Association of Statin Use and High Serum Cholesterol Levels With Risk of Primary Open-Angle Glaucoma

Key Points

Question

Are self-reported elevated cholesterol level and statin use associated with risk of primary open-angle glaucoma?

Findings

In this population-based cohort study of 886 incident cases of primary open-angle glaucoma from 136 782 participants who contributed person-time for up to 15 or more years and provided repeated updated data on statin use and cholesterol levels, 5 or more years of statin use was associated with a 21% lower risk of primary open-angle glaucoma, while every 20-mg/dL increase in total serum cholesterol was associated with a 7% increase in risk of primary open-angle glaucoma.

Meaning

Statin use, which is highly prevalent among older persons at risk for primary open-angle glaucoma, was associated with a lower risk of primary open-angle glaucoma.

Abstract

Importance

The use of statins (hydroxymethylglutaryl coenzyme A inhibitors) has been associated with a lower risk of primary open-angle glaucoma (POAG); however, results have been conflicting, and little is known about the association between high cholesterol levels and POAG.

Objective

To assess the association of elevated cholesterol levels and statin use with incident POAG.

Design, Setting, and Participants

This study used data collected biennially from participants aged 40 years or older who were free of glaucoma and reported eye examinations, within 3 population-based cohorts: the Nurses’ Health Study (N = 50 710; followed up from 2000 to 2014), the Nurses’ Health Study 2 (N = 62 992; 1999-2015), and the Health Professionals Follow-up Study (N = 23 080; 2000-2014). Incident cases of POAG were confirmed by medical record review. The analyses were performed in January 2019.

Exposures

Biennially updated self-reported information on elevated cholesterol level status, serum cholesterol levels, and duration of statin use.

Main Outcomes and Measures

Multivariable-adjusted relative risks (RRs) and 95% CIs were estimated using Cox proportional hazards regression models on pooled data, with stratification by cohort.

Results

Among the 136 782 participants in the 3 cohorts (113 702 women and 23 080 men), 886 incident cases of POAG were identified. Every 20-mg/dL increase in total serum cholesterol was associated with a 7% increase in risk of POAG (RR, 1.07 [95% CI, 1.02-1.11]; P = .004). Any self-reported history of elevated cholesterol was also associated with a higher risk of POAG (RR, 1.17 [95% CI, 1.00-1.37]). A history of any statin use was associated with a 15% lower risk of POAG (RR, 0.85 [95% CI, 0.73-0.99]). Use of statins for 5 or more years vs never use of statins was associated with a 21% lower risk of POAG (RR, 0.79 [95% CI, 0.65-0.97]; P = .02 for linear trend). The association between use of statins for 5 or more years vs never use of statins and risk of POAG was more inverse in those who were older (≥65 years: RR, 0.70 [95% CI, 0.56-0.87] vs <65 years: RR, 1.05 [95% CI, 0.68-1.63]; P = .01 for interaction).

Conclusions and Relevance

Among adults aged 40 years or older, higher serum cholesterol levels were associated with higher risk of POAG, while 5 or more years of statin use compared with never use of statins was associated with a lower risk of POAG.

This population-based cohort assesses the association between elevated cholesterol levels, statin use, and incident primary open-angle glaucoma among participants 40 years or older.

Introduction

Statins (hydroxymethylglutaryl coenzyme A inhibitors) are cholesterol-lowering drugs prescribed for the prevention and treatment of cardiovascular disease.^1,2 The mechanisms by which statins may lower the risk of cardiovascular disease include those independent of cholesterol-lowering properties.^3,4 Statins have pleiotropic effects^5,6 including antioxidant and immunomodulatory effects, effects on thrombosis formation, and effects on the nitric oxide synthase system. Statins may also have beneficial effects on cancers,^5,7 inflammatory diseases,⁸ and neurologic disorders.^9,10,11 In vitro studies have suggested that statins may lower intraocular pressure (IOP)¹² and protect retinal ganglion cells against glaucomatous damage,^{11,13,14,15,16,17,18} indicating statins’ potential role in mitigating glaucoma pathogenesis.

Several observational studies have evaluated the association between statin use and the risk of primary open-angle glaucoma (POAG). However, the results have been inconsistent: some studies have observed inverse associations,^19,20,21 whereas others have observed null²² or even adverse associations.²³ Also, studies reporting inverse associations observed stronger associations with at least 2 years of use,^19,20,21 but data are lacking on the association with longer use of statins.²⁴ Furthermore, for some studies, confounding by indication due to hyperlipidemia (and concomitant hypertension and diabetes) has been raised as a concern,^25,26 and the association between hyperlipidemia and POAG has been unclear.^25,26 Our primary a priori hypothesis was that longer duration of statin use is associated with a lower risk of POAG, and our secondary hypothesis was that higher cholesterol levels are associated with a higher risk of POAG. Therefore, we examined the association of hyperlipidemia as well as statin use with risk of POAG among 50 710 women in the Nurses’ Health Study (NHS), 62 992 women in the NHS2, and 23 080 men in the Health Professionals Follow-up Study (HPFS) followed up for 15 or more years.

