MEDICINE International 3: 10, 2023

Use of β‑blockers and risk of age‑related macular

degeneration among hypertensive patients: An insight from
The National Health and Nutrition Examination Survey
YILI LUO1*, JIANPENG LIU2*, WANGQIANG FENG1, DA LIN1, GUANGWEI SONG1,
MENGJI CHEN1 and HAIHUA ZHENG1

1
Department of Ophthalmology, The Second Affiliated Hospital of Wenzhou Medical University,
Wenzhou, Zhejiang 325027; 2Department of Pathology, The First Affiliated Hospital of
Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China

Received October 12, 2022; Accepted January 26, 2023

DOI: 10.3892/mi.2023.70

Abstract. Although age‑related macular degeneration (AMD) non‑selective BBs exerted a beneficial effect against the risk
is the leading cause of legal blindness, the treatment methods of late‑stage AMD among hypertensive patients. Long‑term
for AMD are limited. The aim of the present study was to treatment with BBs was also associated with lower risk of
examine the association between oral β‑blockers (BBs) and developing AMD. These findings may provide novel strategies
the risk of developing AMD among hypertensive patients. for the management and treatment of AMD.
For this purpose, a total of 3,311 hypertensive patients from
the National Health and Nutrition Examination Survey Introduction
were included in the study. The use of BBs and treatment
duration data were collected using a self‑reported question‑ Age‑related macular degeneration (AMD) is an eye disease
naire. AMD was diagnosed by gradable retinal images. whose incidence rate increases with age and leads to decreased
Multivariate‑adjusted survey‑weighted univariate logistic central vision (1). AMD is the most common cause of legal
regression was used to confirm the association between the use blindness among the population aged >50 years in the western
of BBs and the risk of developing AMD. The results revealed world (2). In the USA, the number of cases of legal blindness
that the use of BBs exerted a beneficial effect (odds ratio (OR), caused by AMD are greater than those caused by glaucoma,
0.34; 95% confidence interval (95% CI, 0.13‑0.92; P=0.04) in cataract and diabetic retinopathy in combination (3). AMD
late‑stage AMD in the multivariate adjusted model. When the may have a severe impact on the quality of life of affected indi‑
BBs were classified into non‑selective BBs and selective BBs, viduals. It is associated with an increased risk of functional
the protective effect in late‑stage AMD was still observed in disabilities, negative effects on daily activities, an increased
the non‑selective BBs (OR, 0.20; 95% CI, 0.07‑0.61; P<0.001). risk of depression and a higher risk of developing cognitive
After accounting for treatment duration, long‑term treat‑ impairments in older adults (4‑6).
ment with BBs (>6 years) was also found to reduce the risk AMD has a variety of classification criteria. It is tradi‑
of late‑stage AMD (OR, 0.13; 95% CI, 0.03‑0.63; P=0.01). In tionally classified into the early and late stage based on color
late‑stage AMD, the long‑term use of BBs was beneficial for fundus images (7). Early‑stage AMD is characterized by large
geographic atrophy (OR, 0.07; 95% CI, 0.02‑0.28; P<0.001). drusen, retinal pseudo‑drusen and pigmentary abnormalities.
On the whole, the present study demonstrates that the use of By contrast, late‑stage AMD is divided into neovascular AMD
(nAMD) and geographic atrophy (GA). Although AMD is the
leading cause of legal blindness, the treatment methods avail‑
able for late‑stage AMD, particularly nAMD, are limited. The
primary treatment for nAMD is based on the inhibition of
Correspondence to: Professor Haihua Zheng, Department of vascular endothelial growth factor (VEGF) (8). Although several
Ophthalmology, The Second Affiliated Hospital of Wenzhou
complement inhibitors are undergoing therapeutic clinical trials
Medical University, 109 Xueyuan West Road, Wenzhou,
Zhejiang 325027, P.R. China (ClinicalTrials.gov Identifiers: NCT05230537, NCT03364153
E‑mail: [email protected] and NCT04465955), there are currently no effective therapeutic
methods available for GA (9). In addition, there is also a lack
*
Contributed equally of effective treatment strategies for preventing and delaying the
progression of early‑ to late‑stage AMD (7). Hence, the develop‑
Key words: age‑related macular degeneration, β‑blocker, National ment of novel therapeutic agents for AMD is mandatory.
Health and Nutrition Examination Survey, hypertension β ‑Adrenergic receptor (β ‑AR) blockers (BBs) are medi‑
cations widely used in the treatment of heart diseases, such
as hypertension, arrhythmias and heart failure. Previous
2 LUO et al: β-BLOCKERS AND AMD AMONG HYPERTENSIVE PATIENTS

