Abstract
OBJECTIVE
To evaluate the association between metformin use and the risk of developing age-related macular degeneration (AMD) among patients with diabetes, with a focus on exposure duration and AMD subtypes.
DESIGN
Retrospective cohort study.
PARTICIPANTS
Patients were identified from the TriNetX network using International Classification of Diseases, 10th Revision (ICD-10), and Current Procedural Terminology (CPT) codes for diabetes and ophthalmologic care. Patients aged ≥ 60 years with diabetes and no documentation of AMD were included in the cohort.
METHODS
Patients were required to have no AMD diagnoses at two eye care visits at least one year apart, with the second visit serving as the index event for analysis. The main exposure was yearly metformin use for at least 5 years, with subanalyses up to 10 years. The outcome was incident AMD. Propensity score matching controlled for potential confounders including demographics, comorbidities, medications, laboratory values, and healthcare utilization. The association between metformin and AMD was assessed using survival analysis. Results were reported as hazard ratios (HRs) with 95% confidence intervals (CIs).
OUTCOME MEASURES
The primary outcome was a new diagnosis of AMD. Secondary outcomes included a new diagnosis of dry AMD and wet AMD.
RESULTS
After propensity score matching, the main cohort analysis included 7,496 patients, of whom 3,748 had ≥ 5 consecutive years of metformin use. Incident AMD was documented in 122 (3.3%) patients who had been exposed to metformin and 184 (4.9%) who had not (HR 0.68, 95% CI 0.54, 0.85). The metformin group had lower rates of both dry AMD (HR 0.69, 95% CI 0.53, 0.90) and wet AMD (HR 0.84, 95% CI 0.50, 1.39), although the association with wet AMD was not statistically significant. Use for ≥ 6 consecutive years showed consistent protective effects; 1-4 years showed weaker associations.
CONCLUSION
Prolonged metformin use in patients with diabetes was associated with a reduction in AMD risk in this claims database. These findings suggest a potential protective role for metformin, warranting further exploration of its long-term effects on AMD prevention.
Keywords: metformin, age related macular degeneration, diabetes mellitus, propensity score
Précis
This large, retrospective cohort study found that prolonged metformin use (≥ 5 consecutive years) was associated with a reduction in AMD risk among patients with diabetes mellitus, with significant differences in dry AMD.
INTRODUCTION
Age-related macular degeneration (AMD) is a leading cause of vision impairment and blindness worldwide, with a significant impact on quality of life.1,2 Current therapies focus primarily on the late-stages of the disease, either the neovascular form of AMD or the non-neovascular stage with geographic atrophy, at which times vision loss may already be advanced.3 Identifying effective preventive strategies could enhance understanding of AMD pathogenesis, reduce disease incidence, and improve long-term outcomes.
Metformin, a widely used antidiabetic drug with antioxidative, anti-inflammatory, and anti-angiogenic properties, has been proposed to reduce AMD risk.4–8 Since oxidative stress, inflammation, and abnormal neovascularization play key roles in AMD development, metformin could theoretically help prevent or delay this sight-threatening condition.9–11 The association between metformin and AMD is increasingly being studied, but results across the literature are inconsistent, with some studies demonstrating a protective effect and others failing to find an association.12–14 Given the slow progression of AMD, duration of therapy would likely be a key mediator of any protective effect of metformin, and it is possible that differences in the ways previous studies have accounted for duration of therapy accounts for some of the heterogeneity in findings. Indeed, the relationship between the duration of metformin exposure and AMD remains poorly characterized. We conducted a study to address this research gap, studying a large cohort of people from a nationwide database to investigate the relationships between various durations of metformin therapy and AMD.
METHODS
Data Source
This retrospective cohort study was performed using the US Collaborative Network within the TriNetX Analytics platform (Cambridge, MA, USA), a federated health research network aggregating de-identified electronic health record (EHR) data from more than 118 million patients across 70 US healthcare organizations, including both academic and non-academic centers with their satellite sites.15 The database contains deidentified data in compliance with Section §164.514(a) of the HIPAA Privacy Rule and is exempt from institutional review board approval. The study adhered to the Declaration of Helsinki and followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines.16 Data analysis was performed between December 2024 and March 2025.
