Drugs & Aging (2021) 38:921–930

https://doi.org/10.1007/s40266-021-00886-y

ORIGINAL RESEARCH ARTICLE

Sex Differences in Association Between Anti‑Hypertensive Medications

and Risk of COVID‑19 in Middle‑Aged and Older Adults
Yue Ma1 · Yuan Zhang1 · Shu Li1 · Hongxi Yang1 · Huiping Li1 · Zhi Cao1,2 · Fusheng Xu1 · Li Sun1,3 · Yaogang Wang1 

Accepted: 8 July 2021 / Published online: 18 August 2021

© The Author(s), under exclusive licence to Springer Nature Switzerland AG 2021

Abstract
Background  There is ongoing debate about the associations between drug therapies targeting the renin–angiotensin–aldos-
terone system (RAAS) and adverse outcomes in coronavirus disease 2019 (COVID-19).
Objective  This study aims to examine the associations between using medications for the cardiovascular system and the
risks associated with COVID-19 in middle-aged and older adults.
Methods  A total of 77,221 participants (aged 50–86 years) from UK Biobank were tested for SARS-CoV-2 RNA. The
medications included angiotensin-converting enzyme inhibitors (ACEI), angiotensin-receptor blockers (ARB), β-blockers,
calcium channel blockers (CCB), statins, and aspirin. COVID-19 outcomes comprised a positive test result and severity of
COVID-19 (defined as mild, hospitalization or death). We evaluated the risk among total participants and for sub-groups
based on sex. Propensity score matching was performed 1:1 and logistic regression models were used.
Results  Among the middle- and older aged participants, no significant associations between any class of medications and
the likelihood of COVID-19 infection were observed. ACEI were associated with a higher mortality risk from COVID-19
(odds ratio [OR] 1.15, 95% confidence interval [CI] 1.01–1.32) and CCB were associated with a lower hospitalization risk
for COVID-19 (OR 0.87, 95% CI 0.79–0.96) among the male patients with COVID-19, while a lower mortality risk from
COVID-19 (OR 0.67, 95% CI 0.47–0.96) was observed with ARB among the female patients with COVID-19.
Conclusions  The study suggested sex differences in the risk of death from COVID-19 with the use of ACEI and ARB among
middle-aged and older adults. Sex differences in the risk of hospitalization for COVID-19 with the use of CCB was observed
as well. It is of clinical importance that clinicians adopt different CVD treatment approaches for female and male patients
with COVID-19.

Key Points 

It is important to determine sex differences in the asso-

ciation between using renin–angiotensin–aldosterone
system (RAAS) inhibitors and the risks of COVID-19.
Sex differences in the association between RAAS inhibi-
tors and risks of COVID-19 may be stronger at older
ages.
There was a potential mortality risk for male patients
* Yaogang Wang with COVID-19 in using angiotensin-converting enzyme
YaogangWANG@tmu.edu.cn inhibitors and a protective effect of using calcium chan-
1
School of Public Health, Tianjin Medical University,
nel blockers. For female patients with COVID-19, using
Tianjin 300070, China angiotensin-receptor blockers was associated with a
2
Department of Epidemiology and Health Statistics, School
lower risk of COVID-19 mortality.
of Public Health, Zhejiang University, Hangzhou, China
3
School of Nursing, Tianjin Medical University, Tianjin,
China

Vol.:(0123456789)