preclinical studies have demonstrated a protective role of BBs

against neovascularization. For example, propranolol treat‑
ment has been shown to reduce 50% of neovascularization in
laser‑induced choroidal neovascularization by reducing the
release of VEGF (10). Reduced corneal neovascularization
with downregulated levels of VEGF and cytokines was also
observed following treatment with timolol in a murine corneal
suture model (11). Hence, several clinical research studies
have explored the possible association between BBs and
AMD (12‑19). However, some conflicting results have been
reported. The studies by Klein et al (17) and Yeung et al (19)
reported an increased risk of developing nAMD in patients
treated with BBs compared to those not treated, while other
studies, such as those by Traband et al (12), Kolomeyer et al (13),
Thomas et al (15), Song et al (16) and Davis et al (18) found
have no association between the use of BBs and nAMD devel‑
opment. Montero et al (14) suggested a beneficial effect of BBs
against nAMD. Moreover, the majority of studies have focused
on nAMD, and not on GA and early AMD. According to their Figure 1. Flowchart demonstrating the number of patients excluded at each
criterion and the final inclusion cohort used for the study. NHANES, National
selectivity for β ‑AR, the BBs used in clinical practice are Health and Nutrition Examination Survey.
divided into two main categories: Selective and non-selective
BBs (20). The majority of research focuses on non‑selective
BBs. The association between the development of AMD and
the use of selective BBs has not been reported to date, at least performed. A flowchart of the process used for the inclusion
to the best of our knowledge. Thus, the present study inves‑ of participants is presented in Fig. 1.
tigated the association between different types of BBs and
the risk of developing different stages of AMD using the data Classification of AMD. In the NHANES database, AMD was
from the National Health and Nutrition Examination Survey classified into three stages as follows: No AMD, early‑stage
(NHANES). AMD and late‑stage AMD. The classification criteria were the
following: Any large (≥125 µm) drusen, or retinal pseudodrusen
Patients and methods or pigmentary abnormalities in the retinal examination were
defined as early‑stage AMD; any GA or exudative neovascu‑
Data source and ethics approval. All data used in the larization in the retinal examination was defined as late‑stage
present study were obtained from the NHANES, which is AMD. Those without any signs of early‑ or late‑stage AMD in
a cross‑sectional survey administered by the Centers for the retinal examination were considered as having no AMD. If
Disease Control and Prevention's National Centre for Health both eyes were affected by AMD, data from the eye with the
Statistics (NCHS) since 1999. It reflects the national status more severe stage of AMD were used.
of health and nutrition in the USA. Since the present study
employed de‑identified information from the NHANES data‑ Use of BBs and treatment duration. The use of BBs was identified
base approved by the institutional review board of the NCHS, according to the self‑reported prescription medications
the Ethics Committee of the Second Affiliated Hospital of questionnaire (https://wwwn.cdc.gov/nchs/nhanes/continuousn‑
Wenzhou Medical University (Wenzhou, China) granted the hanes/questionnaires.aspx?BeginYear=2005). Non‑selective
study an exemption from ethical review. BBs included propranolol, carvedilol, nadolol, sotalol,
pindolol, labetalol, penbutolol and timolol. Selective BBs
Participants enrolled. As the retinal examination was included nebivolol, metoprolol, atenolol, bisoprolol, acebu‑
only available in two NHANES cycles (2005‑2006 and tolol, and betaxolol. The duration of the use of BBs was also
2007‑2008), participants were selected from these two cycles. obtained from the questionnaire, which was divided into four
Since BBs are mainly used in patients with hypertension, all quartiles as follows: First quartile, ≤2 years; second quartile,
the hypertensive participants selected were >40 years of age. 2‑4 years; third quartile, 4‑6 years; fourth quartile, >6 years).
Participants who responded ‘Yes’ to the question ‘have you The long‑term use of BBs in participants was defined as a BB
ever been told by a doctor or other health professional that treatment duration of >6 years.
you had hypertension, also called high blood pressure?’ and
those with an average systolic blood pressure ≥140 mmHg Other variables examined. Other variables included
or average diastolic blood pressure ≥90  mmHg in the demographic characteristics, a history of comorbidities,
examination were defined as being hypertensive. In total, health‑related behaviors and the use of anti‑hypertensive
20,497 participants were included from the two NHANES drugs. Data regarding age, sex, race, economic status and
cycles; 13,416 participants were excluded as they were aged education level were collected under the category of demo‑
<40  years, among whom 4,032 had hypertension. A total graphic characteristics. A history of stroke, heart diseases,
of 3,023 participants were finally enrolled in the present cancer or malignancy, diabetes mellitus, thyroid issues, glau‑
study, for whom a complete retinal examination had been coma and diabetic retinopathy were collected with the history
 MEDICINE International 3: 10, 2023 3