Study Population
Eligible participants were identified using International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes for diabetes mellitus (E08-E13) between March 25, 2005 – March 25, 2025 as analysis was performed on March 25, 2025 (Supplemental Figure S1, available at https://www.aaojournal.org). Patients were required to have at least one year of database observation and a recorded diabetes mellitus diagnosis prior to their first qualifying ophthalmology visit after age 60. The study cohort included patients who had at least two ophthalmology-related eye care visits at least one year apart (Current Procedural Terminology [CPT] code 1012793 for ophthalmology services and procedures or ICD-10 code Z01.0 for general eye and vision examinations), with the first visit occurring at or after 60 years of age. The second ophthalmology-related visit was considered the index event, providing at least a 12-month lookback period (Figure 1). While patients may have had prior ophthalmologic encounters, analyses were anchored to their first two qualifying eye care visits after age 60. Patients were excluded if they had AMD at or prior to either of these two initial ophthalmology-related encounters. The main analysis included those in the overall cohort who had at least 5 years of records in the database prior to the initial ophthalmology encounter, with the 5-year restriction chosen because the goal of the analysis was to determine if sustained metformin use was associated with AMD. Additional cohorts were made that varied this 5-year requirement to explore if the association depended on the length of treatment. The cohort construction query can be found in Supplementary Table S1 (available at https://www.aaojournal.org).
Figure 1. Cohort selection flow diagram.
AMD: age-related macular degeneration.
Exposure and Outcomes
The exposure of interest was metformin use before the first ophthalmology encounter, as classified by the database administrators. Exposure was stratified into yearly intervals ranging from 10 years to 1 year prior to the first ophthalmology encounter, with the requirement that patients must have a diagnosis of diabetes mellitus and at least one recorded instance of metformin use for each year to be considered exposed. Patients who did not meet exposure criteria were included in the comparison group, including individuals with yearly diabetes mellitus diagnoses who had fewer than the required number of consecutive years of metformin use or no metformin use at all. The main analysis was done among patients with database records for at least 5 years, with the exposed group classified as metformin use at least once per year in each of the preceding five years and the unexposed group as less metformin than this. As described above, additional cohorts were constructed depending on how many years of records were available in the database prior to the initial ophthalmology encounter. The definition of exposure was analogous in each of these cohorts (e.g., for the cohort of patients with ≥ 10 years of data preceding the initial ophthalmology encounter, the exposed group was defined as use of metformin at least once per year for 10 years, and non-exposed group as less metformin than this).
The primary outcome was the development of AMD (H35.30-32), further classified into dry AMD (H35.31) and wet AMD (H35.32). Outcomes were right-censored after the earliest occurrence of the following: 1) outcome event, 2) death, 3) loss to follow-up after the index event.
Propensity Score Matching
Propensity score matching was conducted to match metformin and non-metformin cohorts to eliminate confounders and ensure comparability. Matched covariates included age, sex, race and ethnicity (as documented in the EHR), diabetes-related ophthalmic complications (including diabetic retinopathy), cardiovascular disease, chronic kidney disease, peripheral artery disease, dementia, neoplasms, chronic lower respiratory disease, liver cirrhosis, socioeconomic status and psychosocial health hazards, tobacco use, insulin, other hypoglycemic agents, lipid-lowering agents, antihypertensives, AREDS vitamins, body mass index (BMI), hemoglobin A1c (HbA1c), total cholesterol, systolic blood pressure, and healthcare utilization (outpatient, inpatient, and emergency department visits). Supplementary Table S2 (available at https://www.aaojournal.org) provides a comprehensive list of codes used in matching.
Statistical Analysis
All statistical analyses were conducted using the built-in functions of the TriNetX platform. Baseline characteristics were summarized as means (± standard deviations [SD]) for continuous variables and frequencies (percentages) for categorical variables. Propensity score matching (1:1) was performed using greedy nearest-neighbor matching with a caliper distance of 0.1 pooled standard deviations of the logit of the propensity score. Balance between matched groups was assessed using standardized mean differences (SMD), with an SMD < 0.1 indicating acceptable balance. Similar analyses were performed using analogous propensity score-based methods for statin use for at least 5 years (i.e., a positive control) and for insulin/analogue use for at least 5 years (i.e., a negative control). Additionally, we repeated all primary models after excluding patients who had a recorded diagnosis of drusen at or prior to either of their initial two ophthalmology-related visits after age 60. This was done to test whether baseline subclinical retinal changes influenced the observed association between metformin use and AMD risk. Kaplan–Meier survival curves compared the cumulative incidence of AMD between metformin- exposed and unexposed groups. Cox proportional hazards regression models were used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs) for all outcomes. Statistical significance was defined as a two-sided P value < 0.05.
