The interaction between obesity, cardiometabolic disorders and COVID-19 represents a syndemic that requires both social intervention and a multipharmacological approach. The risks associated with diabetes, obesity and hypertension for severe COVID-19 may be confounded by the type of medication for these cardiometabolic factors. Furthermore, endothelial dysfunction is a common feature of the key comorbidities that increase risk for severe COVID-19 such as hypertension, obesity, diabetes mellitus, coronary artery disease or heart failure. Among the drugs used to manage hypertension and diabetes mellitus are angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs) and statins, all of which are known to improve endothelial dysfunction.https://www.mdpi.com/journal/jcmam2022Internal MedicineNuclear Medicin

Alexander, Myriam

Belmans, Luc

Byttebier, Geert

De Spiegeleer, Bart

Fedson, David

Sathekge, Mike Machaba

Saxberg, Bo

Ueckermann, Veronica

UPSpace at the University of Pretoria

Journal ofClinical MedicineEditorialAdjunctive Use of Statins for COVID-19Mike Sathekge 1,2,* , Geert Byttebier 3, Bart De Spiegeleer 4 , Bo Saxberg 5, Veronica Ueckermann 6 ,Luc Belmans 7 , Myriam Alexander 8 and David Fedson 9Citation: Sathekge, M.; Byttebier, G.;De Spiegeleer, B.; Saxberg, B.;Ueckermann, V.; Belmans, L.;Alexander, M.; Fedson, D. AdjunctiveUse of Statins for COVID-19. J. Clin.Med. 2021, 10, 1407. https://doi.org/10.3390/jcm10071407Received: 19 March 2021Accepted: 30 March 2021Published: 1 April 2021Publisher’s Note: MDPI stays neutralwith regard to jurisdictional claims inpublished maps and institutional affil-iations.Copyright: © 2021 by the authors.Licensee MDPI, Basel, Switzerland.This article is an open access articledistributed under the terms andconditions of the Creative CommonsAttribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).1 Department of Nuclear Medicine, University of Pretoria & Steve Biko Academic Hospital,0002 Pretoria, South Africa2 Nuclear Medicine Research Infrastructure (NuMeRI), University of Pretoria,0002 Pretoria, South Africa3 Bioconstat BV, 9000 Ghent, Belgium; geert.byttebier@skynet.be4 Drug Quality and Registration Group, Faculty of Pharmaceutical Sciences, Ghent University,9000 Ghent, Belgium; Bart.DeSpiegeleer@ugent.be5 DDO Strategic Services, Tucson, AZ 85737-8488, USA; bo@saxberg.com6 Department of Internal Medicine, University of Pretoria & Steve Biko Academic Hospital,0002 Pretoria, South Africa; veronica.ueckermann@up.ac.za7 Medaman bv, 2440 Geel, Belgium; luc.belmans@medaman.be8 Open Health, Marlow, Buckinghamshire SL7 2FF, UK; MyriamAlexander@openhealthgroup.com9 57, Chemin du Lavoir, 01630 Sergy Haut, France; davidsfedson@gmail.com* Correspondence: mike.sathekge@up.ac.za; Tel.: +27-12-354-1794The interaction between obesity, cardiometabolic disorders and COVID-19 representsa syndemic that requires both social intervention and a multipharmacological approach.The risks associated with diabetes, obesity and hypertension for severe COVID-19 maybe confounded by the type of medication for these cardiometabolic factors. Furthermore,endothelial dysfunction is a common feature of the key comorbidities that increase risk forsevere COVID-19 such as hypertension, obesity, diabetes mellitus, coronary artery diseaseor heart failure [1–3]. Among the drugs used to manage hypertension and diabetes mellitusare angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs)and statins, all of which are known to improve endothelial dysfunction [1,2].Several therapeutic agents have already been assessed for treating COVID-19, but fewof them have been shown to be efficacious [4]. The lack of treatment options is largely dueto limited information on other potential treatments and the lack of multicentre clinicaltrials evaluating their safety and efficacy [5].Statins are commonly used to treat high-risk patients and are known to reduce cardio-vascular morbidity and mortality [1,3,5]. They are highly effective because of their dual rolein the clearance of cholesterol from intracellular and extracellular compartments. Statinsinhibit 3-hydroxy-3-methyl glutaryl (HMG)-CoA reductase, a rate-limiting enzyme thatcatalyses the conversion of HMG-CoA into L-mevalonate 1, and thereby inhibit cholesterolbiosynthesis [5,6]. Importantly, statins also inhibit the synthesis of isoprenoids, which arevital to cell function. Inhibition of prenylation accounts for much of their anti-inflammatoryactivity [5,7,8].Recent evidence also suggests that statins inhibit virus infection by (a) decreasingL-mevalonate downstream mediators, (b) inhibiting protein prenylation, and (c) upregu-lating angiotensin-converting enzyme 2 [5,8]. These mechanisms underscore the impor-tance of lipid metabolism in the pathogenesis of virus infections. Cholesterol and lipidmetabolism are essential for several steps in the life cycle of many viruses, including virusfusion to cell membranes and cell entry, virus replication and particle assembly, and virusrelease from host cells. Host lipid metabolic pathways are known to promote the replicationand infectivity of several viruses [9].A compelling example was provided by the unconventional and poorly documenteduse of a statin and angiotensin receptor blocker combination to treat patients with Ebola [10].J. Clin. Med. 