A Systematic Review and Meta-analysis of
Systemic Antihypertensive Medications With
Intraocular Pressure and Glaucoma
GARETH LEUNG, ALYSSA GRANT, ANDREW N. GARAS, GISELE LI, AND ELLEN E. FREEMAN
• PURPOSE: We synthesized the literature on the associa-
tion between systemic antihypertensive medications with
intraocular pressure (IOP) and glaucoma. Antihyperten-
sive medications included β-blockers, calcium channel
blockers, angiotensin-converting enzyme inhibitors, an-
giotensin receptor blockers, and diuretics.
• DESIGN: Systematic review and meta-analysis.
• METHODS: Databases were searched for relevant ar-
ticles until December 5, 2022. Studies were eligible if
they examined (1) the association between systemic an-
tihypertensive medications with glaucoma or (2) the as-
sociation between systemic antihypertensive medications
with IOP in those without glaucoma or ocular hyperten-
sion. The protocol was registered at PROSPERO (Inter-
national Prospective Register of Systematic Reviews; reg-
istration ID: CRD42022352028).
• RESULTS: A total of 11 studies were included in the
review and 10 studies in the meta-analysis. The 3 stud-
ies on IOP were cross-sectional, whereas the 8 studies
on glaucoma were primarily longitudinal. In the meta-
analysis, β-blockers were associated with a lower odds of
glaucoma (odds ratio: 0.83, 95% CI: 0.75-0.92, 7 stud-
ies, n = 219,535) and lower IOP (β: −0.53, 95% CI:
−1.05 to −0.02, 3 studies, n = 28,683). Calcium chan-
nel blockers were associated with a higher odds of glau-
coma (odds ratio: 1.13, 95% CI: 1.03-1.24, 7 studies,
n = 219,535) but not with IOP (β: −0.11, 95% CI:
−0.25 to 0.03, 2 studies, n = 20,620). There were no
consistent associations between angiotensin-converting
enzyme inhibitors, angiotensin receptor blockers, or di-
uretics with glaucoma or IOP.
• CONCLUSIONS: Systemic antihypertensive medica-
tions have heterogeneous effects on glaucoma and
IOP. Clinicians should be aware that systemic an-
tihypertensive medications may mask elevated IOP
Supplemental Material available at AJO.com.
Accepted for publication March 14, 2023.
From the School of Epidemiology and Public Health, University of
Ottawa, Ottawa (G. Leung, A.G., E.E.F.), Ontario, Canada; Faculty
of Health Sciences, McMaster University, Hamilton (A.N.G.), Ontario,
Canada; Maisonneuve-Rosemont Hospital, Montréal, Québec (G. Li),
Canada; Ottawa Hospital Research Institute (E.E.F.), Ottawa, Ontario,
Canada; Bruyere Research Institute (E.E.F.), Ottawa, Ontario, Canada
Inquiries to Ellen E. Freeman, School of Epidemiology and Pub-
lic Health, University of Ottawa, Ottawa, Ontario, Canada.; e-mail:
eefreeman@gmail.com
© 2023 THE AUTHOR(S). PUBLISHED BY ELSEVIER INC.
0002-9394/$36.00 THIS IS AN OPEN ACCESS ARTICLE UNDER THE CC BY-NC-ND LICENSE
https://doi.org/10.1016/j.ajo.2023.03.014 ( HTTP://CREATIVECOMMONS.ORG/LICENSES/BY-NC-ND/4.0/)
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or positively or negatively affect the risk of glau-
coma. (Am J Ophthalmol 2023;255: 7–17. ©
2023 The Author(s). Published by Elsevier Inc.
This is an open access article under the CC BY-NC-
ND license (http://creativecommons.org/licenses/by-nc-
nd/4.0/))
P
rimary open-angle glaucoma (POAG) is a lea-
ding cause of blindness in the world.1 The first-line
treatment for POAG is usually the use of topical
antihypertensive medication to lower eye pressure. Many
adults, however, are also taking systemic oral medication to
lower high blood pressure,2 which itself is a risk factor for
elevated intraocular pressure (IOP) and glaucoma.3 , 4 Other
studies have shown that low systemic blood pressure is also
a risk factor for glaucoma.5 The effect of systemic antihyper-
tensive medication on IOP and glaucoma is not well under-
stood. Several studies have examined this topic, but results
have been inconsistent, especially by class of antihyperten-
sive medication.6-14 The purpose of this study was therefore
to synthesize the existing evidence on systemic antihyper-
tensive medication use and IOP and glaucoma.
METHODS
This systematic review and meta-analysis was conducted as
per the PRISMA 2000 (Preferred Reporting Items for Sys-
tematic Reviews and Meta-Analyses) and MOOSE (Meta-
analyses Of Observational Studies in Epidemiology) guide-
lines.15 , 16
• REGISTRATION AND PROTOCOL: The protocol for this
systematic review and meta-analysis is registered at PROS-
PERO (International Prospective Register of Systematic
Reviews; ID: CRD42022352028).17
• ELIGIBILITY CRITERIA: Studies were eligible if they (1)
examined the association between systemic antihyperten-
sive medications with glaucoma or (2) examined systemic
antihypertensive medications with IOP in those without
glaucoma or ocular hypertension. The antihypertensive
medications studied in this review included angiotensin-
converting enzyme inhibitors (ACEis), angiotensin recep-
tor blockers (ARBs), calcium channel blockers (CCBs), β-
blockers (BBs), and diuretics. Only peer-reviewed studies
7
performed in adults published in the English language be-
fore December 5, 2022, were used. Non–English language
studies were excluded to ensure appropriate data extraction
and interpretation of results. Studies using cross-sectional,
cohort, or case-control designs were eligible for inclusion.
• INFORMATION SOURCES: Articles were retrieved from
