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\begin{document}

\title{Effects of previous exposure to different medications on clinical course
of COVID-19 patients in Istanbul, Turkey}



\author[1]{Ülkü Sur Ünal}%
\author[2]{Hasan Yananlı}%
\author[3]{Ömer Ünal}%
\author[4]{Yasemin Doğan Kaya}%
\author[5]{Merve Keskin}%
\author[6]{Fikriye Güngören}%
\author[2]{Atila Karaalp}%
\affil[1]{Uskudar Zeynep Kamil Family Health Center}%
\affil[2]{Marmara University School of Medicine}%
\affil[3]{Maltepe University School of Medicine}%
\affil[4]{Sultanbeyli Jandarma Ustegmen Rahim Celik Family Health Center}%
\affil[5]{Beyoglu 6th Family Health Center}%
\affil[6]{Eyup Islambey Family Health Center}%


\vspace{-1em}



  
  \date{May 25, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Aim: To examine the effects of drug use in the last 6 months before
contracting coronavirus disease-2019 (COVID-19) on the clinical course
of COVID-19. Methods: In this retrospective cohort study, which included
525 patients diagnosed with COVID-19 between March and November 2020
from four different family health centers in Istanbul, the records of
the patients were retrospectively analyzed. In addition to demographic
information, all medications used by the patients in the last 6 months
before the diagnosis of COVID-19 were noted. The effects of demographic
data and medications on the three main endpoints of the study, which
were hospitalization, intensive care unit (ICU) admission, and
mortality, were analyzed by using logistic regression models. Results:
Of the 525 COVID-19 patients included in the study, 109 (20.8\%) were
hospitalized, 18 (3.4\%) were treated in ICU, and 11 (2.1\%) patients
died. While increasing age is associated with hospitalization, ICU
admission and mortality; also, the presence of COVID-19 thoracic
computed tomography (CT) findings and polypharmacy were associated with
an increased hospitalization; living alone and the presence of COVID-19
thoracic CT findings were associated with an increased ICU admission.
When adjusted for age and comorbidity, logistic regression models
revealed that medications for diabetes mellitus (DM) increased the
probability of hospitalization (OR=3.9, 95\% CI 1.2-13.0), and calcium
channel blockers (CCBs) increased the probability of ICU admission
(OR=15.8, 95\% CI 2.1-120.2) and mortality (OR=295.1, 95\% CI
4.6-18946.6). Conclusion: Previously utilization of DM medications and
CCBs may have negative effects on the clinical course of COVID-19.%
\end{abstract}%



\sloppy


\textbf{Effects of previous exposure to different medications on
clinical course of COVID-19 patients in Istanbul, Turkey}

\textbf{Running head:} Chronic drug utilization and COVID-19

\selectlanguage{ngerman}Ülkü Sur Ünal\textsuperscript{1,2*}, Hasan Raci
Yananl\selectlanguage{polish}ı\selectlanguage{english}\textsuperscript{2}, \selectlanguage{ngerman}Ömer Kays Ünal\textsuperscript{3}, Yasemin
Do\selectlanguage{polish}ğ\selectlanguage{english}an Kaya\textsuperscript{4}, Merve
Keskin\textsuperscript{5}11Department of Histology and Embryology,
Istanbul University School of Medicine, Istanbul, Turkey, Fikriye
G\selectlanguage{ngerman}üngören\textsuperscript{6}22Drug Discovery and Safety Master of Science
Programme, Vrije University, Amsterdam, Holland Atila
Karaalp\textsuperscript{2}33Department of Medical Pharmacology, Istanbul
Saglik ve Teknoloji University School of Medicine, Istanbul, Turkey

\textsuperscript{1}Uskudar Zeynep Kamil Family Health Center, Istanbul,
Turkey

\textsuperscript{2}Department of Medical Pharmacology, Marmara
University School of Medicine, Istanbul, Turkey

\textsuperscript{3}Department of Orthopaedics and Traumatology, Maltepe
University School of Medicine, Istanbul, Turkey