Methods

The NHS began in 1976 with 121 700 US female registered nurses (age, 30-55 years) who completed mailed health and lifestyle questionnaires.²⁷ The NHS2 started in 1989 with 116 429 US female registered nurses (age, 30-55 years) who returned similar questionnaires.²⁸ The HPFS began in 1986 with 51 529 US male health care professionals (age, 40-75 years) who also returned health questionnaires.²⁹ Participants were followed up biennially with mailed questionnaires that asked about diseases such as cancer, cardiovascular disease, and glaucoma; the rate of follow-up has been high (>85%). The Human Research Committees of Brigham & Women’s Hospital, Massachusetts Eye and Ear Infirmary, and Harvard T. H. Chan School of Public Health approved this study and allowed participants’ completion of questionnaires to be considered as implied consent.

Because participants were first asked about current and lifetime statin use in 1999 in the NHS2 and in 2000 in the NHS and HPFS, 1999-2000 is considered the baseline for our study. Follow-up ended with a glaucoma diagnosis, incident cancer (as cancer causes profound changes in behavior), death, loss to follow-up, or the study’s end (2014 in NHS and HPFS and 2015 in NHS2), whichever occurred earliest. The analyses were performed in January 2019.

At baseline, we excluded the following participants: (1) 29 233 women in the NHS and 1596 men in the HPFS who did not complete the food frequency questionnaire (in 1980 for NHS and in 1986 for HPFS), because for the NHS and HPFS, the association between diet and glaucoma was the primary aim at initiation and case confirmation occurred only for those with diet data (in the NHS2, there was no such restriction for case confirmation); (2) 16 378 women in the NHS, 8847 men in the HPFS, and 4701 women in the NHS2 who had cancer (except nonmelanoma skin cancer); (3) 5132 women in the NHS, 2321 men in the HPFS, and 543 women in the NHS2 who had prevalent glaucoma; (4) 5083 women in the NHS, 4323 men in the HPFS, and 435 women in the NHS2 who died before baseline; (5) 4591 women in the NHS, 3644 men in the HPFS, and 6523 women in the NHS2 whose last completed questionnaire was at baseline (who were lost to follow-up); (6) 564 women in the NHS, 741 men in the HPFS, and 29 895 women in the NHS2 who never reported an eye examination (in the NHS2, the eye examination question was asked once in 2013); and (7) 7270 women in the NHS, 4408 men in the HPFS, and 7471 women in the NHS2 who did not complete baseline questionnaires or had missing baseline statin use information. After these exclusions, 53 449 women in the NHS, 25 649 men in the HPFS, and 66 861 women in the NHS2 were potentially eligible to ever contribute person-time to the analysis. Among these participants, at each 2-year period of observation, we allowed only those who were 40 years or older, who reported a recent eye examination, and who had information on serum cholesterol levels. Participants who did not meet these provisional criteria at any time were allowed to contribute person-time at later periods when they met these criteria. Overall, 50 710 women in the NHS, 23 080 men in the HPFS, and 62 992 women in the NHS2 ever contributed person-time in this analysis.

POAG Case Ascertainment

We included 886 individuals with confirmed cases of incident POAG (522 women in the NHS, 208 men in the HPFS, and 156 women in the NHS2). Glaucoma cases were first ascertained in biennial questionnaires that asked participants about physician diagnoses of glaucoma. For those self-reporting glaucoma diagnoses, we obtained permission to contact their eye care professionals. We asked the eye care professionals to send visual fields (VFs) with either medical records or a completed glaucoma questionnaire with items on maximal IOP, filtration apparatus status, optic nerve structural information, ophthalmic surgery, and earliest date of VF loss. A glaucoma specialist (L.R.P.) reviewed records to confirm cases using standardized criteria. After medical record review, we excluded participants with isolated elevated IOP or optic disc cupping and other forms of glaucoma (eg, exfoliation, closed-angle, or secondary), as well as unconfirmed reports (eg, supporting medical records could not be obtained or the participant did not give permission to review records).³⁰ Those who self-reported glaucoma but were not considered to have definite or probable POAG were censored as of the date of self-reported diagnosis.

