Increased Risks of Open-Angle Glaucoma in
Untreated Hypertension
JIHEI SARA LEE1, YONG JOON KIM1, SUNYEUP KIM, HYOUNG WON BAE, SUNG SOO KIM,
SEUNG WON LEE2, AND CHAN YUN KIM2
• PURPOSE: Hypertension (HTN) has been associated
with open-angle glaucoma (OAG), but whether elevated
blood pressure (BP) alone is associated with OAG is un-
known. Whether stage 1 hypertension, as per the 2017
American College of Cardiology/American Heart Asso-
ciation (ACC/AHA) BP guidelines, increases the risk of
the disease is uncertain.
• DESIGN: Retrospective, observational, cohort study.
• METHODS: A total of 360,330 subjects who were ≥40
years of age and not taking antihypertensive or antiglau-
coma drugs at the time of health examinations between
January 1, 2002, and December 31, 2003, were included.
Subjects were categorized based on their untreated BP,
into normal BP (systolic BP [SBP] <120 and diastolic
BP [DBP] <80 mm Hg; n = 104,304), elevated BP
(SBP 120-129 and DBP <80 mm Hg; n = 33,139),
stage 1 HTN (SBP 130-139 or DBP 80-89 mm Hg;
n = 122,534), or stage 2 HTN (SBP ≥140 or DBP
≥90mm Hg; n = 100,353). Cox regression analysis was
performed to calculate hazard ratios (HR) of OAG risk.
• RESULTS: The mean age of the subjects was 51.17
± 8.97 years, and 56.2% were male. During a mean
follow-up period of 11.76 ± 1.37 years, 12,841 sub-
jects (3.56%) were diagnosed with OAG. Multivariable-
adjusted HRs (95% CIs) were 1.056 (0.985-1.132) for
elevated BP, 1.101(1.050-1.155) for stage 1 HTN, and
1.114(1.060-1.170) for stage 2 HTN with normal BP as
the reference.
• CONCLUSIONS: The risk for OAG becomes greater
with increases in untreated BP. Stage 1 HTN per the
2017 ACC/AHA BP guidelines is a significant risk factor
for OAG. (Am J Ophthalmol 2023;252: 111–120. ©
2023 Elsevier Inc. All rights reserved.)
Supplemental Material available at AJO.com.
Accepted for publication March 21, 2023.
Department of Ophthalmology, Severance Hospital, Institute of Vi-
sion Research, Yonsei University, South Korea; Department of Data Sci-
ence, Sejong University, College of Software convergence, Seoul, Korea;
Department of Precision MEdicine, Sungkyunkwan University College of
Medicine, Seoul, Korea
Inquiries to Chan Yun Kim, Yonsei University College of Medicine,
Seoul, Korea; e-mail: kcyeye@yuhs.ac
1 Jihei Sara Lee and Yong Joon Kim equally contributed as co−first au-
thors.
a Seung Won Lee and Chan Yun Kim equally contributed to this work
as co−last authors.
0002-9394/$36.00 © 2023 ELSEVIER INC. ALL RIGHTS RESERVED.
https://doi.org/10.1016/j.ajo.2023.03.032
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G
laucoma is one of the leading causes of
blindness worldwide.1 In addition to intraocu-
lar pressure (IOP),2 other additional pathogenic
mechanisms have been suggested as risk factors for the
development and progression of open-angle glaucoma
(OAG). For instance, alterations in blood flow to the op-
tic nerve head are believed to contribute to the patho-
genesis of the disease.3 In support of this view, numerous
large population-based studies have identified cardiovas-
cular disease as 1 of the risk factors for the development
and progression of OAG,4-6 including systemic hyperten-
sion (HTN). Affecting at least 25% of the adult population
worldwide,7 , 8 systemic HTN has been identified to increase
risk for OAG.4
The impact of HTN on OAG, however, is disputed be-
cause antihypertensive medications are believed also to play
a role, whether it be through the mechanism of the medica-
tion itself or treatment-related hypotension.9 Amid the un-
certainty, the American College of Cardiology/American
Heart Association (ACC/AHA) published, in 2017, new
high blood pressure (BP) guidelines, which lowered the def-
inition of HTN.10 According to these guidelines, stage 1
HTN is either systolic BP (SBP) between 130 and 139 mm
Hg, or diastolic BP (DBP) between 80 and 89 mm Hg. This
new definition has resulted in nearly half of the adult pop-
ulation in the United States having high BP, and stage 1
HTN has been associated with significantly increased risks
for cardiovascular disease in young adults aged 20 to 39
years11 ; however, its effect on the prevalence of OAG has
not yet been thoroughly investigated. Using nationwide
health screening data from the Korean National Health In-
surance database, we sought to investigate OAG risks asso-
ciated BP unaffected by antihypertensive medication, and
to compare risks among elevated BP, stage 1 HTN, and stage
2 HTN as defined in the 2017 ACC/AHA BP guidelines.
METHODS
• DATA SOURCE: The data source has been described in
detail in a previous study.12 Briefly, the National Health
Insurance Service (NHIS) is the sole provider of health
care in South Korea, and more than 97% of South Koreans
are currently enrolled.13 The NHIS provides general health
screening to all individuals 40 years and older once every 2
111
years, and the results are collected and available to qualified
researchers upon request. The health screening dataset for
the current study comprised a 10% simple random sample
of all South Korean adult health screening participants in
2002 and 2003 in South Korea. The cohort contained ap-
proximately 510,000 adult NHIS beneficiaries between the
ages of 40 and 79 years as of 2002 (http://nhiss.nhis.or.kr/bd/
ab/bdaba022Heng.do). Their health screening results and
national insurance claims were followed up through 2015.
The cohort selection process and its profile are described
in detail elsewhere.13 The study adhered to the Declaration
of Helsinki and all federal laws in the country. The study
protocol was approved by the Institutional Review Board
of Yonsei University Severance Hospital (approval number
