key: cord-1046495-f426nrhj authors: H. Talasaz, A. H.; Sadeghipour, P.; Aghakouchakzadeh, M.; Dreyfus, I.; Kakavand, H.; Ariannejad, H.; Gupta, A.; Madhavan, M.; Van tassell, B.; Jimenez, D.; Monreal, M.; Vaduganathan, M.; Fanikos, J.; Dixon, D.; Piazza, G.; Parikh, S.; Bhatt, D.; Lip, G.; Stone, G.; Krumholz, H.; Libby, P.; Goldhaber, S.; Bikdeli, B. title: Lipid-Modulating Agents for Prevention or Treatment of COVID-19 in Randomized Trials date: 2021-05-05 journal: medRxiv : the preprint server for health sciences DOI: 10.1101/2021.05.03.21256468 sha: 899e7ac8a3f461deef007d7305143cbaae0997f0 doc_id: 1046495 cord_uid: f426nrhj 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. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cellular entry is mediated by attachment to angiotensin converting enzyme 2 (ACE2). Lipid raftsplasma membrane microdomains mainly composed of cholesterol, glycosphingolipids, and phospholipids, capable of changing their composition in response to stimulimay 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) . 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 We searched ClinicalTrials. gov 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 preprint this version posted May 5, 2021. ; https://doi.org/10.1101/2021.05.03.21256468 doi: medRxiv preprint We screened 255 records, of which 97 required further manual review. Ultimately, 40 RCTs met the eligibility criteria, of which 36 were related to the management of COVID-19: 17 for statins, 10 for omega-3 fatty acids, 3 for fibrates, 5 for niacin, and 1 for dalcetrapib. In addition, 4 RCTs of omega-3 fatty acids were identified for the prevention of COVID-19. We did not identify RCTs for ezetimibe, bile acid sequestrants, PCSK9 inhibitors, evinacumab, mipomersen, lomitapide, bempedoic acid, or CETP inhibitors other than dalcetrapib for the management or the prevention of COVID-19. A summary of methodological features of the ongoing RCTs categorized by drug class is provided in Table 1. In this table, we describe factors such as number of enrollees, comparator types, blinding, type of primary outcomes (clinical or surrogate outcomes), blinded outcome adjudication, and the existence of published design paper are included. For 7 studies, a design paper or study protocol was available (12) (13) (14) (15) (16) (17) (18) . Of all RCTs, only 1 has reported the results (at the National Lipid Association Virtual Scientific Sessions) (19) . Figure 2 illustrates the potential pathways through which lipid modulating drugs that have ongoing RCTs may impact the outcomes in COVID-19. These agents include statins, omega-3 fatty acids, fibrates, niacin, and dalcetrapib. 7 23), and upregulate transforming growth factor beta receptor III, thereby reducing collagen deposition and pulmonary fibrosis (24). Data in observational studies, RCTs, and meta-analyses in patients with sepsis are controversial. Two recent RCTs showed no improvement in acute respiratory distress syndrome (ARDS) versus placebo (25, 26) . However, some studies suggest a benefit associated with statin use. (27) Secondary analysis of the HARP-2 trial, suggested potential improved survival in patients with a high inflammatory status (28) . In a meta-analysis of cohort studies and RCTs of patients with ARDS, statin use was not associated with reduced mortality in patients with acute lung injury, but correlated with increased ventilator-free days and reduced sequential organ failure assessment scores (29) . In COVID-19, a recent single center retrospective study suggested lower adjusted mortality rates in patients with antecedent statin use compared with non-users (30). Omega-3 polyunsaturated fatty acids act as a precursor to lipid mediators that reduce inflammation and may prove beneficial in the COVID-19 inflammatory response (14) . Icosapent ethyl, an ethyl ester of EPA, has demonstrated anti-inflammatory properties (15) . Multiple RCTs have evaluated omega-3 polyunsaturated fatty acids in ARDS. Although individual trial results have been mixed, a meta-analysis showed favorable outcomes with regard to ventilator-free days, length of stay in the intensive care unit (ICU), organ failure, and mortality in patients receiving a diet enriched with EPA and gamma-linolenic acid (31, 32) . In vitro studies suggest that fenofibrate, a fibric acid derivative, destabilizes the receptor binding domain of the SARS-CoV-2 spike protein and inhibits receptor binding domain binding to ACE2. This may reduce viral infectivity by up to 70% (33). Niacin (nicotinic acid, nicotinamide) increases HDL cholesterol and may reduce the inflammatory mediators. Niacin may also possess anti-viral activity through increasing 