RESULTS
A total of 13,741 patients aged 60 years or older with diabetes mellitus were included in the main analysis cohort, including 4,581 with metformin use in each of the five previous years and 9,160 who did not meet exposure criteria. Patients exposed to metformin were slightly younger (mean [SD] age, 68.8 [6.0] vs. 70.3 [6.3] years) than the unexposed group and less likely to have several markers of poor health, including chronic kidney disease, cardiovascular disease, and cerebrovascular disease (Supplemental Table S3, available at https://www.aaojournal.org). After propensity score matching, 3,748 patients remained, with equal numbers in the metformin and control group, and a balanced covariate profile. The metformin cohort was followed for an average of 5.4 (SD 4.5) years while the control cohort was followed for an average of 5.4 (SD 4.1) years.
Among those with ≥ 5 consecutive years of metformin exposure, 122 (3.3%) were diagnosed with any AMD compared to 184 (4.9%) in the non-exposed cohort (Supplementary Figure S1, available at https://www.aaojournal.org). Metformin use was associated with a lower risk of developing any AMD (HR 0.68, 95% CI 0.54, 0.85) (Figure 2). The magnitude of effect was similar for the relationship between metformin and dry AMD (HR 0.69, 95% CI 0.53, 0.90), but less marked and not statistically significant for the association between metformin and wet AMD (HR 0.84, 95% CI 0.50, 1.39) (Table 1). Sensitivity analyses of nested cohorts with varying durations of metformin exposure suggested a consistent protective effect, with a trend toward greater significance at longer exposure periods (≥ 6-10 years of annual metformin use), although these findings may be limited by smaller sample sizes at longer durations (Figure 2).
Figure 2. Risk of developing any AMD stratified by metformin exposure.
Patients with diabetes mellitus were followed for exposure to metformin over different intervals prior to their first ophthalmology encounter after age 60. Hazard ratios (HRs) with 95% confidence intervals (CI) were calculated using a Cox proportional hazards model with censoring applied. For each outcome, the groups were propensity-score matched for covariates related to the outcome, and the outcome was compared between the matched groups. Each eligible individual was followed up from the index event until the occurrence of the outcomes, death, or loss to follow-up, whichever occurred first. AMD: age-related macular degeneration.
Table 1.
AMD incidence and progression among patients with different exposure periods to metformin.
| Exposure period, (n in each matched cohort) | Outcome | Metformin, cases (%) | No metformin, cases (%) | HR (95 CI) |
|---|---|---|---|---|
| 10 years (n=870) | Any AMD | 29 (3.3) | 34 (3.9) | 0.83 (0.50, 1.36) |
| Dry AMD | 23 (2.6) | 27 (3.1) | 0.82 (0.47, 1.43) | |
| Wet AMD | 10 (1.1) | 10 (1.1) | 0.90 (0.68, 1.17) | |
| 9 years (n=968) | Any AMD | 34 (3.5) | 50 (5.2) | 0.69 (0.45, 1.07) |
| Dry AMD | 27 (2.8) | 41 (4.2) | 0.67 (0.41, 1.09) | |
| Wet AMD | 10 (1.0) | 10 (1.0) | 1.04 (0.39, 2.77) | |
| 8 years (n=1203) | Any AMD | 50 (4.2) | 67 (5.6) | 0.77 (0.53, 1.11) |
| Dry AMD | 40 (3.3) | 53 (4.4) | 0.78 (0.52, 1.18) | |
| Wet AMD | 13 (1.1) | 16 (1.3) | 0.88 (0.42, 1.82) | |
| 7 years (n=1667) | Any AMD | 64 (3.8) | 89 (5.3) | 0.72 (0.52, 0.99) |
| Dry AMD | 49 (2.9) | 67 (4.0) | 0.73 (0.51, 1.06) | |
| Wet AMD | 16 (1.0) | 16 (1.0) | 1.03 (0.52, 2.06) | |
| 6 years (n=2103) | Any AMD | 72 (3.4) | 111 (5.3) | 0.67 (0.50, 0.90) |
| Dry AMD | 58 (2.8) | 88 (4.2) | 0.69 (0.50, 0.96) | |
| Wet AMD | 16 (0.8) | 18 (0.9) | 0.97 (0.49, 1.89) | |
| 5 years (n=3748) | Any AMD | 122 (3.3) | 184 (4.9) | 0.68 (0.54, 0.85) |
| Dry AMD | 92 (2.5) | 137 (3.7) | 0.69 (0.53, 0.90) | |
| Wet AMD | 27 (0.7) | 34 (0.9) | 0.84 (0.50, 1.39) | |
| 4 years (n=5209) | Any AMD | 182 (3.5) | 240 (4.6) | 0.77 (0.64, 0.93) |
| Dry AMD | 135 (2.6) | 164 (3.1) | 0.84 (0.67, 1.05) | |
| Wet AMD | 43 (0.8) | 50 (1.0) | 0.88 (0.59, 1.33) | |
| 3 years (n=8119) | Any AMD | 288 (3.5) | 343 (4.2) | 0.87 (0.75, 1.02) |