\textsuperscript{4}Sultanbeyli Jandarma Ustegmen Rahim Celik Family
Health Center, Istanbul, Turkey

\textsuperscript{5}Beyoglu 6th Family Health Center, Istanbul, Turkey

\textsuperscript{6}Eyup Islambey Family Health Center, Istanbul, Turkey

*Corresponding author

Dr. Ülku Sur Ünal, MD, PhD candidate

Uskudar Zeynep Kamil Family Health Center, Validei Atik Mah, Eski
Toptasi Cad. No: 126/2 Istanbul, Turkey

E-mail: ulkusurunal@hotmail.com

ORCID: 0000-0003-4758-4413

The authors confirm that the principal investigator for this study is
Dr. Ülkü Sur Ünal, and that she had direct clinical responsibility for
patients.

\textbf{Keywords:} COVID-19/epidemiology, pharmacoepidemiology,
SARS-CoV-2, hypoglycemic agents, calcium channel blockers

\textbf{Word count:} 3422 (without abstract and references)

\textbf{Table count:} 6

\textbf{Figure count:} 1

\textbf{What is already known about this subject:}

\begin{enumerate}
\tightlist
\item
  A complete consensus has not yet been reached on the effect of
  angiotensin-converting enzyme inhibitors and angiotensin receptor
  blockers on the COVID-19 clinical course.
\item
  Metformin and insulin are associated with better and poor COVID-19
  clinical course, respectively.
\item
  There are inconclusive results about calcium-channel blockers on
  COVID-19 clinical course.
\end{enumerate}

\textbf{What this study adds:}

\begin{enumerate}
\tightlist
\item
  Diabetes mellitus drugs increase the likelihood of hospitalization due
  to COVID-19.
\item
  Calcium-channel blockers increase the probability of ICU
  hospitalization and mortality due to COVID-19.
\item
  No effect of angiotensin-converting enzyme inhibitors and angiotensin
  receptor blockers on COVID-19 clinical course was detected.
\end{enumerate}

\textbf{Abstract}

\textbf{Aim:} To examine the effects of drug use in the last 6 months
before contracting coronavirus disease-2019 (COVID-19) on the clinical
course of COVID-19.

\textbf{Methods:} In this retrospective cohort study, which included 525
patients diagnosed with COVID-19 between March and November 2020 from
four different family health centers in Istanbul, the records of the
patients were retrospectively analyzed. In addition to demographic
information, all medications used by the patients in the last 6 months
before the diagnosis of COVID-19 were noted. The effects of demographic
data and medications on the three main endpoints of the study, which
were hospitalization, intensive care unit (ICU) admission, and
mortality, were analyzed by using logistic regression models.

\textbf{Results:} Of the 525 COVID-19 patients included in the study,
109 (20.8\%) were hospitalized, 18 (3.4\%) were treated in ICU, and 11
(2.1\%) patients died. While increasing age is associated with
hospitalization, ICU admission and mortality; also, the presence of
COVID-19 thoracic computed tomography (CT) findings and polypharmacy
were associated with an increased hospitalization; living alone and the
presence of COVID-19 thoracic CT findings were associated with an
increased ICU admission. When adjusted for age and comorbidity, logistic
regression models revealed that medications for diabetes mellitus (DM)
increased the probability of hospitalization (OR=3.9, 95\% CI 1.2-13.0),
and calcium channel blockers (CCBs) increased the probability of ICU
admission (OR=15.8, 95\% CI 2.1-120.2) and mortality (OR=295.1, 95\% CI
4.6-18946.6).

\textbf{Conclusion:} Previously utilization of DM medications and CCBs
may have negative effects on the clinical course of COVID-19.

\textbf{Inroduction}

The pandemic caused by the coronavirus disease-2019 (COVID-19) has
caused millions of people's death since December 2019 and continues to
do so. Although an effective drug treatment has not yet been found,
vaccines developed against COVID-19 have been applied all over the world
since the last months of 2020. On the other hand, studies on which
factors affect the severity of the disease are still continuing. Studies
to date indicate that age is the primary risk factor for
COVID-19-related hospitalization and/or death. In addition, it has been
revealed that the clinical course of COVID-19 is more severe in patients
with chronic diseases such as hypertension (HT), cardiovascular diseases
(CVD), diabetes mellitus (DM), obesity, chronic kidney failure, and
cancer {[}1--4{]}.