922 Y. Ma et al.

1 Introduction system varied by sex [14, 15]. Sex differences in COVID-

19 are becoming more apparent as mounting data indicate
In 2020, the rapid spreading of coronavirus disease 2019 that males seem to be disproportionately at risk of a severe
(COVID-19) has forced the World Health Organization COVID-19 outcome due to preexisting CVD and COVID-
(WHO) to declare COVID-19 as a global pandemic. Accord- 19-related cardiovascular injury [16].
ing to the WHO COVID-19 dashboard, more than 173 mil- Owing to the growing sex gap in patients with COVID-
lion people were confirmed to have contracted COVID-19, 19 [17], exploring the relationship between cardiovascular
including 3 million deaths [1]. medications and COVID-19 outcomes in different sexes is
As the COVID-19 pandemic has spread, there has been very important for clinical treatment. We sought to estimate
a growing recognition that pre-existing cardiovascular the association between using cardiovascular medications
diseases (CVD) and risk factors in middle-aged and older and the risk of testing positive, hospitalization, and death
adults can increase the severity of COVID-19, leading to from COVID-19 among male and female participants from
the aggravation and decompensation of chronic underlying UK Biobank.
cardiac pathologies as well as acute onset of new cardiac
complications [2]. This phenomenon suggests that severe
acute respiratory syndrome coronavirus 2 (SARS-CoV-2, 2 Methods
the etiological agent of COVID-19) infection may result in
activation of related signaling pathways in the cardiovascular 2.1 Study Population
system [3].
S-proteins located on the surface of SARS-CoV-2 can The study included 77,221 participants who had been tested
bind to the cell receptor, angiotensin-converting enzyme for SARS-CoV-2 RNA from March 16, 2020 to May 19,
(ACE) 2 [4], which is part of the renin–angiotensin–aldos- 2021 from UK Biobank. UK Biobank includes over 500,000
terone system (RAAS) and its neurohormonal pathways middle- and older aged adults who have undergone detailed
[5]. As a result, a heated argument is currently underway medical and cognitive phenotypic assessment. All the UK
about the association between medical therapy for CVD Biobank participants gave written informed consent before
and COVID-19 severity, and thereby the possibility of these data collection. UK Biobank has full ethical approval from
drugs increasing the severity of infection [6]. The most con- the NHS National Research Ethics Service (http://​www.​
troversial argument is that treatment with RAAS inhibitors ukbio​bank.​ac.​uk/​ethics/). This work was conducted under
can increase tissue expression of ACE2 and its presentation UK Biobank application number 45676.
at the cell surface in certain clinical states [7].
The main reason for the heated discussion is the incon- 2.2 Medication and History Assessment
sistent results in previous studies. One study conducted in
the United States suggested that anti-hypertensive medica- Medical history was extracted from UK Biobank that had
tions were associated with no substantial increase in risk for been entered into the medical history or problem list sections
COVID-19 patients [8]. Another study found that hospital- of the medical record or since encounter diagnoses at the
ized patients with COVID-19 using ACE inhibitors (ACEI) time of enrollment (2006–2010) and follow-up period. We
or angiotensin II receptor blockers (ARB) were associated selected the six classes of cardiovascular drugs that require
with lower risk of all-cause mortality compared with non- lifelong prescriptions, including ACEI, ARB, β-blockers,
users [9]. Further fueling these concerns is the observation calcium channel blockers (CCB), statins, and aspirin.
that using ACEI or ARB might increase the risk of COVID- The history of disease was defined as a self-reported,
19 after exposure to SARS-CoV-2 [10]. Except for the com- physician-diagnosed, primary care, or hospital record before
mon anti-hypertensive medications, studies found a higher May 19, 2021. We characterized the participants as having
risk of death was associated with atorvastatin [11], and or not having a history of chronic obstructive pulmonary
safety issues in using aspirin related to the risk of bleeding disease (according to the International Classification of Dis-
and serious liver damage in patients with COVID-19 [12]. eases [ICD] 10th edition [ICD-10] codes J41, J42, J43, J44;
However, these studies have recognized that gender might ICD 9th edition [ICD-9] codes 491, 492, 496), chronic kid-
contribute to the inconsistent results. Gender and age play ney disease (ICD-10: N18; ICD-9: 5859; self-report code:
important roles in drug efficacy and COVID-19 outcomes. 1192), diabetes (ICD-10: E10–E14.9), hypertension (ICD-
A recent study showed that treatment with ACEI or ARB 10: I10–I16, H35.03, I67.4, O10.1–O10.4, O10.9), coronary
could reduce the mortality rate from hyperkalemia and acute artery disease (ICD-10: I20–I25), heart failure (ICD-10:
kidney injury in women, but not men [13]. The expression I50, I11.0, I13.0), stroke (ICD-10: F01, G45, G46, I60–64,
of ACE2 and regulatory mechanisms of the cardiovascular I690, I691, I692, I694, I698, I699), pulmonary embolism
Anti-Hypertensive Medications and Risk of COVID-19 in Middle-Aged and Older Adults 923

