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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/m² 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 ).

SUBMITTER: Chirinos JA

PROVIDER: S-EPMC9640855 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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

Chirinos Julio A JA Lopez-Jaramillo Patricio P Giamarellos-Bourboulis Evangelos J EJ Dávila-Del-Carpio Gonzalo H GH Bizri Abdul Rahman AR Andrade-Villanueva Jaime F JF Salman Oday O Cure-Cure Carlos C Rosado-Santander Nelson R NR Cornejo Giraldo Mario P MP González-Hernández Luz A LA Moghnieh Rima R Angeliki Rapti R Cruz Saldarriaga María E ME Pariona Marcos M Medina Carola C Dimitroulis Ioannis I Vlachopoulos Charalambos C Gutierrez Corina C Rodriguez-Mori Juan E JE Gomez-Laiton Edgar E Cotrina Pereyra Rosa R Ravelo Hernández Jorge Luis JL Arbañil Hugo H Accini-Mendoza José J Pérez-Mayorga Maritza M Milionis Charalampos C Poulakou Garyfallia G Sánchez Gregorio G Valdivia-Vega Renzo R Villavicencio-Carranza Mirko M Ayala-García Ricardo J RJ Castro-Callirgos Carlos A CA Alfaro Carrasco Rosa M RM Garrido Lecca Danos Willy W Sharkoski Tiffany T Greene Katherine K Pourmussa Bianca B Greczylo Candy C Ortega-Legaspi Juan J Jacoby Douglas D Chittams Jesse J Katsaounou Paraskevi P Alexiou Zoi Z Sympardi Styliani S Sweitzer Nancy K NK Putt Mary M Cohen Jordana B JB

Nature metabolism 20221107 12

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 feno ...[more]

PMID: 36344766

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Project description:Despite advances in multimodal therapy approaches such as resection, chemotherapy and radiotherapy, the overall survival of patients with grade 4 glioblastoma (GBM) remains extremely poor (average survival time <2 years). Altered lipid metabolism, which increases fatty acid synthesis and thereby contributes to radioresistance in GBM, is a hallmark of cancer. Therefore, we explored the radiosensitizing effect of the clinically approved, lipid-lowering drug fenofibrate (FF) in different GBM cell lines (U87, LN18). Interestingly, FF (50 μM) significantly radiosensitizes U87 cells by inducing DNA double-strand breaks through oxidative stress and impairing mitochondrial membrane integrity, but radioprotects LN18 cells by reducing the production of reactive oxygen species (ROS) and stabilizing the mitochondrial membrane potential. A comparative protein and lipid analysis revealed striking differences in the two GBM cell lines: LN18 cells exhibited a significantly higher membrane expression density of the fatty acid (FA) cluster protein transporter CD36 than U87 cells, a higher expression of glycerol-3-phosphate acyltransferase 4 (GPAT4) which supports the production of large lipid droplets (LDs), and a lower expression of diacylglycerol O-acyltransferase 1 (DGAT1) which regulates the formation of small LDs. Consequently, large LDs are predominantly found in LN18 cells, whereas small LDs are found in U87 cells. After a combined treatment of FF and irradiation, the number of large LDs significantly increased in radioresistant LN18 cells, whereas the number of small LDs decreased in radiosensitive U87 cells. The radioprotective effect of FF in LN18 cells could be associated with the presence of large LDs, which act as a sink for the lipophilic drug FF. To prevent uptake of FF by large LDs and to ameliorate its function as a radiosensitizer, FF was encapsulated in biomimetic cell membrane extracellular lipid vesicles (CmEVs) which alter the intracellular trafficking of the drug. In contrast to the free drug, CmEV-encapsulated FF was predominantly enriched in the lysosomal compartment, causing necrosis by impairing lysosomal membrane integrity. Since the stability of plasma and lysosomal membranes is maintained by the presence of the stress-inducible heat shock protein 70 (Hsp70) which has a strong affinity to tumor-specific glycosphingolipids, necrosis occurs predominantly in LN18 cells having a lower membrane Hsp70 expression density than U87 cells. In summary, our findings indicate that the lipid metabolism of tumor cells can affect the radiosensitizing capacity of FF when encountered either as a free drug or as a drug loaded in biomimetic lipid vesicles.

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

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

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