Fenofibrate: generic anti-lipid drug may squelch COVID-19 severity

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Jerusalem researchers say they have shown that an existing drug used to lower lipid levels significantly downgrades the intensity of COVID-19, after conducting a comparative study of 1,500 medical records from hospitalized patients.

Fenofibrate, a generic fat-lowering medication that is among the most prescribed drugs in the US, appeared to give patients an “astounding” advantage in fighting the disease, Prof. Yaakov Nahmias of the Hebrew University of Jerusalem told The Times of Israel.

“This is a cheap and widely available drug with minimal side effects, and we were excited to find that all the main biomarkers indicate that it reduces the severity of COVID-19,” Nahmias said on Sunday.  

Nahmias has spent six months analyzing the impact of the numerous different medicines taken by 1,500 coronavirus patients treated at two Israeli hospitals.

The study included 13 subjects who regularly took fenofibrate, and had been doing so before they caught the coronavirus, to address their lipid levels. The result, quicker-than-expected recovery from virus-induced pneumonia, dovetailed with his earlier hypothesis that lipids play a role in the severity of the disease.

Had the 13 patients responded to COVID-19 with the same level of severity as others in the study, there would have been at least two deaths and six ICU admissions among the fenofibrate patients, but there were no deaths and there was only one ICU admission.

Clinical trial results are still needed, but there is now a “very high” chance that fenofibrate will become a common treatment for the coronavirus within a few months, said Nahmias, director of Hebrew University’s Grass Center for Bioengineering.

Even before the patient study was completed, an international clinical trial by the University of Pennsylvania got underway, and he is now starting a clinical trial in the Israeli city of Ashkelon.

Vaccination programs don’t reduce the importance of fenofibrate; it will take a long time before the whole world is vaccinated so his drug research can still save many lives, Nahmias suggested. He noted that even after vaccination, some people will still get infected, so drugs will still be needed.

In June, Nahmias announced that experiments in his lab indicated that fenofibrate could help coronavirus patients.

The medicine, which is sold under a number of brand names, is America’s 73rd most prescribed drug. It is designed to reduce lipids known as triglycerides, the most common type of fat.

His team hypothesized at the time that the novel coronavirus is so vicious because it causes lipids to be deposited in the lungs, and that fenofibrate could break down the lipids and help patients.

“We suggested in June that lipid accumulation is harming COVID patients, and this study shows exactly that,” he said Sunday. “If you encourage lipid breakdown you resolve inflammation faster and you have less mortality.”

Putting this idea to the test, based on patient data from Tel Aviv Sourasky Medical Center and Hadassah Medical Center in Jerusalem, has not only paved the way for a possible new treatment option, but may also throw some light on why patients suffering from obesity and high levels of fat in their body are so badly hit by COVID-19.

Nahmias emphasized that his latest analysis, which must still be peer-reviewed, was carried out using a scientific system called propensity score matching, which means that background diseases, age, gender and other risk factors were identical.

“Our statistics were very strong,” he reported. “Based on the overall sample, the patients who were taking fenofibrate before and during their COVID-19 illness, there should have been two to three deaths, and it should have been about 14 days to resolve their pneumonia.

“But there were no deaths, fewer ICU admissions than expected, and while all [fenofibrate] patients had pneumonia, it took them three to five days to recover from pneumonia. This is astounding.”

Oren Shibolet, a senior doctor at Tel Aviv Sourasky Medical Center who provided data on his institution’s coronavirus patients to Nahmias, said that while only 13 coronavirus patients taking fenofibrate were studied, the results are important.

“The differences seen between them and the other patients was highly statistically significant, meaning that it can’t be explained by chance,” he said. “There is some biological phenomenon in these patients.”

Nahmias said his team also found that patients taking fenofibrate showed indications of better lung function, respiratory functions and C-reactive protein levels, which are an indicator of lung inflammation, than other patients, including those taking statins.

Nahmias recently started a Phase 3a clinical study of the drug on coronavirus patients at Barzilai Hospital in Ashkelon. The study is partly funded by Abbott Laboratories, which sells the drug as Tricor and which has received some scrutiny in academic circles for its zealous marketing. However, Nahmias said that before then, he received no funding from any of the various firms that manufacture drugs based on the fenofibrate generic.


It has been somewhat strange and unexplainable that patients with hypertension and/or metabolic syndromes have been more hurt by the coronavirus pandemic. Partly plausible has it been that hypertension patients treated with ACE inhibitors are more sensitive because, compensatory, they develop more ACE2 molecules which actually have been found to be the receptor of coronaviruses. However, only 1/3 of the hypertension patients take these drugs meaning that for 2/3 of the patients the higher sensitivity is not understood.