For confirmation of POAG, we required (1) results of gonioscopy indicating that the filtration angle was not occludable in either eye (516 cases [58.2%]) or slitlamp biomicroscopy demonstrating open angles and pharmacologic dilation without adverse effects (370 cases [41.8%]); (2) results of slit-lamp biomicroscopy showing no signs in either eye of pigment dispersion syndrome, uveitis, exfoliation syndrome, trauma, or rubeosis iridis; and (3) reproducible VF defects consistent with POAG on 2 or more reliable tests. For VF defects, the type of perimetry was not restricted. However, full static threshold testing was documented in 868 cases (98.0%), and kinetic VFs were documented in 5 cases (0.6%). For static threshold or suprathreshold tests, we used the reliability definitions of fixation loss of 33% or less, false-positive rate of 20% or less, and a false-negative rate of 20% or less; for kinetic VFs, VFs were considered reliable unless there were examiners’ notes to the contrary.

Assessment of High Cholesterol, Total Serum Cholesterol, Statin Use, and Use of Other Cholesterol-Lowering Drugs

Clinician Diagnosis of Elevated Cholesterol

Participants were asked biennially from when the cohorts began about any clinician-diagnosed elevated cholesterol. In addition, participants were asked to report the date when they received a diagnosis of elevated cholesterol. Once a participant reported such a history, she or he was considered to always have a history of elevated cholesterol.

Total Serum Cholesterol Level

Participants were asked about their most recent (≤5 years prior) total serum cholesterol (10 categories from <140 to ≥330 mg/dL [to convert to millimoles per liter, multiply by 0.0259]; asked in 1988, 1990, 1994, 2000, 2004, and 2008 in the NHS; 1986, 1990, 2000, 2004, and 2008 in the HPFS; and 1989, 2005, and 2009 in the NHS2). Self-reported serum cholesterol levels in the NHS were previously validated against actual measured serum cholesterol levels.^31,32 We evaluated cumulative mean serum cholesterol values, which may better represent long-term exposure and have less random measurement error.³³ With cumulative averaging, the mean of all available information as of a risk period was used (eg, in the NHS for the risk period 2008-2010, the mean of the 1988, 1990, 1994, 2000, 2004, and 2008 values was used).

Use of Cholesterol-Lowering Drugs, Including Statins

In the NHS and HPFS, we asked about current use of any cholesterol-lowering drugs in the 1988 through 1998 questionnaire cycles; in 2000, the use of any statins (including lifetime cumulative duration of use) was queried separately from use of nonstatin cholesterol-lowering drugs. In 2004-2012, the use of specific statin types was queried. In the NHS2, the use of statins (including cumulative duration of use) was queried in 1999-2003; in 2005-2013, specific types of statins used were queried. In the NHS2, we also asked about use of nonstatin cholesterol-lowering drugs from 1999 to 2013.

For deriving the status and duration of statin use, if information about statins was missing, we carried forward information for 1 cycle only for never users and current users, as their status remained unchanged more than 75% of the time from cycle to cycle; past users with missing data in the current cycle were skipped from contributing person-time and allowed to contribute in a later cycle when information was available. Participants with missing statin data on 3 consecutive questionnaire cycles were censored as of the date of the first cycle from which data were missing.

Statistical Analysis

After confirming that the results from the 3 cohorts did not show significant heterogeneity (eg, P = .31 for heterogeneity for statin use duration association), we pooled the data for greater statistical power. We calculated POAG incidence by dividing incident cases by person-years for each exposure category. For multivariable analyses, we conducted Cox proportional hazards regression analysis,³⁴ while simultaneously controlling for potential time-varying glaucoma risk factors. To control as finely as possible for confounding by age, calendar time, cohort, and any possible interactions, we stratified the analysis jointly by cohort, age in months, and calendar year of each questionnaire cycle. We also adjusted for the following updated potential covariates: body mass index (calculated as weight in kilograms divided by height in meters squared); cigarette smoking (pack-years); hypertension; history of using β-blockers, diuretics, other blood pressure–lowering medications, or other nonstatin cholesterol-lowering medicines; type 1 or 2 diabetes; physical activity (quartiles of metabolic equivalents of task–hours per week); any cardiovascular or cerebrovascular disease (myocardial infarction, stroke, transient ischemic attack, or coronary artery bypass graft); cumulatively averaged serum cholesterol levels; cumulatively averaged intake of alcohol and caffeine; family history of glaucoma; race/ethnicity; and, among women, age at menopause and postmenopausal hormone use.

We estimated hazard ratios as measures of relative risks (RRs) and 95% CI. We examined the possibly nonlinear association between total serum cholesterol and RR of POAG nonparametrically with restricted cubic splines.³⁵ Tests for nonlinearity used the likelihood ratio test, comparing the model with only the linear term with the model with the linear and the cubic spline terms. All significance tests were 2-sided, and results were deemed statistically significant at P < .05. Analysis was performed with SAS statistical software, version 9.4 (SAS Institute Inc).

