Is fenofibrate the missing piece in COVID-19 management?

Dear editor,

The world nowadays is facing a pandemic of coronavirus disease-19 (COVID-19) [1]. The overall mortality rate of COVID-19 is approaching 1% [2], and it may exceed 60% in those suffering from severe COVID-19 [3]. The mortality rate is higher among elderly and especially those with diabetes mellitus and cardiovascular diseases [4]. The main cause of COVID-19 mortality is the virus infectivity to lungs leading to pulmonary inflammation and pneumonia; in this regard, the virus stimulates the induction of T-cells over-activation, which in turn leads to excessive release of inflammatory mediators like tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), IL-8, IL-10, and vascular endothelial growth factor. All these mediators are associated with increasing risk of pulmonary edema, alveolar damage, acute respiratory distress syndrome (ARDS), and eventually death [5]. In addition to that, some COVID-19 patients may die due to a cytokine storm which characterized by lymphopenia and high levels of IL-6 and fibrinogen [6]. Furthermore, death can occur due to systemic viral sepsis that provokes a systemic inflammatory response and multi-organ damage [5]. Unfortunately, till now, there is no specific treatment for COVID-19. Most of the currently used therapies are aimed to prevent virus entry to the cell and/or viral replication [7]. Anti-inflammatory therapies are usually used for patients with severe disease [8] such as Anakinra (IL-1 receptor antagonist) and Tocilizumab (IL-6 inhibitor) which are undergoing multiple trials and some results are encouraging. Similarly, use of anti-inflammatory cytokines like IL-37 and IL-38 is hypothesized to be useful and is under research [9].

Fenofibrate is an antidyslipidemic agent that acts as peroxisome proliferator-activated receptor-α agonist. Besides its ability to lower triglyceride level, it has pleiotropic effects such as anti-inflammatory, antioxidant, and anti-angiogenesis. In this regard, fenofibrate can lower nuclear factor-KB, TNF-α, IL6, vascular adhesion molecule, cyclooxygenase-2, matrix metalloproteinase, vascular endothelial growth factor-1 signaling, and oxidative stress [10,11]. All these effects seem to be meaningful for reversing the harmful effects of coronavirus on human body organs; besides that fenofibrate is effective to lower fibrinogen, so this means that fenofibrate maybe a highly valuable therapy for patients with severe COVID-19 and especially those suffering from cytokine storm [12].

One drawback for fenofibrate is its ability to increase the expression of angiotensin-converting enzyme-2 (ACE2) [13] which increases the risk of viral entry to cells. This problem can be counteracted by the addition of chloroquine/hydroxychloroquine (approved by food and drug administration (FDA)), at which such medication is shown to be effective in mild-moderate cases of COVID-19 [14] by stopping the glycosylation of ACE2 and thus hinders the binding of viral spike protein to ACE2 and prevent viral cell entrance [15]. Meanwhile, scientists found that ARDS severity is inversely related to ACE2 level [16], this can be a further encouragement for fenofibrate usage in COVID-19 management.

The expected benefits of fenofibrate can be confirmed by scientific suggestions about the benefits of statins to reduce mortality for patients infected with corona virus [17,18]. Meanwhile, fenofibrate has at least comparable systemic anti-inflammatory effect [19,20] and even better than statin among elderly people [21]. Furthermore, fenofibrate maybe superior than statins in reducing mortality due to lung damage by COVID-19 since it increases ApoA1 more than statins [22] and it is well known that ApoA1 plays a protective role against lung damage [23].

To confirm the above claims, clinical trials using fenofibrate as add-on therapy to chloroquine/hydroxychloroquine are highly advocated to elderly people with moderate–severe COVID-19 and without end organ damage..

Disclosure statement

No potential conflict of interest was reported by the author.