Purpose
To evaluate the association between statin use and the risk of ocular hypertension (OHT) and open-angle glaucoma (OAG) among patients with hyperlipidemia across different racial and ethnic subgroups.
Design
Retrospective clinical cohort study.
Methods
We used anonymized TriNetX United States Collaborative Network database. Patients aged ≥40 years with hyperlipidemia and at least 4 statin prescriptions were included and stratified into 4 cohorts: non-Hispanic Whites, non-Hispanic African Americans, non-Hispanic Asians, and Hispanics. Propensity score matching (PSM) was performed separately for each cohort to minimize confounding, incorporating demographic, clinical, laboratory, medication, and socioeconomic variables. The primary outcomes were the development of OHT or OAG at 1- and 5-years postindex date, analyzed using multivariate Cox proportional hazard models.
Results
A total of 309 255 patients were analyzed. After PSM, statin use was significantly associated with a reduced risk of OHT and OAG among non-Hispanic Whites at 1 and 5 years ( P < .0001). Adjusted hazard ratio (aHR) for OHT was 0.5 (95% confidence interval (CI): 0.4-0.6) at 1 year and remained at 0.5 (95% CI: 0.5-0.6) at 5 years, while the aHR for OAG was 0.7 (95% CI: 0.6-0.7) at 1 year and 0.6 (95% CI: 0.5-0.6) at 5 years. Among non-Hispanic African Americans, statin use was associated with a reduction in OAG risk at both time points ( P < .0001), with an aHR of 0.8 (95% CI: 0.6-0.9) at 1 year and 0.6 (95% CI: 0.5-0.7) at 5 years, but no significant effect on OHT risk. In non-Hispanic Asians, statin use did not significantly reduce the risk of OHT or OAG at 1 year, though a reduction in OAG risk was observed by 5 years (aHR: 0.7, 95% CI: 0.5-0.9, P = .007). Similarly, in the Hispanic cohort, statin use did not affect OHT or OAG risk at 1 year but was associated with a lower risk of OAG at 5 years (aHR: 0.7, 95% CI: 0.6-0.8, P = .0003).
Conclusions
Statin use was associated with a reduced risk of OHT and/or OAG in most racial and ethnic groups, with differences in timing and magnitude of effects. These findings underscore the importance of exploring mechanisms underlying racial disparities in outcomes.
O pen-angle glaucoma (OAG) is a leading cause of irreversible blindness, affecting approximately 3.05% of the global population aged 40 to 80 years, with the highest prevalence observed in individuals of African ancestry and from regions like Africa and North America. , Despite advancements in understanding the pathophysiology of OAG involving factors such as intraocular pressure (IOP), vascular dysregulation, and genetic predisposition, the role of systemic medications in modulating risk remains underexplored. For instance, corticosteroids are known to increase glaucoma risk, while beta blockers, glucagon-like peptide 1 (GLP-1) receptor agonists, metformin, and hormone replacement therapy have potential protective effects.
Statins (HMG-CoA reductase inhibitors), widely prescribed for hyperlipidemia and atherosclerotic cardiovascular disease, have emerged as potential modulators of glaucoma risk due to their vascular, anti-inflammatory, and neuroprotective properties. However, existing literature on the association between statin use and glaucoma risk is contradictory. , , For instance, Lee et al reported an increased likelihood of glaucoma among statin users in a diverse United States (US) cohort, suggesting that specific subpopulations (with optimal or high LDL-C levels, and in individuals 60-69 years old) might experience heightened vulnerability. Conversely, Stein et al demonstrated a protective effect of statins against OAG, particularly with prolonged use. These conflicting findings highlight the need for a nuanced understanding of statin-related glaucoma risk, especially across racially and ethnically diverse populations.
Emerging evidence points to genetic, metabolic, and systemic differences as potential contributors to racial disparities in statin-associated glaucoma risk. Genetic polymorphisms, such as those in the ABCG2 gene, have been shown to significantly affect statin pharmacokinetics, leading to higher plasma drug levels in East Asians and potentially altering therapeutic efficacy. Additionally, disparities in healthcare access among racial and ethnic groups may further contribute to variability in glaucoma outcomes. Similarly, a recent study revealed racial and ethnic differences in antihypertensive medication use, with African Americans more frequently prescribed diuretics and calcium channel blockers compared to beta-blockers or angiotensin-converting enzyme inhibitors, suggesting that certain racial groups may respond more favorably to specific medications.