The cellular structure and receptors of the severe acute respiratory
syndrome coronavirus-2 (SARS CoV-2) that causes COVID-19 was found in
March 2020. It was determined that the virus entered the cell with the
angiotensin converting enzyme-2 (ACE2) receptor and the transmembrane
protease serine 2 (TMPRSS2) receptor facilitated the entry of the virus
into the cell {[}5{]}. Since then, the use of drug groups such as ACE
inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) {[}6--8{]},
ibuprofen and other non-steroidal anti-inflammatory drugs (NSAIDs)
{[}9,10{]}, thiazolidinediones {[}11{]} which may cause an increase or
decrease in ACE2 expression, has been investigated in large-scale
studies during the COVID-19 pandemic. In general, it has been
demonstrated that these drugs do not affect the severity or mortality of
COVID-19. Besides, studies in which metformin was associated with
decreased mortality and insulin was associated with increased mortality
were published {[}11--14{]}. Regarding dipeptidyl peptidase-4 (DPP4)
inhibitors, results have been reported that they are associated with
good or poor clinical course of COVID-19 {[}11,15,16{]}.

Considering that the rate of spread of COVID-19 may be related to the
expression status of ACE2 or TMPRSS2 receptors {[}17,18{]} or to some
other genetic factors that are not yet known, data in different parts of
the world are important. With this study, we aimed to examine the
effects of previous drug utilization in the last 6 months before
contracting COVID-19 on the clinical course of COVID-19 by presenting
data from Istanbul, Turkey.

\textbf{Methods}

The study, which is a retrospective cohort type, started in May 2020
under the direction of Marmara University Health Sciences Institute
Medical Pharmacology Department and was carried out between May 2020 and
October 2021. Patients registered at Istanbul Uskudar Zeynep Kamil
Family Health Center (FHC), Sultanbeyli Jandarma Ustegmen Rahim Celik
FHC, Beyoglu 6th FHC and Eyup Islambey FHC were included in the study.
Of these patients, those who were diagnosed with COVID-19 between March
11, 2020 - November 30, 2020, constituted the population of the study.

Inclusion criteria were to be a patient enrolled in the above-mentioned
FHCs and to have a positive COVID-19 PCR test between 11 March 2020 and
30 November 2020 or positive COVID-19 thoracic CT findings despite a
negative test. The exclusion criterion from the study was the inability
to access the medical information of the included patients
via\emph{e-nabiz} (an application that Turkish citizens and health
professionals can access health data collected from health institutions
via the internet and mobile devices).

The records of the patients included in the study were scanned
retrospectively. Data scanning was performed via family medicine
information systems and \emph{e-nabiz} . The data of the patients were
collected by the researcher working in the relevant FHC and
participating in the study. The information obtained from the patient
files were as follows: patient's age, gender, marital status, education
level, employment status, occupation, smoking habit, date of first
diagnosis, first application complaint, COVID-19 PCR test result,
presence of COVID-19 findings in thoracic CT, received COVID-19
pharmacological treatment, presence of comorbidity and medications used
in the previous 6 months. The medications utilized in the previous 6
months were recorded according to the Anatomic Therapeutic Chemical
(ATC) 5 classification. It was then further grouped according to ATC 3.
These data were compared with the three main endpoints of the study,
namely, the need for hospitalization, the need for intensive care unit
(ICU), and mortality in comparative analyses.

