The novel coronavirus (severe acute respiratory syndrome coronavirus 2 – SARS-Cov-2)
disease 2019 (COVID-19) pandemic has been associated with severe respiratory disease
incidence and increased mortality [1]. Angiotensin converting enzyme (ACE) 2 is a
homologue of ACE, but also a receptor for the coronaviruses [2]. ACE2 is highly expressed
in the lungs, heart, gastrointestinal (GI) tract and kidney, thus affecting the cardiovascular
system (CV) and the immune system [3]. The overexpression of ACE2 was reported to
enhance viral entry and replication intracellularly [4]. COVID-19, also called SARS-CoV-2,
may also use ACE2 as a receptor to initiate infection, leading to severe complications
from the heart (acute coronary syndrome (ACS) and fulminant myocarditis), lungs (pneumonia
and acute respiratory distress syndrome (ARDS)) and GI tract (diarrhoea syndrome)
[5].
ACE2 gene expression is affected by several factors, including gender (ACE2 gene is
X-linked), ACE2 gene polymorphisms, comorbidities (increased in the presence of CVD,
hypertension, diabetes), and drug therapy [6]. With regard to drugs, angiotensin II
receptor blockers (ARBs) and mineralocorticoid receptor antagonists (MRA) have been
reported to raise ACE2 activity in human and animal studies [7]. There are only a
few animal studies available showing that statins may also increase ACE2 activity
[8, 9]. In the era of the COVID-19 pandemic, such a drug effect may be considered
as potentially worrying [10]. In this context, it was recently even suggested that
ARBs could be replaced with ACE inhibitors and that statin treatment may be discontinued
during the pandemic, particularly in primary prevention settings [11].
However, before implementing such strategies, we should consider several issues. Firstly,
as the COVID-19 infection progresses, ACE2 is downregulated, thus potentially generating
an inflammatory response leading to impaired cardiac contractility and acute lung
injury [5, 7, 12]. Therefore, reduced ACE2 expression is linked to worse outcomes.
On the other hand, ACE2 overexpression has been associated with several beneficial
effects, i.e. prevention of adverse cardiac remodelling and fibrosis, improvement
of vascular endothelial dysfunction, reduction of blood pressure, and protection from
ARDS [7, 12]. Both statins and ARBs were reported to exert these benefits.
Secondly, a combination of statins/ARBs were used during the 2014 Ebola virus disease
epidemic in Sierra Leone, leading to improved outcomes and increased survival [13].
These drugs can affect the host response to infection, not the virus, especially by
preventing endothelial dysfunction, a shared feature of several virus infections [14].
Their combination seemed to promote a return to homeostasis, allowing patients with
Ebola virus infection to recover on their own [15].
Third, patients with cardiovascular disease (CVD) were shown to be more prone to COVID-19
infection and with worse prognosis [16, 17]. Elevated inflammatory markers, such as
C-reactive protein (CRP) and interleukin-6 (IL-6), have been recognised as predictors
of COVID-19 infection severity and mortality, suggesting a virus-activated “cytokine
storm syndrome” [18, 19]. Therefore, as well as immunomodulation, COVID-19 treatment
should also target reduction of inflammation. In this context, statins have been consistently
reported to exert immunomodulatory and anti-inflammatory properties [20–30]. Also,
it was previously suggested that statins could enhance host defence and suppress inflammation,
thus representing a practical and inexpensive adjunctive or alternative host-directed
treatment for infections by viruses, fungi, protozoa, and bacteria [31]. Similarly,
there are data supporting an anti-inflammatory role for ARBs [32–34].
Fourth, statins may also prevent a viral-induced acute coronary syndrome (also in
COVID-19 positive patients) by stabilising atherosclerotic plaques [35], as well as
prevent acute kidney injury (AKI) [36]. Both acute cardiac injury and AKI are predictors
of COVID-19-induced mortality [37]; statin therapy may prevent these complications
and thus increase survival. Of note, statins can protect against contrast-induced
AKI (CI-AKI) [38–41]. This is of clinical importance, especially in hospitalised patients
who undergo diagnostic or therapeutic procedures involving the administration of contrast
media (e.g. computed tomography of the lungs).
Fifth, effective lipid-lowering therapy (LLT) and significant cholesterol reduction
might significantly suppress coronavirus infection. It was show that for infectious
bronchitis virus (IBV) coronavirus, drug-related cholesterol reduction disrupts lipid
rafts (an important element for the cellular entry of coronavirus) that enable the
binding of the coronavirus with the host cells and, consequently, further infection
[42]. It was also observed, in the studies with porcine deltacoronavirus (PDCoV),
that cholesterol present in the cell membrane and viral envelope (coronaviruses are
positive-sense enveloped RNA viruses) contributes to PDCoV replication by acting as
a key component in viral entry. Thus, the pharmacological sequestration of cellular
or viral cholesterol with effective LLT significantly blocked both virus attachment
and internalisation [43]. All these mechanisms might suggest a critical role of statins
and LLTs in the inhibition of coronavirus infection.