of comorbidities category. Health‑related behaviors provided

information about smoking and alcohol consumption. The use
of anti‑hypertensive drugs included the use of BBs and treat‑
ment duration, renin‑angiotensin system inhibitors (RASIs),
calcium channel blockers (CCBs) and diuretics. Participants
with coronary heart disease, heart attack, angina pectoris or
congestive heart failure were defined as having a history of
heart disease. Participants with anemia or chronic bronchitis
were defined as having a history of lung disease. Participants
with glaucoma were identified by cup‑to‑disc ratios >0.6 in
one eye. Participants with diabetes mellitus were identified
using the following criteria: i) Fasting plasma glucose levels
≥126  mg/ml; ii)  2‑h plasma glucose levels ≥200  mg/dl;
iii) HbA1c ≥6.5%; and iv) answering ‘Yes’ to the question of
‘have you ever been told by a doctor or health professional
that you have diabetes or sugar diabetes?’. Participants with
diabetic retinopathy were identified by any signs of retinopathy
(>14) on fundus images and by a diagnosis of diabetes mellitus.
Dara regarding body mass index (BMI) and waist circumfer‑
ence had been measured during a physical examination at the
Figure 2. Spearman's correlation coefficient (Rho) and linear regression line
time of the survey. Data on triglycerides (TGs), red blood cells
between AMD and BB usage (Rho= 0.06, P<0.05).
(RBCs), white blood cells (WBCs), high‑density lipoprotein
(HDL) and platelet (PLT) levels of each participant had been
obtained through a laboratory examination.
Use of BBs and the risk of AMD in the hypertensive
Statistical analyses. Data were analyzed using a survey package population. The association between the use of BBs and the risk
in R software (version 4.1.3; http://r‑survey.r‑forge.r‑project. of developing AMD was explored among all the participants. A
org/survey/) with sampling weight following the complex significant correlation was found between the use of BBs and
sample design of NHANES. Continuous variables are AMD (Rho=0.06, P<0.05) (Fig. 2). BB treatment increased the
presented as weight‑adjusted mean ± standard error, and risk of developing AMD in the hypertensive population (OR,
qualitative variables as weight‑adjusted proportion ± stan‑ 1.49; 95% CI, 1.21‑1.84; P<0.001) (Table II). When the BBs were
dard error. ANOVA was used for the comparisons of means categorized into non‑selective and selective BBs, a significant
among multiple groups followed by Tukey's post hoc test. association was found between the selective BBs and AMD
Survey‑weighted univariate logistic regression was used to (OR, 1.59; 95% CI, 1.29‑1.97; P<0.001) (Table II). By contrast,
examine the association between different types of BBs and no correlation was found between the use of non‑selective BBs
the various stages of AMD. A generalized additive model and AMD (Rho= 0.07, P>0.05) (Fig. 3). However, no association
and natural cubic spline were used to explore the non‑linear was found between the use of BBs and AMD after adjusting for
association between BB treatment duration and the risk of age, race, stroke history, heart disease history, thyroid disease
developing AMD. A multivariate model adjusted for age, history, glaucoma, RBCs and HDL (Table II).
sex, race, stroke history, heart disease history, thyroid disease
history, glaucoma, RBCs and HDL was applied. The results Use of BBs and the risk of early‑ and late‑stage AMD in the
are presented as odds ratios (ORs) with 95% confidence inter‑ hypertensive population. As the use of BBs did not have a signifi‑
vals (95% CIs). The correlation between the use of BBs and the cant effect on the risk of developing AMD following multivariate
prevalence of AMD was calculated using Spearman's correla‑ adjustment, the present study further explored whether the use of
tion analysis. The correlation between the use of non‑selective BBs was related to the different stages of AMD. Of note, there
BBs and the prevalence of AMD was also calculated using was no significant association between the use of BBs and the
Spearman's correlation analysis. A value of P<0.05 was risk of early‑stage AMD (Table III). Furthermore, no associa‑
considered to indicate a statistically significant difference. tion was found after classifying the BBs into non‑selective and
selective BBs in the adjusted model. (Table III). However, the
Results BBs exerted a beneficial effect (OR, 0.34; 95% CI, 0.13‑0.92;
P= 0.04) against late‑stage AMD in the multivariate adjusted
Characteristics of the participants enrolled. In total, model (Table III). The protective effect for late‑stage AMD was
3,311 participants were enrolled in the present study. The observed in the non‑selective BBs (OR, 0.20; 95% CI, 0.07‑0.61;
participants with AMD tended to be older, of Caucasian or P<0.001) (Table III). By contrast, the selective BBs were not
African‑American origin, were married, had higher BMI and found to be significantly associated with late‑stage AMD (OR,
HDL levels, had low levels of RBCs, and had a history of 0.46; 95% CI, 0.18‑1.15; P=0.09) (Table III).
heart disease, stroke and thyroid disease (Table I). In addition,
a significant difference was found in the use of RASIs and BB treatment duration and risk of AMD. The aforemen‑
BBs between participants with AMD and those with no AMD tioned results indicated the protective effect of BBs against
(Table I). late‑stage AMD. However, the potential cumulative effects of
4 LUO et al: β-BLOCKERS AND AMD AMONG HYPERTENSIVE PATIENTS

Table I. Characteristics of the participants with AMD.

AMD
‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑
Early‑stage Late‑stage
No AMD AMD AMD
Characteristic (n=2,998) (n=272) (n=41) P‑value