(ICD-10: I26; ICD-9: 415), and asthma (ICD-10: J44–46; shown in Supplementary Appendix (see electronic supple-
ICD-9: 493). mentary material [ESM]). The balances of matched covari-
ates were evaluated with SMD, and <10% differences were
considered matched sufficiently [18]. We also conducted
2.3 Outcomes of COVID‑19 stratified analyses by sex (men and women). The interaction
test between sex and each class of medication was performed
The primary outcome was the risk of positive SARS-CoV-2 by using the likelihood ratio test comparing models with
tests, and the secondary outcome was the risk of severity in and without a cross-product term. The association between
COVID-19-positive patients. We assessed the primary and six classes of medication and risk of a COVID-19-positive
secondary outcomes in total patients, and in male and female result and severity of COVID-19 was examined by logistic
participants, separately. Participants were deemed to be posi- regression. We conducted sensitivity analyses using multi-
tive for COVID-19 if any test was positive for SARS-CoV-2 variate adjusted logistic regression rather than propensity-
RNA and negative if all tests were negative. For the patients score matching. Effect of medicine class was considered
with a positive COVID-19 test result, we classified them significant at a p-value <0.05. Analyses were performed
as mild, hospitalized, and dead. Patients were identified as with R statistical software, version 4.0.3 (with the libraries
mild cases of COVID-19 if they were without any record MatchIt and Survival).
for hospitalization or death. COVID-19-specific death was
defined as cause of death due to ICD-10 U07.1 using death
registry data linked to UK Biobank.
3 Results

2.4 Statistical Analysis 3.1 Characteristics of the Participants

The characteristics of the study population were com- A total of 77,221 participants aged from 50 to 86 years who
pared by sex using t tests for continuous variables and had COVID-19 test results in UK Biobank were included.
chi-squared tests for categorical variables. The continu- These participants were classified into two subgroups by sex;
ous variables were described as mean ± SD. The categori- 35,892 (46.5%) were men and 41,329 (53.5%) were women
cal variables were described as sums with percentages. (Fig. 1). Among the male population, 4819 (13.4%) tested
If data was missing for a covariate, we used multiple positive, including 2030 (42.1%) mild cases (tested positive
imputations based on five replications and utilized a without hospitalization or death), 2526 (52.4%) who were
chained-equation method to account for the missing data. hospitalized, and 263 (5.5%) deaths. Among the female
We conducted a complete case analysis to show whether population, 5676 (13.7%) tested positive, including 2612
the imputation process introduced bias to our outcome. (46.0%) mild cases, 2875 (50.7%) hospitalized cases, and
A two-tailed p-value <0.05 was considered statistically 189 (3.3%) deaths.
significant. Men had a higher prevalence of severe COVID-19
To reduce confounding effects of potential risk factors on compared with women (p < 0.001, Table 1). In addition,
outcomes, 1:1 propensity score matching (PSM) was applied more men used the six classes of medication than women
to match users of medications and nonusers into treated and (p < 0.001, Table 1), which underscores the importance of
control groups among total participants. Total participants sex.
were propensity-score matched for age, sex, race, body-mass The complete case analysis showed that the imputation
index, smoking history, systolic and diastolic blood pressure, process introduced no bias to our results (p > 0.05, Supple-
history of chronic obstructive pulmonary disease, chronic mentary Appendix Table S19, see ESM). After 1:1 PSM,
kidney disease, diabetes mellitus, hypertension, coronary medication users and matched nonusers were selected for
heart disease, heart failure, stroke, pulmonary embolism, analysis. In these two groups, the characteristics of the pop-
asthma and other classes of medication. Age was recal- ulation were well balanced (all SMD <0.1 and p > 0.05).
culated at the time of the test results for COVID-19. The Distribution of propensity scores and the histogram of pro-
covariates of PSM for male and female participants are the pensity scores before and after matching in the control and
same as the total participants except for gender. Propensity medication-treated groups among total, male, and female
scores were generated using a multivariable logistic regres- participants are shown in Figs S1–S6 (see ESM).
sion model. PSM was implemented with a nearest-neighbor
strategy, width of caliper was 0.02. No replacement was
allowed, and patients were matched only once. Standard-
ized mean differences (SMD) before and after matching are

