Abstract
Purpose
To investigate the association between statin use and glaucoma risk.
Methods
This is a nationwide nested case-control study including adults with hyperlipidemia from the Taiwan National Health Insurance Research Database between 2009 and 2020. Cases were individuals newly diagnosed with ocular hypertension, primary open-angle glaucoma (POAG), or normal tension glaucoma (NTG). Controls were individuals without any subtypes of glaucoma. Prescription records for statins, fibrates, and other cholesterol-lowering medications were collected. Logistic regression models were applied to assess the association between medication exposure and the risk of glaucoma.
Results
The final analysis included 32,640 participants with ocular hypertension, 20,390 with POAG, 9945 with NTG, and more than 130,560 in the control group. Compared to non-users, statin users had significantly higher risks of developing ocular hypertension (adjusted odds ratio [aOR] = 1.12; 95% confidence interval [CI], 1.09–1.15; P < 0.001) and POAG (aOR = 1.07; 95% CI, 1.04–1.11; P < 0.001), particularly among those prescribed atorvastatin and rosuvastatin. Subgroup analyses by duration of statin prescription (<1 year, 1–3 years, and >3 years) revealed a trend of higher glaucoma risk with longer statin use. Additionally, fibrate use was associated with an increased risk of ocular hypertension (aOR = 1.05; 95% CI, 1.00–1.10; P = 0.032), and POAG (aOR = 1.09; 95% CI, 1.03–1.15; P = 0.002).
Conclusions
Statin use, particularly atorvastatin and rosuvastatin, is associated with an increased risk of ocular hypertension and POAG among patients with hyperlipidemia. The risk appears to increase with longer durations of statin use.
Keywords: statins, ocular hypertension, primary open-angle glaucoma, normal tension glaucoma
Statins are increasingly used in the medical field for their effectiveness in lowering serum cholesterol and providing cardiovascular protection.1,2 Individuals with hyperlipidemia, diabetes, advanced age, a family history of coronary heart disease, atherosclerosis, cerebral infarction, or other risk factors for atherosclerotic cardiovascular disease can benefit from statin medications.3 Previous research has also shown that statins may influence the risk of glaucoma.
Glaucoma is a common age-related eye condition and remains the leading cause of irreversible blindness worldwide. In 2020, out of the 33.6 million adults aged 50 and above who were blind, approximately 3.6 million cases were attributed to glaucoma.4 Globally, an estimated 64.3 million adults aged 40 to 80 were living with glaucoma in 2013, and this number is projected to rise to 111.8 million by 2040.5 Given the increasing global prevalence of glaucoma, it is essential to thoroughly assess and interpret the potential impact of statins on glaucoma risk. However, previous research has reported inconsistent and sometimes conflicting results.
Several studies have demonstrated an association between statin use and an increased risk of glaucoma, particularly with long-term use.6–8 However, other studies have suggested that statins may be associated with a reduced risk of glaucoma,9–12 whereas some have found no significant relationship at all.13 These inconsistent findings may be attributed to differences in statin dosage, duration of use, or the specific types of glaucoma investigated. Additionally, many prior studies on this topic were constrained by limited cohort sizes or methodological limitations inherent to their study designs. Given the aging population and the rising incidence of glaucoma, further large-scale studies are needed to clarify the conflicting findings in current research.
To overcome methodological limitations identified in prior studies, we conducted a nationwide case-control study to investigate the association between statin use and glaucoma in the Taiwanese population. We excluded individuals who were prescribed multiple cholesterol-lowering medications to reduce confounding, and assessed glaucoma risk according to different statin types and durations of exposure. By applying stricter methodology and examining specific subgroups, we aimed to provide deeper insights into the association between statin use and glaucoma.
Method
Study Design and Data Source
This population-based nested case control study investigated the association between the use of cholesterol-lowering medications (statins, fibrates, and others) and the risks of ocular hypertension, primary open-angle glaucoma (POAG), and normal tension glaucoma (NTG) in patients with hyperlipidemia. In this nested case control design, both cases and controls were drawn from a well-defined parent cohort, ensuring that all participants were at risk for the outcome at the time of sampling. The date of outcome occurrence served as the index date for each case, and exposures were assessed during a predefined look-back period preceding this index date. By leveraging a nested structure within an existing cohort, this design preserves the temporal sequence between exposure and outcome and minimizes recall and selection biases commonly associated with traditional case-control studies. Our study utilizes data from the Taiwan National Health Insurance Research Database, a nationwide healthcare program established in March 1995, which currently covers over 99% of Taiwan's 23 million residents. This database includes comprehensive medical records, such as inpatient and outpatient visits, disease diagnoses, treatments, and demographic characteristics. Disease classification was conducted using the International Classification of Diseases, Ninth and Tenth Revisions, Clinical Modification (ICD-9-CM and ICD-10-CM). To protect patient confidentiality, all personal identifiers within the database are encrypted. This study was approved by the Research Ethics Committee of China Medical University and Hospital (CMUH112-REC1-117[CR-1]). Informed consent was not required, because no interventions involving human subjects were conducted.