Demographics
Age (years) 59.15±0.41 70.10±1.27 78.21±1.23 <0.001
Sex, female (%) 50.71±1.64 55.90±6.40 81.85±8.95 0.01
Race (%) <0.001
Caucasian 76.34±2.61 88.83±3.32 97.94±2.14
African‑American 11.44±1.78 3.70±1.76 0.00±0.00
Other 12.22±1.49 7.47±2.46 2.06±2.14
Married or living with a partner (%) 69.75±1.54 57.28±6.88 30.40±7.79 <0.001
Education (high‑school and above) (%) 80.36±1.08 72.13±7.15 66.58±12.28 0.981
Income at or above poverty 86.28±1.22 79.42±3.00 80.81±8.46 0.539
Health‑related behaviors
Smoking ≥100 cigarettes in whole 16.61±2.08 15.87±4.28 10.11±10.19 0.395
lifetime (%)
Alcohol consumption in whole lifetime, 53.76±1.61 63.41±3.03 37.46±6.74 0.266
≥12 drinks (%)
Examinations
BMI (kg/m2) 30.42±0.19 29.76±0.74 27.22±1.29 0.001
Waist circumference (cm) 104.14±0.47 104.68±1.68 99.03±3.35 0.658
Laboratory tests
RBCs (106 cells/µl) 4.73±0.02 4.63±0.05 4.34±0.04 <0.001
WBCs (103 cells/µl) 6.96±0.09 7.11±0.25 7.12±0.27 0.669
PLT (103 cells/µl) 268.45±2.14 258.60±8.87 245.96±11.32 0.079
HDL (mg/dl) 53.71±0.52 57.84±2.05 65.87±2.49 0.002
TG (mg/dl) 160.44±3.09 146.52±12.60 123.43±18.49 0.072
Disease history
Heart diseases (%) 12.84±1.24 21.08±5.29 34.29±8.04 0.019
Stroke (%) 5.24±0.60 16.22±4.23 32.28±18.40 <0.001
Lung diseases (%) 16.56±1.44 12.56±3.11 16.92±7.62 0.111
Cancer or malignancies (%) 14.71±1.08 18.86±3.59 28.83±7.23 0.231
Thyroid issues (%) 14.78±1.34 23.64±4.03 36.27±11.58 <0.001
Diabetes mellitus (%) 17.58±1.18 15.90±3.06 26.89±7.79 0.106
Glaucoma (%) 3.48±0.62 5.76±3.27 9.71±6.96 0.191
Diabetic retinopathy (%) 13.75±1.09 17.88±4.49 0.00±0.00 0.944
Use of anti‑hypertensive drugs
RASIs (%) 46.00±1.12 47.86±5.85 59.80±9.05 <0.001
ACEI 28.84±1.10 27.77±3.86 52.58±10.12 0.213
ARB 18.12±1.33 20.10±4.35 17.07±6.09 0.431
BBs (%) 24.77±1.61 35.96±4.69 12.94±7.04 <0.001
Non‑selective BBs 4.42±0.74 5.82±2.67 0.00±0.00 0.424
Selective BBs 20.42±1.38 30.55±3.97 12.94±7.04 <0.001
CCB (%) 17.00±1.27 17.09±3.07 34.66±10.02 0.018
Diuretics (%) 31.02±1.82 40.80±6.52 64.67±8.19 0.043

AMD, age‑related macular degeneration; BMI, body mass index; RBC, red blood cell; WBC, white blood cell; PLT, platelet; HDL, high‑density
lipoprotein; TG, triglyceride; RASI, renin‑angiotensin system inhibitor; ACEI, angiotensin‑converting enzyme inhibitor; ARB, angiotensin
receptor blocker; BBs, β‑blockers; CCB, calcium channel blocker.
 MEDICINE International 3: 10, 2023 5

Table II. Association between AMD and the use of BBs.

No adjusted Multivariate adjusteda

‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑ ‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑
Parameter OR (95% CI) P‑value OR (95% CI) P‑value

BB use 1.49 (1.21‑1.84) <0.001 0.94 (0.71‑1.25) 0.66

BB category
Non‑selective BBs 0.86 (0.48‑1.57) 0.62 0.69 (0.37‑1.33) 0.26
Selective BBs 1.59 (1.29‑1.97) <0.001 1.01 (0.77‑1.33) 0.92
a
Data were multivariate adjusted for age, sex, race, stroke history, heart disease history, thyroid disease history, glaucoma, red blood cells and
high‑density lipoprotein. AMD, age‑related macular degeneration; BBs, β‑blockers; OR, odds ratio; 95% CI, 95% confidence interval.