924 Y. Ma et al.

Fig. 1  Flowchart of UK Biobank participants selected for analyses

3.2 Anti‑Hypertensive Medication and COVID‑19 significant interactions between use of ACEI (Pinteraction =

in Total Participants 0.031), ARB (Pinteraction = 0.034), and sex on the risk of
death from COVID-19. In addition, the use of CCB showed
A total of 77,221 participants were tested for COVID-19, a significant interaction with sex on the risk of hospitali-
including 10,495 (13.6%) who tested positive for COVID-19 zation for COVID-19 (Pinteraction=0.027, Fig. 2). Sensitiv-
(Table 1). Among the 10,495 (13.6%) COVID-19-positive ity analyses with the use of multivariate logistic regression
patients, 4642 (6.0%) were mild cases, 5401 (7.0%) were showed similar conclusions among the total participants
hospitalized, and there were 452 (0.6%) deaths. (Table S20, see ESM).
The results of PSM quality among total participants are
shown in Tables S1–S6 (see ESM). As shown in Fig. 2, the 3.3 Anti‑Hypertensive Medication and COVID‑19
odds ratio (OR) of death from COVID-19 associated with in Men and Women
ACEI and ARB classes of therapy in the PSM cohort was
1.00 (95% confidence interval [CI] 0.89–1.13) and 0.85 As shown in Fig. 3, using one of the six classes of medi-
(95% CI 0.70–1.02), respectively. No classes of medication cation is not associated with the risk of testing positive
were associated with the risk of SARS-CoV-2 infection for SARS-CoV-2 in men and women after PSM (1:1).
(p > 0.05, Fig. 2). Similar results were also observed in The results of PSM quality for men are shown in Tables
the risk of COVID-19 severity analysis; neither ACEI nor S7–S12, the results for women are shown in Tables
ARB medication was associated with the risk of COVID- S13–S18.
19 severity in total participants (Fig. 2). β-blockers, CCB, Among male participants, the OR for COVID-19
statins, and aspirin are not associated with the risk of being death associated with ACEI was 1.15 (95% CI 1.01–1.32;
COVID-19-positive or of COVID-19 severity in total par- p  =  0.040), compared with an OR of 0.97 (95% CI
ticipants (p > 0.05, Fig. 2). 0.79–1.19) for female participants. ACEI had a 1.15-fold
We also tested the interaction between sex and use of higher risk of COVID-19 death among male participants
medication on the risk of COVID-19 outcomes. We found compared with nonusers, whereas ACEI medication was
Anti-Hypertensive Medications and Risk of COVID-19 in Middle-Aged and Older Adults 925

Table 1  Clinical characteristics of the study population of participants tested for SARS-CoV-2

Characteristic Total Men Women p-Valuea
(n = 77,221) (n = 35,892) (n = 41,329)