| Dry AMD | 209 (2.6) | 240 (3.0) | 0.91 (0.76, 1.10) | |
| Wet AMD | 58 (0.7) | 76 (0.9) | 0.80 (0.57, 1.13) | |
| 2 years (n=12105) | Any AMD | 384 (3.2) | 449 (3.7) | 0.88 (0.77, 1.01) |
| Dry AMD | 287 (2.4) | 339 (2.8) | 0.88 (0.75, 1.03) | |
| Wet AMD | 83 (0.7) | 111 (0.9) | 0.78 (0.59, 1.03) | |
| 1 year (n=24208) | Any AMD | 764 (3.2) | 852 (3.5) | 0.92 (0.83, 1.01) |
| Dry AMD | 545 (2.3) | 596 (2.5) | 0.94 (0.84, 1.06) | |
| Wet AMD | 182 (0.8) | 209 (0.9) | 0.90 (0.74, 1.10) |
AMD: age-related macular degeneration; HR: hazard ratio; CI: confidence interval
Similar analyses were performed with insulin as a negative control and any statin as a positive control, with exposure classified as use of the respective drug in each of the previous 5 years (Supplementary Table S4, available at https://www.aaojournal.org). Insulin use was not significantly associated with any AMD (HR 0.82, 95% CI 0.56, 1.21) or dry AMD (HR 0.90, 95% CI 0.50, 1.45). Statins were associated with a significantly lower incidence of any AMD (HR 0.77, 95% CI 0.62, 0.96) and a non-significantly lower incidence of dry AMD (HR 0.84, 95% CI 0.65, 1.09). Additional sensitivity analyses excluding patients who had drusen at or prior to the initial two eye visits were consistent with the main analysis. (Supplementary Table S5, Supplementary Figure S2, available at https://www.aaojournal.org).
DISCUSSION
Our study demonstrates that yearly metformin exposure for at least 5 years was associated with a decreased risk of developing AMD, with significant differences observed in dry AMD and a non-significant trend in wet AMD. Control analyses that confirmed a protective association of statins for AMD and failed to find an association between insulin exposure and AMD strengthened confidence in the findings.
The observed association between metformin use and reduced AMD risk is consistent with some prior studies, including recent meta-analyses, though other cohort studies have reported mixed results.4,17–19 While previous research has suggested a potential benefit with longer metformin use, it is unclear how varying durations of exposure to metformin may influence AMD development. Skondra et. al demonstrated a dose-dependent reduction in AMD risk, with higher doses and at least 2 years of use providing greater protection.13 However, the effect of prolonged exposure, such as the 5-year exposure analyzed in our study, remains understudied. To strengthen the validity of our findings, we conducted several validation analyses. Our negative control analysis using insulin, a medication not thought to be associated with AMD, found no significant relationship, reinforcing the validity of our findings.20 Additionally, our positive control analysis using statins, which have been previously linked to AMD risk reduction, demonstrated a protective effect similar to that of metformin.21,22 These sensitivity analyses increase confidence in our findings. Together, these results underscore the importance of considering both metformin duration and dosage in future investigations to better clarify its role in AMD prevention.
Metformin use was significantly associated with a reduced risk of any AMD and dry AMD, and a weaker association with wet AMD. This observation aligns with prior research suggesting that metformin does not significantly slow the progression of existing geographic atrophy, reinforcing the idea that its protective effects may be most relevant in earlier stages of disease development.23 When individuals with a prior diagnosis of drusen were excluded from the cohort, these protective effects were not as pronounced. Although the presence of drusen signifies that the AMD disease process has already begun, these findings do not necessarily limit the potential utility of metformin.24 Rather, it remains possible that metformin could exert benefits throughout the disease course and not solely as a preventive measure before structural changes occur. Future studies may want to consider analyses that evaluate metformin’s role in patients both with and without drusen when assessing the effects of therapeutics across all stages of AMD.