Secondary Analyses

We conducted sensitivity analyses where prevalent statin users as of baseline were excluded, and we included only those who first reported statin use at baseline or later to minimize selection bias and to mimic a clinical trial setting.³⁶ Finally, we evaluated whether associations may differ by age, hyperlipidemia diagnosis, sex, or family history of glaucoma. For interaction testing, a product term of the effect modifier and duration of statin use were added to models with the 2 main effects, and the significance of this term was evaluated with Wald tests.

Results

During 1 485 498 person-years of follow-up, we identified 886 individuals with incident POAG (mean [SD] age, 68.5 [9.6] years; mean [SD] mean deviation in the worse eye, –5.6 [5.2] dB). Individuals who used statins for 5 or more years were more likely to have reported a history of elevated cholesterol levels, higher total serum cholesterol levels, and a higher prevalence of cardiovascular disease and risk factors (Table 1). Longer statin use was not associated with known risk factors for glaucoma such as African American race/ethnicity or having a family history of glaucoma.

Table 1. Age-Standardized Characteristics of the Total Accrued Person-Time by Duration of Statin Use in the NHS, NHS2, and HPFS^a.

Characteristic	Duration of Statin Use
	Never User	≤2 y	2-4 y	≥5 y
Person-time, %
NHS	59.5	8.4	11.7	20.4
NHS2	79.8	5.1	6.6	8.5
HPFS	55.2	8.5	12.1	24.2
Age, mean (SD), y
NHS	69.3 (7.5)	70.1 (7.1)	71.5 (6.9)	73.6 (6.7)
NHS2	51.9 (5.9)	54.5 (5.2)	56.2 (5.1)	58.3 (4.9)
HPFS	68.5 (8.5)	68.9 (8.1)	70.2 (7.9)	72.3 (7.7)
Elevated cholesterol, %b
NHS	55.6	93.8	96.3	98.5
NHS2	34.3	91.9	95.1	98.3
HPFS	42.6	83.6	89.8	95.5
Total serum cholesterol, mean (SD), mg/dLc
NHS	196.1 (31.2)	211.6 (31.1)	211.3 (29.9)	212.8 (29.0)
NHS2	176.2 (30.7)	198.1 (33.8)	198.2 (34.6)	200.4 (37.5)
HPFS	191.0 (27.1)	200.3 (27.5)	197.6 (26.3)	195.4 (25.3)
Cardiovascular disease, %d
NHS	8.8	19.5	19.7	21.9
NHS2	1.8	5.3	6.0	7.9
HPFS	10.9	31.4	32.6	40.5
Type 1 or 2 diabetes, %
NHS	6.4	14.7	16.2	19.2
NHS2	2.7	12.9	15.5	21.3
HPFS	6.1	13.5	14.4	15.6
Hypertension, %
NHS	51.3	67.8	70.2	73.8
NHS2	24.1	46.8	49.6	53.9
HPFS	42.8	57.6	59.9	64.6
Body mass index ≥30, %e
NHS	11.6	15.6	16.6	17.4
NHS2	16.3	28.0	30.5	35.4
HPFS	8.3	10.6	10.7	11.3
Cigarette smoking ≥30 pack-years, %
NHS	14.8	17.6	17.1	17.6
NHS2	3.1	4.6	4.8	5.1
HPFS	12.2	14.8	14.3	14.4
Physical activity (top 25th percentile), %
NHS	31.6	27.5	26.0	25.1
NHS2	26.1	20.2	20.2	18.4
HPFS	32.5	28.9	28.4	27.0
Caffeine intake, mean (SD), mg/dc
NHS	170.8 (157.7)	164.5 (152.1)	160.1 (145.8)	157.9 (139.2)
NHS2	196.2 (167.1)	190.0 (162.0)	185.1 (155.1)	178.2 (148.1)
HPFS	175.1 (173.4)	178.9 (175.7)	177.8 (166.5)	178.0 (158.0)
Alcohol intake, mean (SD), g/dc
NHS	5.9 (9.4)	5.4 (9.0)	5.3 (8.7)	5.1 (8.6)
NHS2	5.1 (7.9)	4.5 (7.7)	4.2 (7.3)	4.0 (7.3)
HPFS	11.9 (14.0)	12.0 (13.7)	12.1 (13.4)	12.7 (13.8)
African American race/ethnicity, %
NHS	1.0	1.1	1.0	0.9
NHS2	1.3	1.6	1.6	1.4
HPFS	0.5	0.4	0.4	0.3
Family history of glaucoma, %f
NHS	13.4	13.2	13.1	12.9
NHS2	NA	NA	NA	NA
HPFS	12.2	12.0	12.2	12.1
Age at menopause <45 y, %g
NHS	9.9	10.5	10.7	11.7
NHS2	15.1	16.4	18.3	21.6
Current postmenopausal hormone use, %g
NHS	28.9	24.1	21.6	19.1
NHS2	30.1	27.0	25.9	26.0

Abbreviations: HPFS, Health Professionals Follow-up Study; NHS, Nurses’ Health Study; NHS2, Nurses’ Health Study 2.