In COVID-19-positive patients, the majority of baseline CVD is of atherosclerosis
origin, with the worst prognosis for patients being at the high, and especially very
high and extremely high, risk of CVD [16]; thus, intensive LLT with statins and/or
fixed combination with ezetimibe and proprotein convertase subtilisin/kexin type 9
(PCSK9) inhibitors seems to be critical. Indeed, we should do our best to maximally
improve therapy adherence and thus have a better prognosis for the infected CVD patients
[44, 45]. In this context, there are no premises that PCSK9 inhibitors, because they
are monoclonal antibodies (in relation to the above-mentioned high cytokine storm
during infection), should be discontinued. In contrast, PCSK9 inhibitors should be
continued to achieve further low-density lipoprotein cholesterol (LDL-C) lowering
(based on “the lower, the better” principle), because then we might significantly
stabilise atheroma plaque, reduce the risk of CVD events, and reduce inflammation
[46–48]. Recent available data have confirmed the role of PCSK9 inhibition in reducing
the process of inflammation via decreasing main vascular inflammatory markers, reducing
infiltration of monocytes into the subendothelial layer, and inhibiting monocyte migration.
Apart from the reduction of pro-inflammatory mediators, PCSK9 inhibitors could ameliorate
vascular inflammation [47]. Finally, a direct local anti-inflammatory action of PCSK9
inhibitors, independent of LDL-C reduction, has been shown in animal models; however,
it still merits further investigation [47, 48].
It is of special interest now (due to the fact that coronavirus might also use different
receptors to enter the host cell) that treatment with PCSK9 inhibitors has beneficial
effects on LDL-C lowering via inhibition of LDL-receptors (LDL-R). This might exert
an antiviral effect, among others, on hepatitis C viral (HCV) infection through down-regulation
of the surface expression of LDL-R and cluster of differentiation (CD) 81 on hepatic
cells, and a positive association with increased inflammatory responses, as well as
with septic shock [48]. In a recent paper, we confirmed that there is no association
between PCSK9 levels and resistance to antibiotics or the condition of patients hospitalised
in intensive care units, a finding of clinical importance in the COVID-19 infection
era [49].
Sixth, there are conflicting results regarding the possible effects of statins on
ARDS development and outcomes [50, 51]. It was suggested that statins act beneficially
in ‘hyper-inflammatory’ ARDS patients (defined by increased biomarkers of inflammation,
coagulation and endothelial activation) [52], but not in ‘hypo-inflammatory’ patients
[53, 54]. A potential benefit of ARBs on survival in ARDS patients has also been reported
[55, 56]. Nevertheless, there is a paucity of data on this field, and thus further
research is needed to elucidate the association between statin therapy, ARBs, and
acute lung injury.
Of note, drug-drug interactions should also be considered. In this context, simvastatin
and lovastatin are contraindicated in patients on lopinavir/ritonavir therapy due
to an increased risk of rhabdomyolysis [57]. Atorvastatin, rosuvastatin and other
statins can be used at the lowest possible dose, based on the instructions included
in the summary of product characteristics (spc) [58]. Taking this into account, we
should be careful while treating COVID-19 disease patients with statins being on antiviral
drugs and some antibiotics (including macrolides), because they might increase the
risk of statin-associated muscle symptoms (SAMS) [59, 60]. Therefore, their careful
monitoring is highly recommended to avoid unnecessary drug-related side effects, and
at the same time optimising LLT therapy to achieve the individual’s LDL-C goal. In
this context, in patients at very high CVD risk, requiring intensive LLT, it is reasonable
to initiate therapy with polypills/fixed combinations of statins (at lower doses)
and ezetimibe, with or without PCSK9 inhibitors (as available), aimed at reducing
the risk of SAMS [59, 60].
A position statement of the European Society (ESC) Council (on 13 March 2020) (as
well as of other national and international societies) highlights the lack of evidence
on harmful effects of ACE inhibitors and ARBs on the incidence and progression of
COVID-19 infection and strongly supports the continuation of usual antihypertensive
therapy [6, 61]. Regarding statins, their beneficial effects on inflammation, vascular,
heart, and lung function strongly support the continuation of their use. Due to their
significant effect on CVD prevention, PCSK9 inhibitors should also be continued, as
available. Physicians should wait for strong evidence and recommendations from international
scientific societies before altering their patients’ drug therapy in the COVID-19
era.