Study Population
Cases were defined as individuals aged 18 years or older who were newly diagnosed with ocular hypertension (ICD-9 codes 365.04 and ICD-10 codes H40.05), POAG (ICD-9 codes 365.11 and ICD-10 codes H40.11), or NTG (ICD-9 codes 365.12 and ICD-10 codes H40.12) between 2009 and 2020 after a prior diagnosis of hyperlipidemia. Controls were individuals aged 18 years or older who had hyperlipidemia and had no record of any glaucoma subtype (ICD-9 codes 365 and ICD-10 codes H40) in the database. Glaucoma and hyperlipidemia diagnoses were confirmed by at least two outpatient visits or one inpatient record, and individuals with only a single outpatient record of glaucoma were excluded from both case and control groups.
Cases with ocular hypertension, POAG, or NTG were propensity score matched to random controls at a 1:4 ratio based on sex, age, region of dwelling, urbanization, monthly income, comorbidities (coronary artery disease, ischemic stroke, peripheral artery disease, atrial fibrillation, heart failure, hypertension, diabetes mellitus, chronic kidney disease, asthma, chronic obstructive pulmonary disease, cirrhosis, thyroid diseases, depression, dementia, alcoholism, nicotine dependence, cancer, and ophthalmological conditions), and prior use of cholesterol-lowering medications. Controls were not allowed to be matched to multiple cases. The index event for cases was defined as their first diagnosis of ocular hypertension, POAG, or NTG, whereas controls were assigned the same index year as their matched case.
Subjects meeting any of the following criteria were excluded from the study: (i) a history of glaucoma surgery before the index date; (ii) no information on age, sex, region of dwelling, or urbanization; (iii) concurrent use of different classes of cholesterol-lowering medications such as statins, fibrates, or other cholesterol-lowering medications; (iv) concurrent use of two or more types of statins, including atorvastatin, rosuvastatin, fluvastatin, pravastatin, lovastatin, simvastatin, or pitavastatin. All diagnoses, including hyperlipidemia, glaucoma, and comorbidities used in the propensity score matching, were confirmed by at least two outpatient visits or one hospitalization record with the corresponding ICD-9-CM and ICD-10-CM codes (Supplementary Table S1A).
Definition of Drug Exposure and Duration
Prescription records of cholesterol-lowering medications, including statins, fibrates, bile acid sequestrants, nicotinic acid and derivatives, or others, between the diagnosis of hyperlipidemia and the index date were extracted. Drug exposure was defined as individuals who had three or more prescription records of cholesterol-lowering medications within the five years before the index date. Those without any of the prescriptions during this period were classified as unexposed. The Anatomical Therapeutic Chemical codes used to define medication prescriptions are listed in Supplementary Table S1B.
To evaluate potential dose-response associations between statin use and risk of glaucoma, statin users were further categorized into three groups based on their duration of statin exposure (<1 year, 1–3 years, and >3 years). Duration was defined based on the total length of statin prescriptions that were actually filled by the patients between the index date and the end of follow-up. If the prescription was not filled, it would not be included in the duration calculation.
Sensitivity Analysis
To reduce the potential influence of loss to follow-up, we conducted a sensitivity analysis excluding patients with less than five years of observation between hyperlipidemia diagnosis and the onset of ocular hypertension, POAG, or NTG.
Statistical Analysis
The distribution of categorical variables between the study and control groups was compared using the χ2 test, whereas continuous variables were compared by use of the t-test. Differences in all variables between the two groups were also assessed using the standardized mean difference (SMD), where an SMD ≤0.1 indicates negligible differences. Logistic regression models were used to analyze the relationship between medication use and outcomes, with odds ratios (ORs) and 95% confidence intervals (CIs) calculated to investigate potential associations. Both the crude ORs and ORs adjusted for all covariates in the propensity score matching were presented. All statistical analyses were conducted using SAS software version 9.4 (SAS Institute, Cary, NC, USA), with a two-tailed significance threshold set at 0.05.
