Quick Study Analysis: Pfizer, Aldehydes, and Heart Disease
tl;dr: A drug which is an aldehyde is pulled from the market due to excess mortality. Seed oils to follow?
Pfizer Inc. just pulled a drug from the market, due to excess mortality.
“Pfizer's decision is based on the totality of clinical data that now indicates the overall benefit of OXBRYTA no longer outweighs the risk in the approved sickle cell patient population. The data suggest an imbalance in vaso-occlusive crises and fatal events which require further assessment.”
Oxbryta (voxelotor) is a drug to treat sickle-cell anemia. A “vaso-occlusive crisis” is one of the reasons sickle-cell anemia is an unpleasant disease:
”A vaso-occlusive crisis is a common painful complication of sickle cell anemia in adolescents and adults…. This can rapidly result in death.”
That’s unfortunate, the drug seems to make the condition worse in some circumstances, although they don’t seem entirely sure yet about what has happened.
I found out about this drug via Derek Lowe’s “In The Pipeline” blog. He’s a pharmaceutical chemist, and so long as he’s not discussing COVID-19, he’s been an interesting source of information for years.
“The mechanism was pretty interesting: their lead molecule was an aldehyde, a functional group that traditionally we medicinal chemists avoid. That's because they're rather reactive - they can pick up water and turn into 1,1-diols (the hydrate form), or air-oxidize into carboxylic acids, or especially react with amines, of which there are a great many in biochemistry.”
All of which can lead to unpleasant outcomes.
Aldehydes, Huh?
Aldehydes are of interest to me, because many of the toxic effect of seed oils are mediated by aldehydes.
Obesity, for instance.
Or heart disease:
Physicians have been prescribing seed oils to prevent heart disease since 1961 (Page, 1961). Unlike Pfizer, however, when they discovered in 1973 that seed oils increase heart disease rather than decrease it, they didn’t do what Pfizer did here.
Instead, they hid the evidence (Ramsden, 2016).
In 1989, it was discovered that what initiates heart disease is an aldehyde produced by oxidizing seed oils (Steinberg, 1989; Brown, 1990):
“During its incubation with cells, the LDL particle undergoes a large number of structural changes that alter its metabolism in important ways. All these changes, however, depend on a common initiating step -- the peroxidation of polyunsaturated fatty acids in the LDL lipids.
“Whatever the details of the initiating steps may be, once the LDL contains fatty acid lipid peroxides, there follows (especially in the presence of metal ions) a rapid propagation that amplifies dramatically the number of free radicals and leads to extensive fragmentation of the fatty acid chains. Esterbauer and coworkers have shown that a broad spectrum of shorter-chain aldehydes (e.g., malondialdehyde and 4-hydroxynonenal) is generated…”
Physicians again didn’t do what Pfizer did here, but instead continued to prescribe seed oils.
The initial reason for the prescription of seed oils was because they lower “cholesterol”. Specifically what they do is lower the production and excretion of the containers of cholesterol and fats from the lipid, the ApoB-100 molecules we call VLDL and LDL. Seed oils (and all polyunsaturated fats) do this because they are unstable and susceptible to oxidation. This process can be measured, in part, by the TBARS test, and the production of TBARS reduces the production of ApoB-100 cholesterol (Pan, 2004).
TBARS as a Predictor of Heart Disease
TBARS (Thiobarbituric Acid Reactive Substances) is a test that determines the levels of, effectively, the toxic aldehydes from oxidized seed oils.
"Serum levels of TBARS were strongly predictive of cardiovascular events in patients with stable [coronary artery disease], independently of traditional risk factors and inflammatory markers."
"At baseline, patients with TBARS levels in the highest quartile had a relative risk (RR) of 3.30 (95% confidence interval [CI] 1.47 to 7.42; p = 0.038) for major vascular events, RR of 4.10 (95% CI 2.55 to 6.60; p < 0.0001) for nonfatal vascular events, and RR of 3.84 (95% CI 2.56 to 5.76; p < 0.0001) for major vascular procedures.
"The effect of TBARS on events and procedures was also seen in a multivariate model adjusted for inflammatory markers (C-reactive protein, soluble intercellular adhesion molecule-1, interleukin-6), and other risk factors (age, low-density lipoprotein, high-density lipoprotein, total cholesterol, triglycerides, body mass index, and blood pressure)."