4-2022-0632). The NHIS approved the use of their data
for the present study (approval number NHIS-2022-2-335).
Informed consent was waived because of the retrospective
study design and de-identified and routinely collected na-
ture of the data.
• STUDY POPULATION: The study population was selected
as shown in Figure 1. A total of 514,791 adults 40 years and
older underwent national health screening between January
2002 and December 2003. Subjects with missing BP data
were excluded (n = 334). Those with any previous hospi-
tal claims of any form of glaucoma (n = 33,989) according
to International Classification of Diseases, 10th Revision (ICD-
10) coding (H40.x, H42.x, and Q15.0) before the baseline
examination were excluded. Those prescribed antihyper-
tensive medication in claims data prior to the baseline ex-
amination (n = 117,343) were excluded as well. Antihy-
pertensive medications were identified in the claims data
according to the protocol developed by the Korean Society
of Hypertension.14 Subjects with prior prescriptions of top-
ical glaucoma medication (n = 383) and less than 1 year of
follow-up from the baseline (n = 2,412) were also excluded,
leaving a final sample of 360,330 subjects for analysis. The
study protocol was adapted from the work by Lee et al.11
• BLOOD PRESSURE CLASSIFICATION: During the health
screening, at least 2 repeated BP measurements were taken
by trained medical personnel in 5-minute intervals us-
ing auscultatory or oscillometric methods.15 Subjects were
given a minimum of 5 minutes of rest in a seated position
before the measurement. For the purpose of our analysis, the
subjects were categorized into 8 mutually exclusive groups
based on the BP measurements obtained from the baseline
examination: (1) normal BP (SBP <120 mm Hg and DBP
<80 mm Hg); (2) elevated BP (SBP 120-129 mm Hg and
DBP <80 mm Hg); (3) stage 1 isolated diastolic hyperten-
sion (IDH; SBP <130 mm Hg and DBP 80-89 mm Hg); (4)
stage 1 isolated systolic hypertension (ISH; SBP 130-139
mm Hg and DBP <80 mm Hg); (5) stage 1 systolic and di-
astolic hypertension (SDH; SBP 130-139 mm Hg and DBP
80-89 mm Hg); (6) stage 2 IDH (SBP <140 mm Hg and
DBP ≥90 mm Hg); (7) stage 2 ISH (SBP ≥140 mm Hg
112 AMERICAN JOURNAL OF OPHTHALMOLOGY
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and DBP <90 mm Hg); and (8) stage 2 SDH (SBP ≥140
mm Hg and DBP ≥90 mm Hg). Individuals’ status on to-
bacco smoking (never, past, or current), alcohol consump-
tion (none, 1-2 times/wk, or ≥3 times/wk), and physical ex-
ercise (none, 1-2 times/wk, or ≥3times/wk) were collected
from self-reports. Body mass index (BMI), serum fasting
glucose, and serum total cholesterol levels were obtained
during the examinations. Prescription histories of glucose-
lowering16 and lipid-lowering medications within 1 year
before the baseline examination were obtained from the
claims data.
• OUTCOME: The primary outcome was diagnosis of OAG,
which was considered to be present if both of the following
criteria were satisfied: (1) at least 2 outpatient/ambulatory
visits between 2004 and 2015 containing ICD-10 codes of
OAG (H40.10x, H40.13x, and H40.19x); and (2) prescrip-
tions of topical glaucoma medication at least once during
the same period.17 The first date on which both criteria
were satisfied was counted as the outcome. Outcomes were
available through December 31, 2015.
• STATISTICAL ANALYSES: Continuous data were pre-
sented as mean ± SD, and categorical data were reported
as frequency and percentage. The incidence rates of OAG
were calculated for each BP group, and the cumulative in-
cidence of OAG for each BP group was estimated using the
Kaplan−Meier method. The hazard ratios (HR) and 95%
confidence intervals (CI) for OAG events in each BP group
were calculated using Cox proportional hazards models, in
which the normal BP group served as the reference. The
end of the observation was the date of the primary outcome,
that is, the last follow-up or December 31, 2015, whichever
came first. The HRs were adjusted for age, sex, household
income, residential area, total cholesterol, fasting glucose,
lipid-lowering agents, and glucose-lowering agents, selected
a priori on the basis of their known associations with BP and
OAG.18 , 19
Follow-up BP measurements between 2007 and 2010
were available in 301,408 of the subjects included in the
study (Supplementary Figure 1). The 4-year follow-up pe-
riod was chosen to maximize the number of individuals with
follow-up BP measurements, as individuals undergo health
screenings every 2 years. The year 2010 allowed for 5 years
of additional follow-up within the study period after sec-
ond BP measurement. Use of antihypertensive medication
at the time of BP follow-up measurement was not an indica-
tion for exclusion. This subset of subjects was additionally
categorized based on changes in BP from the baseline exam-
ination (2002-2003) to the follow-up examination (2007-
2010). For those with multiple BP measurements during the
follow-up period, the last recorded BP was used for classifi-
cation. The HR and 95% CI for OAG events for all com-
binations of changes in BP groups were calculated. For the
purpose of the analysis, the stage 2 IDH, ISH, and SDH
were merged into a single-stage 2 HTN group. A sensitivity
MONTH 2023
FIGURE 1. A flowchart of study population selection. From 514,791 subjects who underwent health examinations between January
1, 2002, and December 31, 2003, those with a previous glaucoma diagnosis (n = 33,989), previous antihypertensive medication
prescription (n = 117,343), previous glaucoma medication prescription (n = 383), and less than 1 year of follow-up (n = 2,412)
were excluded, to obtain a total of 360,330 subjects as the final study population.