The purpose of the current study is to clarify the association between statin use and the risks of ocular hypertension (OHT) and OAG in patients with hyperlipidemia, stratified by race and ethnicity.
MATERIALS AND METHODS
This retrospective cohort study utilized anonymized patient data from the TriNetX database, a comprehensive resource encompassing over 250 million deidentified patients from more than 30 countries. Data were drawn from nearly 100 global healthcare organizations (HCOs) and included demographic, clinical, and laboratory information, as well as genomic data. Records from 68 HCOs within the “US Collaborative” network were accessed for the current analysis in December 2024. As the study relied exclusively on anonymized data, it was exempt from Institutional Review Board (IRB) approval by the University of Arkansas for Medical Sciences (UAMS). The study was conducted following the principles of the Declaration of Helsinki (2013 version).
INCLUSION/EXCLUSION CRITERIA AND STUDY GROUPS
Patients included in the study were aged 40 years or older, carried a diagnosis of disorders of lipoprotein metabolism (hyperlipidemia) identified by International Classification of Diseases (ICD)-10 code [E78], and had documented evidence of at least 4 statin (ATC: C10AA) prescriptions before the index date. Exclusion criteria encompassed a prior diagnosis of glaucoma (ICD-10 codes [H40-42]), OHT (ICD-10 code [H40.05]), or glaucoma suspect (ICD-10 code [H40.0]) status at or before the index date.
Participants were stratified into 4 cohorts based on self-reported race and ethnicity:
1. Non-Hispanic Whites
2. Non-Hispanic African Americans
3. Non-Hispanic Asians
4. Hispanics
The index date was the first time a patient met all inclusion criteria within the study period, from January 1, 2005, to January 1, 2023. To ensure adequate ophthalmologic follow-up, eligible patients must have undergone at least one eye examination during the first year after the index date and at least one additional exam between 1 and 5 years from the index date.
PROPENSITY SCORE MATCHING
To mitigate confounding effects, propensity score matching (PSM) was employed separately within each racial and ethnic cohort to match patients using and not using statins. Covariates included in the matching process encompassed demographic and clinical variables such as age, sex, myopia, and body mass index (BMI), alongside systemic comorbidities, laboratory findings, medication use, and socioeconomic factors. Specific systemic comorbidities included diabetes mellitus (ICD-10 [E08-E13]), hypertensive diseases ([I10-I1A]), ischemic heart disease ([I20-I25]), chronic lower respiratory disease ([J40-J4A]), sleep disorders ([G47]), obesity ([E66]), thyroid disorders ([E00-E07]), nicotine dependence ([F17]), chronic kidney disease ([N18]), and cerebrovascular disease ([I60-I69]). Systemic medication use, including beta blockers ([CV1000]) and corticosteroids ([H02]), was also included.
Additionally, laboratory findings such as serum cholesterol, LDL levels, and hemoglobin A1C (HbA1C) were included, along with socioeconomic factors such as problems related to education and literacy ([Z55]), employment and unemployment ([Z56]), occupational exposure to risk factors ([Z57]), and physical environmental challenges ([Z58]). To address potential detection bias and account for differences in ophthalmologic care, ophthalmologic service codes (Current Procedural Terminology (CPT) codes: 92002, 92004, 92012, 92014) were also incorporated into the PSM process.
PSM was performed using a 1:1 nearest neighbor matching algorithm with a caliper width of 0.1 standardized difference to ensure robust matching between statin users and nonusers. , The effectiveness of PSM was evaluated by comparing standardized differences for covariates before and after matching.
