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Lipid-Modulating Agents for Prevention or Treatment of COVID-19 in Randomized Trials
Azita H. Talasaz, PharmD,
1,2,3
Parham Sadeghipour, MD,
4
Maryam Aghakouchakzadeh,
PharmD,
1
Isaac Dreyfus, MD,
5
Hessam Kakavand, PharmD,
1
Hamid Ariannejad, MD,
2
Aakriti
Gupta, MD, MS,
5,6,7
Mahesh V. Madhavan, MD, MS,
5,6
Benjamin W. Van Tassell, PharmD,
3,8
David Jimenez, MD, PhD,
9
Manuel Monreal, MD, PhD,
10
Muthiah Vaduganathan, MD, MPH,
11
John Fanikos, R.Ph, MBA,
12
Dave L Dixon, PharmD,
3,8
Gregory Piazza, MD, MS,
11
Sahil A.
Parikh, MD,
5,6
Deepak L. Bhatt, MD, MPH,
11
Gregory YH Lip, MD,
13,14
Gregg W. Stone, MD,
6,15
Harlan M. Krumholz, MD, SM,
7, 16, 17
Peter Libby, MD,
11
Samuel Z. Goldhaber, MD,
11
and
Behnood Bikdeli, MD, MS
7,8,11,*
Total Words Count: 7,771 (including text, tables, Figure legends, but not online supplement)
Affiliations
1. Department of Clinical Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences,
Tehran, Iran.
2. Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran.
3. Department of Pharmacotherapy and Outcome Science, School of Pharmacy, Virginia
Commonwealth University, Richmond, Virginia, USA.
4. Cardiovascular Intervention Research Center, Rajaie Cardiovascular Medical and Research
Center, Iran University of Medical Sciences, Tehran, Iran.
5. NewYork-Presbyterian Hospital/Columbia University Irving Medical Center, New York, New
York
6. Clinical Trials Center, Cardiovascular Research Foundation, New York, NY, USA.
7. Center for Outcomes Research and Evaluation (CORE), Yale School of Medicine, New Haven,
CT, USA.
8. Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, School of
Pharmacy, Virginia Commonwealth University, Richmond, Virginia, USA.
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(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprintthis version posted May 5, 2021. ; https://doi.org/10.1101/2021.05.03.21256468doi: medRxiv preprint
NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.
2
9. Respiratory Department, Hospital Ramón y Cajal and Medicine Department, Universidad de
Alcalá (Instituto de Ramón y Cajal de Investigación Sanitaria), Centro de Investigación
Biomédica en Red de Enfermedades Respiratorias, Madrid, Spain.
10. Department of Internal Medicine, Hospital Universitari Germans Trials i Pujol, Universidad
Católica San Antonio de Murcia, Barcelona, Spain.
11. Division of cardiovascular Medicine Division, Brigham and Women’s Hospital, Harvard
Medical School, Boston, MA, USA.
12. Department of Pharmacy, Brigham and Women’s Hospital, Harvard Medical School, Boston,
MA, USA.
13. Liverpool Centre for Cardiovascular Science, Liverpool Heart and Chest Hospital, University
of Liverpool, Liverpool, United Kingdom.
14. Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.
15. Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount
Sinai, New York, NY, USA.
16. Department of Health Policy and Administration, Yale School of Public Health, New Haven,
CT, USA.
17. Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of
Medicine, New Haven, CT, USA.
FUNDING: None
ADDRESS FOR CORRESPONDENCE:
Dr. Bikdeli, Cardiovascular Medicine Division,
Brigham and Women’s Hospital, 75Francis Street, Shapiro 5, Suite 5156. Boston, MA 02115;
Phone: (617) 732-6984, Fax: (617) 738-7652, Email: bbikdeli@bwh.harvard.edu,
Behnood.bikdeli@yale.edu
ABSTRACT
All rights reserved. No reuse allowed without permission.
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprintthis version posted May 5, 2021. ; https://doi.org/10.1101/2021.05.03.21256468doi: medRxiv preprint
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Coronavirus disease 2019 (COVID-19) is associated with systemic inflammation, endothelial
activation, and multi-organ manifestations. Lipid modulating agents may be useful in treating
patients with COVID-19. They may inhibit viral entry by lipid raft disruption or ameliorate the
inflammatory response and endothelial activation. In addition, dyslipidemia with lower high-
density lipoprotein cholesterol and higher triglycerides portends worse outcome in patients with
COVID-19. Upon a systematic search, 40 RCTs with lipid modulating agents were identified,
including 17 statin trials, 14 omega-3 fatty acids RCTs, 3 fibrates RCTs, 5 niacin RCTs, and 1
dalcetrapib RCT for management or prevention of COVID-19. This manuscript summarizes the
ongoing or completed randomized controlled trials (RCTs) of lipid modulating agents in COVID-
19 and the implications of these trials for patient management.
