Thread by @TuckerGoodrich

1/ Why do CETP inhibitors fail to improve CVD outcomes?

en.wikipedia.org/wiki/CETP_inhi…

@ethanweiss #lcl6 @FatEmperor @LDLSkeptic

2/ (They work by increasing HDL in the blood. HDL is supposed to be the "good" cholesterol.)

3/ But HDL is "good" because it uses CETP to remove the "bad" fats from LDL. These bad fats are overwhelmingly oxidized LA-cholesterol esters.

#lcl6

4/ HDL takes these bad fats from LDL, detoxifies them partially, and rapidly delivers them to the liver to be detoxified and removed.

5/

6/ In the context of CETP inhibitors, this crucial function of HDL, the removal of oxidized n-6 toxins, is impaired. This is what raises HDL, it seems, as the HDL is no longer full of toxins, and is not cleared by the liver.

7/ Thus toxic n-6 metabolites are free to further damage the system, particularly the liver, resulting in NAFLD and insulin resistance. These are both associated with higher CVD risk, of course.

8/ This is a perhaps classic example of the consequences of not understanding a mechanism. If (as it appears) oxidized n-6 is driving CVD, then drugs that prevent detoxification should produce worse outcomes.

They do.

9/ So the claims that HDL are not important to preventing CVD, since these drugs do not work are totally upside down.

CETP inhibitors appear to raise HDL by breaking it, preventing its CVD-risk lowering function. 🙄

10/10.

"Exchange of ox. cholesteryl linoleate between LDL and HDL mediated by [CETP]"

pubmed.ncbi.nlm.nih.gov/8558089/

"CETP Inhibition Improves HDL Function but Leads to Fatty Liver and [IR] in CETP-Expressing Transgenic Mice on a High-Fat Diet"
doi.org/10.2337/db18-0…