Embase, MEDLINE, Web of Science, and PubMed.
• SEARCH STRATEGY: The search strategy was developed
by trainees and a research librarian based on other peer-
reviewed systematic reviews and meta-analyses and re-
ported in the Supplementary Tables.18-21
• SELECTION PROCESS: Two reviewers (G.L. and A.N.G.)
screened titles and abstracts independently using the
Rayyan software and classified studies as eligible, ineligible,
or possibly eligible based on the inclusion and exclusion cri-
teria. Any discrepancies that arose during the process were
reviewed by a third team member (A.G.), and a final deci-
sion was made. Full-text articles were retrieved, and studies
were then further examined for eligibility using the same
process.
• DATA COLLECTION PROCESS: A standardized data ex-
traction form was used by reviewers to obtain data from the
studies. Any disagreements were resolved through consen-
sus.
• DATA ITEMS: The following clinically relevant data were
extracted: sample size, study location, participant age, study
design, antihypertensive medication and its method of as-
sessment, health outcomes (glaucoma, IOP) and their mea-
surement, and the reported associations of antihypertensive
medication and health outcomes, their confidence inter-
vals, and any adjustment variables.
• SYNTHESIS METHODS: Studies were analyzed separately
by medication class (ACEis, ARBs, CCBs, BBs, and diuret-
ics). Pooled estimates and 95% CIs were estimated using a
random-effects meta-analysis model in which study weights
were inversely related to the total variance. Between-study
variability was determined using restricted maximum like-
lihood. The percentage of variance due to heterogeneity
was determined using the I2 statistic. To investigate het-
erogeneity, we performed sensitivity analyses stratified by
study design (cohort vs case-control) and glaucoma sub-
types (all glaucoma vs only POAG). Leave-one-out anal-
yses, in which pooled meta-analysis estimates are obtained
leaving out 1 study at a time, were also conducted to iden-
tify highly influential studies and evaluate the robustness of
findings. Analyses were conducted in Stata SE version 17
(StataCorp).
• EFFECT MEASURES: Our primary outcome was the asso-
ciation of systemic antihypertensive medications with glau-
coma or IOP. Studies reporting on quantitative effect size
estimates (β coefficients, risk ratios, odds ratios [ORs], and
hazard ratios) with corresponding 95% CIs were included.
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• RISK-OF-BIAS ASSESSMENT: Risk of bias was determined
by 2 reviewers (A.G. and E.E.F.) independently using the
Newcastle-Ottawa Scale.22 For case-control and cohort
studies, risk of bias was rated as high (3 points or less), in-
termediate (4-6 points), or low (7 or more points).23 For
cross-sectional studies, risk of bias was rated as high (5
points or less), intermediate (6 points), or low (7 points
or more).24 These thresholds were used in previous re-
search.23 , 24 Agreement between reviewers was determined
using the Cohen κ statistic.
• REPORTING BIAS ASSESSMENT: Because of the small
number of studies eligible for inclusion in the meta-analysis,
it was not feasible to apply statistical tests to evaluate funnel
plot asymmetry.
RESULTS
• STUDY SELECTION: A study flow diagram, which out-
lines the results of our search strategy, is presented in
Figure 1. The search identified 2204 records that were
screened by title and abstract and resulted in 31 articles for
full-text review. After the inclusion/exclusion criteria were
implemented, a total of 11 articles involving 249,295 par-
ticipants were included in the review.
• STUDY CHARACTERISTICS: The characteristics of the
included studies on systemic antihypertensive medica-
tion use with IOP and glaucoma are summarized in
Table 1.6-14 , 25 , 26 The first 3 studies in Table 1 focus on IOP
as the outcome, excluding people who have a history of
glaucoma or ocular hypertension. The last 8 studies focus
primarily on the incidence of glaucoma through their use
of prospective cohort or nested case-control study designs.
The results of each study are presented in Table 2. None
of the studies excluded participants who were taking more
than 1 class of medication. Therefore, a person could be
present in analyses for both BB and CCB if they were taking
systemic antihypertensive drugs from both of those medica-
tion classes.
• RISK OF BIAS IN STUDIES: Risk-of-bias assessments are
presented in Table 3. Using the Newcastle-Ottawa Scale,22
8 studies were considered to have a low risk of bias.6-10 , 12 , 13
Three studies were considered to have an intermediate risk
of bias due to very small sample size resulting in impreci-
sion and an inability to adjust well for confounding,11 a
lack of information on losses to follow-up,11 a lack of clear
case and control definitions and information about adjust-
ment,14 and a self-reported outcome.25 The Cohen κ was
0.85, indicating strong inter-rater agreement.
• RESULTS OF SYNTHESES: Meta-analyses were conducted
on the results of 4 medication classes and glaucoma for those
studies that used the same statistical model (logistic regres-
sion). First, the forest plot of the 7 studies that examined
NOVEMBER 2023
 VOL. 255
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TABLE 1. Characteristics of Studies Included in the Systematic Review