Age 68.58 ± 8.28 69.06 ± 8.25 68.16 ± 8.29 < 0.001

Race, n (%) < 0.001
 White 72,225 (93.5) 33,609 (93.6) 38,616 (93.4)
 Asian 2120 (2.7) 1127 (3.1) 993 (2.4)
 Black 1559 (2.0) 626 (1.7) 933 (2.3)
 Other 1317 (1.7) 530 (1.5) 787 (1.9)
Smoking status < 0.001
 Never 40,518 (52.5) 16,742 (46.6) 23,776 (57.5)
 Previous 28,640 (37.1) 14,920 (41.6) 13,720 (33.2)
 Current 8063 (10.4) 4230 (11.8) 3833 (9.3)
 BMI 27.89 ± 4.97 28.26 ± 4.39 27.56 ± 5.40 < 0.001
Comorbidities, n (%)
 COPD 5662 (7.3) 3038 (8.5) 2624 (6.3) < 0.001
 Chronic kidney disease 5879 (7.6) 3048 (8.5) 2831 (6.8) < 0.001
 Diabetes mellitus 10,045 (13.0) 5929 (16.5) 4116 (10.0) < 0.001
 Hypertension 33,333 (43.2) 17,520 (48.8) 15,813 (38.3) < 0.001
 Coronary heart disease 12,971 (16.8) 8195 (22.8) 4776 (11.6) < 0.001
 Heart failure 4549 (5.9) 2847 (7.9) 1702 (4.1) < 0.001
 Stroke 4718 (6.1) 2730 (7.6) 1988 (4.8) < 0.001
 Pulmonary embolism 1960 (2.5) 1051 (2.9) 909 (2.2) < 0.001
 Asthma 9739 (12.6) 3917 (10.9) 5822 (14.1) < 0.001
 TDI − 1.17 ± 3.14 − 1.16 ± 3.19 − 1.17 ± 3.10 0.671
Medications, n (%)
 ACEI 9187 (11.9) 5738 (16.0) 3449 (8.3) < 0.001
 ARB 3354 (4.3) 1779 (5.0) 1575 (3.8) < 0.001
 β-blocker 6360 (8.2) 3731 (10.4) 2629 (6.4) < 0.001
 CCB 6158 (8.0) 3732 (10.4) 2426 (5.9) < 0.001
 Statin 15,044 (19.5) 9276 (25.8) 5768 (14.0) < 0.001
 Aspirin 12,471 (16.1) 7753 (21.6) 4718 (11.4) < 0.001
 Diastolic BP 82.17 ± 10.22 83.91 ± 10.11 80.66 ± 10.08 < 0.001
 Systolic BP 138.27 ± 18.71 141.41 ± 17.65 135.55 ± 19.18 < 0.001
COVID-19 status < 0.001
 Negative 66,726 (86.4) 31,073 (86.6) 35,653 (86.2)
 Positive 10,495 (13.6) 4819 (13.4) 5676 (13.7)
 Mild COVID-19 cases 4642 (6.0) 2030 (5.6) 2612 (6.3)
 Hospitalized for COVID-19 5401 (7.0) 2526 (7.0) 2875 (6.9)
 Death from COVID-19 452 (0.6) 263 (0.7) 189 (0.4)

Note: Mild COVID-19 cases comprise the participants that tested positive for COVID-19 without hospitalization or death
ACEI angiotensin converting enzyme inhibitor, ARB angiotensin receptor blocker, BMI body mass index, BP blood pressure, CCB calcium chan-
nel blocker, COPD chronic obstructive pulmonary disease, COVID-19 coronavirus disease 2019, TDI Townsend deprivation index
a
  Comparison between men and women groups

not associated with the risks of COVID-19 among female death from COVID-19 by 33% in women compared with non-
participants. users, whereas ARB medication is not associated with the risk
Interestingly, the OR for COVID-19 death associated with of death in men. From the above, ACEI medication is a risk
ARB was 0.67 (95% CI 0.47–0.96; p = 0.028) among female factor for COVID-19 death in men, while ARB is a protective
participants, compared with an OR of 1.38 (95% CI 0.87–1.78; factor for death from COVID-19 in women.
p = 0.062) for the male population. ARB decreased risk of

926 Y. Ma et al.

Fig. 2  Association between medications and the risk of COVID-19 Pinteraction, p-value for interaction between the medication and sex on
after propensity score matching in total participants. ACEI angioten- the risk of COVID-19
sin converting enzyme inhibitor, ARB angiotensin receptor blocker,

