,31
and protecting against apoptosis in the central nervous system.3
There is some evidence that increased plasma nitric oxide lowers intraocular pressure.32,33
Statins may lower intraocular pressure via other mechanisms as well; research has shown that statins affect various molecular intermediaries in the aqueous outflow pathways, including Rho kinase activity and Myosin II ATPase activity, which all increase aqueous outflow facility through the trabecular meshwork and result in a reduction of intraocular pressure, a known risk factor for glaucoma34,35
A secondary aim of this analysis was to identify, to the best of our abilities and within the limitations of a retrospective review of claims data, whether statins are protective against OAG early or later in the disease course. We found that statins conferred a protective effect against the development of OAG from no prior OAG diagnosis, the conversion from a diagnosis of suspected glaucoma to OAG, and the need for a medical therapy for OAG suggesting these medications may be beneficial early in the disease process. In order to evaluate whether statins are beneficial in more advanced glaucoma, we also assessed differences in the need for glaucoma surgery among persons with OAG who were and were not taking statins and found no significant reduction in the need for surgery among statin users. (p=0.68).
Study Strengths and Limitations
The strengths of this study include its large sample size and the ability for us to follow patients over time to assess the relationship between cholesterol lowering medication exposure and subsequent development of OAG. Unlike other studies on this subject that were conducted at specific medical centers, the patients in this study come from communities throughout the United States. In addition, instead of relying on patient self-report to identify medical conditions and exposure to medications, the data from this study were obtained from providers and pharmacy records, and thus may be more accurate. (Patty LE, Wu S, Torres M, Varma R. LALES Group, Doheny Eye Institute/Keck- USC School of Medicine. Validity of self-reported diagnosis and treatment among Latinos in the Los Angeles Latino Eye Study. Poster session 516. Correlates and Outcomes of Eye Diseases. Association of Research and Vision in Ophthalmology, May 6, 2010, Fort Lauderdale, Florida.) Finally, in this analysis we were able to adjust for a variety of potential confounding factors, including other components of metabolic syndrome, which have previously been documented to be associated with OAG.
There are several limitations that need to be acknowledged. The data source used in this analysis does not contain clinical information such as intraocular pressure, central corneal thickness, and findings from visual field and optic nerve evaluations. Therefore, we cannot tell with certainty whether all of the beneficiaries who were diagnosed with OAG indeed had this condition, nor could we fully capture disease severity to incorporate into our analyses. Second, our analysis did not consider results of laboratory testing such as levels of different types of cholesterol and triglycerides. Third, since all of the enrollees in this plan had insurance, one must be cautious in generalizing our study findings to other populations such as uninsured individuals and those residing outside the United States. The fact that our study findings are consistent with findings from the research done by McGwin and colleagues4
, which was conducted at a VAMC in the United States, and the study by Leung and colleagues5
, which was conducted in China, suggest that the relationship between statin use and OAG may be applicable to other groups. Fourth, it is possible that enrollees who take statins are more health conscious than others with hyperlipidemia who are not prescribed these medications and this may impact their use of eye care services. If these individuals have greater use of eye care services, we would expect this to increase, not decrease, their risk of receiving an OAG diagnosis. On the other hand, those who have untreated hyperlipidemia may have more severe ocular co-morbidities, such as diabetic retinopathy, which would necessitate more eye care services, and increase their chance of being diagnosed with OAG. In our analysis we attempted to deal with this issue by controlling for other ocular co-morbidities, though there may be additional confounders not adequately captured in claims data. Fifth, we have no way of knowing with certainty whether enrollees actually consumed all of the prescribed medications. The presumption in this type of analysis is that a patient will not keep filling prescriptions if they are not taking the drug. Thus while these data cannot provide assurance that a specific patient took a prescribed statin drug on a specific date, the expectation is that those who repeatedly filled prescriptions were actually taking the prescribed statin medication as opposed to those who were never prescribed the statin medication, and that a tally of the number of days for which prescriptions were filled is a reasonable surrogate measure of drug consumption. In addition, poor adherence with medications, if anything, should bias our findings to the null, and yet we are finding statins to be protective against OAG.
Finally, it is important to also acknowledge that our findings may not be generalizable to individuals who do not have hyperlipidemia. Statins may not exert a protective effect against developing OAG if the person does not have a derangement in their lipid metabolism. However, in McGwin’s study of glaucoma patients at a VAMC, statins had a protective effect against developing OAG in patients with hyperlipidemia as well as for the subset of persons who were taking statins for other reasons besides treatment of hyperlipidemia.4
The findings of the present analysis support earlier studies demonstrating that treating hyperlipidemia with a statin plays a protective role in patients with OAG, especially in early stages of the disease. After adjustment for important confounding influences, we found that enrollees taking statins had a decreased hazard of developing OAG, of progressing from suspected glaucoma to OAG, and of requiring pressure-lowering medications. Moreover, our study shows a dose-response effect of statin exposure whereby the longer an enrollee was prescribed these medications, the greater the protective effect. Given the mounting evidence of statin protection against OAG including both basic science and observational clinical studies, an interventional prospective study might provide additional insights into the role of statins in the prevention of early OAG.