Figure 4. Dose‑response association between the predisposition to AMD and

BB treatment duration. The solid line is the smooth curve. The dashed lines
Figure 3. Spearman's correlation coefficient (Rho) and linear regression line are the 95% confidence intervals.
between AMD and non‑selective BB usage (Rho= 0.07, P>0.05).

significant difference compared with the patients not on BB

time were not previously considered in the literature, at least treatment (Table V). Similar results were found when exam‑
to the best of our knowledge. Hence, in the present study, the ining the association between BB treatment duration and
association between the use of BBs and the risk of developing late‑stage AMD. Only the fourth quartile of BB treatment
AMD was further investigated. It was found that BB treatment duration exhibited a significant association with the risk of
duration had no association with the risk of developing AMD late‑stage AMD compared with the BB non‑users (OR, 0.13;
(OR, 0.98; 95% CI, 0.94‑1.02; P= 0.231; R 2= 0.114) (Table IV). 95% CI, 0.03‑0.63; P= 0.01) (Table V). Furthermore, with the
In addition, no liner association was found between BB treat‑ increasing duration of BB treatment, a significant decrease
ment duration and AMD using line regression analysis (OR, in the magnitude of associations with the risk of late‑stage
0.998; 95% CI, 0.996‑1.001; P= 0.275; R 2= 0.061) (Table IV). AMD was observed (P for trend= 0.048) (Table V). The other
A generalized additive model and natural cubic spline were quartiles did not exhibit a significant association with the BB
introduced to examine the non‑linear association. Thought non‑users (Table V). By contrast, for the early stage of AMD,
the smoothing splines curve, the predisposition to AMD no significant difference was found in BB treatment duration
exhibited a trend to first increase, and to then decrease with compared with the BB non‑users (Table V).
the increasing treatment duration of BBs (Fig. 4). Thus, the
BB treatment duration was we divided into four quartiles Long‑term use of RASIs and different subtypes of AMD. The
as follows: ≤2  years, 2‑4  years, 4‑6  years, and >6  years. aforementioned results suggested that a BB treatment duration
Compared to the patients not on BB treatment, a decreased >6 years may decrease the risk of developing AMD. Therefore,
risk of developing AMD was only found in the last quartile of the long‑term use of BBs was defined as a BB treatment
BB treatment duration (OR, 0.65; 95% CI, 0.43‑0.98; P= 0.04; duration >6 years the present study. Since the previous assess‑
R 2 = 0.493) (Table  V). The other groups did not exhibit a ments only focused on nAMD without considering GA and
6 LUO et al: β-BLOCKERS AND AMD AMONG HYPERTENSIVE PATIENTS

Table III. Association between different stages of AMD and various category of BBs.

Early‑stage AMDa Late‑stage AMDa

‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑ ‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑
Parameter OR (95% CI) P‑value OR (95% CI) P‑value

BB use 1.13 (0.85‑1.5) 0.39 0.34 (0.13‑0.92) 0.04

BB category
Non‑selective BBs 0.86 (0.45‑1.64) 0.638 0.20 (0.07‑0.61) <0.001
Selective BBs 1.17 (0.89‑1.53) 0.244 0.46 (0.18‑1.15) 0.09
a
Data were multivariate adjusted for age, sex, race, stroke history, heart disease history, thyroid disease history, glaucoma, red blood cells and
high‑density lipoprotein. AMD, age‑related macular degeneration; BBs, β‑blockers; OR, odds ratio; 95% CI, 95% confidence interval.

Table IV. Association between AMD and BB treatment duration in the different modelsa.

Model OR (95% CI) P‑value R2

Logistic regression 0.98 (0.94‑1.02) 0.231 0.114

Linear regression 0.998 (0.996‑1.001) 0.275 0.061
a
Data were multivariate adjusted for age, sex, race, stroke history, heart disease history, thyroid disease history, glaucoma, red blood cells
and high‑density lipoprotein. Non‑users were used as a reference. AMD, age‑related macular degeneration; BBs, β‑blockers; OR, odds ratio;
95% CI, 95% confidence interval.

Table V. Association between AMD and BB treatment duration in the generalized additive model.