SI conversion factor: to convert cholesterol to millimoles per liter, multiply by 0.0259.

^aValues are standardized to the age distribution of the study population.

^bElevated cholesterol: a report of a physician’s diagnosis of high cholesterol or total serum cholesterol levels ever being ≥240 mg/dL.

^cCumulatively updated mean based on the mean of all the information available at any given update in the covariate.

^dCardiovascular disease defined as a history of myocardial infarction, stroke, transient ischemic attack, or coronary artery bypass graft.

^eCalculated as weight in kilograms divided by height in meters squared.

^fFamily history of glaucoma was not asked in NHS2 (not applicable).

^gAmong postmenopausal women only.

Any history of elevated cholesterol (defined as a self-report of a physician’s diagnosis of high cholesterol or ever reporting a total serum cholesterol of ≥240 mg/dL) was associated with a higher risk of POAG (multivariable-adjusted RR, 1.17; 95% CI, 1.00-1.37) (Table 2). We observed that every 20-mg/dL increase in total serum cholesterol was associated with a 7% increase in risk of POAG (RR, 1.07; 95% CI, 1.02-1.11; P = .004) in all participants, particularly those with total serum cholesterol levels of more than 250 mg/dL, and a 6% increase in risk of POAG (RR, 1.06; 95% CI, 1.00-1.12; P = .04) among those who never used cholesterol-lowering drugs (Figure). When those with no history of elevated cholesterol levels were divided into 2 categories (with and without cholesterol-lowering treatment) and those with elevated cholesterol were divided into 4 categories (no treatment, history of nonstatin drug use only, history of statin use only, and history of having used both statins and nonstatins), we did not observe major differences in risk of POAG compared with those with no elevated cholesterol, likely because of the limited power (Table 2). However, all the categories that are defined by statin use, whether in those with or without elevated cholesterol, were consistently inversely associated, indicating support for a possible inverse association with statin use.

Table 2. Multivariable-Adjusted Relative Risks for the Association Between Elevated Cholesterol, Treatment Status, and Serum Cholesterol Levels and Primary Open-Angle Glaucoma in the Nurses’ Health Study, Nurses’ Health Study 2, and Health Professionals Follow-up Study^a,b.

Characteristic	No Elevated Cholesterol		Elevated Cholesterol
	No Treatment	History of Any Treatment	No Treatment	History of Nonstatin Use Only	History of Statin Use Only	History of Statin and Nonstatin Use
Cases/person-years	280/617 148	12/25 011	254/382 929	38/37 284	266/370 271	36/52 854
Age-adjusted model, RR (95% CI)	1 [Reference]	0.65 (0.36-1.15)	1.13 (0.95-1.34)	1.32 (0.94-1.85)	0.98 (0.83-1.16)	0.92 (0.65-1.30)
Multivariable model, RR (95% CI)c	1 [Reference]	0.63 (0.35-1.13)	1.12 (0.94-1.33)	1.30 (0.92-1.84)	0.96 (0.80-1.16)	0.91 (0.63-1.30)

Abbreviation: RR, relative risk.

^aTotal of 292 cases of POAG per 642 159 person-years among those with no history of elevated cholesterol and 594 cases of POAG per 843 338 person-years among those with any history of elevated cholesterol (age-adjusted model: RR, 1.08; 95% CI, 0.93-1.24; and multivariable model: RR, 1.17; 95% CI, 1.00-1.37). Any elevated cholesterol was defined as a physician’s diagnosis of high cholesterol or ever having a report of total serum cholesterol level of 240 mg/dL or higher (to convert to millimoles per liter, multiply by 0.0259).