2021, 10, 1407. https://doi.org/10.3390/jcm10071407 https://www.mdpi.com/journal/jcmJ. Clin. Med. 2021, 10, 1407 2 of 3Treatment was followed by a significant decrease in mortality, presumably by restoringendothelial cell function and supporting tissue repair [10,11].There is rapidly growing evidence supporting the potential benefit of treating COVID-19patients with statins [2,9,12–17]. Importantly, the use of statins correlates significantly withlower mortality in patients with COVID-19, consistent with the findings in patients withpneumonia (Figure 1). Furthermore, the National Institutes of Health COVID-19 Treat-ment Guidelines recommend that patients who are already taking statins for the treatmentor prevention of cardiovascular disease should continue statin treatment if they developCOVID-19 [18].J. Clin. Med. 2021, 10, x FOR PEER REVIEW 2 of 3   A compelling example was provided by the unconventional and poorly documented use of a statin and angiotensin receptor blocker combination to treat patients with Ebola [10]. Treatment was followed by a significant decrease in mortality, presumably by restor-ing endothelial cell function and supporting tissue repair [10,11]. There is rapidly growing evidence supporting the potential benefit of treating COVID-19 patients with statins [2,9,12–17]. Importantly, the use of statins correlates sig-nificantly with lower mortality in patients with COVID-19, consistent with the findings in patients with pneumonia (Figure 1). Furthermore, the National Institutes of Health COVID-19 Treatment Guidelines recommend that patients who are already taking statins for the treatment or prevention of cardiovascular disease should continue statin treatment if they develop COVID-19 [18]. However, there are no data or prospective trials to support the idea of starting de novo statin therapy in patients with mild and moderate COVID-19 with the aim of pre-venting its progression to more severe disease. There is also limited information on the potential drug–drug interactions, particularly with drugs that are metabolized by the same cytochromes as statins. In view of their record of efficacy and affordability, the adjunctive use of statins is an attractive option for treating COVID-19 patients. We urge investigators to undertake ad-ditional observational studies n  clinical trials of statins, ACE inhibitors, and ARBs in these patients.  Figure 1. Survival within 60 d in severe acute respiratory syndrome coronavirus 2-infected patients and a retrospective cohort of hospitalized pneumonia patients between January and June 2019 (overall cohort). (A) Comparison of statin-treated vs. statin-nontreated coronavirus disease 2019 (COVID-19) patients (adjusted). (B) Comparison of statin-treated vs. statin-nontreated COVID-19 and hospitalized pneumonia patients between January and June 2019 (retrospective co-hort, adjusted) [17].  Author Contributions: Conceptualization, M.S.; G.B.; D.F. investigation, M.S.; G.B.; B.S.; V.U.; L.B.; M.A.; D.F.; resources, M.S.; G.B.; B.S.; L.B.; writing—original draft preparation, M.S; writing—re-view and editing, M.S.; G.B.; B.S.; B.D.S.; V.U.; L.B.; M.A.; D.F.; visualization, M.S.; D.F.; project ad-ministration, M.S.; G.B. All authors have read and agreed to the published version of the manu-script.  Funding: This research received no external funding. Conflicts of Interest: The authors declare no conflict of interest. Figure 1. Survival within 60 d in severe ac te res iratory syndrome coronavirus 2-infected patients and a retrospectivecohort of hospitalized pneumonia patients between January and June 2019 (overall cohort). (A) Comparison of statin-treated vs. statin-nontreated coronavirus disease 2019 (COVID-19) patients (adjusted). (B) Comparison of statin-treated vs.statin-nontreated COVID-19 and hospitalized pneumonia patients between January and June 2019 (retrospective cohort,adjusted) [17].However, there are no data or prospective trials to support the idea of starting de novostatin therapy in patients with mild and moderate COVID-19 with the aim of preventing itsprogression to more severe disease. There is also limited information on the potential drug–drug interactions, particularly with drugs that are metabolized by the same cytochromesas statins.In view of their record of efficacy and affordability, the adjunctive use of statins isan attractive option for treating COVID-19 patients. We urge investigators to undertakeadditional observational studies and clinical trials of statins, ACE inhibitors, and ARBs inthese patients.Author Contributions: Conceptualization, M.S.; G.B.; D.F. investigation, M.S.; G.B.; B.S.; V.U.; L.B.;M.A.; D.F.; resources, M.S.; G.B.; B.S.; L.B.; writing—original draft preparation, M.S.; writing—reviewand editing, M.S.; G.B.; B.S.; B.D.S.; V.U.; L.B.; M.A.; D.F.; visualization, M.S.; D.F.; project administra-tion, M.S.; G.B. All authors have read and agreed to the published version of the manuscript.Funding: This research received no external funding.Conflicts of Interest: The authors declare no conflict of interest.J. Clin. 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Adjunctive use of statins for COVID-19

Sathekge, Mike

Ghent University Academic Bibliography

Adjunctive use of statins for COVID-19

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