AMDa Early‑stage AMDa Late‑stage AMDa

‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑ ‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑ ‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑
BB duration OR (95% CI) P‑value OR (95% CI) P‑value OR (95% CI) P‑value

Reference (non‑users) Reference (non‑users) Reference (non‑users)

<2 years 0.93 (0.59‑1.47) 0.76 1.06 (0.69‑1.64) 0.77 0.47 (0.12‑1.84) 0.26
2‑4 years 1.73 (0.87, 3.40) 0.11 2.03 (0.97‑4.24) 0.06 0.40 (0.04‑3.90) 0.40
4‑6 years 1.08 (0.57, 2.02) 0.81 1.27 (0.72‑2.24) 0.39 0.38 (0.04‑3.64) 0.38
>6 years 0.65 (0.43, 0.98) 0.04 0.82 (0.54‑1.27) 0.36 0.13 (0.03‑0.63) 0.01
P for trend 0.94 (0.87, 1.03) 0.21 1.00 (0.92‑1.09) 0.96 0.46 (0.40‑0.99) 0.048
a
Data were multivariate adjusted for age, sex, race, stroke history, heart disease history, thyroid disease history, glaucoma, red blood cells and
high‑density lipoprotein. Non‑users were used as a reference. The R2 value of this model was 0.493. AMD, age‑related macular degeneration;
BBs, β‑blockers; OR, odds ratio; 95% CI, 95% confidence interval.

early‑stage AMD, the long‑term use of BBs was investigated in Discussion

order to assess its influence on the different subtypes of AMD.
Two major subtypes of early‑stage AMD were mainly consid‑ In the present study, although there was insufficient
ered in the present study, including pigmentary abnormalities evidence for the exact association between the use of BBs
and soft drusen. However, there was no association between and AMD, a decreased association was found between
the long‑term use of BBs and the two subtypes of early‑stage the use of BBs and late‑stage AMD among hypertensive
AMD (Table VI). In late‑stage AMD, the long‑term use of BBs participants from NHANES. The use of BBs, particularly
was a protective factor for GA (OR, 0.07; 95% CI, 0.02‑0.28; long‑term BB treatment, was found to exert a protective
P<0.001) (Table  VI). However, it was considered that the effect against late‑stage AMD. Even though a significant
result of the long‑term use of BBs for GA was not reliable as protective effect of the long‑term use of BBs against GA was
the number of GA cases was very small. There was also no found, due to the limited number of number cases of GA in
significant association between the long‑term use of BBs and the NHANES database, the outcome cannot be considered
nAMD (Table VI). reliable. However, this result may provide the basis for the
 MEDICINE International 3: 10, 2023 7

