Lipid-modulating therapies could mitigate COVID-19-associated multiorgan damage through anti-inflammatory, antiviral and pleiotropic effects, experts wrote in a review paper as they await results from dozens of trials to this end.
The review was published Monday online ahead of the Oct. 19 issue of the Journal of the American College of Cardiology, led by Azita H. Talasaz, PharmD, from Tehran University of Medical Sciences, Iran, and Virginia Commonwealth University, Richmond.
The researchers identified 40 randomized controlled trials (RCTs) via ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform with lipid-modulating agents for the management (36 trials) or prevention (four trials) of COVID-19, including: 17 statin trials, 14 omega-3 fatty acids RCTs, three fibrate RCTs, five niacin RCTs, and one dalcetrapib RCT.
The vast majority had not reported any preliminary data at date of the last search, on March 21, 2021, and none of the studies had been peer-reviewed at that time.
Mechanism of lipid-modulation
Systemic inflammation, endothelial activation, and multiorgan manifestations are all now believed to be associated with COVID-19, the reviewers noted, broadening the perspective of the disease state from just pneumonia.
“The neutral results of recent RCTs of escalated-dose anticoagulation in critically ill patients with COVID-19 [Sadeghipour et al., and Goligher et al.] may indicate the significance of the maladaptive immune response in severe COVID-19,” they said.
It is believed that lipid-modulating agents could be useful in the treatment or prevention of COVID-19 effects, for instance, potentially inhibiting viral entry by lipid raft disruption; plasma membrane microdomains mainly composed of cholesterol, glycosphingolipids and phospholipids. These rafts are capable of changing their composition in response to stimuli that may play a critical role in this process, the researchers noted.
Lipid-modulating agents could also help to enhance the body’s inflammatory response and endothelial activation, they said, both key effects of severe COVID-19, since the virus can trigger cytokine storms and resultant endothelial injury.
COVID-19 has also been associated with worse outcomes in those with dyslipidemia with lower high-density lipoprotein cholesterol and higher triglyceride levels, they said, meaning lipid-modulating drugs could, therefore, play a role.
For statins, potential mechanisms include inhibition of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase and the production of isoprenoid intermediates that are critical for viral entry, immune signaling, and the inflammatory cascade, the researchers noted.
Nevertheless, results from statin studies have been “controversial” with two RCTs (McAuley et al. and Truwit et al.) showing no improvement in acute respiratory distress syndrome (ARDS) versus placebo, while others suggest potential improved survival in patients with a high inflammatory status.
Additionally, a meta-analysis of cohort studies and RCTs in patients with ARDS showed that, despite missed mortality endpoints, statins use correlated with more ventilator-free days and reduced Sequential Organ Failure Assessment scores, as well as lower adjusted mortality rates in those taking statins.
Meanwhile omega-3 polyunsaturated fatty acids act as a pre-cursor to lipid mediators that reduce inflammation, and could be beneficial in the COVID-19 inflammatory response, the researchers noted.
“Icosapent ethyl, an ethyl ester of [eicosapentaenoic acid] EPA, has exhibited anti-inflammatory properties,” they said.
As for statins, there have been some mixed results thus far, but similarly, meta-analyses found favorable outcomes on ventilator-free days, as well as 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.
The mechanism of fibrates – as suggested in in vitro studies of fenofibrate – is believed to be the destabilization of receptor-binding domain of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein and inhibition of the receptor-binding domain that binds to angiotensin-converting enzyme 2 (ACE2), which could reduce viral infectivity by up to 70%.
Niacins including nicotinic acid and nicotinamide, meanwhile, work by increasing high-density lipoprotein (HDL) cholesterol levels and could reduce inflammatory mediators, the researchers said. “Niacin may also possess antiviral activity through increasing nicotinamide adenine dinucleotide (NAD), as nicotinamide restores poly-adenosine diphosphate–ribose polymerase functions, which inhibit the viral replication and support innate immunity to SARS-CoV-2,” they added.
Finally, cholesteryl ester transfer protein (CETP) inhibitors such asdalcetrapid are also known to raise HDL cholesterol levels, which could have anti-inflammatory properties and inhibit platelet activation. “However, off-target effects should be considered,” the authors warned, citing the ILLUMINATE trial, in which another CETP inhibitor – torcetrapib – had favorable effects on lipids but showed an increase in death due to sepsis and increased systolic blood pressure.
Nevertheless, despite potential within the mechanisms of lipid-modulating agents, the reviewers pointed out some limitations to the ongoing trials.
“The moderate immunomodulating effect of these agents lessens the chance of excessive immunosuppression and superinfection, commonly seen with other anti-inflammatory agents,” the reviewers said, but “despite such hope,” issues such as small sample size, use of primary surrogate outcomes, and lack of blinded outcome adjudication “hamper the rigor of the trials.”
Only 21 of the 40 RCTs for lipid-modifying therapies had a double-blind design, they stressed.
“Despite the scientific rationale summarized in this paper, translation to clinical benefit is not assured. Among the immune-modulating therapies, only steroids have shown consistent efficacy in patients with COVID-19,” they added.
“The neutral results with ivermectin and hydroxychloroquine, and the mixed results with colchicine and tocilizumab, remind us that biological plausibility may not translate into meaningful treatment.”
Talasaz AH, Sadeghipour P, Aghakouchakzadeh M, et al. Investigating Lipid-Modulating Agents for Prevention or Treatment of COVID-19: JACC State-of-the-Art Review. J Am Coll Cardiol 2021;78:1635-1654.
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