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 preprint this version posted May 5, 2021. ; https://doi.org/10.1101/2021.05.03.21256468 doi: medRxiv preprint nicotinamide adenine dinucleotide (NAD) -as nicotinamide restores poly-adenosine diphosphate (ADP)-ribose polymerases functions -which inhibit the viral replication and support innate immunity to SARS-CoV-2 (34). CETP inhibitors (e.g., dalcetrapib) raise HDL cholesterol, which may have antiinflammatory properties and inhibit platelet activation (35). However, off-target effects should be considered. In the ILLUMINATE (Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events) trial, torcetrapib -another CETP inhibitor -had favorable effects on lipids but showed an increase in death due to sepsis, and increased the systolic blood pressure (36) . A graphical summary of design features of all RCTs for statins, omega-3 fatty acid preparations, fibrates, and niacin for the management of COVID-19 is illustrated in Figures 3, 4 , 5, and 6, respectively. In addition, the section on RCTs for the management of patients with diagnosed COVID-19 begins with statin therapy RCTs, followed by RCTs of omega-3 fatty acid preparations, fibrates, niacin, and dalcetrapib. This sequence does not describe treatment preference. Figure 7 illustrates a graphical summary of design features of RCTs for the prevention of COVID-19 (only omega-3 fatty acid had such RCTs). In each section, discussion of these trials is provided according to the clinical setting. Ongoing RCTs of statin therapy 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 preprint this version posted May 5, 2021. ; https://doi.org/10.1101/2021.05.03.21256468 doi: medRxiv preprint Seventeen RCTs of statin therapy have been registered: 16 in the hospitalized setting and 1 in postdischarge setting. These trials assess either moderate-intensity statin therapy (with simvastatin 40 to 80 mg daily or atorvastatin 20 mg daily or rosuvastatin 5 mg daily) or high-intensity statin therapy (with atorvastatin 40 to 80 mg daily or rosuvastatin 40 mg daily) (37) . 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. High-intensity statin therapy is being assessed in 11 of 14 ongoing RCTs with a total of 8,977 hospitalized non-ICU patients with COVID-19. These 11 RCTs are studying high-intensity statin therapy compared with no treatment (2 of 11) or SOC (5 of 11) or placebo (4 of 11). Mortality during hospitalization or within 10 to 30 days is the most common primary outcome in 5 of 11 RCTs with high-intensity statins for hospitalized non-ICU patients (13, 18) . The HEAL-COVID INSPIRATION-S is the only trial of moderate-intensity statin therapy versus placebo in ICU patients. A composite of all-cause mortality, venous or arterial thrombotic events, and treatment with extracorporeal membrane oxygenation within 30 days is the study primary outcome 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. Figure 3 . 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 preprint this version posted May 5, 2021. ; https://doi.org/10.1101/2021.05.03.21256468 doi: medRxiv preprint There are 10 ongoing RCTs evaluating the role of omega-3 fatty acid preparations for the management of COVID-19: 6 RCTs in hospitalized non-ICU patients and 4 ongoing RCTs in the outpatient setting. Omega-3 fatty acids are being evaluated in 6 RCTs with the number of participants ranging from (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Additional details about ongoing RCTs of omega-3 fatty acid preparations for treatment of COVID-19 are described in Figure 4 . (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 20) . FERMIN and PER-099-20 also enrolled outpatients. The sample size of these studies ranges from 50 to 700 patients. The main outcomes in the FENOC include improvement in laboratory markers, the ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2), and mortality. The composite endpoint as the primary outcome for FERMIN and PER-099-20 trials will be a global rank score that grades patients based on survival, need for respiratory/mechanical support, the fraction of inspired oxygen/ percent oxygen saturation (FiO2/ SpO2), the number of days out of the hospital for outpatient participants who are hospitalized after enrollment, and the modified borg dyspnea scale for the outpatient subset not hospitalized. All these trials consider drug-drug interactions prior to the enrollment. Patients with active liver disease are excluded in all 3 of these trials. Additional information about these RCTs is summarized in Figure 5 . Five RCTs of niacin therapy were identified: 2 in hospitalized non-ICU patients, 1 in outpatient setting, and 2 ongoing RCTs in post-acute COVID-19. All