Results
This study includes three distinct cohorts, including the ocular hypertension, POAG, and NTG cohorts. Among 163,200 participants in the ocular hypertension cohort, 32,640 were identified as cases and 130,560 as controls. In the POAG cohort, 101,950 participants were included, with 20,390 cases and 81,560 matched controls. The NTG cohort comprised 49,725 individuals, including 9,945 cases and 39,780 controls. Figure 1 presents the flowchart outlining the inclusion and exclusion process. The baseline characteristics between the case and control groups are mostly well balanced and are detailed in Tables 1 to 3.
Figure 1.
Study flowchart. Participants with hyperlipidemia were categorized into the ocular hypertension (OHT), POAG, and NTG cohorts. Those who met the inclusion criteria for cases and controls were then propensity score matched in a 1:4 ratio, forming the final study population for analysis. NTG, normal tension glaucoma; OHT, ocular hypertension; POAG, primary open-angle glaucoma.
Table 1.
Baseline Demographics: Ocular Hypertension
| Variable | Case (n = 32,640) | Control (n = 130,560) | SMD |
|---|---|---|---|
| Lipid-lowering agent usage | 0.042 | ||
| No | 18,396 (56.36%) | 76,321 (58.46%) | |
| Yes | 14,244 (43.64%) | 54,239 (41.54%) | |
| Lipid-lowering agent type | |||
| Statin | 11,279 (34.56%) | 42,799 (32.78%) | 0.038 |
| Fibrates | 2874 (8.81%) | 11,148 (8.54%) | 0.009 |
| Others | 91 (0.28%) | 292 (0.22%) | 0.011 |
| Sex | 0.025 | ||
| Female | 17,522 (53.68%) | 71,716 (54.93%) | |
| Male | 15,118 (46.32%) | 58,844 (45.07%) | |
| Age (yrs), mean (SD) | 58 (13.44) | 59 (13.44) | 0.055 |
| Region of dwelling, n (%) | |||
| Northern | 20,143 (61.71) | 71,342 (54.64) | 0.144 |
| Central | 8229 (25.21) | 31,107 (23.83) | 0.032 |
| Southern | 3687 (11.30) | 24,790 (18.99) | 0.216 |
| Eastern | 581 (1.78) | 3321 (2.54) | 0.053 |
| Urbanization | |||
| 1 | 335 (1.03%) | 1082 (0.83%) | 0.021 |
| 2 | 2046 (6.27%) | 8862 (6.79%) | 0.021 |
| 3 | 11,458 (35.10%) | 49,295 (37.76%) | 0.055 |
| 4 | 18,801 (57.60%) | 71,321 (54.63%) | 0.060 |
| Monthly income (NTD), mean (SD) | |||
| <18000 | 8701 (26.66) | 32,801 (25.12) | 0.035 |
| 18,000–34,999 | 13,442 (41.18) | 59,830 (45.83) | 0.094 |
| ≥35,000 | 10,497 (32.16) | 37,929 (29.05) | 0.067 |
| Comorbidities | |||
| Coronary artery disease | 7392 (22.65%) | 30,068 (23.03%) | 0.009 |
| Ischemic stroke | 1262 (3.87%) | 5442 (4.17%) | 0.015 |
| Peripheral artery disease | 2312 (7.08%) | 8754 (6.70%) | 0.015 |
| Atrial fibrillation | 4175 (12.79%) | 17,583 (13.47%) | 0.020 |
| Heart failure | 1314 (4.03%) | 5734 (4.39%) | 0.018 |
| Hypertension | 19,904 (60.98%) | 80,058 (61.32%) | 0.007 |
| Diabetes mellitus | 14,773 (45.26%) | 60,707 (46.50%) | 0.025 |
| Chronic kidney disease | 1187 (3.64%) | 5434 (4.16%) | 0.027 |
| Asthma | 2303 (7.06%) | 9807 (7.51%) | 0.018 |
| COPD | 2378 (7.29%) | 9927 (7.60%) | 0.012 |
| Cirrhosis | 253 (0.78%) | 1,53 (0.88%) | 0.012 |
| Thyroid diseases | 4039 (12.37%) | 16,188 (12.40%) | 0.001 |
| Depression | 3032 (9.29%) | 12,186 (9.33%) | 0.002 |
| Dementia | 646 (1.98%) | 2993 (2.29%) | 0.022 |
| Alcoholism | 156 (0.48%) | 687 (0.53%) | 0.007 |
| Nicotine dependence | 843 (2.58%) | 3231 (2.47%) | 0.007 |
| Cancer | 1769 (5.42%) | 7950 (6.09%) | 0.029 |
| Ophthalmological conditions | 17,658 (54.10%) | 70,900 (54.30%) | 0.004 |
| Charlson comorbidity index | 0.000 | ||
| 1 | 28,304 (86.72%) | 111,410 (85.33%) | 0.040 |
| 2–3 | 3459 (10.60%) | 14,580 (11.17%) | 0.018 |
| >3 | 877 (2.69%) | 4570 (3.50%) | 0.047 |
COPD, chronic obstructive pulmonary disease; NTD, New Taiwan dollar; SD, standard deviation.
