Is PCSK9 the Next Wonder Drug?

Henry R. Black, MD; Howard S. Weintraub, MD


September 27, 2013

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LDL: How Low Do You Go?

Henry R. Black, MD: Hi. I'm Dr. Henry Black. I'm an Adjunct Clinical Professor of Medicine at the Langone NYU School of Medicine, and I'm here with my friend and colleague, Dr. Howard Weintraub.

Today we're going to talk about issues in hyperlipidemia in its management and work-up.

Howard S. Weintraub, MD: Hi, Henry. I'm Howard Weintraub. I'm the Clinical Director of the NYU Center for the Prevention of Cardiovascular Disease and a Clinical Professor of Medicine at the NYU Langone School of Medicine.

Now, PCSK9 is probably the most exciting group of drugs in the lipid field, and it is one that is being developed. It's an injectable drug, so far. PCSK9 is a protein that modulates the appearance of low-density lipoprotein (LDL) receptors. When the protein is there, the LDL receptors internalize and get catabolized, so there are no receptors for LDL to bind to. Of note, the statins upregulate PCSK9, so statins could even do better if there was an inhibition of PCSK9.

They've identified people who genetically have no PCSK9. Their LDL cholesterols are below 30 and sometimes below 20. And -- surprise -- they don't have cardiovascular disease. So this got [researchers] excited, and they were hoping to God that this was not another cholesteryl ester transfer protein (CETP) wild goose chase. Very smartly, they are not just studying homozygous familial hypercholesterolemia (FH) patients, but they are studying people with heterozygous FH.

We are starting 2 different studies at NYU in about a month. One of them is in post-acute coronary syndrome patients, and another is in patients whose LDLs are above 70 but below 100. And a third study we are probably going to get into is in those who are statin-intolerant. In a study a year and a half ago in the New England Journalof Medicine using atorvastatin along with the PCSK9 inhibitor, the LDLs approached lower than 50 and lower than the 40 range.[1] This brought back thoughts that no one has had for a while, which is: How low do you want the LDL to be? The only bad thing that we've ever gotten to [with low LDL] is mostly in people with renal insufficiency, and that is hemorrhagic stroke. You've have seen Scott Grundy's graph. It is a continuous, linear line down to the left.[2]

Dr. Black: They haven't found a J-curve yet.

Dr. Weintraub: No, they have not, as they have with blood pressure. What we are probably going to find, because we are born with an LDL of 30 to 40, is that getting to that level is not such a terrible thing. I'm asked frequently what I would do if someone's LDL was 20. I'd say, have a party. I would tell them that maybe there is one food that they haven't been eating and they are dying to have -- let them have it.

Dr. Black: Congratulations.

Dr. Weintraub: Yes, exactly; have a party. There seems to be a wide threshold, and [getting LDL below it] seems, by and large, to turn off the production of plaque. We used to think it was below 70, but now we believe it is probably closer to 60. In people with diffuse atherosclerosis in whom you can get the LDL down, it's a great thing to do.


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