Abstract
Purpose This population-based, retrospective cohort study was to investigate whether metformin is associated with a lower risk of subsequent age-related macular degeneration (AMD) in patients with type 2 diabetes. Methods Using the Taiwan National Health Insurance Research Database from 2001 to 2013, 68205 subjects with type 2 diabetes were enrolled in the study cohort. Among them, 45524 were metformin users and 22681 were nonusers. The metformin and nonmetformin groups were followed until the end of 2013. Cox regression analyses were used to estimate hazard ratios (HRs) for AMD development associated with metformin use. Confounders included for adjustment were age, sex, and comorbidities (hypertension, hyperlipidemia, coronary artery disease, obesity, diabetic retinopathy, chronic kidney disease, and insulin treatment). Furthermore, propensity score (PS) matching method was used to choose the matched sample, and PS-adjusted Cox regression was performed. Finally, how HRs changed according to metformin treatment duration and dose was also evaluated in the metformin group. Results After adjusting for confounders, the metformin group had a significantly lower risk of AMD (adjusted HR = 0.54; 95% confidence interval [CI], 0.50–0.58). In the PS-matched sample, the significance remained (adjusted HR = 0.57; 95% CI, 0.52–0.63). In the metformin group, the adjusted HRs for the second (1.5–4 years) and third (≥4 years) tertiles of metformin treatment duration were 0.52 and 0.14, respectively, compared with the first tertile (<1.5 years). We also found significant trends of lower HRs (all p-value for trend <0.05) with increasing total and average doses. Conclusions Among patients with type 2 diabetes, those who use metformin are at a significantly lower risk of developing AMD relative to individuals who do not use metformin. Also, the trend of a significantly lower AMD risk was found with a higher dose of metformin.
Highlights
Metformin, classified as biguanide, is the first-line and most widely used medication for patients with type 2 diabetes
Unlike diabetic retinopathy that is a classical complication of diabetes, Age-related macular degeneration (AMD) is not directly induced by hyperglycemia. erefore, the possible association between metformin and a lower AMD risk may not be related to the glucose-lowering effect of metformin
Taiwan’s National Health Insurance program covers more than 99% of the country’s 23 million residents. e National Health Insurance Research Database (NHIRD) is maintained by the National Health Research Institutes of Taiwan and consists of inpatient and outpatient medical benefit claims, including diagnostic codes, prescriptions, operative procedures, and insurance registry data. e identification of all patients included in the database was encrypted prior to the release of data for research purposes. is study utilized the Longitudinal Health Insurance Database (LHID), which is a representative database containing data from 1000000 individuals sampled randomly from all beneficiaries in NHIRD. e Institutional Review Board waived the requirement for informed consent because the secondary data were scrambled and deidentified before release. is study was approved by the ethics committee of Yang-Ming University Hospital (2015A018)
Summary
Metformin, classified as biguanide, is the first-line and most widely used medication for patients with type 2 diabetes. In addition to its main effect of inhibiting hepatic glucose production [1], metformin has been found to decrease oxidative stress [2, 3]. E number of patients with AMD is estimated to reach 196 million by 2020 and 288 million by 2040, based on population-aging demographics [7]. Its pathogenesis is not fully understood but has been found to be Journal of Ophthalmology related to oxidative stress, inflammation, and immune reaction [8,9,10]. As metformin has been found to have antioxidative and anti-inflammatory properties, it is relevant to propose that metformin may be associated with the lower occurrence of AMD. Erefore, the possible association between metformin and a lower AMD risk may not be related to the glucose-lowering effect of metformin Unlike diabetic retinopathy that is a classical complication of diabetes, AMD is not directly induced by hyperglycemia. erefore, the possible association between metformin and a lower AMD risk may not be related to the glucose-lowering effect of metformin
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