Cases refer to individuals diagnosed with the respective glaucoma event, whereas controls are those without any documented glaucoma.
Table 3.
Baseline Demographics: NTG
| Variable | Case (n = 9945) | Control (n = 39,780) | SMD |
|---|---|---|---|
| Lipid-lowering agent usage | 0.033 | ||
| No | 5890 (59.23%) | 22,917 (57.61%) | |
| Yes | 4055 (40.77%) | 16,863 (42.39%) | |
| Lipid-lowering agent type | |||
| Statin | 3266 (32.84%) | 13,528 (34.01%) | 0.025 |
| Fibrates | 761 (7.65%) | 3229 (8.12%) | 0.017 |
| Others | 28 (0.28%) | 106 (0.27%) | 0.003 |
| Sex | 0.039 | ||
| Female | 4724 (47.50%) | 19,671 (49.45%) | |
| Male | 5221 (52.50%) | 20,109 (50.55%) | |
| Age (yrs), mean (SD) | 62 (12.52) | 63 (12.77) | 0.070 |
| Region of dwelling | |||
| Northern | 6161 (61.95%) | 21,570 (54.22%) | 0.157 |
| Central | 2089 (21.01%) | 9551 (24.01%) | 0.072 |
| Southern | 1408 (14.16%) | 7611 (19.13%) | 0.134 |
| Eastern | 287 (2.89%) | 1048 (2.63%) | 0.015 |
| Urbanization | |||
| 1 | 89 (0.89%) | 343 (0.86%) | 0.004 |
| 2 | 497 (5.00%) | 2824 (7.10%) | 0.088 |
| 3 | 3675 (36.95%) | 15,195 (38.20%) | 0.026 |
| 4 | 5684 (57.15%) | 21,418 (53.84%) | 0.067 |
| Monthly income (NTD), mean (SD) | |||
| <18000 | 2931 (29.47) | 11,166 (28.07) | 0.031 |
| 18,000–34,999 | 3599 (36.19) | 17,662 (44.40) | 0.168 |
| ≥35,000 | 3415 (34.34) | 10,952 (27.53) | 0.148 |
| Comorbidities | |||
| Coronary artery disease | 2802 (28.17%) | 12,277 (30.86%) | 0.059 |
| Ischemic stroke | 495 (4.98%) | 2661 (6.69%) | 0.073 |
| Peripheral artery disease | 745 (7.49%) | 3664 (9.21%) | 0.062 |
| Atrial fibrillation | 1572 (15.81%) | 6979 (17.54%) | 0.047 |
| Heart failure | 521 (5.24%) | 2714 (6.82%) | 0.067 |
| Hypertension | 5744 (57.76%) | 23,177 (58.26%) | 0.010 |
| Diabetes mellitus | 3827 (38.48%) | 16,374 (41.16%) | 0.055 |
| Chronic kidney disease | 368 (3.70%) | 2155 (5.42%) | 0.082 |
| Asthma | 688 (6.92%) | 3499 (8.80%) | 0.070 |
| COPD | 869 (8.74%) | 4514 (11.35%) | 0.087 |
| Cirrhosis | 100 (1.01%) | 706 (1.77%) | 0.066 |
| Thyroid diseases | 1373 (13.81%) | 5733 (14.41%) | 0.017 |
| Depression | 1114 (11.20%) | 4986 (12.53%) | 0.041 |
| Dementia | 330 (3.32%) | 1677 (4.22%) | 0.047 |
| Alcoholism | 49 (0.49%) | 369 (0.93%) | 0.052 |
| Nicotine dependence | 207 (2.08%) | 1111 (2.79%) | 0.046 |
| Cancer | 721 (7.25%) | 3801 (9.56%) | 0.083 |
| Ophthalmological conditions | 6042 (60.75) | 24,371 (61.26) | 0.010 |
| Charlson comorbidity index | 0.000 | ||
| 1 | 8516 (85.63%) | 31,741 (79.79%) | 0.155 |
| 2–3 | 1169 (11.75%) | 6017 (15.13%) | 0.099 |
| >3 | 260 (2.61%) | 2022 (5.08%) | 0.129 |
Cases refer to individuals diagnosed with the respective glaucoma event, whereas controls are those without any documented glaucoma.