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Author, Year Study Population Key Exclusions Study Design Sample Size Measurement of Exposure Measurement of Outcome

Ho et al, Singapore History of glaucoma or ocular Cross-Sectional 8063 Question about medication use. Those IOP: Goldman applanation tonometer,
20176 Epidemiology of Eye hypertension, previous ocular analysis answering yes were asked to show single reading
Diseases study surgery or trauma, asymmetric medication containers
IOP
Hohn et al, Gutenberg Health Previous ocular surgery, use of Cross-Sectional 13,527 Participants were asked to bring the IOP: Nidek noncontact tonometer,
SYSTEMIC ANTIHYPERTENSIVE MEDICATIONS AND GLAUCOMA

20177 Study glaucoma medication analysis packages of all their medications to the mean of 3 readings per eye
study visit
Khawaja EPIC-Norfolk Eye History of glaucoma medication Cross-Sectional 7093 Participants were asked to bring the IOP: Ocular Response Analyzer
et al, Study use or glaucoma procedure, analysis packages of all their medications to the noncontact tonometer, best signal of 3
20148 asymmetric IOP study visit readings per eye
Asefa Lifelines Cohort Those with AMD or who had Cross-Sectional 86,841 Question about medication use. Those Algorithm including self-report of
et al, Study (the laser or surgery for diabetes or analysis answering yes were asked to show glaucoma and NEI-VFQ questionnaire
202025 Netherlands) retinal detachment medication containers
Langman General Practitioner No exclusions listed Matched (1:1) 54,160 Medications prescribed in the GPRD in Glaucoma diagnoses in GPRD
et al, Research Database case-control the previous 1095 days before the index between 1990 and 1999
200514 in UK study date
Miglior EGPS randomized People with IOP ≤21 or with Cohort analysis 1077 Participants were asked to bring the Ophthalmic examination including
et al, controlled clinical trial glaucoma at baseline of RCT packages of all their medications to the Goldman applanation tonometry,
200726 (dorzolamide versus study visit automated static perimetry, and
placebo) stereophotography of the optic disc
Müskens Rotterdam Study No exclusions listed Prospective 3842 Prescriptions filled at 7 area pharmacies Ophthalmic examination including
et al, cohort Goldmann applanation tonometry,
20079 visual field screening, ophthalmoscopy,
and stereoscopic fundus photography
Owen United Kingdom Cases had to be registered for at Nested matched 17,556 Medications prescribed in the previous Glaucoma defined based on
et al, DIN-LINK Database least 5 years and ages 40-90 at (1:1) 5 years before the index date as listed combination of glaucoma or ocular
201010 diagnosis; Controls had to have case-control in the DIN-LINK database hypertension diagnostic codes and
5 years of registration at case study codes for prescriptions specific to the
diagnosis and could not treatment of glaucoma
subsequently be diagnosed with
glaucoma
(continued on next page)
9
 10
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TABLE 1. (continued)
AMERICAN JOURNAL OF OPHTHALMOLOGY

