Cholesterol and cholesterol-lowering in COVID-19: why we should not let our guard down
A response in the BMJ states that reduced plasma cholesterol levels might be the cause instead of the consequence of COVID-19 (1,2). The acute cholesterol-lowering impact of infections is largely documented in prospective observations (3) and recently also in COVID-19 (1). Malnutrition-inflammation-cachexia may explain such an effect. Thus, reverse causality (i.e., infections cause cholesterol reduction) instead of causality should be considered in interpreting the association between cholesterol and infections.
The proposed ability of LDLs to inactivate and protect rats from bacterial toxins is intriguing (2); however, it should be weighed against additional evidence. PCSK9 loss-of-function mutations are associated with significant LDL cholesterol reductions, but not with infection risk (4,5); they improve, instead, survival in patients with septic shock (6). Also, no reduced risk of infections is reported in patients with severe familial hypercholesterolemia.
The inverse association between total cholesterol and mortality discussed by Dr. Ravnskov should be interpreted with caution in the light of the limitations declared by the Authors of the original papers (7,8) (e.g., design of the study, ecological nature of some associations, no data on cholesterol subfractions, single cholesterol measurement, lack of adjustment for important confounders). In particular, chronic wasting diseases may distort even the long-term association between cholesterol and survival. Also, the epidemiological findings need to distinguish different lipoproteins, particularly HDLs, which possess antimicrobial and immune-modulatory properties. Therefore, the net reduction in plasma total cholesterol, which commonly involves HDL cholesterol, might reflect reduced anti-microbial actions of HDLs predisposing to infectious diseases (9).
The protective role of cholesterol-lowering cannot be disclaimed. Statins reduce cholesterol and cardiovascular risk (10) without negatively affecting prognosis in septic patients (11). Statins improve prognosis in patients with bacterial and viral infections (12-14) and reduce viral load in patients with chronic hepatitis C (15). Finally, statins increase the expression of ACE2, the entry receptor for SARS-CoV-2 (16), whose cell surface expression is supposed to be reduced after viral binding. Reduced ACE2 expression upon SARS-CoV-2 binding should increase levels of the pro-inflammatory/pro-fibrotic angiotensin II, potentially exacerbating tissue inflammation and damage. Thus, statins may protect tissues from the deleterious impact of angiotensin II. This is additional to the reported efficacy of statins in mitigating myocarditis and thrombotic events, which are lethal features of COVID-19 (17,18).
In our opinion, available data do not allow us to affirm that low plasma cholesterol levels and the use of cholesterol-lowering drugs may worsen the outcome of patients with COVID-19. Oppositely, a clinical benefit may derive from lowering LDL cholesterol in these conditions, irrespective of the infection-related hypocholesterolemia. The rational for the use of statins is particularly emphasized if we consider the high burden of cardiovascular complications of COVID-19 (19). As in other critical situations, attention should be paid when using multi-drug regimens including statins, antibiotics and antiretroviral drugs.
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Competing interests: No competing interests