Table 2.
Baseline Demographics: POAG
| Variable | Case (n = 20,390) | Control (n = 81,560) | SMD |
|---|---|---|---|
| Lipid-lowering agent usage | 0.023 | ||
| No | 11,177 (54.82%) | 45,643 (55.96%) | |
| Yes | 9213 (45.18%) | 35,917 (44.04%) | |
| Lipid-lowering agent type | |||
| Statin | 7245 (35.53%) | 28,535 (34.99%) | 0.011 |
| Fibrates | 1892 (9.28%) | 7208 (8.84%) | 0.015 |
| Others | 76 (0.37%) | 174 (0.21%) | 0.029 |
| Sex, n (%) | 0.065 | ||
| Female | 9780 (47.96) | 41,757 (51.20) | |
| Male | 10,610 (52.04) | 39,803 (48.80) | |
| Age (yrs), mean (SD) | 62 (13.11) | 63 (13.21) | 0.050 |
| Region of dwelling | |||
| Northern | 12,323 (60.44%) | 43,963 (53.90%) | 0.132 |
| Central | 4153 (20.37%) | 19,862 (24.35%) | 0.096 |
| Southern | 3354 (16.45%) | 15,580 (19.10%) | 0.069 |
| Eastern | 560 (2.75%) | 2155 (2.64%) | 0.006 |
| Urbanization | |||
| 1 | 185 (0.91%) | 767 (0.94%) | 0.003 |
| 2 | 1142 (5.60%) | 5599 (6.86%) | 0.052 |
| 3 | 7364 (36.12%) | 31,195 (38.25%) | 0.044 |
| 4 | 11,699 (57.38%) | 43,999 (53.95%) | 0.069 |
| Monthly income (NTD), mean (SD) | |||
| <18,000 | 6134 (30.08) | 22,692 (27.82) | 0.050 |
| 18,000–34,999 | 7969 (39.08) | 36,961 (45.32) | 0.126 |
| ≥35,000 | 6287 (30.83) | 21,907 (26.86) | 0.088 |
| Comorbidities, n (%) | |||
| Coronary artery disease | 5305 (26.02%) | 21,767 (26.69%) | 0.015 |
| Ischemic stroke | 965 (4.73%) | 4261 (5.22%) | 0.023 |
| Peripheral artery disease | 1593 (7.81%) | 6617 (8.11%) | 0.011 |
| Atrial fibrillation | 2962 (14.53%) | 12,266 (15.04%) | 0.014 |
| Heart failure | 1072 (5.26%) | 4605 (5.65%) | 0.017 |
| Hypertension | 13,087 (64.18%) | 53,334 (65.39%) | 0.025 |
| Diabetes mellitus | 9105 (44.65%) | 39,696 (48.67%) | 0.081 |
| Chronic kidney disease | 822 (4.03%) | 4387 (5.38%) | 0.064 |
| Asthma | 1429 (7.01%) | 6234 (7.64%) | 0.024 |
| COPD | 1698 (8.33%) | 7496 (9.19%) | 0.031 |
| Cirrhosis | 205 (1.01%) | 1091 (1.34%) | 0.031 |
| Thyroid diseases | 2378 (11.66%) | 11,989 (14.70%) | 0.090 |
| Depression | 2129 (10.44) | 8613 (10.56%) | 0.004 |
| Dementia | 688 (3.37%) | 3157 (3.87%) | 0.027 |
| Alcoholism | 107 (0.52%) | 535 (0.66%) | 0.017 |
| Nicotine dependence | 474 (2.32%) | 2014 (2.47%) | 0.009 |
| Cancer | 1364 (6.69%) | 5923 (7.26%) | 0.022 |
| Ophthalmological conditions | 12,062 (59.16%) | 48,495 (59.46%) | 0.006 |
| Charlson comorbidity index | 0.000 | ||
| 1 | 17,321 (84.95%) | 67,290 (82.50%) | 0.066 |
| 2–3 | 2433 (11.93%) | 10,615 (13.01%) | 0.033 |
| >3 | 636 (3.125) | 3655 (4.48%) | 0.071 |
Cases refer to individuals diagnosed with the respective glaucoma event, whereas controls are those without any documented glaucoma.