SPSS 21.0 was used for statistical analysis. Frequency analysis was
performed by specifying numbers and percentages for categorical
variables. Normal distribution was tested using Kolmogorov--Smirnov
test. Mean and standard deviation were used for continuous variables,
and median and range of values \selectlanguage{english}\selectlanguage{english}were used for non-parametric variables,
as measures of central tendency and dispersion, respectively. Logistic
regression was used to compare the independent variables with the three
dependent variables. The direction of the comparisons was confirmed by
correlation analysis and Pearson chi-square test. All logistic
regression models were adjusted for age and comorbid conditions.
Demographic data were also compared between outpatients,
hospitalization, ICU admission and mortality using Pearson-chi square
test, when needed Fisher's exact test. For parameters with nonnormal
distribution, ranks were compared using Kruskal--Wallis test. For
normally distributed parameters, means were compared using one-way
analysis of variance (ANOVA) test. In the presence of significant
variables Tukey's post hoc test was performed after ANOVA test, Dunn
test was performed after Kruskal-Wallis test and Pearson chi-square or
Fisher's exact test in pairs were performed after Pearson chi-square or
Fisher's exact test.

To obtain study data from family medicine information systems
and\emph{e-nabiz} , permission was obtained from the Turkish Republic
Ministry of Health General Directorate of Health Services Scientific
Research Platform on 29.04.2020. Before starting to collect the study
data, an application was made for the approval of the Marmara University
Faculty of Medicine Clinical Research Ethics Committee and the ethics
committee approval was obtained on 08.05.2020 with the protocol code
09.2020.552. The study was carried out in accordance with the principles
in the Declaration of Helsinki.

\textbf{Results}

Between March 2020 and November 2020, a total of 525 patients with
COVID-19 PCR positive (n=504; 96.0\%) or PCR negative and CT positive
(n=21; 4.0\%) were included in the study from the previously determined
FHCs. Demographic and baseline characteristics were compared between
outpatient, hospitalized, ICU, and dead patients (Table 1). While the
most common complaint in outpatients was fatigue, the most common
complaint in patients admitted to the hospital or ICU or who died was
cough. Cough, fever, and shortness of breath were more common in
patients who were hospitalized or in the ICU or who died compared to
outpatients (p \textless{} 0.01) (Table 1). Education level, employment
status and occupation data were not included in the analyzes because the
relevant data were not available for all of the study population.

The COVID-19 treatment approach varied in time from March 2020, to
November 2020 (Figure 1). While in April 2020 the predominant treatment
was hydroxychloroquine, by November 2020 the predominant treatment was
favipiravir according to guidelines of Turkish Ministry of Health.
Considering the mortality, ICU admission and hospitalization rates by
month, the highest mortality rate was seen in June 2020 with 4.8\%. The
highest rate of hospitalization and ICU admission was seen in March
2020; 92.9\% and 14.3\%, respectively (Table 2).

Increasing age was associated with an increased probability of
hospitalization (p\textless{}0.05), ICU admission, and mortality
(p\textless{}0.01). In addition, the presence of thoracic CT findings
increased the probability of hospitalization 21 times
(p\textless{}0.01), polypharmacy increased the probability of
hospitalization by two times (p\textless{}0.05). Those with thoracic CT
findings were 18 times more likely to be admitted to the ICU than those
without (p\textless{}0.01). Being married was associated with a reduced
probability of ICU admission (p\textless{}0.05) (Table 3).

The number of patients with asthma/chronic obstructive pulmonary disease
(COPD) was 48 (Table 1). In 62.5\% of these patients, COVID-19 thoracic
CT findings were positive. Asthma/COPD was associated with developing
thoracic CT findings; x\textsuperscript{2}(1) = 23.667;
p\textless{}0.01.

There was no statistically significant difference in developing COVID-19
thoracic CT findings between never smoked/quit smoking and being a
smoker (p\textgreater{}0.05). The same was true when non-smokers were
compared with quitting/smoking (p\textgreater{}0.05).

The effects of medications used in the previous 6 months before
contracting COVID-19 on hospitalization, ICU admission or dead were
analyzed using the logistic regression models adjusted for age and
comorbidity. DM medications increased the probability of hospitalization
3 times (p\textless{}0.05) (Table 4), while CCBs increased the
probability of admission in the ICU 155 times (p\textless{}0.01) (Table
5), and the probability of mortality 295 times (p \textless{} 0.01)
(Table 6). When DM drugs are subdivided into metformin, sulfonylureas,
meglitinides, thiazolidinediones, \selectlanguage{greek}α-\selectlanguage{english}glucosidase inhibitors, GLP-1
agonists, DPP4 inhibitors, SGLT-2 inhibitors, and insulin, in the
logistic regression model adjusted for age and comorbidity, there was no
statistically significant difference between the subgorups of DM
medications in terms of effects on hospitalization, ICU admission or
mortality (p\textgreater{}0.05).