What is more, the OR of hospitalization for COVID-19 with the use of multivariate logistic regression showed simi-
associated with CCB in men was 0.87 (95% CI 0.79–0.96; lar conclusions among the male and female participants
p =0.005), compared with an OR of 1.03 (95% CI 0.86–1.15; (Table S20, see ESM).
p = 0.529) for women. This suggests that CCB could decrease
the risk of hospitalization for COVID-19 in men by 13%,
while CCB is not associated with the risk of hospitalization
for COVID-19 in women. β-blockers, statins, and aspirin were
not associated with COVID-19 outcomes in both females and
males, similar to the total participants. Sensitivity analyses
Anti-Hypertensive Medications and Risk of COVID-19 in Middle-Aged and Older Adults 927

Fig. 3  Association between medications and the risk of COVID-19 women. The effect of medicine classes was considered significant at a
after propensity score matching in men and women. The blue square p-value of <0.05. *p < 0.05 compared with COVID-19-negative par-
is the odds ratio for the risk of COVID-19 outcomes in men. The ticipants; **p < 0.01 compared with COVID-19-negative participants
red square is the odds ratio for the risk of COVID-19 outcomes in

4 Discussion using CCB was associated with a lower risk of hospitaliza-

tion for COVID-19, while using ARB was associated with
This prospective cohort study suggested that treatment a lower risk of death from COVID-19 among the female
with medications (including ACEI, ARB, β-blockers, COVID-19 patients in our cohort. This finding may con-
CCB, statins and aspirin) acting on CVD was not associ- tribute to the fierce debate since the discovery of SARS-
ated with the risk of testing positive for COVID-19 in CoV-2 in the clinical community about whether patients
female, male, and overall participants. Among middle- with COVID-19 should continue to use the six classes of
aged and older adults, the use of ACEI and ARB had dif- CVD medication.
ferent effects on the risk of death from COVID-19 and the Our data suggested that using ACEI increased the risk of
use of CCB had different effects on the risk of hospitaliza- death for COVID-19 in men and using ARB decreased the
tion for COVID-19 in females and males. Among the male risk in women. These findings could be attributed to two
patients with COVID-19 in our cohort, using ACEI was aspects. First, and most importantly, because the expression
associated with a higher risk of death for COVID-19 and of ACE2 on the X chromosome can be influenced by estro-
gen, the ACE/ACE2 ratio may be shifted towards the ACE2/

928 Y. Ma et al.

Angiotensin (Ang)-(1-7)/MAS receptor axis more in women renin-angiotensin system. Immunological differences
than in men [19, 20]. Some studies have described that the suggest that females mount a rapid and aggressive innate
increased ACE2/Ang-(1-7)/MAS pathway activity in the immune response, and the attenuated antiviral response in
female reproductive system can be an important mechanism males may confer enhanced susceptibility to severe disease
to counteract the actions of the Ang II-AT1R pathway [21]. [28]. Although previous studies rarely reported sex differ-
The activity of the ACE2/Ang-(1-7)/MAS pathway is ben- ences in the use of RAAS inhibitors among patients with
eficial for the prognosis of CVD in women (the mechanism COVID-19, the sex differences have been established in
is shown as Fig. 4) [22]. In contrast, the expression of ACE2 terms of CVD onset, pathophysiology, manifestation, sus-
was found more in men than in women, which could cause ceptibility, prevalence, treatment responses and outcomes
higher incidence and fatality rate of COVID-19 in men [23]. in animal models and clinical populations [29]. Apart from
We also found that CCB was associated with a lower risk that, many clinical studies have found that there was no dif-
of hospitalization for COVID-19 in males. The potential ference in the prevalence of COVID-19 between females
mechanism may be that inhibited calcium entry into cells and males, but male patients had significantly higher risk of
can affect vital steps in the life cycle of the viruses [24, 25] severe illness or death than female patients [30–32].
(Fig. 4) and the modulation of calcium channel responsive- Furthermore, a cohort study using data from the Korean
ness is sex-specific. Animal studies have proved that male National Health Insurance Service including 1,374,381
papillary heart muscle is more sensitive to calcium than residents found that there was a significantly lower risk of
female due to the regulation of calcium channel expression COVID-19 for participants using ARB and CCB medication
and current by estrogen and testosterone [26, 27]. [33]. Studies have shown the association between ARB and
Sex differences in cardiovascular disease and COVID- the lower risk of death for COVID-19, while ACEI was not
19 share mechanistic foundations, namely, the involve- associated with severity of COVID-19 [34, 35]. The effect
ment of both the innate immune system and the canonical of ACEI and ARB on ACE2 may be different [36]. A study