Figure 2 illustrates the adjusted ORs (aORs) and 95% CIs for ocular hypertension, POAG, and NTG associated with different cholesterol-lowering medications. Compared to non-users, statin users have statistically significant higher risks of developing ocular hypertension (aOR = 1.12; 95% CI, 1.09–1.15; P < 0.001) and POAG (aOR = 1.07; 95% CI, 1.04–1.11; P < 0.001). Similarly, fibrate use is associated with increased risks of ocular hypertension (aOR =1.05; 95% CI, 1.00–1.10; P = 0.032) and POAG (aOR = 1.09; 95% CI, 1.03–1.15; P = 0.002). However, there is no statistically significant association observed between the use of statins (aOR = 0.99; 95% CI, 0.94–1.04; P = 0.717), fibrates (aOR = 0.97; 95% CI, 0.89–1.05; P = 0.463), or other cholesterol-lowering agents (aOR = 1.10; 95% CI, 0.72–1.68; P = 0.644) and the risks of developing NTG. Supplementary Table S2 presents the number of cases and controls across each drug exposure group.
Figure 2.
Risk of glaucoma between different types of cholesterol-lowering medications. The comparative risks of developing ocular hypertension (OHT), primary open-angle glaucoma (POAG), and normal tension glaucoma (NTG) among users of cholesterol-lowering medications compared to non-users are reported as adjusted odds ratios with 95% confidence intervals. *P < 0.05; **P < 0.01; ***P < 0.001.
Figure 3 illustrates the associations between different types of statins and the risks of developing ocular hypertension, POAG, and NTG. The results show that atorvastatin (aOR = 1.19; 95% CI, 1.15–1.23; P < 0.001) and rosuvastatin (aOR = 1.11; 95% CI, 1.06–1.16; P < 0.001) are significantly associated with higher risks of ocular hypertension. Atorvastatin (aOR = 1.09; 95% CI, 1.04–1.14; P < 0.001), rosuvastatin (aOR = 1.07; 95% CI, 1.01–1.13; P = 0.019), fluvastatin (aOR = 1.23; 95% CI, 1.10–1.38; P < 0.001), and pravastatin (aOR = 1.16; 95% CI, 1.03–1.30; P = 0.011) are associated with increased risks of POAG. In contrast, pitavastatin is associated with lower risks of POAG (aOR = 0.88; 95% CI, 0.79–0.98; P = 0.018). Supplementary Table S3 presents the number of cases and controls for each type of statin.
Figure 3.
Risk of glaucoma between different types of statins. The comparative risks of developing ocular hypertension (OHT), primary open-angle glaucoma (POAG), and normal tension glaucoma (NTG) among participants using different types of statins are reported as adjusted odds ratios with 95% confidence intervals, with participants having no history of statin prescriptions serving as the reference group. *P < 0.05; **P < 0.01; ***P < 0.001.
Further examination based on prescription duration reveals a trend indicating that a longer duration of statin use was associated with higher risks of ocular hypertension, POAG, and NTG (Fig. 4). Compared to non-statin users, individuals who had used atorvastatin (aOR = 1.92; 95% CI, 1.69–2.17; P < 0.001), rosuvastatin (aOR = 1.88; 95% CI, 1.62–2.19; P < 0.001), fluvastatin (aOR = 2.04; 95% CI, 1.37–3.03; P < 0.001), and pravastatin (aOR = 1.84; 95% CI, 1.12–3.01; P = 0.016) for more than three years exhibit significantly higher risks of developing ocular hypertension. Likewise, the risks of POAG are significantly higher among individuals who had used atorvastatin (aOR = 2.09; 95% CI, 1.80–2.44; P < 0.001), rosuvastatin (aOR = 2.00; 95% CI, 1.65–2.41; P < 0.001), fluvastatin (aOR = 2.33; 95% CI, 1.47–3.71; P < 0.001), and lovastatin (aOR = 2.17; 95% CI, 1.06–4.46; P = 0.035) for more than three years. Patients who had used atorvastatin (aOR = 1.38; 95% CI, 1.09–1.75; P = 0.008), rosuvastatin (aOR = 1.67; 95% CI, 1.28–2.17; P < 0.001), fluvastatin (aOR = 2.14; 95% CI, 1.09–4.21; P = 0.027), pravastatin (aOR = 4.12; 95% CI, 1.61–10.53; P = 0.003), and pitavastatin (aOR = 4.55; 95% CI, 1.12–18.49; P = 0.034) for over three years also have significantly increased risks of developing NTG. Supplementary Table S4 provides details on the number of cases and controls by type of statin and duration of use.