Regarding COVID-19 pharmacological treatments, according to the
chi-square analysis that included only hospitalized patients, different
COVID-19 pharmacological treatments were not associated with ICU
admission and mortality (p\textgreater{}0.05).

\textbf{Discussion}

In this study, which was carried out in the first wave of COVID-19, the
effects of demographic data and drugs utilized in the last 6 months
before contracting COVID-19 on the probability of hospitalization, ICU
admission or mortality were examined. Increasing age was associated with
all three main endpoints of the study, which were listed as
hospitalization, ICU admission, and mortality. In addition, the presence
of COVID-19 thoracic CT findings and polypharmacy was associated with an
increased probability of hospitalization and being alone and the
presence of COVID-19 thoracic CT findings were associated with an
increased probability of ICU admission. When the effects of drugs used
in the last 6 months before contracting COVID-19 were examined, it was
seen that DM medications increased the probability of hospitalization,
and CCBs increased the probability of ICU admission and mortality.

Increasing age and the presence of comorbidity have been shown to be an
important risk factor for the severe clinical course of COVID-19 since
the beginning of the COVID-19 pandemic {[}1,2,4{]}. We also obtained
similar results in our study; HT, DM, hyperlipidemia, asthma/COPD,
cardiovascular, kidney and cerebrovascular diseases were associated with
the clinical course of COVID-19. It was observed that HT increased the
probability of ICU admission (Table 5), while CVD increased the
probability of mortality 73 times (Table 6).

Numerous studies have been conducted since the beginning of the pandemic
that ACEI/ARBs are associated with COVID-19 in harmful or protective
ways. According to data from most large-scale studies and meta-analyses,
RAS blockers do not change the clinical course of COVID-19
{[}7,19,20{]}. Similar findings were obtained in our study; it was
observed that ACEI and ARBs had no effect on the clinical course of
COVID-19.

In our study, it was also observed that DM medications increased the
probability of hospitalization three fold (Table 4). However, it had no
effect on ICU admission and mortality. In the logistic regression
analysis when DM medications were divided into subgroups as metformin,
sulfonylureas, meglitinides, thiazolidinediones, \selectlanguage{greek}α-\selectlanguage{english}glucosidase
inhibitors, GLP-1 agonists, DPP4 inhibitors, SGLT-2 inhibitors and
insulin, no significant difference was observed between the drug groups
in terms of their effects on hospitalization. However, chi-square
analysis revealed that all DM drug subgroups were associated with
hospitalization, and SGLT-2 inhibitors were also associated with
mortality and admission in the ICU. In the literature, it is stated that
the use of metformin is generally associated with a decrease, while the
use of insulin is associated with an increase in mortality due to
COVID-19 {[}11,12,21{]}. Regarding other DM drug groups, there are
publications that show different results from each other. In a study
involving 2.85 million patients with type 2 DM in the UK, statistical
evidence was presented that patients receiving metformin, SGLT2
inhibitors and sulfonylurea treatments had a lower risk of death than
those who did not take these drugs {[}11{]}. In the same study, it was
determined that the risk of death was higher in those whose given
insulin and DPP-4 inhibitors than those who did not {[}11{]}.