Fig. 4  Mechanisms for engagement of RAAS with SARS-CoV-2 in favoring tissue injury among men. SARS-CoV-2 may interact with
different sexes. Angiotensinogen is produced in the liver and hydro- calcium channels to facilitate entry of ­Ca2+ and create a suitable
lyzed into angiotensin I (AngI). Angiotensin converting enzyme environment for replication and survival. Calcium channel blockers
(ACE) converts AngI into angiotensin II (AngII). ACE2 converts (CCB) inhibit the utilization of calcium channels by SARS-CoV-2 for
AngII into angiotensin 1-7 (Ang 1-7), which binds to Mas receptor survival. ACEI angiotensin converting enzyme inhibitor, ARB angio-
(MasR) and favors tissue protection, mainly by hypotensive and anti- tensin receptor blocker, RAAS renin–angiotensin–aldosterone system,
inflammatory pathways among women. Conversely, ACE converts ROS reactive oxygen species,  SARS-CoV-2 severe acute respiratory
Ang I into Ang II that binds to angiotensin II type 1 receptor (AT1R), syndrome coronavirus 2
Anti-Hypertensive Medications and Risk of COVID-19 in Middle-Aged and Older Adults 929

conducted in the National Health Insurance (NHI) program Acknowledgements  The present analyses were conducted using the
of Taiwan found that the use of ACEI is associated with an UK Biobank resource under Application 45676. We would like to
thank all UK Biobank participants and staff, and all health-care work-
increased risk of lung cancer compared with the use of ARB. ers involved in the diagnosis and treatment of COVID-19 patients. We
Patients using ARB have a significantly lower risk of lung acknowledge support to Y.G.W. The funding sources had no involve-
cancer than non-ARB users [37]. In our study, β-blockers, ment in the study design, collection, analysis, or interpretation of data.
statins, and aspirin were found to have no association with
the risks of COVID-19, and these findings are in line with Declarations 
previous studies [5, 38, 39].
A population-based case-control study from the Lom- Funding  This study was supported by The National Natural Science
Foundation of China (71910107004).
bardy region of Italy have identified no sex differences or
effects of using ACEI/ARB on the risk of COVID-19 [40].
Conflicts of interest  The authors declare no conflict of interest.
Another Italian observational multicenter survey found no
significant interference between hypertension or anti-hyper- Ethics approval  This article does not contain any studies with human
tensive therapy on COVID-19 lethality [41]. Differences in participants or animals performed by the authors.
the research design and covariates or other methodological
Data availability  The authors can confirm that all relevant data are
differences between our study and the two studies from Italy included in the article and/or its supplementary information files.
might contribute to the different findings. For example, in
our study, the covariates include nine kinds of comorbidities Authors' contributions  YW directed the study. YW and YM designed
and the case control includes four kinds of comorbidities. the study and analyzed data. YM developed the first manuscript draft.
YW, SL, HY and YZ edited the manuscript. All authors critically
The obvious advantage of our study compared with pre- revised the manuscript, and all authors contributed to the final version.
vious studies is the detailed and validated data in a well
characterized cohort including types of cardiac medica-
tions and potential confounding risk factors for both females
and males. Our findings might help to allay concerns that References
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