Statin Therapy and COVID-19 Infection

Statins reduce intracellular cholesterol synthesis by interfering with the limiting enzyme
HMGCoA reductase. A lower intracellular cholesterol concentration leads to activation of the
transcription factor SREBP 2 upregulating LDL receptor synthesis. In general, intracellular
cholesterol homeostasis achieves a new physiological equilibrium at lower cholesterol
concentrations. Moreover, the effect of cholesterol pathway inhibition has also an effect on
farnesyl and geranyl molecules formation influencing protein prenylation leading to changes
on inflammation and immunomodulation in vitro.

Changes in intracellular cholesterol alter cell membrane composition, particularly the
structures referred to cholesterol rafts that accommodate a huge number of cell surface
proteins as receptors. Theoretically, alterations in cholesterol rafts could derange the
function of some receptors Some preliminary studies on cell models have suggested that
statins could interfere the activity of some membrane viral receptors blunting its entry to
cell (Berraondo P et al CIMA nonpublished data). SARS-cov-2 goes into cells through the
Angiotensin Converser Enzyme 2 (ACE2) which is located in the surface of several cells
including lung cells. It has been suggested that simvastatin could have a role in SARS-cov-2
infection by blocking the virus entry to cell. However, atorvastatin has been shown to
increase ACE2 expression in animal models. Moreover, intracellular cholesterol content seems
to influence the virus uptake.

Severe SARS-cov-2 infection is mediated by an inflammatory storm resulting in a deep tissue
injury, endothelial damage, prothrombotic state and multiorgan failure. As mentioned above,
statins also have some potent anti-inflammatory effects as modulating TNF, the NFkB
transcription factor or blocking some members of the Tool Like Receptor family as TLR4-9 and
its downstream cofactor MYD88. This anti-inflammatory effect has been implicated in a better
prognosis of some diseases as HBV or HCV chronic infection, limiting the progression of
hepatic damage to chronic liver disease or hepatocarcinoma. The impact of statin use on
influenza epidemics has been repetitively assessed but contradictory or non-conclusive
results have been obtained. The combination of statins and angiotensin receptor blockers have
shown an important protective effect on other epidemics as Ebola, probably to their action on
endothelium protection. A protective effect of statins on pulmonary hypertension development
in a primate HIV model has also been reported. Although, in general all these pleiotropic
effects of statins have been shown in vitro and its clinical impact is not clear, a clinical
assay to test the efficacy of simvastatin on SARS-cov-2 is going on. Recently an
observational study including more than 8000 patients infected by Sars-Cov-2 showed the
protective effect of being on statins or ACE inhibitors. Taken into account its widespread
use and putative effects on viral entry, inflammation, immune mechanisms and endothelial
function, the use of standard therapies as statins have been postulated to target the host
response to new virus pandemics.