Author, Year Study Population Key Exclusions Study Design Sample Size Measurement of Exposure Measurement of Outcome

Pappelis Groningen None listed Prospective 112 Complete medical file was examined Ophthalmic examination including
et al, Longitudinal cohort study of along with a semistructured interview of standard automated perimetry;
201911 Glaucoma Study glaucoma each patient glaucoma conversion defined as at
suspects least 2 abnormal VF tests in 1 eye
Yuan et al, 45 and Up Study in People who took antiglaucoma Nested matched 20,244 At least 3 claims records of a At least 3 claims records of ocular
202212 Australia with Linkage medications during the 5-year (2:1) medication in the 1-5 years before the antihypertensive medications from 2009
to Health Records look-back period; people who case-control index date to 2016
had only 1 or 2 antiglaucoma study
medications during the follow-up
(as opposed to 3).
Zheng US Truven Health Diagnostic codes for non-POAG Nested matched 36,780 Outpatient pharmacy prescription At least 1 glaucoma procedure and
et al, MarketScan glaucoma; glaucoma procedure (5:1) claims from 5 years to 30 days before glaucoma diagnosis code
201713 Commercial and in the 5 years before the index case-control the index date; more than 90 days of
Medicare date; controls had to have study supply = exposed
Supplemental routine cataract surgery and no
Insurance Databases glaucoma diagnosis,
medications, or procedures

AMD = Age-related macular degeneration, EGPS = European Glaucoma Prevention Study, EPIC = European Prospective Investigation of Cancer, GPRD = General Practice Research
Database, IOP = intraocular pressure, NEI-VFQ = National Eye Institute Visual Function Questionnaire, POAG = primary open-angle glaucoma, RCT = randomized controlled trial, VF = visual
field.
NOVEMBER 2023
 TABLE 2. Overview of the Reported Associations From Studies Included in the Systematic Review

Author, Year Outcome Statistical Model Adjustment Factors Measures of Association and 95% CIs

