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EW GLAUCOMA 40 December 2014 is a norepinephrine and dopamine reuptake inhibitor that secondarily lowers TNF alpha levels. There is an- ecdotal evidence that it is effective in the management of TNF-mediat- ed conditions such as psoriasis, atop- ic dermatitis, and Crohn's disease. "We asked whether bupropion use among enrollees in a large nationwide U.S. managed care network affects their risk of developing open-angle glaucoma," Dr. Stein said. He and colleagues analyzed a database of more than 14 million health plan participants to find those who had been in the plan for at least 4 years, were at least 35 years of age, and had seen an eyecare provider at key time points during the study without being diagnosed with glaucoma. Ultimately, nearly 640,000 patients met these criteria. They then ascertained who had used bupropion (and for how many days), and also who went on to develop open-angle glaucoma. "Overall, about 7% of the group had used bupropion for an average of 466 days," Dr. Stein said. Also, 2.4% of the enrollees in the study cohort developed incident open- angle glaucoma. Interestingly, 2.4% of non-users of bupropion developed glaucoma, while only 1.8% of bupropion users developed glaucoma. This difference was significant (p<0.001). There was also a significant trend in that the longer a patient used bupropion, the lower the risk of open-angle glaucoma became. Those who were prescribed bupropion for 4 years had roughly a 29% reduced risk of open-angle glaucoma compared with non-users of bupropion. Use of other anti-depressant classes, such as selective serotonin reuptake inhibitors and tricyclic antidepres- sants, was not associated with this protective effect, he added. Database studies have a num- ber of important limitations, so Dr. Stein interpreted these findings with appropriate caution. "If prospective studies confirm the findings of this analysis, this may identify a novel therapeutic target for open-angle glaucoma and may also help explain Investigating ways of finding new therapeutic targets for glaucoma treatment M any major clinical trials have demonstrated that lowering IOP is an effective means of reducing the risk of glaucoma progression. In virtually every study, however, some patients with seemingly adequate IOP control continued to progress. "These findings suggest factors beyond IOP control might contrib- ute to or perpetuate optic nerve damage in patients with open-angle glaucoma," said Joshua Stein, MD, MS, University of Michigan, Ann Arbor. Identifying such factors—and then proving that they are truly relevant to the glaucoma progression process—has remained elusive. A series of recent studies has identified several potential therapeutic targets for glaucoma management that may operate independent of IOP reduction. Tumor necrosis factor inhibition Tumor necrosis factor (TNF) is a neuroinflammatory cytokine that is produced in response to stressors such as elevated IOP, Dr. Stein said. "The TNF receptor 1 is upregulat- ed in humans with glaucoma, and intravitreal injection of TNF mimics glaucoma in mice." When TNF binds to its receptor in a mouse model of glaucoma, retinal ganglion cells die. In animal models, this cell death can be prevented by use of a TNF blocker, he added. These observations raise an important question: Are there any FDA-approved drugs that have anti-TNF activity, and if so, can their use reduce the risk of developing open-angle glaucoma? Enter bupropion. "Bupropion is an antidepres- sant that is also used to assist with smoking cessation, seasonal affec- tive disorder, and attention deficit disorder," said Dr. Stein. The drug by Tony Realini, MD, MPH Beyond IOP why glaucoma often progresses despite normalization of IOP," Dr. Stein said. Calorie restriction The discovery in recent years that calorie restriction can greatly boost longevity in animals inspired Julia Richards, PhD, University of Mich- igan, to ask whether drugs that mimic the physiologic effects of calorie restriction can also reduce the risk of aging-related diseases such as glaucoma. Using a methodology similar to that of Dr. Stein, she and colleagues obtained data on more than 150,000 diabetics and monitored informa- tion on medications used to control blood glucose, including metformin. Metformin, available as a generic, is a caloric restriction mimetic, she explained. In their cohort, 3.9% of the diabetics developed incident open-angle glaucoma. The use of metformin (at least 1,100 cumula- tive grams over 2 years) was asso- ciated with a 25% reduction in the relative risk of developing glaucoma compared to diabetics not treated with metformin (p=0.017). "This risk reduction was dose-dependent and independent of glycemic control," Dr. Richards added. She was also cautious about interpretation of the findings, but offered a greater potential benefit in the future. "If confirmed by pro- spective clinical trials, these findings would offer new treatments for this sight-threatening disease and per- haps other diseases of aging, too." Sartan drugs Sartan drugs, such as losartan, are angiotensin II receptor antagonists commonly used to treat systemic hypertension. Recently, sartans have been shown to be an effective treat- ment for Marfan syndrome, a dis- ease caused by microfibril deficien- cies. Previous work from Dr. Rachel Kuchtey's laboratory has provided evidence that glaucoma may also result from microfibril deficiencies, suggesting sartan drugs as a possible glaucoma therapy. John Scichilone, BS, and col- leagues at Vanderbilt University, Nashville, Tenn., reported a data- base study evaluating the protective benefit of sartan drugs in relation to open-angle glaucoma. This study included nearly 14,000 patients using sartan drugs and nearly 90,000 controls. "Overall, 1.82% of patients not using sartan drugs developed incident open-angle glaucoma, compared to only 0.74% of patients using sartan drugs," he said. This was highly statistically significant (p<0.0001). Of note, some of this effect may not be unique to IOP reduction. "Previous studies have shown the beneficial effect of sartan drugs on reducing intraocular pressure and retinal ganglion cell death," he said. A combination of both IOP-mediat- ed and IOP-independent effects may explain the substantial magnitude of the protective effect in this study. Practical implications Granted, these are all exploratory studies and their results need to be confirmed in well-designed prospec- tive trials. It is encouraging, how- ever, that non IOP-based therapies may play a role in preventing or delaying the onset of open-angle glaucoma. These drugs are widely used for various systemic conditions and are generally well tolerated. Other approved systemic drugs, such as the cholesterol-lowering statin drugs, are also being evaluated for their protective effects on glaucoma. In the future, therapy for glaucoma may focus on systemic prevention rather than topical IOP reduction. EW Editors' note: Dr. Stein, Dr. Richards, and Mr. Scichilone have no financial interests related to this article. Contact information Stein: jdstein@med.umich.edu Richards: richj@umich.edu Scichilone: john.m.scichilone@vanderbilt.edu