analysis was conducted, in which BP measurements from
2004 to 2005 were used to calculate HRs for OAG risk.
Statistical analyses were performed using SAS version 9.4
(SAS Institute Inc) and R version 3.5.3 (R Foundation for
Statistical Computing).
RESULTS
• BASELINE CHARACTERISTICS: A total of 360,330 sub-
jects were included in this study (51.17 ± 8.97 years,
56.2% male) (Table 1). None of the participants were tak-
ing antihypertensive medication or IOP-lowering medica-
tion at baseline. When subjects were divided by their BP
at baseline, 104,304 subjects had normal BP; 33,139 sub-
jects had elevated BP; 122,534 subjects had stage 1 HTN;
and 100,353 subjects had stage 2 HTN. Among those
having stage 1 HTN, 66,463 subjects had IDH, 13,738
had ISH, and 42,333 had SDH. As for those with stage
2 HTN, 27,388 had IDH, 23,163 had ISH, and 49,802
had SDH.
• ASSOCIATION BETWEEN OAG RISK AND BASELINE BP:
During a mean follow-up period of 11.76 ± 1.37 years,
12,841 subjects (3.56%) were diagnosed with OAG
(Figure 2). The OAG incidence rates per 100,000 person-
years were 251.0 for normal BP, 294.7 for elevated BP, 306.5
for stage 1 HTN, and 354.8 for stage 2 HTN (Figure 3).
The cumulative incidence of OAG was highest in the
stage 2 HTN group, followed by the stage 1 hyperten-
sion group. When age, sex, household income, residential
area, fasting glucose, total cholesterol, and the use of lipid-
lowering and glucose-lowering agents were adjusted, ele-
vated BP was not associated with higher OAG risk in com-
parison to normal BP (Figure 3). However, stage 1 HTN

