title: Association of Geroprotective Effects of Metformin and Risk of Open-Angle Glaucoma in Persons With Diabetes Mellitus.
abstract: OBJECTIVE
  Caloric restriction mimetic drugs have geroprotective effects that delay or reduce risks for a variety of age-associated systemic diseases, suggesting that such drugs might also have the potential to reduce risks of blinding ophthalmologic conditions for which age is a major risk factor.
  
  
  OBJECTIVE
  To determine whether the caloric restriction mimetic drug metformin hydrochloride is associated with reduced risk of open-angle glaucoma (OAG) in persons with diabetes mellitus.
  
  
  METHODS
  Retrospective cohort study of patients aged 40 years or older with diabetes mellitus and no preexisting record of OAG in a large US managed care network from January 1, 2001, through December 31, 2010.
  
  
  METHODS
  Quantity of metformin and other prescribed diabetes medications as captured from outpatient pharmacy records.
  
  
  METHODS
  Risk of developing OAG.
  
  
  RESULTS
  Of 150 016 patients with diabetes mellitus, 5893 (3.9%) developed OAG. After adjusting for confounding factors, those prescribed the highest quartile of metformin hydrochloride (>1110 g in 2 years) had a 25% reduced OAG risk relative to those who took no metformin (hazard ratio = 0.75; 95% CI, 0.59-0.95; P = .02). Every 1-g increase in metformin hydrochloride use was associated with a 0.16% reduction in OAG risk (adjusted hazard ratio = 0.99984; 95% CI, 0.99969-0.99999; P = .04), which predicts that taking a standard dose of 2 g of metformin hydrochloride per day for 2 years would result in a 20.8% reduction in risk of OAG. After accounting for potential confounders, including metformin and diabetic medications, the risk of developing OAG was increased by 8% (hazard ratio = 1.08; 95% CI, 1.03-1.13; P = .003) for each unit of increase in glycated hemoglobin level.
  
  
  CONCLUSIONS
  Metformin use is associated with reduction in risk of developing OAG, and risk is reduced even when accounting for glycemic control in the form of glycated hemoglobin level. Other diabetes medications did not confer a similar OAG risk reduction. This study suggests that metformin may be affecting OAG risk on multiple levels, some involving improved glycemic control and some involving mechanisms outside glycemic control such as neurogenesis, inflammatory systems, or longevity pathways targeted by caloric restriction mimetic drugs. If confirmed by prospective clinical trials, these findings could lead to novel treatments for this sight-threatening disease.
authors.affiliation: Department of Applied Health Science, Indiana University, Bloomington.
authors.forename: Hsien-Chang
authors.initials: HC
authors.lastname: Lin
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor3Institute for Health Care Policy and Innovation, University of Michigan, Ann Arbor.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Stein
authors.affiliation: Department of Biostatistics, University of Michigan, Ann Arbor.
authors.forename: Bin
authors.initials: B
authors.lastname: Nan
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor5Center for Statistical Consultation and Research, University of Michigan, Ann Arbor.
authors.forename: David
authors.initials: D
authors.lastname: Childers
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor3Institute for Health Care Policy and Innovation, University of Michigan, Ann Arbor.
authors.forename: Paula Anne
authors.initials: PA
authors.lastname: Newman-Casey
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor6Department of Biological Chemistry, University of Michigan, Ann Arbor.
authors.forename: Debra A
authors.initials: DA
authors.lastname: Thompson
authors.affiliation: Department of Epidemiology, University of Michigan, Ann Arbor.
authors.forename: Julia E
authors.initials: JE
authors.lastname: Richards
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D032701:Biomimetics; D001786:Blood Glucose / Q000032:analysis; D031204:Caloric Restriction; D003920:Diabetes Mellitus / Q000097:blood / Q000188:drug therapy*; D005260:Female; D005902:Glaucoma, Open-Angle / Q000097:blood / Q000517:prevention & control*; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008297:Male; D008687:Metformin / Q000627:therapeutic use*; D008875:Middle Aged; D012189:Retrospective Studies; D012307:Risk Factors
chemical_list: D001786:Blood Glucose; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D008687:Metformin; C517652:hemoglobin A1c protein, human