EyeWorld Asia-Pacific March 2015 Issue

March 2015 48 EWAP GLAUCOMA by Tony Realini, MD, MPH Beyond IOP 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 contribute 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 upregulated 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 antidepressant that is also used to assist with smoking cessation, seasonal affective disorder, and attention deficit disorder,” said Dr. Stein. The drug is a norepinephrine and dopamine reuptake inhibitor that secondarily lowers TNF alpha levels. There is anecdotal evidence that it is effective in the management of TNF-mediated conditions such as psoriasis, atopic 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 antidepressants, was not associated with this protective effect, he added. Database studies have a number 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 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 Michigan, 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 information 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 cumulative grams over 2 years) was associated 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.