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 114

TABLE 1. Baseline Characteristics of Study Population According to BP Groups.

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Normal Elevated Stage 1 HTN (n=122,534) Stage 2 HTN (n=100,353)

BP BP
(n = 104,304) (n = 33,139) Stage1 IDH (n = 66,463) Stage1 ISH (n = 13,738) Stage1 SDH (n = 42,333) Stage2 IDH (n = 27,388) Stage2 ISH (n = 23,163) Stage2 SDH (n = 49,802)

Age, y, n (%)
40-49 62,298(17.29) 17,149 (4.76) 38,588(10.71) 5637 (1.56) 20,737 (5.76) 15,209 (4.22) 7087 (1.97) 19,995 (5.55)
50-59 26,663 (7.4) 8897 (2.47) 18,004 (5.00) 3807 (1.06) 12,431 (3.45) 7981 (2.21) 6563 (1.82) 15,864 (4.4)
60-69 12,292 (3.41) 5460 (1.52) 8062 (2.24) 3095 (0.86) 7266 (2.02) 3497 (0.97) 6648 (1.84) 10,573 (2.93)
70-79 2958 (0.82) 1582 (0.44) 1756 (0.49) 1156 (0.32) 1834 (0.51) 679 (0.19) 2743 (0.76) 3239 (0.90)
AMERICAN JOURNAL OF OPHTHALMOLOGY

≥80 93 (0.03) 51 (0.01) 53 (0.01) 43 (0.01) 65 (0.02) 22 (0.01) 122 (0.03) 131 (0.04)
Sex, n (%)
Male 45,528 (12.64) 17,038 ± 4.73 40,483 (11.23) 7270 (2.02) 26,429 (7.33) 19,061 (5.29) 13,068 (3.63) 33,746 (9.37)
Female 58,776(16.31) 16,101 ± 4.47 25,980 (7.21) 6468 (1.80) 15,904 (4.41) 8327 (2.31) 10,095 (2.80) 16,056 (4.46)
SBP (mm Hg) 106.40 ± 7.24 121.91 ± 2.77 118.56 ± 5.16 131.99 ± 2.76 131.38 ± 2.59 128.38 ± 5.53 145.07 ± 7.32 149.95 ± 11.71
DBP (mm Hg) 66.73 ± 5.97 70.83 ± 4.52 80.65 ± 1.77 71.72 ± 4.55 81.44 ± 2.61 90.88 ± 2.66 80.03 ± 5.45 95.05 ± 7.31
BMI (kg/m2 ) 23.01 ± 2.72 23.62 ± 2.8 23.71 ± 2.83 23.88 ± 2.85 24.10 ± 2.87 24.31 ± 2.89 24.20 ± 3.03 24.61 ± 3.04
Fasting glucose (mg/dL) 92.90 ± 28.58 96.01 ± 30.75 95.44 ± 30.77 98.68 ± 33.25 98.04 ± 32.91 97.74 ± 33.78 102.01 ± 38.43 101.70 ± 38.23
reserved.