CLINICAL ENDPOINTS AND STATISTICAL ANALYSIS
The primary clinical endpoints were the development of OHT (ICD-10 [H40.05]) and OAG (ICD-10 [H40.11]) at 1 and 5 years following the index date. Patients who entered the cohort closer to 2023 and lacked sufficient follow-up to reach the 5-year time point were excluded from the 5-year outcome analysis but remained eligible for inclusion in the 1-year analysis.
Adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for the association between statin use and each outcome were estimated using multivariate Cox proportional hazards models, adjusting for the above-mentioned covariates. The proportional hazards assumption was assessed using the generalized Schoenfeld method.
Kaplan-Meier survival analyses were performed to estimate time-to-event probabilities for OHT and OAG within each matched cohort. Hazard ratios (rather than risk ratios) were selected to account for differential follow-up durations and right-censoring, including patients who were lost to follow-up or had not yet experienced the outcome by the end of the study period.
Descriptive statistics were used to summarize baseline characteristics, including means and standard deviations (SD) for continuous variables and proportions for categorical variables. All statistical analyses were conducted using the TriNetX analytics platform, with statistical significance defined as a 2-sided P -value <.05.
RESULTS
Before PSM, the study cohorts consisted of (1) 242 381 Non-Hispanic White patients with hyperlipidemia, of whom 172 695 were on statins, (2) 46 215 Non-Hispanic African American patients with hyperlipidemia, with 37 399 on statins, (3) 12 011 Non-Hispanic Asian patients, with 8648 were on statins; and (4) 35 167 Hispanic patients, with 25 880 on statins ( Figure 1 ). Among those on statins, the proportion of male patients was 51.6% for non-Hispanic whites, 37.7% for African Americans, 48.4% for Asians, and 45.4% for Hispanics. The mean ages at the index event were 66.3 ± 11.3 years for Non-Hispanic Whites, 62.1 ± 11 years for African Americans, 64.2 ± 11.4 years for Asians, and 61.5 ± 11.2 years for Hispanics.
After applying PSM, equally sized groups of statin users and nonusers were identified within each racial and ethnic cohort. At the index date, 60 575 Non-Hispanic White patients were matched in each group (statin and nonstatin users), as shown in Table 1 .
| Characteristics | Before Matching | After Matching | Standardized Difference | |||
|---|---|---|---|---|---|---|
| Non-Hispanic Whites with Statins (n = 172 695) | Non-Hispanic Whites without Statins (n = 69 686) | Standardized Difference | Non-Hispanic Whites with Statins (n = 60 575) | Non-Hispanic Whites without Statins (n = 60 575) | ||
| Age at Index, Mean (SD) | 66.3 (11.3) | 63.3 (13.8) | 0.2 | 64.4 (11.5) | 64 (13.6) | 0.04 |
| Sex, N (%) | ||||||
| Male | 89 156 (51.6) | 26 468 (37.9) | 0.3 | 24 421 (40.3) | 24 658 (40.7) | 0.008 |
| Female | 83 531 (48.4) | 43 217 (62) | 0.3 | 36 151 (59.7) | 35 916 (59.3) | 0.007 |
| Hypertensive Disease, N (%) | 139 451 (80.8) | 39 191 (56.2) | 0.5 | 37 381 (61.7) | 37 180 (61.4) | 0.006 |