Ho et al, IOP Linear regression Adjusted for age, sex, body mass index BB (β: −0.45, 95% CI: −0.65 to −0.25)
20176 with GEE to (BMI), cultural/ethnic background, health ACE (β: 0.33, 95% CI: 0.08 to 0.57)
account for conditions, blood pressure, LDL cholesterol, ARB (β: 0.40, 95% CI: 0.05 to 0.75)
inter-eye insulin, and other medication use
correlation
Hohn et al, IOP Linear regression Adjusted for, age, sex, BMI, central corneal BB (β: −0.14, 95% CI: −0.25 to −0.02)
20177 thickness, and SBP CCB (β: −0.10, 95% CI: −0.27 to 0.06)
ACE (β: 0.11, 95% CI: −0.01 to 0.24)
ARB (β: −0.07, 95% CI: −0.21 to 0.08)
Diuretic (β: −0.11, 95% CI: −0.31 to 0.08)
Khawaja et al, IOP Linear regression Adjusted for age, sex, and BMI BB (β: −1.04, 95% CI: −1.30 to −0.79)
20148 CCB (β: −0.13, 95% CI: −0.38 to 0.13)
ACE (β: −0.03, 95% CI: −0.26 to 0.19)
ARB (β: 0.07, 95% CI: −0.27 to 0.40)
Diuretic (β: -0.03, 95% CI: −0.27 to 0.20)
Asefa et al, Glaucoma odds Generalized Adjusted for age, sex, and BMI BB (OR: 1.06, 95% CI: 0.94 to 1.19)
202025 linear mixed CCB (OR: 1.19, 95% CI: 1.01 to 1.40)
models ACE (OR: 1.35, 95% CI: 1.18 to 1.55)
ARB (OR: 1.16, 95% CI: 0.98, 1.37)
Diuretic (OR: 1.09, 95% CI: 0.95 to 1.25)
Langman Glaucoma odds Unstated Matched on age and sex BB (OR: 0.77, 95% CI: 0.73 to 0.83)
et al, 200514 CCB (OR: 1.16, 95% CI: 1.09 to 1.24)
ACE (OR: 1.34, 95% CI: 1.24 to 1.44)
Diuretic (OR: 1.08, 95% CI: 1.03 to 1.14)
Miglior et al, Incidence of Cox proportional Adjusted for age, IOP, treatment arm, BB (HR: 1.12, 95% CI: 0.48 to 2.59)
200726 open-angle hazards cup-to-disc ratio, central corneal thickness, ACE (HR: 1.19, 95% CI: 0.54 to 2.62)
glaucoma regression diabetes, and systemic hypertension Diuretic (HR: 2.94, 95% CI: 1.35 to 6.40)
Müskens et al, Incidence of Logistic Adjusted for age, sex, time spent in the BB (OR: 0.6, 95% CI: 0.4 to 1.1)
20079 open-angle regression study, cardiovascular disease, IOP, and CCB (OR: 1.9, 95% CI: 1.1 to 3.3)
glaucoma IOP-lowering medication ACE (OR: 0.9, 95% CI: 0.5 to 1.7)
BB and CCB showed dose response
(P < .05)
Owen et al, Incidence of Conditional Matched for age, sex, practice. Further BB (OR: 0.87, 95% CI: 0.80 to 0.94)
201010 glaucoma logistic regression adjusted for SES, diabetes, angina, MI, CCB (OR: 1.03, 95% CI: 0.94 to 1.12
asthma, COPD, and other antihypertensive ACE (OR: 0.99, 95% CI: 0.91 to 1.08)
medications Diuretic (OR: 1.13, 95% CI: 1.04 to 1.23)
Pappelis et al, Incidence of Logistic Considered: age, sex, BMI, IOP, central BB (OR: 0.53, 95% CI: 0.22 to 1.28)
201911 primary regression corneal thickness, baseline MD, glaucoma CCB (OR: 0.50, 95% CI: 0.17 to 1.44)
open-angle surgery, and number of glaucoma ACEi (OR: 0.24, 95% CI: 0.07 to 0.78)
glaucoma medications ARB (OR: 0.11, 95% CI: 0.01 to 0.87)
Diuretic (OR: 0.20, 95% CI: 0.07 to 0.59)

Yuan et al, Incidence of Conditional Matched on age, sex, and CVD. Further BB (OR: 0.82, 95% CI: 0.75 to 0.90)
202212 primary logistic regression adjusted for baseline hyperlipidemia, CCB (OR: 1.00, 95% CI: 0.92 to 1.09)
open-angle hypertension, diabetes, education, BMI, ACEi (OR: 0.99, 95% CI 0.91 to 1.07)
glaucoma smoking, alcohol use, and exercise habits ARB (OR: 0.97, 95% CI: 0.90 to 1.05)
Diuretic (OR: 0.85, 95% CI 0.77 to 0.95)

Zheng et al, Incidence of a Logistic Matched on age, sex, US geographic BB (OR: 0.77, 95% CI: 0.72 to 0.83)
201713 procedure to regression region; further adjusted for employment CCB (OR: 1.26, 95% CI: 1.18 to 1.35)
treat primary status, insurance plan type, and total
open angle number of drugs
glaucoma

ACE = angiotensin-converting enzyme inhibitors, ARB = angiotensin receptor blocker, BB = β-blocker, CCB = calcium channel blocker,
COPD = chronic obstructive pulmonary disease, CVD = cardiovascular disease, GEE = generalized estimating equation, HR = hazard ratio,
IOP = intraocular pressure, LDL = low-density lipoprotein, OR = odds ratio, SBP = systolic blood pressure, SES = socioeconomic status.

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FIGURE 1. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow chart of included studies.

