Thread by @RichardAFerraro

PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) inhibitors have changed the landscape of cardiology forever.

This is a Tweetorial🧵on why.

And it starts in 1999, with a French family named HC2.

At the time Varret and colleagues were evaluating familial hypercholesterolemia (FH) in a French pedigree.

Most known FH at the time exhibited mutations in APOB or LDLR genes. In the HC2 pedigree, neither of these genes were affected. But a third area was…

Fast forward to 2003. Abifadel and Varret discover mutations to a gene in this area called PSCK9.

PCSK9 encodes a newly discovered protease expressed in the liver and found to be important to cholesterol metabolism.

And mutations here could lead to some pretty wild stuff. How?

It’s all about low-density lipoprotein (LDL), the main thing we discuss on lipid panels and a major culprit of cholesterol badness

For more detail/explanation see:

https://twitter.com/RichardAFerraro/status/1517518264317792256

And check out @CardioNerds lipid series, like this incredible episode with Dr. @a_l_bailey

Briefly, LDL is removed at the liver by LDL-receptors (LDLR) on hepatocytes. The more of these there are, the more cholesterol we remove

These lead to⬇️ bloodstream cholesterol, which means⬇️cholesterol around to cause #ASCVD

See excellent figure by Barale et al below:

Makes sense then why LDLR gene would be an early target for familial lipid disorders right?

Less LDLRs, Less hepatic uptake of LDL, and blood cholesterol stays ⬆️⬆️ causing heart disease and other badness

So. PCSK9.

PCSK9 is sneakier. Once the LDLR picks up LDL from the bloodstream, it drops it off at the lysosome for digestion and goes back to the cell surface to repeat the process

But some LDL particles, 1:500-1000, have a PCSK9 molecule attached. And it’s tragic…

When an LDLR snags one of these LDL/PCSK9 complexes they don’t go back to the surface. They get degraded at the lysosome too!

And so the overall surface density of LDLRs goes ⬇️ with ⬆️ PCSK9

Less LDL is absorbed, so blood cholesterol ⬆️⬆️

And so a genetic mutation that⬆️ PCSK9, could worsen this process.

And the reverse is true as well.

Individuals with non-sense mutations, meaning PCSK9 is ⬇️ or nonexistent, exhibit huge reductions in CHD (88% by one @NEJM study below)

So let's recap:
⬆️PCSK9 in hepatocytes leads to⬇️LDLR on hepatocytes cell surface

⬇️ LDLR on the cell surface leads to⬆️ LDL in the bloodstream

⬆️ LDL in the bloodstream leads to ⬆️coronary artery disease, peripheral artery disease, and plaque generally

But what if we could inhibit PCSK9?

More LDLR gets recycled to the cell surface leading to ⬆️cholesterol absorption from the blood stream and ⬇️ LDL available to cause plaque. #ASCVD is over!

See another excellent graphic by @DrMichaelShapir and colleagues

So drug companies got to work addressing the issue.

And it took a long time, but today we have spectacular results and options for patients.

Take the FOURIER trial, which used the PCSK9 monoclonal antibody evolocumab in 27,564 pts ALREADY on statin showing a median LDL⬇️of 59%

Or the ODYSSEY OUTCOMES trial, which used alirocumab in 18,924 pts with recent ACS, ALREADY on high-intensity statin, and showed a 62.7% reduction in LDL and a 17% reduction in all-cause mortality

Incredible right, why wouldn’t we just use these on everyone?

Well $ is one issue, for sure. You’re not going to find these in the $4 aisle

The exact price varies all the time as well as across countries, making cost effectiveness studies obsolete very quickly. In the US, you can expect thousands of $ per year

Also, these monoclonal antibodies don’t stick around very long.

So subcutaneous injections need to be given frequently, every two weeks…

But what if there was another way. What if we could make the effects of PCSK9 inhibition last longer? What if we could make them last forever?

PCSK9 Tweetorial Part II. Coming soon

If you want to learn more about lipids and dyslipidemia in general, see our review Contemporary Management of Dyslipidemia below.

Thanks to Drs. @TLeucker, @maciejbanach, @SethShayMartin, Jones, and Toth for the mentorship!

pubmed.ncbi.nlm.nih.gov/35303294/

Thanks to the indefatigable @AmitGoyalMD for reviewing this and to all my #Medtwitter #CardioTwitter #FOAMed colleagues for the support