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Covid-19: a remote assessment in primary care

BMJ 2020; 368 doi: (Published 25 March 2020) Cite this as: BMJ 2020;368:m1182

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Cholesterol and cholesterol-lowering in COVID-19: why we should not let our guard down

Dear Editor,

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.

1. Hu, X, Chen D, Wu L, He G, Ye W. Low Serum Cholesterol level among patients with COVID-19 infection in Wenzhou, China (February 21, 2020). Available at SSRN:
2. Ravnskow U. Cholesterol-lowering treatment may worsen the outcome of a Covid-19 infection. BMJ 2020;368:m1182.
3. Feingold KR, Grunfeld C. The Effect of Inflammation and Infection on Lipids and Lipoproteins. [Updated 2019 Jan 8]. In: Feingold KR, Anawalt B, Boyce A, et al., editors. Endotext [Internet]. South Dartmouth (MA):, Inc.; 2000-. Available from:
4. Feng Q, Wei WQ, Chaugai S, Carranza Leon BG, Kawai V, Carranza Leon DA, Jiang L, Zhong X, Liu G, Ihegword A, Shaffer CM, Linton MF, Chung CP, Stein CM. A Genetic Approach to the Association Between PCSK9 and Sepsis. JAMA Netw Open. 2019 Sep 4;2(9):e1911130.
5. Mitchell KA, Moore JX, Rosenson RS, Irvin R, Guirgis FW, Shapiro N, Safford M, Wang HE. PCSK9 loss-of-function variants and risk of infection and sepsis in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort. PLoS One. 2019 Feb 6;14(2):e0210808.
6. Momtazi AA, Banach M, Sahebkar A. PCSK9 inhibitors in sepsis: a new potential indication? Expert Opin Investig Drugs. 2017 Feb;26(2):137-139.
7. Jacobs D, Blackburn H, Higgins M, Reed D, Iso H, McMillan G, Neaton J, Nelson J, Potter J, Rifkind B. Report of the conference on low blood cholesterol: Mortality associations. Circulation 1992; 86:1046–60.
8. Iribarren C, Jacobs DR Jr, Sidney S, Claxton AJ, Feingold KR. Cohort study of serum total cholesterol and in-hospital incidence of infectious diseases. Epidemiol Infect 1998; 121:335–47.
9. Pirillo A., Catapano A.L., Norata G.D. (2015) HDL in Infectious Diseases and Sepsis. In: von Eckardstein A., Kardassis D. (eds) High Density Lipoproteins. Handbook of Experimental Pharmacology, vol 224. Springer, Cham
10. Johnston TP, Korolenko TA, Pirro M, Sahebkar A. Preventing cardiovascular heart disease: Promising nutraceutical and non-nutraceutical treatments for cholesterol management. Pharmacol Res. 2017 Jun;120:219-225.
11. Pertzov B, Eliakim-Raz N, Atamna H, Trestioreanu AZ, Yahav D, Leibovici L. Hydroxymethylglutaryl-CoA reductase inhibitors (statins) for the treatment of sepsis in adults - A systematic review and meta-analysis. Clin Microbiol Infect. 2019 Mar;25(3):280-289.
12. Wang ST, Sun XF. Role of Statins in Treatment and Prevention of Community-acquired Pneumonia:A Meta-analysis. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2018 Feb 28;40(1):30-40.
13. Zheng YX, Zhou PC, Zhou RR, Fan XG. The benefit of statins in chronic hepatitis C patients: a systematic review and meta-analysis. Eur J Gastroenterol Hepatol. 2017 Jul;29(7):759-766.
14. Uthman OA, Nduka C, Watson SI, Mills EJ, Kengne AP, Jaffar SS, Clarke A, Moradi T, Ekström AM, Lilford R. Statin use and all-cause mortality in people living with HIV: a systematic review and meta-analysis. BMC Infect Dis. 2018 Jun 5;18(1):258.
15. Grammatikos G, Farnik H, Bon D, Böhlig A, Bader T, Berg T, Zeuzem S, Herrmann E. The impact of antihyperlipidemic drugs on the viral load of patients with chronic hepatitis C infection: a meta-analysis. J Viral Hepat. 2014 Aug;21(8):533-41.
16. South AM, Diz DI, Chappell MC. COVID-19, ACE2, and the cardiovascular consequences. Am J Physiol Heart Circ Physiol. 2020 May 1;318(5):H1084-H1090.
17. Guan J, Sun X, Liang Y, Dong W, Zhang L, Zhu J, Wang G. Atorvastatin attenuates Coxsackie virus B3m-induced viral myocarditis in mice. J Cardiovasc Pharmacol. 2010 Nov;56(5):540-7.
18. Chaffey P, Thompson M, Pai AD, Tafreshi AR, Tafreshi J, Pai RG. Usefulness of Statins for Prevention of Venous Thromboembolism. Am J Cardiol. 2018 Jun 1;121(11):1436-1440.
19. Zheng YY, Ma YT, Zhang JY, Xie X. COVID-19 and the cardiovascular system. Nat Rev Cardiol. 2020 May;17(5):259-260.

Competing interests: No competing interests

01 May 2020
Matteo Pirro
Chief of the Unit of Internal Medicine
Vanessa Bianconi, Amirhossein Sahebkar
Department of Medicine, University-Hospital of Perugia, Perugia, Italy
Piazzale Menghini, 1 - 06129, Perugia, Italy