Figure 4.
Risk of glaucoma between different types of statins and duration of prescription. The comparative risks of developing ocular hypertension (OHT), primary open-angle glaucoma (POAG), and normal tension glaucoma (NTG) among participants using different types of statins and varying durations of statin exposure are reported as adjusted odds ratios with 95% confidence intervals, with participants having no history of statin prescriptions serving as the reference group. *P < 0.05; **P < 0.01; ***P < 0.001.
The sensitivity analysis, which excluded individuals with less than five years of observation between hyperlipidemia diagnosis and the occurrence of ocular hypertension, POAG, or NTG, showed that statin use remained associated with an increased risk of ocular hypertension (aOR = 1.13; 95% CI, 1.08–1.18; P < 0.001) and POAG (aOR = 1.11; 95% CI, 1.05–1.17; P < 0.001), consistent with the main analysis (Supplementary Table S5).
Discussion
This nationwide nested case-control study included a large dataset of Asian individuals, incorporated a dose–response analysis, examined the associations of different statin types with glaucoma risk, and excluded patients using multiple cholesterol-lowering medications to minimize bias, thereby addressing key limitations of previous studies. Our findings show that statin use, particularly atorvastatin and rosuvastatin, is associated with an increased risk of ocular hypertension and POAG in patients with hyperlipidemia. There is also a trend showing that longer durations of statin use, especially exceeding three years, are linked to higher risks of ocular hypertension, POAG, and NTG.
Our results are consistent with recent studies reporting an increased risk of glaucoma associated with prolonged statin use.6–8,14,15 A network meta-analysis conducted by Pan et al. in 2025 reported that rosuvastatin, simvastatin, and pravastatin were associated with an increased risk of developing glaucoma.6 Based on a 10-year nested case-control study consisting of 27,179 participants conducted by Yuan et al.,7 those taking rosuvastatin were at a higher risk of developing glaucoma than those taking other types of statins. Also, a longer duration of statin (>3 years) use was associated with a higher risk of glaucoma compared to short-term use (<1 year).7 In a nested case-control study by Chen et al.14 involving 14,036 participants, higher accumulated defined daily doses per year may correlate with higher risk of open-angle glaucoma. McGwin et al.15 reported that compared to statin non-users, those with longer durations of statin use were associated with a progressively higher risk of developing glaucoma. A cross-sectional study by Lee et al.,8 involving 79,742 individuals with hyperlipidemia, also found that statin use was associated with a higher prevalence of glaucoma. However, some earlier studies have suggested that statins are associated with either a reduced risk of glaucoma9–12 or no relationship at all,13 which contrasts with our findings. Kang et al.13 demonstrated that higher total serum cholesterol levels and statin use were not linked to higher risk of POAG.
Inconsistent findings across different research likely originate from methodological differences across studies, including variations in study designs such as case-control and cohort studies, differences in inclusion criteria based on whether participants were restricted to those diagnosed with hyperlipidemia, follow-up durations ranging from one to 10 years, inconsistent definitions of drug exposure, variability in patient ethnicity and race, and variations in statin intensity. Our study aimed to address these methodological limitations by selecting an Asian population, excluding individuals prescribed multiple cholesterol-lowering agents to eliminate potential confounding from drug-drug interactions, and separately evaluating individual statin types and prescription durations. By adhering to strict inclusion criteria and conducting multiple subgroup analyses, our study provides a comprehensive understanding of statin-associated glaucoma risks, demonstrating that different statin types and prescription durations are associated with varying levels of risk and may partly explain the inconsistent findings of previous studies. Nonetheless, the relationship between statin use and glaucoma risk is highly complex and influenced by numerous uncontrollable factors. Evidence from randomized controlled trials is needed before definitive conclusions can be drawn.