of these trials are studying niacin compared with placebo. Niacin is being assessed in 2 ongoing RCTs for 100 hospitalized non-ICU patients in each trial: and NR-COVID19 (Effects of Nicotinamide Riboside on the Clinical Outcome of Covid-19 in the Elderly) trials. The primary outcomes of these trials are the alteration of blood NAD+ level within 10 days and need for oxygen therapy with a follow-up duration of 90 days, respectively. In 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 preprint this version posted May 5, 2021. ; https://doi.org/10.1101/2021.05.03.21256468 doi: medRxiv preprint disease are being excluded. The COVit-2 (Improvement of the Nutritional Status Regarding Nicotinamide (Vitamin B3) and the Disease Course of COVID-19) trial is the only trial of niacin therapy versus placebo in outpatient setting with 840 patients planned to be enrolled. The frequency of complete symptom resolution within 2 weeks is the primary outcome. Figure 6 . 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. trial is the only trial of dalcetrapib (900mg, 1,800mg, and 3,600mg daily) versus placebo in 208 outpatients with mild-to-moderate COVID-19. The primary outcome is time to sustained symptom resolution within 28 days. Patients with liver disease are excluded from NCT04676867 trial. Drugdrug interactions are being considered before enrollment. Use of omega-3 fatty acid preparations as a preventive measure against COVID-19 is being (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (49) , and the mixed results with colchicine 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 preprint this version posted May 5, 2021. ; https://doi.org/10.1101/2021.05.03.21256468 doi: medRxiv preprint (50, 51) and tocilizumab (52, 53) , remind us that biological plausibility may not translate to meaningful treatment. Hence, the ongoing lipid modulating therapy RCTs are of particular interest. Despite initial concern that statins might increase expression of ACE2 and facilitate SARS-CoV- patients, but not in the outpatient setting. Anti-inflammatory effects (55) and potential impact on ARDS progression (56) make omega-3 fatty acids worthwhile agents for investigation. Functional limitations and quality of life are evaluated exclusively in outpatient trials, while mortality and clinical improvement are evaluated 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. Several limitations apply to the omega-3 fatty acid RCTs: The total number of patients enrolled in omega-3 fatty acids trials for management of COVID-19 is relatively few (Figure 4) . Heterogeneity in use of various formulations (EPA, DHA, or EPA-DHA; ethyl esters vs. free fatty acids)and impurities, and/or oxidative alterations in unregulated supplement preparations makes it more difficult to determine the specific effects of each. Icosapent ethyl will be studied in two large outpatient studies (PREPARE-IT 1 and MITIGATE) trials as a preventive agent, but not in the inpatient setting. Despite the declining use for cardiovascular risk reduction (57), fibrates may decrease viral entry and SARS-CoV-2 infectivity by increasing sulfatide levels (58) and inhibiting the receptor binding domain to ACE2 (33) . Strengths of ongoing fibrate trials include endpoint selection: death, ARDSrelated outcomes, inflammatory markers and invasive mechanical support are the primary outcome under evaluation. Drug interactions were generally considered with fenofibrate initiation. However, fenofibrate is the only fibrate under investigation in RCTs including patients with COVID-19, and its lack of benefit in cardiovascular disease prevention may raise skepticism regarding its utility in COVID-19. Anti-inflammatory effects (34) and potential protection against lung injury (59) have made niacin a target for investigation in COVID-19. Niacin is under evaluation in both acute and post-acute 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 preprint this version posted May 5, 2021. ; https://doi.org/10.1101/2021.05.03.21256468 doi: medRxiv preprint settings. Clinical improvement and symptom resolution are primary outcomes in the majority of RCTs. RCTs in the post-COVID-19 setting will evaluate fatigue and cognitive function for 3 to 6 months. As with fenofibrate, lack of benefit and presence of adverse effects with nicotinamide seen in prior cardiovascular RCTs (60, 61) may dampen excitement for use in COVID-19. Trials in the inpatient and post-acute setting are limited by small sample size and variability in niacin dosing may lead to heterogenous results. Low HDL is associated with increased severity of COVID-19 and correlates with approved biomarkers such as ferritin and D-dimer levels (6) . Dalcetrapib