According to the results of Yang et al.'s meta-analysis, which included
17 studies and analyzed data from a total of approximately 21.000
patients, metformin was associated with significantly reduced mortality
in COVID-19 patients with DM {[}12{]}. Regarding insulin therapy; in Yu
et al.'s study, in addition to matching other medical characteristics,
propensity score matching was applied to HbA1c levels, and insulin
therapy was associated with increased mortality. It has been stated that
the use of insulin therapy at a more advanced stage in type 2 DM may be
a residual confounding factor, although pairings have been made
{[}21{]}. Although age and comorbidity were added to the logistic
regression models as confounding factors when analyzing the effects of
chronically used drugs on hospitalization, ICU admission, and mortality,
we could not make a match based on the clinical level of DM in the case
of DM drugs. In our study, which included 525 COVID-19 patients in
total, 64 of these patients were diagnosed with DM and 64 were receiving
DM medication. When divided DM medications into subgroups, there was no
difference between the subgroups in terms of their effects on the three
main endpoints of this study, which may due to the small patient groups.
According to two meta-analyses examining the relationship between
DPP4-inhibitors and mortality due to COVID-19, contrary to the results
of Khunti et al.'s study on DPP4-inhibitors {[}11{]}, Rakhmat et al.
stated in their study that the use of DPP-4 inhibitors was associated
with lower mortality in COVID-19 patients {[}15{]}. In the study by
Hariyanto et al., they stated that DPP-4 inhibitors did not change the
results of COVID-19 {[}16{]}.

According to the results of our study, CCB use is closely related to ICU
admission and increased mortality. There were studies showing parallel
findings with our study regarding CCBs {[}22,23{]}. In the study of
Mendez et al., 245 patients hospitalized due to COVID-19 and diagnosed
with HT were included; the data of 75 patients using CCBs and 175
patients not using CCBs were compared. Those who received
dihydropyridine group CCBs had a significantly increased risk of
intubation or death compared to those who did not {[}22{]}. In the study
conducted by Jackson et al., which included 297 patients, the need for
mechanical ventilation and mortality were investigated in patients
hospitalized with the diagnosis of COVID-19. ARB or CCB use before
hospitalization for COVID-19 was found to double the probability of
death (aORs, 2.02 {[}95\% CI, 1.03-3.96{]} and 1.91 {[}95\% CI, 1.03-3,
55{]}) {[}23{]}. According to a population case-control study examining
the development of symptoms and contracting COVID-19 with chronically
used drugs, the risk of developing COVID-19 symptoms in people with HT
who received CCBs was significantly increased (OR) = 1.73; 95\% CI
1.2--2.3), disease risk was significantly lower in ARB and diuretic
users (OR = 0.22; 95\% CI 0.15--0.30, and OR = 0.30; 95\% CI,
respectively). 0.19-0.58) {[}24{]}. On the other hand, studies
indicating that CCBs reduce the mortality of COVID-19 or the possibility
of serious illness have also been published {[}25,26{]}. In a study by
Chouchana et al., which included 3686 patients with HT hospitalized for
COVID-19, demonstrated that CCBs reduced the probability of mortality
{[}25{]}. In a meta-analysis, it was stated that there was a significant
reduction in all-cause mortality and disease severity in CCB users
{[}26{]}.

Considering why CCBs may worsen the COVID-19 clinic, as in our study;
CCBs can inhibit type II pneumocyte secretion, leading to alveolar
collapse {[}27{]}. In addition, precapillary vasodilation due to CCBs
may cause alveolar edema {[}28--31{]}. Another reason may be that CCBs
may cause hypoxic pulmonary vasoconstriction in patients with pulmonary
disease, leading to profound hypoxemia {[}22,32--35{]}. On the other
hand, when we evaluate why CCBs may improve the clinical course of
COVID-19; since calcium is necessary for virus penetration into the
cell, viral gene expression, processing of viral proteins, and viral
maturation and extracellular release, CCBs cause depletion in
intracellular calcemia, thus negatively interfering with the life cycle
of the virus. CCBs can inhibit viral replication by reducing
intracellular calcium levels {[}36,37{]}. On the other hand, in vitro
studies suggest that CCBs can be used in therapy by reducing
intracellular calcium levels, which provide the environment for virus
entry {[}38{]}. Additionally, some studies have demonstrated the
anti-inflammatory and anticoagulant effects of CCBs {[}37,39{]}.