^bMultivariable model stratified by age in months, calendar time, and cohort, and adjusted for race (white, African American, or Asian), family history of glaucoma (yes, no, or missing), self-reported diabetes, body mass index (<22, 22-23, 24-25, 26-27, 28-29, and ≥30 [calculated as weight in kilograms divided by height in meters squared]), hypertension (yes or no), history of β-blocker use, history of diuretic use, history of other blood-pressure lowering medication use, cigarette smoking (0, 1-9, 10-19, 20-29, or ≥30 pack-years), cumulative mean caffeine intake (mg/d), cumulative mean alcohol intake (g/d), physical activity (quartiles of metabolic equivalents of task–hours per week), any cardiovascular disease (myocardial infarction, stroke, transient ischemic attack, or coronary artery bypass graft), duration of statin use (never, <2 years, 2-4 years, or ≥5 years), and current use of other cholesterol-lowering drugs, and (in the Nurses’ Health Study, Nurses’ Health Study 2 only) additionally adjusted for age at menopause (20-44, 45-49, 50-53, or ≥54 years) and postmenopausal hormone status (premenopausal, postmenopausal and current user, postmenopausal and past user, or postmenopausal and nonuser).

^cSame as footnote b, but the covariates adjusted for do not include duration of statin use or current use of other cholesterol-lowering drugs.

Figure. Association Between Total Serum Cholesterol Level and Risk of Primary Open-Angle Glaucoma.

A Cox proportional hazards regression cubic spline plot showing the association (with 95% CI bands) between total serum cholesterol and relative risk of primary open-angle glaucoma using 3 knots and increments of 20 mg/dL (to convert to millimoles per liter, multiply by 0.0259). The test for whether a nonlinear association vs a simple linear association is a better fit to the data was not significant (P = .44); therefore, a linear association can be considered a good fit to the data. Every 20-mg/dL increase in total serum cholesterol was associated with a 7% increase in risk of primary open-angle glaucoma (relative risk, 1.07; 95% CI, 1.02-1.11; P = .004).

In models adjusted for current use of nonstatin cholesterol-lowering drugs, cumulatively updated total serum cholesterol levels, and other covariates, any statin use (eTable in the Supplement) showed an inverse association with POAG (RR, 0.85; 95% CI, 0.73-0.99). The RR was 0.76 (95% CI, 0.53-1.10) for past statin use and was 0.86 (95% CI, 0.73-1.00) for current use. We did not observe major differences by type of statin currently used; for the most commonly used statin (atorvastatin calcium), the RR was 0.83 (95% CI, 0.64-1.08).

We observed greater inverse associations with POAG with longer statin use (Table 3). Compared with never users, the RR was 0.97 (95% CI, 0.76-1.24) for those who used statins for less than 2 years, 0.84 (95% CI, 0.66-1.05) for those who used statins for 2 to 4 years, and 0.79 (95% CI, 0.65-0.97) for those who used statins for 5 or more years (P = .02 for trend). The inverse associations were slightly stronger when 5 or more years of use was evaluated among current users. Each year of statin use was associated with a 3% lower risk of POAG (RR, 0.97; 95% CI, 0.95-0.99; P = .01). To allow for comparison with previous studies that evaluated shorter use durations, we evaluated the association of 2 or more years of statin use with POAG and found a multivariable-adjusted RR of 0.81 (95% CI, 0.68-0.96). When we evaluated even longer durations of statin use, the multivariable-adjusted RR for 5 to 9 years of statin use was 0.88 (95% CI, 0.71-1.09) and the multivariable-adjusted RR for 10 or more years of statin use was 0.60 (95% CI, 0.42-0.85).

Table 3. Multivariable-Adjusted Relative Risks for the Association Between Duration of Statin Use and Primary Open-Angle Glaucoma in the Nurses’ Health Study, Nurses’ Health Study 2, and Health Professionals Follow-up Study.

Characteristic	Never User	Any Use <2 y	Any Use 2-4 y	Any Use ≥5 y	P Value for Trend	Current Use ≥5 y	P Value for Trend
Cases/person-years	574/1 041 928	76/99 372	90/134 805	146/209 393	NA	133/192 854	NA
Age-adjusted model, RR (95% CI)	1 [Reference]	1.04 (0.82-1.32)	0.89 (0.71-1.11)	0.84 (0.70-1.01)	NA	0.83 (0.68-1.00)	NA
Multivariable model, RR (95% CI)a	1 [Reference]	0.97 (0.76-1.24)	0.84 (0.66-1.05)	0.79 (0.65-0.97)	.02	0.78 (0.64-0.96)	.01

Abbreviations: NA, not applicable; RR, relative risk.

^aAdjusted for the same covariates as described in footnote b in Table 2, but without statins, as statins are the main exposure, and with the addition of cumulatively updated total serum cholesterol (<180, 180-199, 200-219, 220-239, 240-259, and ≥260 mg/dL).

