A randomized clinical trial of lipid metabolism modulation with fenofibrate for acute coronavirus disease 2019

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cytotoxicity may involve inhibition of peroxisome proliferator-activated receptor alpha. Fenofibrate activates peroxisome proliferator-activated receptor alpha and inhibits SARS-CoV-2 replication in vitro. Whether fenofibrate can be used to treat coronavirus disease 2019 (COVID-19) infection in humans remains unknown. Here, we randomly assigned inpatients and outpatients with COVID-19 within 14 d of symptom onset to 145 mg of oral fenofibrate nanocrystal formulation versus placebo for 10 d, in a double-blinded fashion. The primary endpoint was a severity score whereby participants were ranked across hierarchical tiers incorporating time to death, mechanical ventilation duration, oxygenation, hospitalization and symptom severity and duration. In total, 701 participants were randomized to fenofibrate (n = 351) or placebo (n = 350). The mean age of participants was 49 ± 16 years, 330 (47%) were female, mean body mass index was 28 ± 6 kg/m 2 and 102 (15%) had diabetes. Death occurred in 41 participants. Compared with placebo, fenofibrate had no effect on the primary endpoint. The median (interquartile range) rank in the placebo arm was 347 (172, 453) versus 345 (175, 453) in the fenofibrate arm (P = 0.819). There was no difference in secondary and exploratory endpoints, including all-cause death, across arms. There were 61 (17%) adverse events in the placebo arm compared with 46 (13%) in the fenofibrate arm, with slightly higher incidence of gastrointestinal side effects in the fenofibrate group. Overall, among patients with COVID-19, fenofibrate has no significant effect on various clinically relevant outcomes (NCT04517396).Infection with SARS-CoV-2, the virus responsible for COVID-19, is an important public health problem. Available data suggest that COVID-19 progression is dependent on metabolic mechanisms 1 . Individuals with COVID-19 who developed acute respiratory distress syndrome and death are characterized by older age and a higher prevalence of hypertension, obesity, diabetes and cardiovascular diseases compared to individuals with milder disease [1][2][3][4][5][6] . Hyperglycaemia and hyperlipidaemia are also risk factors for acute respiratory distress in patients with COVID-19 disease 1,7 . Indeed, type 2 diabetes mellitus and the metabolic syndrome are associated with a markedly increased risk of death in the setting of 5 ).Several experimental studies suggest a mechanistic link between abnormal metabolism and the severity of SARS-CoV-2 and other coronavirus infections. Palmitoylation of the SARS-CoV-2 spike protein has been shown to be essential for virus-cell fusion and infectivity [8][9][10] . Gene expression analyses in cultured human bronchial cells infected with

Adjunctive therapy with lipid-lowering agents in COVID-19: a systematic review and meta-analysis of randomized controlled trials

“…The initial search with the keywords explained in supplementary table 1 resulted in 1,607 studies. Finally, after removing duplicates and screening by title and abstract and then full-text of studies, 10 articles remained to be included in our study [ 13 – 16 , 21 – 26 ]. A letter [ 27 ] was excluded from our systematic review due to the same population as the study by Pawelzik et al [ 26 ].…”

“…The baseline features of the studies included in this review are shown in Table 1 . Atorvastatin was assessed in five trials [ 14 , 21 – 24 ], omega-3 in two [ 13 , 26 ], nicotinamide in one [ 15 ], fenofibrate in one [ 16 ], and PCSK9 inhibitors in one [ 25 ]. Most of the studies included hospitalized patients, except for Bikdeli et al [ 21 ] trial which was on COVID-19 cases admitted to ICU, Doaei et al [ 13 ] al.…”

“…Moreover, in another pathway, the anti-inflammatory role of statins in cardiovascular diseases [ 11 ] might be a mediator in lessening the severity of COVID-19, since cardiovascular comorbidities and complications have been reported as essential contributors to the poor prognosis of COVID-19 [ 12 ]. In this regard, several randomized controlled trials (RCTs) identified the effects of lipid-modulating medications such as omega-3 supplementation [ 13 ], statins [ 14 ], nicotinamide [ 15 ], and fenofibrate [ 16 ] on the outcomes and severity of COVID-19. The findings of these studies have not been fully conclusive, with some demonstrating benefit in improving the outcomes [ 13 – 15 ], while others failing to find significant effects [ 16 ].…”

“…In this regard, several randomized controlled trials (RCTs) identified the effects of lipid-modulating medications such as omega-3 supplementation [ 13 ], statins [ 14 ], nicotinamide [ 15 ], and fenofibrate [ 16 ] on the outcomes and severity of COVID-19. The findings of these studies have not been fully conclusive, with some demonstrating benefit in improving the outcomes [ 13 – 15 ], while others failing to find significant effects [ 16 ]. Discrepant results also exist with respect to previous meta-analyses [ 17 ], as these included observational studies that are usually accompanied by uncontrolled confounding bias.…”

Treating COVID-19: Targeting the Host Response, Not the Virus

“…It attenuates the interaction between SARS-CoV-2 and ACE2, which could directly reduce infection-related inflammation. Unfortunately, an RCT has shown that fenofibrate has no effect on COVID-19 outcomes [ 153 ]. Pioglitazone and rosiglitazone are peroxisome proliferator activated receptor gamma (PPAR-γ,) agonists (thiazolidinediones) that also have anti-inflammatory activities in COVID-19 patients and have been suggested for treatment [ 154 , 155 ].…”