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Work exploring the potential use of lipid-modulating agents for the prevention and treatment of COVID-19 infection is ongoing. A new analysis has identified and reviewed 40 randomized clinical trials (RCTs) investigating the potential use of such agent, including statins, omega-3 fatty acids, fibrates, niacin, and dalcetrapib, to prevent or treat COVID-19.
“The impetus behind this study was that we wanted to systematically understand the status of RCTs for different types of lipid-modifying agents being used to prevent or treat COVID-19,” lead author Behnood Bidkeli MD, MS, clinical cardiologist, Cardiovascular Medicine Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, told theheart.org | Medscape Cardiology.
Of these studies, only two — one focusing on omega-3 fatty acids and one focusing on statins — have released preliminary findings, and these findings were inconclusive, Bikdeli reported.
The authors wanted to “summarize the potential mechanisms of action, potential benefits and harms [of lipid-modifying agents for preventing and treating COVID-19] and assess where we stand with the evidence,” said Bikdeli, who is also an investigator at the Center for Outcomes Research and Evaluation, Yale University School of Medicine, New Haven, Connecticut, and the Cardiovascular Research Foundation.
“Patients who are taking these agents for indications outside COVID-19, at the discretion of their clinician, should continue taking them, but taking them de novo, for the specific purpose of preventing or treating COVID-19, shouldn’t happen unless the patient is enrolled in an RCT because there isn’t enough evidence to support that at this point,” he said.
The review was published in the October 19 issue of the Journal of the American College of Cardiology.
Inflammation Implicated
In the SARS-CoV-2 virus, cellular entry is “mediated by attachment to angiotensin-converting enzyme 2 (ACE2),” the authors write. Plasma membrane microdomains, composed primarily of cholesterol, glycosphingolipids, and phospholipids, which are called lipid rafts, “may play a critical role in this process,” with the virus triggering an “uncontrolled innate inflammatory response (cytokine storm) leading to local and systemic tissue damage commonly seen in advanced COVID-19.”
They note that lipid-modulating agents have pleiotropic effects, and “may limit inflammation and thromboinflammation in COVID-19 by exerting antiviral, anti-inflammatory, immunomodulatory, and antithrombotic effects.”
The researchers review the potential pathways through which specific lipid-modulating agents can affect COVID-19 outcomes.
In particular, statins inhibit 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase and the production of isoprenoid intermediates, which are “critical for viral entry, immune signaling, and the inflammatory cascade.” They induce transcription factors that limit inflammation and prothrombotic functions of activated endothelial cells.
In addition, statins have antioxidant and antiapoptotic effects, potentiate nitric oxide production, and upregulate transforming growth factor beta receptor III, leading to less collagen deposition and pulmonary fibrosis.
Omega-3 polyunsaturated fatty acids “act as a precursor to lipid mediators that reduce inflammation” and may therefore be beneficial in addressing the COVID-19 inflammatory response. Fenofibrate, a fibric acid derivative, has been found to destabilize the receptor-binding domain of the SARS-CoV-2 spike protein in in vitro studies, and inhibit the receptor-binding domain that binds to ACE2, reducing viral infectivity by perhaps as much as 70%.
Niacin increases HDL cholesterol levels, may reduce inflammatory mediators, and may also possess antiviral activity. And dalcetrapib, a CETP inhibitor, raises HDL cholesterol levels, “which may have anti-inflammatory properties and inhibit platelet aggregation.
Bikdeli said that previous research has suggested that low levels of HDL cholesterol or high triglycerides are associated with worse outcomes in patients with COVID-19.
Additionally, he has been involved with other studies in which patients who used statins “had better outcomes, compared to those not taking statins. We know that a lot of lipid-modulating agents have anti-inflammatory properties and we have learned by now that there is some form of inflammation going on in cases of COVID-19, more so in those who have developed severe disease.”
However, “there aren’t a lot of high-quality studies, randomized controlled trials, as opposed to observational trials. We wanted to see what RCTs were going on, how many had shared preliminary findings, and where we go from there,” he said.
Not Ready for Prime Time
The researchers searched ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform, as well as MEDLINE, Google Scholar, and preprint servers for published design papers or final results manuscripts.
Forty RCTs met the eligibility criteria were included in the analysis.
| COVID-19 RCTs by Agent and Indication | |||
| Class of Agent | RCTs | COVID-19 Indication | Total Participants |
|---|---|---|---|
| Statins (moderate- to high-intensity) | 17 | Management | 18,215 |
| Omega-3 fatty acids | 10 | Management | 21,898 |
| Omega-3 fatty acids | 4 | Prevention | 20,700 |
| Fibrates | 3 | Management | 1050 |
| Niacin | 5 | Management | 1200 |
| Dalcetrapib | 1 | Management | 227 |
Of these trials, four ongoing RCTs are investigating omega-3 fatty acid preparations for the prevention of COVID-19, and two are examining niacin in patients beyond the acute phase of COVID-19 illness.
Bidkeli noted that the INSPIRATION-S trial (n = 587 randomized patients), on which he is an investigator, is the only one comparing moderate-intensity statin therapy with placebo in ICU patients, with a primary outcome consisting of the composite of all-cause mortality, venous or arterial thrombotic events, and treatment with extracorporeal membrane oxygenation within 30 days.
Preliminary results, presented at the 2021 American College of Cardiology Annual Session, showed that atorvastatin 20 mg once daily did not result in a significant reduction in the primary composite outcome. However, there was a “hypothesis-generating reduction” in the odds of the primary outcome in the prespecified analysis of patients hospitalized in the 7 days after symptom onset.
“Within certain subgroups we saw interesting signals with potential for benefit [of statins] but this is only hypothesis-generating, and we need additional corroboration before it is ready for prime time,” Bikdeli said.
Initial findings from the VASCEPA COVID-19 CardioLink-9 trial of the oral use of icosapent ethyl (an omega-3 fatty acid), compared with usual care in 100 outpatients, showed that it reduced high-sensitivity C-reactive protein (CRP) and led to symptom improvement in outpatients with COVID-19 after 14 days.
“Anti-inflammatory effects and potential impact on ARDS progression make omega-3 fatty acids worthwhile agents for investigations,” the authors conclude.
Reduced Mortality
Commenting on the study for theheart.org | Medscape Cardiology, Robert Rosenson, MD, professor of medicine (cardiology), Mount Sinai Icahn School of Medicine, New York City, said that there have been “multiple registry studies showing that statin therapy reduces mortality in patients with COVID-19.”
His own group, reporting on data from more than 5200 patients in the Mount Sinai Health System, found that high-intensity statin therapy was associated with lower mortality rate than a low to intermediate dose or no use of statin therapy, especially among patients with the highest level of cardiovascular risk.
Rosenson, who is also the director of the Cardiometabolics Unit at Mount Sinai and was not involved with the study, suggested that patients who are already taking statin therapy should remain on the therapy if they develop COVID-19, and individuals who are candidates for statin therapy but have not yet initiated treatment with a statin should be put on a high-intensity agent.
Funding sources for the research of individual investigators are listed on the original paper. Bikdeli reports being a consulting expert on behalf of the plaintiff for litigation related to two specific brand models of inferior vena cava filters. The other authors’ disclosures are listed on the original paper. Rosenson reports no relevant financial relationships.
J Am Coll Cardiol. 2021;78:1635-1654. Abstract
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