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Julia E Richards, Hsien-Chang Lin, Bin Nan, Nidhi Talwar, David Childers, Paula Anne Newman-Casey, Debra A Thompson, Joshua D Stein, ; Targeting aging: Geroprotective Drug Metformin Reduces Risk of Adult-onset Open-angle Glaucoma. Invest. Ophthalmol. Vis. Sci. 2014;55(13):1668.
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Caloric-restriction (CR) and CR-mimetic drugs have geroprotective effects that delay or reduce some risks of aging. This study tested the hypothesis that the CR-mimetic drug metformin can reduce the risk of developing the late-onset trait open-angle glaucoma (OAG).
We analyzed nine years of longitudinal data from a large US health claims database (2001-2009). Diabetics, aged 40 and above with no pre-existing OAG, were monitored for incident OAG. The key predictor was exposure to metformin. A Cox proportional hazard model tested the effect of metformin on the hazard of developing OAG, adjusting for sociodemographic factors, glycemic control (HbA1c level), other diabetes medications, and other ocular and systemic conditions. The University of Michigan Institutional Review Board deemed use of this anonymized database to be exempt.
Of 150,016 diabetics, 5,893 (3.9%) developed incident OAG. Use of >1,110 cumulative grams of metformin over two years was associated with a 25% reduction in relative risk of developing OAG (HR=0.75; 95% CI=0.59-0.95; p=0.017) compared with no metformin use. Every 1 gram increase in metformin was associated with a 0.01% reduced hazard of developing OAG (p=0.001). Thus someone receiving a normal dose of metformin (2 grams per day) over two years would show a 13% reduction in absolute risk of OAG relative to someone not taking metformin. When we stratified by baseline OAG risk and HbA1c level, the greatest absolute metformin-induced risk reduction was seen for those with the highest baseline risk and the highest HbA1c levels. Although HbA1c levels were associated with increased risk of OAG (HR=1.08; 95% CI=1.03-1.13; p=0.003), other hypoglycemic drugs did not reduce risk of OAG, and OAG risk-reduction in response to metformin occurred when HbA1c levels were taken into account.
Metformin use was associated with reduced risk of OAG. This OAG risk reduction was dose-dependent and independent of glycemic control; other diabetes medications did not confer a similar risk reduction. Thus, systems beyond glycemic control, such as neurogenesis, longevity pathways, and/or reduced inflammation may be involved in metformin-induced OAG risk-reduction. If confirmed by prospective clinical trials, these findings would offer novel treatments for this sight-threatening disease and perhaps other diseases of aging too.
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