Total cholesterol (mg/dL) 194.12 ± 36.98 197.65 ± 37.11 199.05 ± 37.4 200.04 ± 37.99 201.26 ± 38.03 202.95 ± 38.44 202.46 ± 39.32 204.97 ± 39.48
Smoking, n (%)
Never 70,748(19.63) 21,364 (5.93) 39,169(10.87) 8894 (2.47) 25,036 (6.95) 14,784 (4.10) 14,570 (4.04) 28,010 (7.77)
Former 7145 (1.98) 2592 (0.72) 6240 (1.73) 1114 (0.31) 3958 (1.10) 2957 (0.82) 1995 (0.55) 4792 (1.33)
Current 22,144 (6.15) 7890 (2.19) 18,059 (5.01) 3195 (0.89) 11,542 (3.20) 8364 (2.32) 5628 (1.56) 14,875 (4.13)
Alcohol consumption, n (%)
None 80,001 (22.2) 24,017 (6.67) 45,046 (12.5) 9690 (2.69) 27,847 (7.73) 16,674 (4.63) 15,611 (4.33) 29,305 (8.13)
1-2/wk 14,375 (3.99) 5235 (1.45) 12,515 (3.47) 2089 (0.58) 8123 (2.25) 6286 (1.74) 3741 (1.04) 10,735 (2.98)
≥3/wk 7880 (2.19) 3258 (0.90) 7684 (2.13) 1666 (0.46) 5661 (1.57) 4010 (1.11) 3315 (0.92) 9073 (2.52)
Household income, n (%)
Q1, lowest 21,329 (5.92) 7315 (2.03) 13,977 (3.88) 3297 (0.91) 9721 (2.70) 5732 (1.59) 6195 (1.72) 12,937 (3.59)
Q2-Q3 32,726 (9.08) 10,562 (2.93) 21,263 (5.9) 4646 (1.29) 14,228 (3.95) 8919 (2.48) 8269 (2.29) 17,499 (4.86)
Q4, highest 50,249(13.95) 15,262 (4.24) 31,223 (8.67) 5795 (1.61) 18,384 (5.10) 12,737 (3.53) 8699 (2.41) 19,366 (5.37)
Residence, n (%)
Metropolitan 49,492(13.74) 15,258 (4.23) 29,871 (8.29) 6062 (1.68) 19,111 (5.30) 12,519 (3.47) 9505 (2.64) 21,578 (5.99)
Rural 54,812(15.21) 17,881 (4.96) 36,592(10.16) 7676 (2.13) 23,222 (6.44) 14,869 (4.13) 13,658 (3.79) 28,224 (7.83)
Follow-up, y 11.82 ± 1.23 11.78 ± 1.36 11.79 ± 1.32 11.72 ± 1.52 11.76 ± 1.41 11.78 ± 1.36 11.69 ± 1.60 11.72 ± 1.50

BMI = body mass index; BP = blood pressure; DBP = diastolic blood pressure; HTN = hypertension; IDH = isolated diastolic hypertension; ISH = isolated systolic hypertension; SBP = systolic
MONTH 2023

blood pressure; SDH = systolic and diastolic hypertension.

Data are presented as mean ± SD or as number (percentage).
FIGURE 2. Cumulative open-angle glaucoma (OAG) incidence of BP groups by Kaplan−Meier methods. Cumulative incidence of
OAG was calculated over the follow-up period. BP = blood pressure.

FIGURE 3. Cox regression analysis of open-angle glaucoma (OAG) risks in association with baseline blood pressure (BP groups).
Cox regression model was adjusted for age, sex, household income, residential area, total cholesterol, fasting glucose, lipid-lowering
agents, and glucose-lowering agents. The incidence rates are per 100,000 person-years. HR = hazard ratio.