TABLE 3. Risk of Bias Assessed Using the Newcastle-Ottawa Scale

Study Selection Comparability Exposure/Outcome Total Score

Cross-sectional studies 10 total points

Ho et al6 3 2 3 8 (low risk of bias)
Hohn et al7 4 2 3 9 (low risk of bias)
Khawaja et al8 2 2 3 7 (low risk of bias)
Asefa et al25 2 2 2 6 (intermediate)
Cohort studies 9 total points
Müskens et al9 4 2 2 8 (low risk of bias)
Pappelis et al11 4 0 2 6 (intermediate risk of bias)
Miglior et al26 3 2 3 8 (low risk of bias)
Case-control studies 9 total points
Langman et al14 2 1 2 5 (intermediate risk of bias)
Owen et al10 4 2 3 9 (low risk of bias)
Yuan et al12 4 2 2 8 (low risk of bias)
Zheng et al13 4 2 3 9 (low risk of bias)

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FIGURE 2. Forest plot of studies examining systemic β-blockers and glaucoma. OR = odds ratio, REML = restricted maximum
likelihood.

FIGURE 3. Forest plot of studies examining systemic calcium channel blockers and glaucoma. OR = odds ratio, REML = restricted
maximum likelihood.

associations of systemic BBs and glaucoma is presented in
Figure 2. The pooled OR for BB use and glaucoma was 0.83
(95% CI: 0.75-0.92). The I2 value was 85%. Next, the for-
est plot of the 7 studies that examined the associations of
CCB use and glaucoma is presented in Figure 3. The pooled
OR was 1.13 (95% CI: 1.03-1.24), and the I2 value was
77%. The pooled OR of the 6 studies examining the associ-
ations of ACEi use and glaucoma was 1.10 (95% CI: 0.92-
1.31). The forest plot is presented in Supplemental Figure
1, and the I2 value was 91%. The forest plot of the 3 stud-
ies that reported on ARB use and glaucoma is presented in
Supplemental Figure 2. The pooled OR was 1.03 (95% CI:
0.87-1.22), and the I2 was 57%. Last, the forest plot of the
5 studies examining diuretics and glaucoma is available in
Supplemental Figure 3. The pooled OR for diuretic use and
glaucoma was 1.00 (95% CI: 0.87-1.16), and the I2 value
was 88%.
Meta-analyses were also conducted on the results of 3
medication classes and IOP. First, 3 studies assessed the as-
sociations of BBs and IOP. The pooled β-coefficient esti-
mate was −0.53 (95% CI: −1.05 to −0.02) and hetero-
geneity was high (I2 = 96%). The forest plot is presented
in Figure 4. Second, the pooled estimate from the 2 studies
that looked at CCBs and IOP was −0.11 (95% CI: −0.25
to −0.03). The I2 value was 0%. The forest plot is pre-
sented in Supplemental Figure 4. The pooled estimate from
the 3 studies on the association of ACEi use and IOP was
0.13 (95% CI: −0.05 to 0.30). The I2 value was 58%. The
forest plot is available in Supplemental Figure 5. Last, the
pooled estimate from the 3 studies reporting on the associ-
ation of ARBs and IOP was 0.10 (95% CI: −0.17 to 0.37)
(I2 = 67%). The corresponding forest plot is presented in
Supplemental Figure 6.
Stratification by study design or glaucoma subtype did not
reduce I2 values (data not shown).
• RESULTS OF INDIVIDUAL STUDIES: In this section, we
will highlight studies that were not included in the meta-