will be the first CETP inhibitor to be tested in patients with mild to moderate COVID-19 with time to symptom resolution as the primary outcome. Of note, dalcetrapib did not improve clinical outcomes in those with acute coronary syndromes (62) . Among CETP inhibitors, only anacetrapib showed a modest cardiovascular benefit (9% relative risk reduction) (63), whereas torcetrapib (64, 65) led to increase in systolic blood pressure and worse cardiovascular outcomes. Findings from dal-COVID will help clarify whether dalcetrapib merits further testing in COVID-19. Based on the knowledge from RCTs in cardiovascular diseases, important adverse effects should be monitored when the results of these RCTs accrue. Myopathy is the most common adverse effect of statin use and is managed by conversion to other statin formulations. Severe muscle complications (i.e., rhabdomyolysis) are exceedingly rare (66) . Rise in liver enzymes is another 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 preprint this version posted May 5, 2021. ; https://doi.org/10.1101/2021.05.03.21256468 doi: medRxiv preprint potential but infrequent adverse effect. Fibrates may also increase the risk of myopathy and hepatocyte injury (67) . Drug-drug interactions play an important role in this increased risk, and is considered in the ongoing COVID-19 RCTs (68) . Other risks associated with statin use including hemorrhagic stroke in those with previous stroke are not of clinically important magnitude (69) (70) (71) . New-onset or worsening of atrial fibrillation is a concern with omega-3 fatty acids (72) (73) (74) and increased bleeding due to the effects on platelet aggregation should be monitored in the RCT results. The adverse effects of niacin include flushing, pruritus, gastrointestinal disorder, thrombocytopenia, hyperuricemia, hyperglycemia, myopathy, and hepatotoxicity (75) . Only the NIRVANA trial assesses thrombocytopenia as a safety outcome and excluded patients with liver disease. These potential risks are limited by the short duration of treatment in most trials. Of note, the adverse events in massive event-driven cardiovascular trials result from multiple months to years of treatment, whereas the current COVID-19 trials generally have much shorter treatment duration. The possible adverse effects of lipid modulating agents are illustrated in Figure 2 . (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. • Lipid modulating agents have pleiotropic effects, including anti-viral, immunomodulatory, and antithrombotic properties that might help treat COVID-19. • 36 RCTs are evaluating the impact of lipid modulating agents including statins, omega-3, fibrates, niacin, and CETP inhibitors for treatment of COVID-19. • Omega-3 fatty acid preparations are being investigated for prevention of COVID-19 in 4 ongoing RCTs. • Niacin is being assessed in 2 RCTs for post-acute-COVID-19. 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. (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 preprint this version posted May 5, 2021. ; https://doi.org/10.1101/2021.05.03.21256468 doi: medRxiv preprint nitric oxide synthase. Statins may also alleviate collagen deposition and pulmonary fibrosis via upregulation of transforming growth factor beta receptor III. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (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 preprint this version posted May 5, 2021. ; https://doi.org/10.1101/2021.05.03.21256468 doi: medRxiv preprint 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. 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 preprint this version posted May 5, 2021. ; https://doi.org/10.1101/2021.05.03.21256468 doi: medRxiv preprint 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. 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Caption: Omega-3 fatty acid preparations are evaluating in moderate to high risk for COVID-19 * : The full list of inclusion and exclusion criteria should be found in the original trial records. ACE: Angiotensin Converting Enzyme; AF: Atrial Fibrillation; ASCVD: Atherosclerotic Cardiovascular Disease; IL-1: Interleukin-1; IPE: Icosapent Ethyl; PCI: Percutaneous Coronary Intervention; RT-PCR: Reverse Transcription Polymerase Chain Reaction Central Illustration: Summary of ongoing lipid modulating agents' trials in COVID-19. Caption: Statins are the most frequently studied lipid modulating agents in RCTs of patients with COVID-19. Omega-3 fatty acid preparations are the only studied lipid modulating agents in prevention of COVID-19. Niacin is the only lipid modulating agent being studied for post-acute COVID-19. For more details please review Figure 3, 4 and 5. COVID-19: Coronavirus Disease