increased OAG risk by a factor of 1.101 (95% CI = 1.050-
1.155), and stage 2 HTN increased the risk by a factor
of 1.114 (95% CI = 1.060-1.170). When stages 1 and 2
HTN were further divided into IDH, ISH, and SDH (Sup-
plementary Figure 1), incidence rates per 100,000 person-
years were 282.9 for stage 1 IDH, 367.7 for stage 1 ISH,
323.9 for stage 1 SDH, 287.3 for stage 2 IDH, 409.7 for
stage 2 ISH. and 366.7 for stage 2 SDH (Supplementary
Figure 2). The multivariable adjustment revealed that all
types of stage 1 HTN were significantly associated with
higher risks for OAG in comparison to normal BP (stage
1 IDH, HR = 1.088, 95% CI = 1.029-1.151; stage 1
ISH, HR = 1.116, 95% CI = 1.019-1.223; stage 1 SDH,
HR = 1.114, 95% CI = 1.046-1.185), as well as stage 2
SDH (HR = 1.135, 95% CI = 1.071-1.204) and stage 2
ISH (HR = 1.107, 95% CI = 1.030-1.190) (Supplemen-
tary Figure 2).
• ASSOCIATION BETWEEN OAG RISK AND STAGE 1 HTN
REVERSAL OVER TIME: Of the 360,330 subjects included
in the study, 301,408 had undergone additional BP mea-
surements between 2007 and 2010. Of the subjects with

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 TABLE 2. Numbers of Subjects According to BP Changes Over Time.

Baseline Follow-up Examination

Normal BP Elevated BP Stage 1 HTN Stage 2 HTN

Normal BP 46,403 (51.80) 11,276 (12.59) 25,961 (28.98) 5,938 (6.63)

Elevated BP 9,593 (34.38) 4,127 (14.79) 10,670 (38.24) 3,513 (12.59)
Stage 1 HTN 28,965 (28.13) 12,350 (11.99) 44,280 (43.00) 17,385 (16.88)
Stage 2 HTN 13,075 (16.15) 7,366 (9.10) 35,269 (43.57) 25,237 (31.18)

BP = blood pressure; HTN = hypertension.

Data are presented as number (percentage).

FIGURE 4. Cox regression analysis of open-angle glaucoma (OAG) risks in association with stage 1 hypertension (HTN) reversal
over time. Cox regression model was adjusted for age, sex, household income, residential area, total cholesterol, fasting glucose, lipid-
lowering agents, and glucose-lowering agents. Incidence rates are per 100,000 person-years. BP = blood pressure; HR = hazard
ratio.

normal BP at baseline, 51.8% (n = 46,403) maintained
normal BP on follow-up, and 6.63% (n = 5938) developed
stage 2 HTN (Table 2). Among subjects with stage 1 HTN
at baseline, 43.0% (n = 44,280) maintained stage 1 HTN,
and 28.13% (n = 28,965) showed return to normal BP. We
evaluated whether normalization or reversal of stage 1 HTN
over time attenuated OAG risk (Figure 4). Decreases from
stage 1 to elevated BP were not associated with reduced
OAG risk. However, subjects whose BP changed from stage
1 HTN to normal BP showed increased risks (HR = 1.183,
95% CI = 1.043-1.342). To identify types of BP change as-
sociated with increased risk, stage 1 HTN was further di-
vided into ISH, IDH, and SDH (Supplementary Table 1). A
return to normal BP from either stage 1 IDH (HR = 1.166,
95% CI = 1.006-1.350) or stage 1 SDH (HR = 1.258, 95%
CI = 1.044-1.517) was associated with increased risk.
DISCUSSION
In this study using nationwide health screening data of Ko-
rean adults aged 40 years or older, we evaluated risks of
OAG associated with untreated HTN, stratified according
to the 2017 ACC/AHA BP classification. The results in-
dicated that adults with stage 1 HTN, SDH and IDH in
particular, had significantly higher risks for OAG in com-
parison with normal BP. Stage 2 HTN, especially SDH, was
associated with greater risks for OAG in comparison to nor-
mal BP.
Several studies in the past have pointed to HTN as
an important risk factor for development and progression
of OAG.4 , 6 The Blue Mountains Eye Study reported that
HTN increased the risk of OAG by more than 50%, and
that a 10mm Hg increase in SBP increased the OAG
prevalence by 10%.4 The Baltimore Eye Survey also found
an association between OAG and HTN.20 Our group
has demonstrated similar findings in the past. A meta-
analysis of population-based studies on the effect of sys-
temic HTN on OAG estimated a pooled odds ratio of 1.22
(95% CI = 1.09-1.36).6 An analysis of health screening
data found that persons with HTN were more likely to
have OAG than those without HTN (HR = 1.16, 95%
CI = 1.09-1.24) when HTN was defined either as expo-
sure to antihypertensive medication or as BP higher than
140/80 mm Hg.12 However, reports on the association be-
tween HTN and OAG are not consistent. The relationship
between BP and OAG were found to be not significant in a
number of prior studies, including the Barbados Eye Study
and the Proyecto Ver Studies.21 , 22 A negative association
has also been reported, whereby glaucoma risks were lower
in individuals with elevated BP.23 In 1 longitudinal study,