There are several biological mechanisms through which metformin may help reduce AMD progression. AMD is driven by oxidative stress, chronic inflammation, and abnormal angiogenesis, all of which are processes that metformin has been shown to modulate. Metformin activates AMP-activated protein kinase, which regulates cellular metabolism and reduces oxidative damage.25 Additionally, metformin suppresses inflammatory pathways, such as NF-κB signaling, which are implicated in AMD pathogenesis.6,26 Furthermore, its anti-angiogenic effects may counteract abnormal choroidal neovascularization, a hallmark of AMD progression.27 These mechanisms provide a plausible biological basis for the observed association between metformin use and reduced AMD risk.
Several limitations of our study and the TriNetX platform must be acknowledged.28 The retrospective cohort design precludes any comment on causality between metformin exposure and AMD. The cohort selection and statistical analysis was performed within the parameters of the TriNetX online platform. We did not access the raw data. We were unable to model metformin as a time-varying covariate using the TriNetX platform. Reliance on EHR data introduces potential coding errors, misclassification, and missing information, with variations in ICD-10 and CPT code accuracy across healthcare systems potentially underestimating or misrepresenting chronic health conditions used in propensity score matching. We tried to reduce coding error by requiring multiple instances of a code or related code in our study definitions (e.g., requiring both an ICD-10 diagnosis code for AMD and a CPT procedural code for ophthalmology services; requiring multiple documented diagnoses of diabetes mellitus). The main cohort analysis only included those patients with health encounters at least annually for the 5 years prior to the index date, potentially excluding those who changed institutions or had gaps in care. This cohort construction could have led to bias if the relationship between metformin and AMD was different among those with gaps in EHR data on the TriNetX platform. A lack of data on medication dosage, adherence, and prescription patterns over time limits our ability to assess treatment consistency. While metformin exposure was classified based on prescription history, we cannot confirm whether patients consistently took the medication or if interruptions in therapy influenced outcomes. TriNetX is not an ophthalmology-specific database, limiting our ability to analyze visual acuity, imaging findings, and AMD progression by disease stage. Additionally, some ophthalmologic encounters may have been recorded using general or non-specialty-specific visit codes rather than ophthalmology-specific CPT or ICD codes, potentially leading to underascertainment of relevant visits. While propensity score matching was applied to balance baseline characteristics, residual confounding is possible, as differences in follow-up frequency, access to care, socioeconomic status, and concurrent diabetes treatments could still influence results. Analyses were done in a series of nested cohorts with varying durations of preceding data. The patterns observed between the cohorts with longer and shorter durations of metformin are therefore not independent and should be interpreted with caution. The study was confined to patients on the TriNetX platform with sufficient longitudinal data who were 60 years or older with diabetes. Though TriNetX includes patients from 70 academic and nonacademic HCOs across the United States, the findings may not be generalizable to other populations or to other EHR platforms that draw from different geographical regions or different types of facilities.
In conclusion, this large retrospective cohort study using administrative data demonstrated that prolonged metformin use may be associated with a reduced risk of AMD. These findings build on previous literature highlighting potential benefits of metformin to reduce AMD development in patients with diabetes mellitus. Prospective randomized trials are needed to clarify the underlying mechanisms, assess long-term benefits, and explore broader clinical implications to optimize ocular care strategies in diabetic populations.
Supplementary Material
This article contains additional online-only material. The following should appear online-only: Supplementary Table S1–S5, Supplementary Figure S1–S2.
Financial Support:
Supported in part by the National Eye Institute (Core Grant for Vision Research, EY002162); Research to Prevent Blindness, Inc., New York, NY; All May See Foundation, Inc., San Francisco, CA. The funding organizations had no role in the design or conduct of this research.
Abbreviations:
- AMD
age-related macular degeneration
- BMI
body mass index
- CI
confidence interval
- CPT
Current Procedural Terminology
- DM
diabetes mellitus
- EHR
electronic health record
- HR
hazard ratio
- ICD-10
International Classification of Diseases, 10th Revision
- SD
standard deviation
- SMD
standardized mean differences
Footnotes
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Human Subjects: This study did not meet the criteria for human subjects research as it was an analysis of existing anonymized and aggregated data.
Institutional Review Board: TriNetX is a federated network and received an exemption from University of Southern California IRB due to the use of de-identified, aggregated data.
Conflict of Interest: JMS: Consultant – Carl Zeiss, Merck, Valitor, Long Bridge, Twenty Twenty, Science, Oculgen; Personal Financial Interest – Long Bridge, Valitor, Science; all unrelated to the present study. ATH: None; IYL: None; JDK: None
Disclosures: All authors have completed and submitted the ICMJE disclosures form. The author(s) have no proprietary or commercial interest in any materials discussed in this article.
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