| Disorders of Thyroid Gland, N (%) | 49 481 (28.7) | 19 901 (28.6) | 0.002 | 17 382 (28.7) | 17 258 (28.5) | 0.004 |
| Chronic Lower Respiratory Diseases, N (%) | 63 454 (36.7) | 20 225 (29) | 0.2 | 18 400 (30.4) | 18 322 (30.2) | 0.002 |
| Diabetes Mellitus, N (%) | 76 599 (44.4) | 13 252 (19) | 0.6 | 12 871 (21.2) | 13 135 (21.7) | 0.01 |
| Sleep Disorders, N (%) | 67 460 (39.1) | 20 717 (29.7) | 0.2 | 19 114 (31.6) | 18 973 (31.3) | 0.005 |
| Ischemic Heart Diseases, N (%) | 63 742 (36.9) | 9108 (13.1) | 0.6 | 8683 (14.3) | 9002 (14.9) | 0.01 |
| Cerebrovascular Diseases, N (%) | 36 222 (20.9) | 5935 (8.5) | 0.4 | 5688 (9.4) | 5810 (9.6) | 0.006 |
| Chronic Kidney Disease, N (%) | 31 339 (18.1) | 6080 (8.7) | 0.3 | 5916 (9.7) | 5877 (9.7) | 0.002 |
| Nicotine Dependence, N (%) | 36 386 (21.1) | 9182 (13.2) | 0.2 | 8500 (14) | 8657 (14.3) | 0.007 |
| Body Mass Index, mean (SD) | 32.9 (17.2) | 35.3 (141) | 0.02 | 32 (19.9) | 35.6 (145) | 0.03 |
| Serum Cholesterol in LDL, Mean (SD) | 90.3 (36.3) | 118 (34) | 0.8 | 100 (36.5) | 117 (34.2) | 0.5 |
| HbA1C, Mean (SD) | 6.6 (1.6) | 5.9 (1.2) | 0.5 | 6.2 (1.4) | 5.9 (1.2) | 0.2 |
| Systemic Corticosteroids | 129 238 (74.8) | 45 066 (64.7) | 0.2 | 41 436 (68.4) | 40 858 (67.5) | 0.02 |
| Beta-Blockers | 99 901 (57.8) | 19 675 (28.2) | 0.6 | 19 463 (32.1) | 19 366 (31.9) | 0.003 |
The risk of OHT was lower in the statin group at 1 year (0.3% vs 0.5% in the nonstatin group, P < .0001) and 5 years (0.9% vs 1.4% in the nonstatin group, P < .0001). Similarly, the risk of OAG was significantly lower in the statin group at 1 year (1.0% vs 1.6% in the nonstatin group, P < .0001) and 5 years (1.4% vs 2.5% in the nonstatin group, P < .0001). A multivariate Cox proportional hazard model revealed that statin use significantly reduced the risk of OHT and OAG. The aHR for OHT in the statin group was 0.5 (95% CI: 0.4-0.6, P < .0001) at 1 year and remained 0.5 (95% CI: 0.5-0.6, P < .0001) at 5 years compared to the nonstatin group. Similarly, the risk of OAG was reduced with an aHR of 0.7 (95% CI: 0.6-0.7, P < .0001) at 1 year and 0.6 (95% CI: 0.5-0.6, P < .0001) at 5 years.
At the index date, 7540 non-Hispanic African American patients were matched in each group ( Table 2 ). The risk of OHT was similar in both groups at 1 year (0.4% in the statin group vs 0.5% in the nonstatin group, P = .4) and 5 years (1.6% in the statin group vs 1.6% in the nonstatin group, P = .9). A multivariate Cox proportional hazard model showed that statin use was not associated with a reduction in the risk of OHT, with an aHR of 0.8 (95% CI: 0.5-1.1, P = .2) at 1 year and 0.8 (95% CI: 0.7-1.0, P = .1 at 5 years. However, the risk of OAG was significantly lower in the statin group at 1 year (2.7% in the statin group vs 3.6% in the nonstatin group, P = .004) and 5 years (3.4% in the statin group vs 5% in the nonstatin group, P < .0001). The aHRs of OAG development in the statin group were 0.8 (95% CI: 0.6-0.9, P = .0004) at 1 year and 0.6 (95% CI: 0.5-0.7, P < .0001) at 5 years compared to nonstatin users.