Table VI. Association between AMD subtypes and long‑term hypertensive patients with CCBs (12). The aforementioned
BB treatmenta. studies focused on the injection incidence. In comparison,
other clinical studies have paid attention to the association
OR (95% CI) P‑value between the risk of developing AMD and the use of BBs, and
found negative results. For example, Davis et al (18) found no
Early‑stage AMD manifestations difference in the use of BBs between patients with GA and wet
Pigmentary abnormalities 1.05 (0.72‑1.52) 0.79 AMD. Thomas et al (15) also found there was no significant
Any soft drusen 0.81 (0.56‑1.15) 0.22 association between the use of BB and choroidal neovascu‑
Late‑stage AMD subtypes larization in nAMD. However, the Beaver Dam Eye Study
Exudative AMD 0.35 (0.05‑2.48) 0.27 (BDES) revealed opposite results (17). BB treatment was asso‑
Geographic atrophy 0.07 (0.02‑0.28) <0.001 ciated with an increased 5‑year incidence of exudative AMD
over a 20‑year period. That study also had limitations, such
a
Data were multivariate adjusted for age, sex, race, stroke history, as not considering BB treatment duration. Furthermore, two
heart disease history, thyroid disease history, glaucoma, red blood longitudinal studies on BB treatment duration and AMD were
cells and high‑density lipoprotein. Patients taking BBs for <6 years conducted to explore the association between BB treatment
were used as the reference group. AMD, age‑related macular degen‑
duration and nAMD. Yeung et al (19) found that the contin‑
eration; BBs, β‑blockers; OR, odds ratio; 95% CI, 95% confidence
uous use of BBs was associated with a higher risk of nAMD
interval.
compared with non‑users. By contrast, Kolomeyer et al (13)
reported that patients using BBs were significantly less likely
to develop nAMD at 90 and 180 days than patients using
CCBs. The aforementioned studies concentrated on nAMD,
future clinical use of BBs and may guide future treatment while the study by Song et al (16) focused on GA; they found
strategies patients with AMD. no significant association between BBs and nAMD.
Several experimental studies have reported that β ‑AR Several researchers have examined the association
plays a critical role in the development and progression of between BBs and AMD. Although several of the outcomes
AMD, and suggest that BBs may be prophylactic drugs for were negative, further studies are required to fully elucidate
nAMD. For example, propranolol was found to reduce retinal the association. In the present study, the use of BBs was not
neovascularization and vascular leakage and was considered found to be significantly associated with early‑stage AMD
to downregulate retinal VEGF and insulin‑like growth factor and nAMD compared with non‑users, reflecting the conclu‑
1 expression (21). Carvedilol has also been demonstrated to sions of some studies (12,13,15,18). However, long‑term
modulate the expression of VEGF and hypoxia‑inducible treatment with non‑selective BBs had a protective effect
factor‑1α induced by hypoxia (22). Dal Monte et al (23) also against late‑stage AMD. Since β ‑AR in the retina has an
found that β‑AR activation increased the expression of VEGF by age‑related overexpression and a super‑sensitivity effect,
