Statins upregulate LDL receptors but do not lower Lp(a), while PCSK9 inhibitors appear to lower Lp(a).

“Statin therapy is known to raise Lp(a) concentration in some patients”

“you can inhibit the synthesis of cholesterol which in turn also activates the clearance or you can just go directly after the clear and so the former would be how a statin works the latter would be how a pcsk9”

“what's the best explanation for why a statin which causes the liver to up regulate LDL receptors does not lower LP little a or LP little a or LP little a and there's nothing to LDL particles and that drug is under investigation right now it's an April a synthesis inhibitor where your liver is going to stop making the vast quantities of April wait at these people who genetically inherit their propensity is courtesy Isis yeah so what infused with hold our breath button so until then are there people in the lipid ology world who would say Tom until then I'm gonna continue to use niacin because lowering it has to work I've been around too long this thing singing lowers this and lowers that and they don't work so I cook is nice and gonna have the same tux to see it I think it has an other people in LP little I don't know but if you want to use that because you want to make a patient happy cuz you're improving some metric be my yes I would not I know many lipid ologists who would not but there are ones and look Samsa Mekas is probably the world authority under Sam uses niacin in his practice too and I hope Peter has him on one they would have podcast he would tell you until we did our data on these other drugs I'll try and lower it a little bit if nothing else um he'll hash tea and I'm lowering April be a little bit too and I'm if I don't know if it matters but I'm raising whatever HDL metric but way although fibrates are probably our best available drug now to raise HDL particle count niacin which blows away fibrates on raising HDL cholesterol that's nothing to HDL particle counts I didn't mention that before cuz nice and makes this is about to say that could actually suggest it's worsening LDL HDL function yeah you're right so but the nice and people will convince you that the big hdls or protective it's laughable and the small age gels are harmful where's the VA has the opposite because the lipid poor HCL's are the ones ones they shoot so you know you're never gonna have definitive answers on any of that but yeah there's a lot of BS around so what's the best explanation for why a statin which causes the liver to up regulate LDL receptors does not lower LP little a whereas a pcsk9 inhibitor which also net results in more or a longer transiency of LDL receptors seems too low or LP little a even though that's not its primary objective and by the way the data shortly tells us now that the main determine of LP little a master LP little a particle concentrations a PO a production in the liver not clearance so until we can really inhibit production of a PO a who knows what you're doing but until then let's in here so how do LDL receptors clear these particles well earlier I think I mentioned that LDL receptor is looking for a bowi or a section of the a PO B that it can latch on to there's a very specific area on the a PO B protein on any of the april-b particles that because of surface charges will bind to a specific part of the LDL receptor that area on a pole B is called the LDL receptor binding domain so if here comes an LDL particle and that domain is sticking right out it'll stick right to any expressed LDL receptor but what if there's something camouflaging that a PO a are that LDL receptor binding domain on a probe a such as an interloper like Apryl protein little a I could see where that would slow the clearance of an LP little a particle because it's not gonna bind as rapidly and as vividly to an LDL receptor so most of these people have to wait too many LDL particles we express whatever LDL particles we want we try and express more with the stat and what are they gonna grab first the LDL particles that don't have April little a attached and only then would they maybe then start even grabbing April little a particles or so and do we all really have enough LDL receptors most of this variety reasons do not utter things the clearance to you know with the April c3 I talked about other proteins that may be affecting clearance to so they're just other factors at play but right now my guess is a po is affecting totally efficacious binding to an LP little egg particle its camouflaging the LDL receptor binding domain on April B and therefore I better learn how to inhibit synthesis of it so Sam will obviously hopefully we do get Sam on the show and we'll talk about this but that the this antisense oligonucleotide is basically going after the jugular issue which is you inhibits the synthesis of april little a yeah and hopefully you do that you know the million-dollar question has always been why do we even have april little a to begin with it never served some physiologic function or is it important in any other aspect of human life I guess we'll know it if we eliminate it and there's some bad outcomes in that trial and obviously it absolutely will be looked at for every safety aspect anybody can ever think of right now is there developing that drug so right now I don't think there's anything they're worried about say I'm what no more than I but yeah so if we can reduce statin I don't know that we can shut it down completely but he can dress of a lower April little a in LP little a-levels too so you know everybody thinks either habit you don't there's a lot of people who have what's considered a physiologic or a non-adversarial concentration of LP little a in your system so you don't have to make it go to zero you know where risk is concerned in fact the only people are ever going to study this drug is in people like you just meant you have an LP little a mass or particle count open at 600 range or something you're not gonna take people with borderline LP little a's and risk a clinical trial on them just like the first statin trials were done in sort of fh”

“so if we can reduce statin I don't know that we can shut it down completely but he can dress of a lower April little a in LP little a-levels too”

“Why is it that statins which are probably the most potent drug until five years ago to lower ldl and by definition then lower apob concentration have virtually no effect on lp little a but this new class of drug that's been around for five years called pcsk9 inhibitors well even more potent in lowering ldl seem to also be able to lower lp little a”

“why is it remind us that statins don't lower lp little a you would think well we know why statins get the ldl receptor to be more dense that should do it so the the the obvious explanation here is ldl receptors don't clear lp little a”

“under the assumption that lpa is catabolized by the ldl receptor you would think that statins would actually reduce lpe levels whereas we we see that there's not really a lowering effect of statins on on lpa and there's even been more than one studies that have shown that if you put somebody on a statin you'll even have a small increase in uh in lpa levels”

“and yet that does nothing to offset the amount of lp little a which goes back to the explanation that started your journey here which was why is it that some people respond really well to statins and some don't and obviously it would be the higher your lp little a the worse your statin responds because there's a subset of your ldl that are not responding to the statin”