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FIGURE 4. Forest plot of studies examining systemic β-blockers and IOP. REML = restricted maximum likelihood.
analysis, that were clear outliers, or that reported on dose
response. Eight studies reported on the associations of sys-
temic BB use and glaucoma.9-14 , 25 The pooled OR for
BB use and glaucoma was 0.83 (95% CI: 0.75-0.92). Al-
though the overall OR was below 1, there were 2 stud-
ies that had ORs greater than 1 (Table 2). The study by
Miglior and associates26 was not included in the meta-
analysis because they used survival analysis rather than lo-
gistic regression. They reported a null association of BBs
and glaucoma (hazard ratio: 1.12, 95% CI: 0.48-2.59).26
Asefa and associates25 also reported an OR greater than
1 (OR: 1.06, 95% CI: 0.94-1.19). One study showed the
evidence of a dose-response relationship. In a prospective
cohort study, Müskens and associates9 studied the asso-
ciations of systemic antihypertensive medication use and
incident POAG and found that systemic BBs were asso-
ciated with a reduced odds of POAG, although this did
not reach statistical significance (OR: 0.6, 95% CI: 0.3-
1.02). They did see statistically significant evidence of
a dose-response relationship with increasing duration of
use associated with a lower odds of developing POAG.9
Leave-one-out analyses resulted in pooled estimates very
similar to the overall pooled estimate indicating robust
findings.
Seven studies reported on the associations of CCBs with
glaucoma.9-14 , 25 The pooled OR was 1.13 (95% CI: 1.03-
1.24). However, 2 studies had quite different results. Pap-
pelis and associates11 (n = 112) did not find that CCBs were
significantly associated with the odds of glaucoma suspect
conversion in unadjusted (OR: 0.50, 95% CI: 0.17-1.44) or
adjusted models (OR: 1.70, 95% CI: 0.32-9.19). The au-
thors wrote that the unadjusted estimate fits the data bet-
ter according to the AIC.11 Müskens and associates9 found
that CCB use was associated with a 1.8-fold (95% CI: 1.04-
3.20) increased odds of developing POAG during the av-
erage follow-up of 6.5 years. Two studies examined dose
response but with different conclusions. Zheng and asso-
ciates13 found that CCBs were associated with an increased
odds of POAG requiring a procedure (OR: 1.26, 95% CI:
1.18-1.35) but did not find evidence of a dose-response re-
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lationship. Müskens and associates9 did see evidence of a
dose-response relationship with increasing duration of CCB
use associated with a higher odds of POAG. Leave-one-
out analyses resulted in pooled estimates very similar to the
overall pooled estimate indicating robust findings.
The research on the relationship between ACEi use and
glaucoma has been less consistent. The pooled OR from 6
studies was 1.10 (95% CI: 0.92-1.31), which was not sta-
tistically significant. One study reported an OR that was
very different. Pappelis and associates11 found that people
on ACEi had a lower odds of POAG (OR: 0.24, 95% CI:
0.07-0.78). Leave-one-out analyses resulted in pooled ORs
closer to the null when leaving out either Langman and as-
sociates14 (OR: 1.03, 95% CI: 0.85-1.26) or Asefa and as-
sociates25 (OR: 1.04, 95% CI: 0.84-1.27).
There was also inconsistency in the research on ARBs
and glaucoma. The pooled OR from 3 studies was 1.03
(95% CI: 0.87-1.22). However, again the study by Pappelis
and associates had very different results. Pappelis and asso-
ciates11 found that ARB use was associated with a reduced
risk of glaucoma suspect conversion (OR: 0.11, 95% CI:
0.01-0.87). Leave-one-out analyses indicated that leaving
out either the Yuan and associates12 (OR: 0.47, 95% CI:
0.05-4.44) or Asefa and associates25 (OR: 0.44, 95% CI:
0.06-3.42) studies resulted in pooled ORs closer to the Pap-
pelis and associates finding. However, neither pooled result
from the leave-one-out analysis was statistically significant.
More inconsistency was found on studies examining the
association of diuretic use and glaucoma with 2 studies re-
porting a negative association, 3 studies reporting a posi-
tive association, and 1 study having null results. The pooled
OR was 1.00 (95% CI: 0.87-1.16). Pappelis and associates’
study11 again had very different results. They found a lower
odds of POAG suspect conversion in diuretic users in un-
adjusted analyses (OR: 0.20, 95% CI: 0.07-0.59).11 Leave-
one-out analyses resulted in pooled estimates very similar
to the overall pooled estimate indicating robust findings.
The β coefficients from the 3 studies that examined BBs
and IOP were all below zero and statistically significant, but
they varied substantially in size. The pooled β estimate was
NOVEMBER 2023
−0.53 (95% CI: −1.05 to −0.02). Leave-one-out analyses
resulted in very different pooled estimates when exclud-
ing the Hohn and associates7 (β: −0.74, 95% CI: −1.32
to −0.16) or Khawaja and associates8 (β: −0.28, 95% CI:
−0.59 to 0.02) studies.
Results from the Ho and associates6 study were different
from the other studies for ACEi and ARB drugs and IOP.
However, leave-one-out analyses excluding Ho and asso-