| Characteristics | Before Matching | After Matching | Standardized Difference | |||
|---|---|---|---|---|---|---|
| Non-Hispanic AA with Statins (n = 37 399) | Non-Hispanic AA without Statins (n = 8816) | Standardized Difference | Non-Hispanic AA with Statins (n = 7540) | Non-Hispanic AA without Statins (n = 7540) | ||
| Age at Index, Mean (SD) | 62.1 (11) | 58.8 (13.2) | 0.3 | 60.1 (11) | 59.9 (13) | 0.02 |
| Sex, N (%) | ||||||
| Male | 14 104 (37.7) | 2778 (31.5) | 0.1 | 2407 (31.9) | 2443 (32.4) | 0.01 |
| Female | 23 295 (62.2) | 6038 (68.5) | 0.1 | 5133 (68.1) | 5097 (67.6) | 0.01 |
| Hypertensive Disease, N (%) | 35 124 (93.9) | 6525 (74) | 0.6 | 6075 (80.6) | 6084 (80.7) | 0.003 |
| Disorders of Thyroid Gland, N (%) | 8547 (22.9) | 1906 (21.6) | 0.03 | 1677 (22.2) | 1662 (22) | 0.005 |
| Chronic Lower Respiratory Diseases, N (%) | 13 491 (36.1) | 2339 (26.5) | 0.2 | 2133 (28.3) | 2122 (28.1) | 0.003 |
| Diabetes Mellitus, N (%) | 26 436 (70.7) | 3407 (38.6) | 0.7 | 3307 (43.9) | 3350 (44.4) | 0.01 |
| Sleep Disorders, N (%) | 14 802 (39.6) | 2441 (27.7) | 0.3 | 2277 (30.2) | 2247 (29.8) | 0.008 |
| Ischemic Heart Diseases, N (%) | 11 806 (31.6) | 1062 (12.04) | 0.5 | 1018 (13.5) | 1041 (13.8) | 0.008 |
| Cerebrovascular Diseases, N (%) | 8599 (22.9) | 770 (8.7) | 0.4 | 719 (9.5) | 754 (10) | 0.01 |
| Chronic Kidney Disease, N (%) | 10 984 (29.4) | 1290 (14.6) | 0.4 | 1214 (16.1) | 1235 (16.4) | 0.007 |
| Nicotine Dependence, N (%) | 10 651 (28.5) | 1526 (17.3) | 0.3 | 1408 (18.7) | 1435 (19) | 0.009 |
| Body Mass Index, Mean (SD) | 34.7 (8.2) | 34.1 (8.9) | 0.06 | 32.8 (7.2) | 34.6 (9.3) | 0.2 |
| Serum Cholesterol in LDL, Mean (SD) | 97 (42.6) | 114 (37.4) | 0.4 | 108 (45.1) | 113 (36.9) | 0.1 |
| HbA1C, Mean (SD) | 7.1 (2.2) | 6.1 (1.6) | 0.5 | 6.8 (2.1) | 6.2 (1.7) | 0.3 |
| Systemic Corticosteroids | 26 897 (71.9) | 5210 (59.1) | 0.3 | 4734 (62.8) | 4677 (62) | 0.01 |
| Beta-Blockers | 23 350 (62.4) | 2703 (30.6) | 0.7 | 2750 (36.4) | 2656 (35.2) | 0.02 |
For non-Hispanic Asian patients, 2623 individuals were matched in the statin and nonstatin groups at the index date ( Table 3 ). The risk of OHT was similar in both groups at 1 year (0.4% in the statin group vs 0.3% in the nonstatin group, P = .3) and 5 years (0.7% in the statin group vs 0.9% in the nonstatin group, P = .3). The multivariate analysis revealed no significant difference in the risk of OHT at 1 year (aHR: 1.0, 95% CI: 0.4-2.5, P = .9) or at 5 years (aHR: 0.9, 95% CI: 0.5-1.6, P = .6). The risk of OAG was similar between both groups at 1 year (2.4% vs 2.9%, P = .2); however, it was lower in the statin group at 5 years (3.05% vs 3.9% in the nonstatin group, P = .03). A multivariate Cox proportional hazard model revealed no difference in the risk of OAG at 1 year (aHR: 1.1, 95% CI: 0.7-1.5, P = .8). However, by 5 years, a significant reduction in OAG risk was observed in the statin group, with an aHR of 0.7 (95% CI: 0.5-0.9, P = .007).