increasing nitric oxide (NO) production, while β‑AR blockers it is possible that continuous BB treatment exerts a protec‑
exerted the opposite effect by decreasing NO levels. BBs can tive effect against AMD (29). However, the positive effect
reduce neovascularization. In addition, they can also improve identified in GA in the present study was different from
the survival of retinal neurons. Betaxolol has been shown to the study of Song et al (16), which found the use of BBs
exert neuroprotective effects in the retina by decreasing the had no association with the incidence of GA. There were
expression of neuronal nitric oxide synthase (24). Betaxolol some explanations accounting for this difference. On the
also reduces the death of neurons, reducing the calcium ion one hand, the participants enrolled were different. In the
influx and sodium ion influx (25,26). In summary, BB treat‑ present study, hypertensive patients not treated with BBs
ment has been shown to exert therapeutic effects against were set as the controls, while other studies did not consider
neovascularization, which is the main pathophysiological hypertension (14,15,16,18). On the other hand, the BB treat‑
mechanism of nAMD, and against the death of retinal neurons, ment duration may differ, as it was not considered in other
which is the dominant mechanism of GA (27,28). studies (12‑18). Thus, a prolonged BB therapeutic duration
Although preclinical studies have indicated that BBs may may result in a different outcome.
be an effective treatment for AMD, clinical research on AMD The present study has certain strengths. Firstly, hyper‑
and BBs has not yielded ideal results. A positive outcome tensive participants were enrolled to avoid confounding bias.
was reported in the retrospective study by Montero et al (14). In addition, a number of confounding factors aside from
They found that the need for bevacizumab injections was hypertension were adjusted for in the multivariate analysis.
decreased in patients with nAMD treated with oral systemic Secondly, the effect of different categories of BBs was
BBs compared to the BB non‑users (14). However, that study investigated, while the majority of previous studies (12‑16).
was limited by small sample size. As hypertension is a risk only focused on non‑selective BBs. Non‑selective BBs
factor for AMD, using participants not treated with BBs as block β1‑AR and β2‑AR, while selective BBs mainly inhibit
the control group may possibly introduce confounding bias. β1‑AR. However, all the subtypes of β‑AR are expressed in
A retrospective study involving the database of large national retinal cells (30). The further examination of selective BBs
USA insurers found a opposite outcome (12). A comparator in AMD is thus warranted. Herein, the association between
medication class with similar diseases was selected to address the use of selective BBs and AMD was explored, revealing no
the bias. The effects of injections of anti‑VEGF agents in significant association. Moreover, the association between the
hypertensive patients with BBs did not differ from those on use of BBs and early‑stage AMD was not explored in other
8 LUO et al: β-BLOCKERS AND AMD AMONG HYPERTENSIVE PATIENTS

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