KEY WORDS COVID-19, lipid modulating agent, statin, fibrate, omega3, niacin
ABBREVIATIONS AND ACRONYMS
ACE2 = angiotensin converting enzyme 2
ARDS = acute respiratory distress syndrome
CETP = cholesterol ester transfer protein
COVID-19 = coronavirus disease 2019
HDL = high-density lipoprotein
HMG-CoA = 3-hydroxy-3-methyl-glutaryl-coenzyme A
ICU = intensive care unit
NAD = nicotinamide adenine dinucleotide
RCT = randomized controlled trial
SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2
All rights reserved. No reuse allowed without permission.
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprintthis version posted May 5, 2021. ; https://doi.org/10.1101/2021.05.03.21256468doi: medRxiv preprint
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INTRODUCTION
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cellular entry is mediated by
attachment to angiotensin converting enzyme 2 (ACE2). Lipid rafts – plasma membrane
microdomains mainly composed of cholesterol, glycosphingolipids, and phospholipids, capable of
changing their composition in response to stimuli – may play a critical role in this process (1).
SARS-CoV-2 can trigger an uncontrolled innate inflammatory response (cytokine storm) leading
to local and systemic tissue damage commonly seen in advanced coronavirus disease 2019
(COVID-19) (2). Inflammation and resultant endothelial injury may lead to a hypercoagulable
state and predispose patients to micro and macrothrombosis (3, 4).
Lipid modulating agents may limit inflammation and thromboinflammation in COVID-19
by exerting anti-viral, anti-inflammatory, immunomodulatory, and antithrombotic effects (5).
Moreover, lower high-density lipoprotein (HDL) cholesterol and higher triglycerides are
associated with worse outcomes in patients with COVID-19 (6). Through lipid raft disruption (7),
lipid profile improvement, and other effects, lipid modulating agents may impact the outcomes of
patients with COVID-19. Moreover, as previously seen in other SARS infections, SARS-CoV-2
infection may lead to the MYD88 gene being highly induced with resultant activation of the
nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) pathway (8, 9). Statins had
inhibitory effects on this pathway, (and a reduction in type 1 interferon) and hyperinflammation
(10, 11).
This manuscript summarizes systematically the randomized controlled trials (RCTs)
evaluating lipid modulating therapies for the prevention or treatment of COVID-19. The presumed
mechanisms of action, existing knowledge of RCTs, as well as knowledge gaps that may influence
the design of future trials will be highlighted.
All rights reserved. No reuse allowed without permission.
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprintthis version posted May 5, 2021. ; https://doi.org/10.1101/2021.05.03.21256468doi: medRxiv preprint
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METHODS
Data Source and Search Strategy
We searched ClinicalTrials.gov and the World Health Organization International Clinical Trials
Registry Platform (WHO-ICTRP) for the identification of RCTs investigating lipid modulating
agent trials in COVID-19 (date of last search: March 31, 2021). We used key words for COVID-
19 or SARS-CoV-2 or coronavirus disease 2019 and statins (including atorvastatin, rosuvastatin,
simvastatin, fluvastatin, lovastatin, pitavastatin, and pravastatin), fibrates (including fenofibrate,
clofibrate, bezafibrate, gemfibrozil, and pemafibrate), ezetimibe, bile acid sequestrants
(colesevelam, cholestyramine, colestipol), proprotein convertase subtilisin/kexin type 9 (PCSK9)
inhibitors (including, alirocumab, evolocumab, and inclisiran), omega-3 fatty acids (including
icosapent ethyl, eicosapentaenoic acid [EPA], and docosahexaenoic acid [DHA]), niacin, nicotinic
acid, nicotinamide, vitamin B3, evinacumab, mipomersen, lomitapide, bempedoic acid, and
cholesteryl ester transfer protein (CETP) inhibitors (anacetrapib, dalcetrapib, evacetrapib,
torcetrapib, and TA-8995).
We separated the RCTs in which these agents were used for treatment of patients with
COVID-19 versus those used for prevention of the development (or severity) of COVID-19. Study
eligibility criteria for inclusion in this review were RCT design with a lipid modifying agent and
description of inclusion and exclusion criteria and the primary outcome at clinicaltrials.gov or
WHO-ICTRP. Figure 1 describes the search strategy and screening of the studies. For RCTs that
met the above eligibility criteria, we searched MEDLINE with PubMed Interface, Google scholar,
and pre-print servers including medrxiv.org and biorxiv.org for published design papers or final
result manuscripts.
All rights reserved. No reuse allowed without permission.
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprintthis version posted May 5, 2021. ; https://doi.org/10.1101/2021.05.03.21256468doi: medRxiv preprint