116 AMERICAN JOURNAL OF OPHTHALMOLOGY MONTH 2023

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HTN reduced the risk of OAG by nearly 50% during 4 years
of follow-up.23 Currently, the relationship between BP and
OAG is believe to follow a U-shape, in which both high and
low BP are risk factors for the disease.24-26 In addition, anti-
hypertensive medication is also suspected to contribute to
the progression and development of OAG9 by inducing ex-
aggerated nocturnal hypotensive episodes, which compro-
mise blood flow to the optic nerve head. Antihypertensive
therapy also complicates studies on the association between
OAG and HTN because it is used for several medical condi-
tions other than HTN, such as Raynaud disease, tachycar-
dia, and renal stones, just to name a few.27 In this context,
we sought to reaffirm our previous findings by investigating
the relationship between OAG and untreated BP.
Our analysis of the relationship between untreated BP
and OAG revealed that increasing BP increased OAG risk.
According to our results, stage 1 HTN increased OAG
risk by a factor of 1.101 (95% CI = 1.050-1.155). Stage
2 HTN was found to increase the risk further, by a factor
of 1.114 (95% CI = 1.060-1.170). Systemic BP may con-
tribute to the pathogenesis of glaucoma in a number of ways.
One postulated mechanism is overproduction of aqueous
humor, which results from elevated ciliary flow and capil-
lary pressure.28 , 29 Another possible mechanism is impaired
outflow of aqueous humor subsequent to elevated episcleral
venous pressure.30 , 31 Systemic inflammation and metabolic
stress are also possible mechanisms, resulting in disrupted
axonal transport and retinal ganglion cell death.24 , 32 For
instance, increases in systemic pro-inflammatory cytokines
such as tumor necrosis factor−α (TNF-α) have been ob-
served in both HTN and OAG,33-35 in association with
vascular endothelial apoptosis36 and retinal ganglion cell
death,37 respectively. Based on the results of our study,
HTN may be a risk factor for OAG independent of medical
therapy.
The results of our investigation further indicate that stage
1 HTN may increase OAG risk through chronic and perma-
nent damage. This is because the reversal or normalization
of BP from stage 1 hypertension in the subgroup of subjects
with additional BP measurements was not associated with
reduced risk of OAG over time. Transient acute elevations
in systemic BP are believed to have little effect on blood
flow to the optic nerve head under normal circumstances, as
autoregulatory mechanisms maintain a constant flow.38 In
fact, acute increases in BP have been shown to protect reti-
nal function against IOP elevation in rats.39 Also, in young
adults, HTN showed a protective effect against OAG, likely
by improving ocular perfusion pressure.40 In comparison,
chronic increases in systemic BP are associated with im-
paired autoregulation41 and vascular remodeling,34 causing
reduced perfusion to end-organs such as the optic nerve
head. Chronic damages in vascular walls in HTN, such as
arteriosclerosis, and increased wall-to-lumen ratio in pre-
capillary arterioles,42 are also visible in ocular vessels, as
demonstrated in reduced retinal capillary density43 and reti-
nal arterial and venous narrowing.44 Subsequent use of an-
VOL. 252 GLAUCOMA AND UNTREATED BLOOD PRESSURE
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tihypertensive medications in response to chronic increases
in BP may also be relevant to the finding. The mechanism
through which HTN affects the development and progres-
sion of OAG is likely multifactorial and evolving with time;
further studies are necessary to discover the complex nature
of the relationship between the 2 diseases.
Increased OAG risk in individuals whose BP changed
from stage 1 HTN to normal range over time was rather
surprising. In an attempt to single out subjects with in-
creased risk, we further divided subjects with stage 1 HTN
into those with stage 1 SDH, IDH, and ISH. We found that
normalization of stage 1 IDH and SDH were associated with
increased risks, whereas that of stage 1 ISH was not (Supple-
mentary Figure 3). From these results, we extrapolate that