There are several reasons linking statin use to an increased risk of glaucoma. First, statins lower cholesterol levels by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, an essential enzyme in cholesterol and coenzyme Q10 synthesis.16,17 Clinical studies have confirmed that statin treatment decreases serum levels of coenzyme Q10,18,19 while animal studies have indicated that statin-induced inhibition of coenzyme Q10 could result in mitochondrial dysfunction.20,21 Given that retinal ganglion cell axons contain abundant mitochondria,22 it is reasonable to assert that statins may contribute to the development of glaucoma by impairing normal mitochondrial function. Second, an in vitro study indicated that while low concentrations of statins may reverse cell death, high doses of statins could lead to cell apoptosis and neuron cell death, resulting in neuronal damage.23 However, it remains unknown whether this effect has similar impacts on humans. Third, there are studies suggesting that statins may potentially elevate intraocular pressure,24–26 offering another explanation for the association between statin use and POAG. Fourth, the risk of glaucoma may be influenced by both the dose and intensity of statin therapy. Our study found that a longer duration of statin exposure, especially more than 3 years, as well as the use of high-intensity statins, such as atorvastatin and rosuvastatin, are associated with an increased risk of ocular hypertension and POAG. This observation aligns with previous research showing that high-intensity statins are also linked to a greater risk of muscle-related adverse events.27,28
Our study showed that not all statin types are associated with a significantly increased risk of glaucoma. Only atorvastatin and rosuvastatin are linked to higher risks of ocular hypertension and POAG. Because both are high-intensity statins, we hypothesize that their greater potency may correlate with increased glaucoma risk, consistent with previous studies reporting stronger associations between high-intensity statins and adverse events such as myopathy.28,29 On the other hand, pitavastatin was associated with a borderline lower risk of POAG, largely driven by the higher proportion of patients with less than one year of use. This pattern likely reflects the fact that pitavastatin received approval from the Food and Drug Administration and was available in Taiwan later than other statins. However, a trend toward increased POAG risk with longer pitavastatin exposure remains, a pattern similar to that observed with other statin types. Given the relatively small number of pitavastatin users in our cohort, further studies are needed to clarify its association with glaucoma.
Although our study demonstrated that longer duration of statin use was associated with an increased risk of ocular hypertension and POAG, the effect size was small, indicating that the difference in glaucoma risk between statin users and non-users may be marginal. Considering the well-established cardiovascular benefits and cost-effectiveness of statins, our findings alone may not justify changes to current statin prescribing practices based on glaucoma risk.30,31 Nonetheless, our results indicate that individuals with prolonged statin use may benefit from close monitoring for glaucoma risk.
Limitations and Future Research
There are several potential limitations in this study. First, although we used a longitudinal design and observed a temporal relationship between statin use and glaucoma development, it remains uncertain whether statins directly cause glaucoma or whether individuals prescribed statins possess characteristics such as cardiovascular disease or metabolic risk factors that predispose them to glaucoma. Confirmation of a causal relationship would require evidence from randomized controlled trials. Second, as our study relies on a claims database with diagnoses identified through medical codes, there is a potential risk of disease misclassification that may have influenced our findings. Third, although we defined drug exposure and duration based solely on prescriptions that were actually filled by patients, we cannot be certain that patients adhered to the prescribed regimen. Fourth, given that cerivastatin is not approved for use in Taiwan, we were unable to investigate its association with glaucoma. As there are a limited number of studies exploring the impact of cerivastatin on glaucoma, future research could prioritize this issue. Fifth, because our study primarily focused on the Asian population, it remains unclear whether our findings can be generalized to statin users in other regions and ethnicities. We suggest that future research investigate whether distinct results exist across different ethnicities.
Conclusions
This nationwide population-based study shows that statins, particularly atorvastatin and rosuvastatin, may be associated with an elevated risk of ocular hypertension and POAG. There is also a trend indicating that longer durations of statin use are associated with greater risk of glaucoma.
Supplementary Material
Acknowledgments
The authors thank Health Data Science Center, China Medical University Hospital for providing administrative, technical, and funding support.
Supported in part by Taiwan Ministry of Health and Welfare Clinical Trial Center (MOHW113-TDU-B-212-114009), China Medical University Hospital (DMR-111-105; DMR-112-087; DMR-113-009; DMR-113-156; DMR-114-046; DMR-114-139). The funders had no role in the study design, data collection and analysis, the decision to publish, or preparation of the manuscript. No additional external funding was received for this study.
Disclosure: S.-Y. Pan, None; C.-H. Weng, None; P.-T. Tien, None; Y.-A. Lu, None; Y.-H. Huang, None; H.-J. Lin, None; Y.-D. Cheng, None; Y.-W. Hsieh, None; W.-T. Ho, None; S.-P. Huang, None; D.-Y. Cho, None; H.-J. Lin, None; I.-J. Wang, None; C.-C. Chou, None
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