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, α-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.