The association with longer duration of statin use did not differ by family history of glaucoma (no history: RR, 0.74; 95% CI, 0.58-0.93; vs history: RR, 0.80; 95% CI, 0.50-1.28; P = .99 for interaction) or sex (female: RR, 1.00; 95% CI, 0.78-1.27; vs male: RR, 0.79; 95% CI, 0.51-1.22; P = .27 for interaction) (Table 4). The inverse association between use of statins for 5 or more years and risk of POAG was stronger among those who were 65 years or older than among those younger than 65 years (≥65 years: RR, 0.70 [95% CI, 0.56-0.87] vs <65 years: RR, 1.05 [95% CI, 0.68-1.63]; P = .01 for interaction).

Table 4. Multivariable-Adjusted Relative Risks for the Association Between Duration of Statin Use and Primary Open-Angle Glaucoma by Family History, Sex, and Age in the Nurses’ Health Study, Nurses’ Health Study 2, and Health Professionals Follow-up Study.

Characteristic	Duration of Statin Use				P Value for Trend	P Value for Interaction
	Never User	<2 y	2-4 y	≥5 y
By Age
<65 y (36.1%)
Cases, No.	201	30	28	27	NA	NA
RR (95% CI)a	1 [Reference]	1.51 (1.01-2.25)	1.21 (0.80-1.84)	1.05 (0.68-1.63)	.84	NA
≥65 y (63.9%)
Cases, No.	373	46	62	119	NA	NA
RR (95% CI)a	1 [Reference]	0.78 (0.57-1.06)	0.71 (0.53-0.93)	0.70 (0.56-0.87)	.002	.01
By Sex
Female (86.7%)
Cases, No.	446	57	63	112	NA	NA
RR (95% CI)a	1 [Reference]	0.96 (0.72-1.28)	0.86 (0.65-1.13)	1.00 (0.78-1.27)	.93	NA
Male (13.3%)
Cases, No.	128	19	27	34	NA	NA
RR (95% CI)a	1 [Reference]	0.94 (0.56-1.58)	1.14 (0.72-1.78)	0.79 (0.51-1.22)	.32	.27
By Family History of Glaucomab
No (87.0%)
Cases, No.	366	50	56	104	NA	NA
RR (95% CI)a	1 [Reference]	0.88 (0.65-1.19)	0.71 (0.53-0.95)	0.74 (0.58-0.93)	.01	NA
Yes (13.0%)
Cases, No.	100	11	17	26	NA	NA
RR (95% CI)a	1 [Reference]	0.78 (0.41-1.48)	0.90 (0.53-1.54)	0.80 (0.50-1.28)	.40	.99

Abbreviation: NA, not applicable; RR, relative risk.

^aMultivariable models stratified by age in months, calendar time, and cohort, and adjusted for race (white, African American, or Asian), family history of glaucoma (yes, no, or missing), self-reported diabetes, body mass index (<22, 22-23, 24-25, 26-27, 28-29, and ≥30 [calculated as weight in kilograms divided by height in meters squared]), hypertension (yes or no), history of β-blocker use, history of diuretic use, history of other blood-pressure lowering medication use, cigarette smoking (0, 1-9, 10-19, 20-29, or ≥30 pack-years), cumulative mean caffeine intake (mg/d), cumulative mean alcohol intake (g/d), physical activity (quartiles of metabolic equivalents of task–hours per week), any cardiovascular disease (myocardial infarction, stroke, transient ischemic attack, or coronary artery bypass graft), duration of statin use (never, <2 years, 2-4 years, or ≥5 years) and current use of other cholesterol-lowering drugs, and (in the Nurses’ Health Study, Nurses’ Health Study 2 only) additionally adjusted for age at menopause (20-44, 45-49, 50-53, or ≥54 years) and postmenopausal hormone status (premenopausal, postmenopausal and current user, postmenopausal and past user, or postmenopausal and nonuser).

^bAnalyses were restricted to the Nurses’ Health Study and Health Professionals Follow-up Study, as family history was not ascertained in the Nurses’ Health Study 2 cohort.

In sensitivity analyses in which statin users were restricted to those who initiated statin use on or after 1999-2000 (402 individuals with POAG), we observed similar associations of lower risk of POAG with use of statins for 5 or more years (RR, 0.66; 95% CI, 0.39-1.13; P = .10 for trend), providing support for the inverse associations in the main analyses. Because the use of nonstatin cholesterol-lowering drugs was specifically asked about from 1999 to 2000, we evaluated the association with duration of use of nonstatin cholesterol-lowering drugs in these analyses (although the statistical power was low), and we observed a weak inverse association (≥5 years’ duration: RR, 0.77; 95% CI, 0.19-3.14; P = .38 for trend).