ciates still resulted in pooled estimates that were not sta-
tistically significant.
DISCUSSION
In our systematic review and meta-analysis, we looked at 5
classes of systemic antihypertensive medications. We found
the most consistent results for systemic BBs in that 6 of the 7
effect estimates were less than the null value for both IOP
and glaucoma. Our pooled results indicated that systemic
BBs are inversely associated with both IOP (β: −0.53, 95%
CI: −1.05 to −0.02, 3 studies, n = 28,683) and glaucoma
(OR: 0.83, 95% CI: 0.75-0.92, 7 studies, n = 219,535) with
one study showing evidence of a dose-response relationship
with glaucoma. We also found somewhat consistent results
for CCBs but in the opposite direction. Four of 7 effect es-
timates for the relationship between CCBs and glaucoma
were greater than 1 with the pooled OR 1.13 (95% CI:
1.03-1.24, 7 studies, n = 219,535). However, CCBs were
not associated with IOP (β: −0.11, 95% CI: −0.25 to 0.03,
2 studies, n = 20,620).
The association between systemic BBs and IOP is consis-
tent with prior small clinical studies in both people with
and without glaucoma.27 , 28 The mechanism of action is
thought to be that enough systemic BB medication reaches
the anterior chamber to reduce the formation of aqueous
humor and reduce IOP. Thus, systemic BBs likely protect
against glaucoma by reducing IOP. Conversely, the mecha-
nism by which systemic CCBs may increase the risk of glau-
coma is thought to act via an IOP-independent mechanism
given that CCBs were not associated with IOP. Our findings
on CCBs may be in contrast to prior research, which sug-
gested that CCBs may be protective against normal-tension
glaucoma possibly by dilating ocular vessels and improving
optic nerve perfusion.29 , 30 Although the reviewed studies
did not look separately at normal-tension glaucoma, our
pooled results are not consistent with a protective effect of
CCBs.
Our results are in disagreement with a Mendelian ran-
domization study on hypertension and glaucoma. Liu and
Funding/Support: This work was supported by a grant from the Canadian Institutes of Health Research (MOP 133560).
Financial Disclosures: The authors indicate no financial support or conflicts of interest. All authors attest that they meet the current ICMJE criteria for
authorship.
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associates31 used single nucleotide polymorphism instru-
mental variables that affected the target protein of 12 dif-
ferent antihypertensive medications. Using this approach,
they did not find statistically significant associations be-
tween any of the 12 classes of antihypertensive medications
and glaucoma using data from the UK Biobank. However,
glaucoma was self-reported, and the CIs were extremely
wide.
The risk of bias for most studies was low. In particular, 6
of the 8 studies on glaucoma were longitudinal (prospective
cohort or nested case control) and therefore were able to ex-
clude people at baseline who already had glaucoma, thereby
capturing the temporality of the medication exposure and
the onset of glaucoma. Three of the 8 studies on glaucoma
used the gold standard ophthalmic examination to diag-
nose glaucoma, whereas the rest relied on claims data. All of
the studies on IOP evaluated medication exposure using a
very high quality approach in that participants were asked
to bring in their medication containers to the study visit.
Methodological limitations of the studies are that claims
data will only identify patients with glaucoma if they have
been diagnosed by an eyecare professional. Also, having a
medication container does not mean that the medication
was always taken as prescribed. Very few studies evaluated
the duration of medication use, which would have provided
stronger certainty of evidence. Finally, studies were not able
to differentiate the type of glaucoma.
This work may have clinical implications. For those
people with systemic hypertension needing pharmacologic
treatment who have a family history of glaucoma, the pre-
scription of a systemic BB may delay the onset of the need
for ocular treatment. Eyecare professionals should be aware
that a glaucoma suspect taking a systemic BB may be con-
sidered as already treated depending on the target IOP and
optic nerve head appearance. Conversely, the use of sys-
temic CCBs in people needing treatment for systemic hy-
pertension who have a family history of glaucoma (in par-
ticular, normal-tension glaucoma) may need to consider
switching classes of antihypertensives. For those in whom a
CCB is the best choice systemically, closer ophthalmologic
follow-up may be needed. For those with normal-tension
glaucoma, 24-hour blood pressure monitoring to exclude re-
peated nocturnal hypotension should also be considered.
To conclude, systemic BBs to treat systemic hypertension
may be beneficial in those at risk for glaucoma, whereas sys-
temic CCBs may be harmful. Further randomized clinical
trial research may be needed to fully understand the opti-
mal treatment approach for people with both systemic hy-
pertension and risk of glaucoma.
15
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