changes in DBP may possibly be associated with increased
risk of OAG. Numerous studies have identified DBP as an
important factor in OAG in the past.9 , 23 , 45 , 46 The Thes-
saloniki Eye Study reported that DBP lower than 90 mm
Hg as a result of antihypertensive treatment was associated
with increased cupping.9 , 45 The Barbados Eye Study23 as
well as the Rotterdam Study46 also found increased risks of
developing glaucoma when diastolic ocular perfusion pres-
sure was low. Because low DBP is increasingly found to be
critical in OAG,34 more flexible HTN management to pos-
sibly aim for moderate increases in DBP has been previ-
ously suggested.47 In light of this view, our results suggest
that increases in DBP above normal range may not neces-
sarily be protective against OAG, as none of the subjects
who showed isolated elevation in DBP (whether it be from
normal BP to stage 1 IDH, from elevated BP to stage 1 IDH,
or maintenance of stage 1 IDH) demonstrated reduced risk
for OAG. The role of DBP in glaucoma development and
progression needs to be investigated in greater depth in the
future.
Finally, the results of the present study raise a number of
factors to consider in the management of glaucoma patients
in a clinical setting. First, our analysis supports prior stud-
ies that HTN is a risk factor for OAG. Second, the newly
defined stage 1 HTN according to the 2017 ACC/AHA BP
guidelines, which, prior to the update, was considered to fall
within a normal range, was associated with increased risk for
OAG. The resultant rise in the prevalence of HTN suggests
that a greater number of individuals may be at risk for glau-
coma than previously believed. Finally, further investiga-
tions may be needed to clearly identify whether antihyper-
tensive medication plays a role in the pathogenesis of OAG,
as greater proportions of patients are now recommended for
antihypertensive treatment following the changes in the
guidelines.
The limitations of the study are as follows. First, the
study population consists of Korean adults under a universal
health insurance and screening program. Normal-tension
glaucoma is more prevalent among Korean adults,19 and
systemic vascular dysregulation is believed to play a more
important role in the pathogenesis of normal-tension glau-
coma in comparison to primary open-angle glaucoma,48 so
117
the results may not be generalizable to other ethnic groups
or other populations under different health care systems.
Second, the number of OAG patients might have been un-
derestimated, given its asymptomatic nature in the early
stages. Some diagnosed OAG may have also been moni-
tored without medication because of low IOP. Third, sub-
jects’ BP in this study were the average value of multi-
ple BP measurements during a single visit, whereas the
2017 ACC/AHA guidelines recommend BP readings on
at least 2 separate visits for classification of hypertension
stage. Fourth, individuals’ BP might have been affected by
“white coat syndrome.”49 Fifth, follow-up BP measurements
may have been affected by numerous means of BP modifi-
cation, including lifestyle changes, antihypertensive med-
ication and dietary changes. Finally, ocular factors such
as IOP were not available in this administrative claims
database.
In conclusion, untreated stage 1 HTN as defined by the
2017 ACC/AHA BP guideline increased the risk of OAG
in comparison to normal BP among adults 40 years and
older. OAG risk associated with untreated stage 2 HTN was
even higher. Routine ophthalmic evaluation and screening
may be necessary in individuals with HTN for early diagno-
sis of OAG.

Funding/Support: This paper was funded by the Basic Science Research Program through the National Research Foundation of Korea (No. NRF-2019
R1A2C1091089).
Financial Disclosures: The authors report no financial disclosures or conflicts of interest. All authors attest that they meet the current ICMJE criteria for
authorship.
Acknowledgments: Jihei Sara Lee and Yong Joon Kim equally contributed as co−first authors.
Seung Won Lee and Chan Yun Kim equally contributed to this work as co−last authors.

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