"Serum Levels of Thiobarbituric Acid Reactive Substances Predict Cardiovascular Events in Patients with Stable Coronary Artery Disease: A Longitudinal Analysis of the PREVENT Study" (Walter, 2004)
It’s difficult to imagine how many people have died of heart attacks as a result of these toxic aldehydes since seed oils were first prescribed in 1961.
How many deaths caused Pfizer to pull this drug?
“In a study of 236 people , there were eight deaths in patients taking Oxbryta and two deaths in the placebo arm.” (Satija, 2024)
Will physicians ever do what Pfizer did?
(Stupid lawyer tricks: Pfizer is withdrawing this drug because it is more likely to kill you than it is to benefit you. Nevertheless the press release include the whole drug safety section about side effects and the like.
Everything except the fact that the drug is now considered so dangerous that Pfizer will no longer sell it to you.
If you wonder why so much stupid stuff happens in the modern world, blame a lot of it on lawyers.)
References
Brown, M. S., & Goldstein, J. L. (1990). Scavenging for Receptors. Nature, 343(6258), 508–509. https://doi.org/10.1038/343508a0
Lowe, D. (2024, September 26). All New Drugs Are Investigational Drugs: A Reminder [Blog]. Science: In The Pipeline. https://www.science.org/content/blog-post/all-new-drugs-are-investigational-drugs-reminder
Page, I. H., Allen, E. V., Chamberlain, F. L., Keys, A., Stamler, J., & Stare, F. J. (1961). Dietary Fat and Its Relation to Heart Attacks and Strokes. Circulation, 23(1), 133–136. https://doi.org/10.1161/01.CIR.23.1.133
Pan, M., Cederbaum, A., Zhang, Y., Ginsberg, H., Williams, K., & Fisher, E. (2004). Lipid Peroxidation and Oxidant Stress Regulate Hepatic Apolipoprotein B Degradation and VLDL Production. The Journal of Clinical Investigation, 113(9). https://doi.org/10.1172/JCI19197
Pfizer Inc. (2024, September 25). Pfizer Voluntarily Withdraws All Lots of Sickle Cell Disease Treatment OXBRYTA® (voxelotor) From Worldwide Markets [Advertisement]. Pfizer Inc. https://www.pfizer.com/news/press-release/press-release-detail/pfizer-voluntarily-withdraws-all-lots-sickle-cell-disease
Ramsden, C. E., Zamora, D., Majchrzak-Hong, S., Faurot, K. R., Broste, S. K., Frantz, R. P., Davis, J. M., Ringel, A., Suchindran, C. M., & Hibbeln, J. R. (2016). Re-Evaluation of the Traditional Diet-Heart Hypothesis: Analysis of Recovered Data from Minnesota Coronary Experiment (1968-73). BMJ, 353. https://doi.org/10.1136/bmj.i1246
Satija, B., Burger, L., Shamsi, M., & Potter, M. (2024, September 26). Pfizer Withdraws Sickle-Cell Disease Treatment. Reuters. https://www.reuters.com/business/healthcare-pharmaceuticals/pfizer-withdraws-sickle-cell-disease-treatment-all-markets-2024-09-25/
Steinberg, D., Parthasarathy, S., Carew, T. E., Khoo, J. C., & Witztum, J. L. (1989). Beyond Cholesterol. Modifications of Low-Density Lipoprotein That Increase Its Atherogenicity. The New England Journal of Medicine, 320(14), 915–924. https://doi.org/10.1056/NEJM198904063201407
Walter, M. F., Jacob, R. F., Jeffers, B., Ghadanfar, M. M., Preston, G. M., Buch, J., Mason, R. P., & PREVENT study. (2004). Serum Levels of Thiobarbituric Acid Reactive Substances Predict Cardiovascular Events in Patients with Stable Coronary Artery Disease: A Longitudinal Analysis of the PREVENT Study. Journal of the American College of Cardiology, 44(10), 1996–2002. https://doi.org/10.1016/j.jacc.2004.08.029
Seed oils are huge business, just think how long the connection of cancer and tobacco was suppressed. I do explain to people but they probably think I'm a crank. The selfish positive is that it leaves plenty of good fats for us who avoid those oils.