Thiazolidinediones, aspirin and famotidine, which are among the
medications whose effects on the clinical course of COVID-19 were
examined in previous studies, were included in the logistic regression
models within their main groups (diuretics, anticoagulants, stomach
drugs; respectively) in our study. However, they were found to have no
effect on all three study endpoints. A meta-analysis of aspirin suggests
that aspirin use is associated with a lower risk of death from COVID-19
{[}40{]}. In a case-control study, however, aspirin had no effect on the
COVID-19 clinic {[}41{]}. Regarding famotidine, in the study of
Yeramaneni et al., 7158 patients were included and it was stated that
famotidine had no effect on mortality due to COVID-19 {[}42{]}.

When we examined the effect of marital status on the clinical course of
COVID-19, we found that being married reduced the possibility of ICU
admission. In the literature, we could not find any other study
examining the effect of marital status on the clinical course of
COVID-19. In addition, there are publications investigating the
relationship between being married or living alone with the frequency of
anxiety and depression during the COVID-19 pandemic; in these studies,
it was stated that the frequency of depression was higher in the
COVID-19 pandemic in those who were single {[}43,44{]}. This may lead to
suppression of the immune system and be associated with a worse clinical
course of COVID-19. It needs to be confirmed by larger studies.

As far as we know, our study was the first study in Turkey investigating
the relationship between drug utilization in chronic diseases and
COVID-19 clinical course using primary care data. In the study by Senkal
et al., 611 hospitalized COVID-19 patients were included in the study
and they aimed to reveal the possibility of severe COVID-19 clinics in
patients under ACEI or ARB treatment. It was concluded that chronic ACEI
exposure was associated with a reduced likelihood of serious disease
{[}45{]}. Since our study presented primary care data, we had the
opportunity to compare the effects of chronically used drugs on the
clinical course of COVID-19 between outpatients diagnosed with COVID-19
and patients who were admitted to the hospital, ICU or dead. It is known
that some genetic and ethnic factors under investigation, especially
ACE2 and TMPRSS2 expression, may predispose to COVID-19. Accordingly, it
had been reported that some patients may experience the disease more
severely or mildly {[}17,18,46--49{]}. In this context, studies
conducted in different countries that reveal the factors affecting the
clinical course of COVID-19 gain importance.

One of the limitations of our study is that it was not possible to
exclude all confounders, since this study was retrospective. For
example, since the antropometrics of the patients were not known, the
presence of overweight status was unknown if the obesity diagnosis was
not stated in the patient records. Other than that, when the study
population of 525 was subdivided, there was a small number of patients
for comparison. Regarding CCBs; although the established logistic
regression models have been adjusted for age and comorbidity, it should
be considered that they are mostly used in the elderly hypertensive
population.

To conclude, we have demonstrated that increasing age, HT, and CVD are
associated with the severe clinical course of COVID-19; being married
reduces the probability of ICU admission due to COVID-19. In addition,
DM medications increased the probability of hospitalization three fold;
while CCBs increased the probability of ICU admission 155 fold and the
probability of mortality 295 fold. On the other hand, it was observed
that RAS blockers (ACEIs and ARBs) did not affect the clinical course of
COVID-19. In conclusion, larger cohort studies and meta-analyses as with
ACEI and ARBs, are needed for CCBs and DM medications.

\textbf{Acknowledgements}

We would like to thank our physician friends at family health centers
for their contributions in the data collection phase of our study.

\textbf{Contributors}

\selectlanguage{ngerman}Ü.S.Ü and A.K. proposed the concept, involved in the design of the study
and preparation of the manuscript. Ü.S.Ü was the principal investigator
for the study. Ü.S.Ü, Y.D.K., M.K. and F.G. collected the data. Ü.S.Ü,
H.R.Y. and Ö.K.Ü. involved in the analysis and interpretation of data.
A.K. and H.R.Y. revised the manuscript. All authors reviewed and
approved the final manuscript.

\textbf{Conflict of interest statement}

None of the other authors declared any competing financial interests.

\textbf{Availability of data}

The data that support the findings of this study are available from the
corresponding author upon reasonable request.

\textbf{Funding information}

No funding was obtained or used for the presented research project.

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