Also, it is odd that children and even small kids who usually are very sensitive to virus infections, are not sensitive to the infection or do not develop serious symptoms after infection of the coronavirus. How can these obvious paradoxes be explained?

Sulfatide has been connected to various infections. Sulfatide is a glycosphingolipid consisting of two fat chains on the backbone of a ganglioside molecule consisting of serine. To this is attached sugar molecules and in the case of sulfatide it is galactose.

The length of the fat chains can vary. Thus the molecule consist of a hydrophobic end and a hydrophilic end thus it is a detergent. Among other organs it is synthetized in the liver and it depends on the supply of serine which is a non-essential amino acid. It is ubiquitously present in the neural system as it is an important component of sphingomyelin which insulate the nerve fibers. Also it is present in the beta cells in which it has important role for manufacturing and secretion of insulin [1].

It is present in the blood and it is easy to determine by mass spectrophotometry. Due to its physical properties as described and due to its presence on many cell surfaces mostly in the carvioli crypts, it has been considered whether sulfatide might be a virus receptor, which has turned out not to be the case [2].

However, highly interesting sulfatide regulates negatively the fusion process for the entrance of a virus through the cell membrane [3]. In beta cells, sulfatide has a role in exocytosis of insulin by fusing the membranes of secretory granules to the cell membrane [1].

In contrast, sulfatide seems to play a role in the opposite process of infusion of human paravirus influenza type 3 [3]. This has been shown by a three times lower infection of Cos cells after loading these with sulfatide. Also treatment of sulfatide containing cells with monoclonal sulfatide antibodies highly enhanced infection status of the cells [3].

It has been described that patients being part of the lowest one third percentile of sulfatide in the blood, have a two times increased risk of hypertension compared to persons with the highest sulfatide amount [4].

This has further been elaborated by Guo et al. who found that patients with hypertension and/or metabolic syndromes display lower amount of sulfatide in their blood [5]. Furthermore, there is no precise data on the amount of sulfatide in children, but both in rats and in mice, young offsprings before puberty have higher levels of sulfatide than adults [6].

Thus, hypertension is associated with low amount of sulfatide, whereas kids might have high levels. Regarding Corona virus, it could be that high amounts of sulfatide (children) might reduce the infection ability or the disease severity, whereas low levels (hypertension) may do the opposite.

This could quite easily be examined in an experimental virus laboratory. Also in a population, treatment with agents that increase sulfatide levels such as fenofibrate or serine [7], [8] should be investigated for a beneficial effect against coronavirus infection.

References

  • 1. Buschard K., Hoy M., Bokvist K. Sulfatide controls insulin secretion by modulation of ATP-sensitive K(+)-channel activity and Ca(2+)-dependent exocytosis in rat pancreatic beta-cells. Diabetes. 2002;51:2514–2521. [PubMed] [Google Scholar]
  • 2. Blomqvist M., Osterbye T., Mansson J.E., Horn T., Buschard K., Fredman P. Sulfatide is associated with insulin granules and located to microdomains of a cultured beta cell line. Glycoconj J. 2002;19:403–413. [PubMed] [Google Scholar]
  • 3. Takahashi T., Ito K., Fukushima K. Sulfatide negatively regulates the fusion process of human parainfluenza virus type 3. J Biochem. 2012;152:373–380. [PubMed] [Google Scholar]
  • 4. Buschard K., Fredman P., Bog-Hansen E. Low serum concentration of sulfatide and presence of sulfated lactosylceramid are associated with Type 2 diabetes. The Skaraborg Project. Diabet Med. 2005;22:1190–1198. [PubMed] [Google Scholar]
  • 5. Guo R., Hu X., Yamada Y. Effects of hypertension and antihypertensive treatments on sulfatide levels in serum and its metabolism. Hypertens Res. 2019;42:598–609. [PubMed] [Google Scholar]
  • 6. Blomqvist M., Kaas A., Mansson J.E. Developmental expression of the type I diabetes related antigen sulfatide and sulfated lactosylceramide in mammalian pancreas. J Cell Biochem. 2003;89:301–310. [PubMed] [Google Scholar]
  • 7. Holm L.J., Haupt-Jorgensen M., Giacobini J.D., Hasselby J.P., Bilgin M., Buschard K. Fenofibrate increases very-long-chain sphingolipids and improves blood glucose homeostasis in NOD mice. Diabetologia. 2019;62:2262–2272. [PMC free article] [PubMed] [Google Scholar]
  • 8. Holm L.J., Haupt-Jorgensen M., Larsen J., Giacobini J.D., Bilgin M., Buschard K. L-serine supplementation lowers diabetes incidence and improves blood glucose homeostasis in NOD mice. PLoS ONE. 2018;13 [PMC free article] [PubMed] [Google Scholar]

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