| Characteristics | Before Matching | After Matching | Standardized Difference | |||
|---|---|---|---|---|---|---|
| Non-Hispanic Asians with Statins (n = 8648) | Non-Hispanic Asians without Statins (n = 3363) | Standardized Difference | Non-Hispanic Asians with Statins (n = 2623) | Non-Hispanic without Statins (n = 2623) | ||
| Age at Index, Mean (SD) | 64.2 (11.4) | 59.5 (14) | 0.4 | 61.4 (11.4) | 61.2 (13.8) | 0.02 |
| Sex, N (%) | ||||||
| Male | 4183 (48.4) | 1221 (36.3) | 0.2 | 1020 (38.9) | 1041 (39.7) | 0.01 |
| Female | 4464 (51.6) | 2142 (63.7) | 0.2 | 1603 (61.1) | 1582 (60.3) | 0.01 |
| Hypertensive Disease, N (%) | 6713 (77.6) | 1673 (49.7) | 0.6 | 1477 (56.3) | 1510 (57.6) | 0.02 |
| Disorders of Thyroid Gland, N (%) | 2272 (26.3) | 871 (25.9) | 0.008 | 702 (26.8) | 678 (25.8) | 0.02 |
| Chronic Lower Respiratory Diseases, N (%) | 1763 (20.4) | 527 (15.7) | 0.1 | 459 (17.5) | 434 (16.5) | 0.02 |
| Diabetes Mellitus, N (%) | 5447 (62.9) | 917 (27.3) | 0.8 | 863 (32.9) | 900 (34.3) | 0.02 |
| Sleep Disorders, N (%) | 2213 (25.6) | 596 (17.7) | 0.2 | 520 (19.8) | 516 (19.7) | 0.003 |
| Ischemic Heart Diseases, N (%) | 2333 (26.9) | 311 (9.2) | 0.5 | 294 (11.2) | 298 (11.4) | 0.004 |
| Cerebrovascular Diseases, N (%) | 1491 (17.2) | 224 (6.7) | 0.3 | 234 (8.9) | 210 (8) | 0.03 |
| Chronic Kidney Disease, N (%) | 1361 (15.7) | 206 (6.1) | 0.3 | 210 (8) | 196 (7.5) | 0.02 |
| Nicotine Dependence, N (%) | 646 (7.5) | 142 (4.2) | 0.1 | 119 (4.5) | 122 (4.7) | 0.005 |
| Body Mass Index, Mean (SD) | 26.4 (4.6) | 26.8 (5.5) | 0.08 | 25.6 (3.1) | 26.5 (5.1) | 0.2 |
| Serum Cholesterol in LDL, Mean (SD) | 87.3 (36.7) | 117 (32.9) | 0.8 | 98.9 (37.9) | 114 (32.8) | 0.4 |
| HbA1C, Mean (SD) | 6.8 (1.4) | 6.01 (1.02) | 0.6 | 6.4 (1.2) | 6.1 (1.1) | 0.2 |
| Systemic Corticosteroids | 5665 (65.5) | 1809 (53.8) | 0.2 | 1507 (57.5) | 1503 (57.3) | 0.003 |
| Beta-Blockers | 4050 (46.8) | 646 (19.2) | 0.6 | 638 (24.3) | 616 (23.4) | 0.01 |
In the Hispanic cohort, 6357 patients were matched in each group at the index date ( Table 4 ). At 1 year, the risks of OHT (0.5% in the statin group vs 0.5% in the nonstatin group, P = 1) and OAG (1.1% in the statin group vs 1.2% in the nonstatin group, P = .9) were similar between both groups. At 5 years, the risk of OHT was comparable between both groups (1.1% in the statin group vs 1.3% in the nonstatin group, P = .4); however, the statin group was associated with a lower risk of OAG (1.7% in the statin group vs 2.3% in the nonstatin group, P = .01). A multivariate Cox proportional hazard model revealed that statin use did not significantly affect the risk of OHT at 1 year (aHR: 1.1, 95% CI: 0.7-1.6, P = .8) or at 5 years (aHR: 0.7, 95% CI: 0.6-1, P = .02). Similarly, no significant difference in the risk of OAG was observed at 1 year (aHR: 0.9, 95% CI: 0.7-1.2, P = .6), but a significant reduction emerged at 5 years, with an aHR of 0.7 (95% CI: 0.6-0.8, P = .0003). Figure 2 summarizes the aHR across different racial and ethnic subgroups.