Discussion

In this study of 136 782 participants followed for 15 or more years, higher serum cholesterol levels were associated with a higher risk of POAG. Longer statin use (≥5 years), compared with never use, was associated with a lower risk of POAG. Carefully determining the association with hyperlipidemia is important to help evaluate the possibility of confounding by indication³⁷ where associations with cholesterol-lowering drugs, such as statins, have been reported. Consistent with other studies^26,38 (eg, a meta-analysis²⁶ reported an RR of 1.40 [95% CI, 0.73-2.68] for hyperlipidemia history), we observed a trend of higher risk of POAG with higher serum cholesterol levels. This finding indicates that if (1) statins truly lower the risk of POAG and (2) higher cholesterol levels are associated with elevated POAG risk and (3) higher cholesterol levels were associated with being prescribed more statins, then the confounding bias would have been toward the null.

As in other studies,^19,22,23 a history of statin use was modestly inversely associated with POAG in our study. As in reports by McGwin et al¹⁹ (RR, 0.60; 95% CI, 0.39-0.92), Marcus et al²¹ (RR, 0.46; 95% CI, 0.23-0.92), and Stein et al²⁰ (RR, 0.92; 95% CI, 0.87-0.98), we observed that longer duration of statin use compared with never use was associated with a lower risk of POAG. Previous studies defined long-duration statin use as 2 or more years; however, our study provides the first data showing that 5 or more years of use was associated with a 21% lower risk (RR, 0.79; 95% CI, 0.65-0.97) and that 10 or more years of use was associated with a 40% lower risk of POAG (RR, 0.60; 95% CI, 0.42-0.85). Also, similar to findings in 2 other studies,^20,23 we did not observe notable associations with any of the 5 statin types. The stronger inverse associations observed in those aged 65 years or older may be owing to greater power in this age group, because statin use, like POAG risk, is low in younger persons.²¹

The potential mechanisms by which statins may lower the risk of POAG include IOP-lowering and neuroprotective mechanisms. Statins affect the activities of myosin II adenosine triphosphatase and ρ kinase in the trabecular meshwork that increase nitric oxide production and aqueous outflow facility, which may lead to some IOP lowering.^39,40,41 Also, greater production of nitric oxide would increase the blood flow to the optic nerve.^42,43 Other neuroprotective effects^{10,11,41,44,45,46,47,48} of statins include anti-excitotoxic,^11,49,50 anti-apoptotic,^45,46 and anti-inflammatory⁴⁷ properties that may protect retinal ganglion cells. Several genes involved in cholesterol metabolism (ABCA1, CAV1, ARHGEF12, and DGKG) have also been associated with IOP and POAG in large genome-wide association studies.^51,52 Thus, more studies on hyperlipidemia, statins, and their role in glaucoma^53,54 are warranted.

Limitations

Although our study was large, with a long follow-up, repeated assessment of statin use and hyperlipidemia, and the availability of key covariates, our study had several limitations. We likely had misclassification of statin use and cholesterol levels, as we did not measure participants’ recall errors. This misclassification would have biased associations toward the null. Our case ascertainment method had low sensitivity; however, methodologically, RR estimates are still valid if the case definition is highly specific and the case ascertainment is unassociated with exposure.⁵⁵ Also, as participants were mostly white health care professionals all free of cancer, our results may not be generalizable to other community-dwelling older populations with different underlying risks for POAG (eg, in predominantly African American populations). Despite our adjusting for many potential confounders, there may still have been some residual confounding. Also, to comprehensively evaluate the association between hyperlipidemia, cholesterol-lowering treatment, and POAG, we performed many secondary analyses; many of these results showed weak associations. Any notable findings (eg, possible interaction with age for statin duration) may have been owing to chance; thus, they must be interpreted with caution and confirmed in other studies. Finally, our study was observational, but a definitive means of assessing the association between statin use and POAG would be to conduct a randomized clinical trial (although more observational studies are warranted to determine ideal dosage, statin type, and target population).

Conclusions

In this large study of 136 782 participants with overall follow-up duration of 15 or more years, higher serum cholesterol levels were associated with higher risk of POAG, and 5 or more years of statin use, when compared with never use, was associated with a lower risk of POAG. As our study had limitations of imprecise exposures based on self-recall and possible chance findings, further studies are warranted to confirm these results, especially given the widespread use of statins in older persons at particular risk for POAG.

Supplement.

eTable. Multivariable-Adjusted Relative Risks and 95% CIs for the Association Between Statin Use Status, Type of Statin Use, and Primary Open-Angle Glaucoma in the Nurses’ Health Study (NHS; N = 50 710; 2000-2014), NHS2 (N = 62 992; 1999-2015) and the Health Professionals Follow-up Study (HPFS; N = 23 080; 2000-2014)