Lipids: Pharmaceutical Interventions with Dr. Dayspring (Episode 3)

So a lot of information. So I'll make a transition now to therapies which you've kind of alluded to and you mentioned there's four major therapies to get in this world. One of the things like in the functional medicine world we focus on inflammation, the homocysteine, hscrp, inflammatory markers, all that kind of stuff. So what I want to do is I want to focus on like the medication therapies that you kind of talked about to get these things down. So what are these four major class.

Is referred to so easy. It was so hard for most of my life because first we had an unusable drug called a steer. I mean we had niacin which proved that we were probably hurting people. Vibrates very selective.

Where's well called you consider well call.

You put that with chart bioassancy question has the ability to bind to bile acids and you excrete them in the stool urelium can't reabsorb them. Your liver uses up cholesterol which induces LDL receptors. Bile acids equestrians can only bind to X number of bile acids. Well, call was an engineered molecule that binds to way, way, way more bile acids than can the bile acid sequestrate. So it's called a bile acid polymer. So you will just excrete a lot more bile acids if you use well coal, which is a more usable than the old. I don't hope anybody's not using cholestyramine anymore. Well, cold it turns out through other actions can actually lower glucose improvements and sensitivity. So there are other reasons to consider. Well call and it's not absorbed, so it's great for a pregnant woman. A drug you can putz around with cholesterol if you need to. So that's where well call sits. So right now if I want to lower apob, my therapies have to make the liver produce more LDL receptors or whatever. LDL receptors exist, let them recycle, live longer. I told you. LDL receptors grab the apob particles, pulling them into the liver. What should happen is the LDL particle gets dissolved in the lysosome, but the LDL receptor is freed up to go back to the surface. So if that happens, LDL receptors can recycle many times over a few days. But if your lysosome decides to destroy the LDL receptor, it cannot recycle. So just keep that in mind. So it would be good if we could trick our lysosomes into recycle the LDL receptors, please. Because we need them. But once the LDL receptors at the surface of the liver, extending into plasma, you clear APOB particles a lot more. So the drugs that we now can write to lower apob and there's typically an algorithm we go through because of cost. If we didn't, cost wasn't aside, we'd all be using maybe the most expensive one because it's the most potent way of lowering apob. But here's where we start. So how do I make your liver make more LDL receptors? What determines how many LDL receptors the liver makes? The pool of cholesterol in the liver. If the liver pool is full, it doesn't make any LDL receptors. You can't clear APOB particles. But if all of a sudden you can make the liver have a deficient cholesterol pool, the liver is going to, I got to get LDL cholesterol. I got to get cholesterol. It's going to manufacture and express LDL receptors. They make them at the endoplasmic reticulum, and they transmigrate to the surface of the liver. Grab the apob, pull it in. All right, so how would I deplete the amount of cholesterol in your liver? I got a couple of ways. The most commonly used one is, let me just tell the liver to stop synthesizing cholesterol. And that's where the statins came into play. And they discovered that in animals long before they knew, let's try it in humans. And it worked. And before they even knew it worked, somebody had to discover LDL receptors. And two guys who did that, Goldstein and Brown, won the Nobel prize for discovering LDO receptors. So if I prescribe a statin, you inhibit cholesterol synthesis in your liver. By the way, the liver, because of its size, is the king organ in the body in expressing LDL receptors. And the only one that, once it clears APOB particles, can digest them and get rid of them. You don't want other cells internalizing LDL particles. So fortunately, we inhibit most of the synthesis of cholesterol is going to be in the liver. Less cholesterol, the liver makes more LDL receptors. You clear more LDL particles, APO B goes down, LDL cholesterol goes down. Usually, LDL cholesterol goes down a little more at APOB. That's why you should follow up with APOB because you may normalize LDL receptor and not normalize apob. So it's wise to do the best blood test now that it's readily available. Any insurance company is not Strangling you to tell you not to order a pool. All right, so is there another way I can deplete the cholesterol pool in your body? Well, what is a big source of cholesterol other than de novo synthesis? Our intestines absorb cholesterol and they put it in our biggest lipoprotein, a chylomicron. The intestine takes absorbed cholesterol, puts it on both the surface in the core of the chylomicron, secretes it into the lymphatics. It goes out through the thoracic duct into the systemic circulation. Primary purpose is deliver all the fatty acids which are incorporated into triglycerides to your muscles. Hey muscles, here's your energy for supper tonight. So the tissues that express the most triglyceride dissolving enzyme, lipoprotein lipase, are your muscular bends. So here's the chylomicron particle attaches to lipoprenting lipase matter. Free fatty acids, they just enter the muscle cell. The chylomicron shrinks down carrying very little triglycerides, mostly cholesterol. No cholesterol was given to the muscle cell. The muscle makes all its own cholesterol. Doesn't mean a cholesterol delivery. So the chylomicron then is cleared rapidly within minutes by the liver. And the liver recognizes something on a chylomicron that induces its clearance. The APOB on a chylomicron is half the size of the APOB on all our other particles. APOB 100 on V alleles and alleles APOB 48. Coming out of each acid we have a receptor that binds to APOB48, LDL receptor related protein LRP. But what is the major line game for LRP? APOE? Chylomicrons carry several copies of APOE. Once the chylo shrinks, APOE conforms to a ligand binding conformation. Your chylomicron is gone in minutes. The half life of a chylomicron is in minutes. Plasma residence time, a couple of hours. So absorbed cholesterol gets brought right to the liver. Thank you. The liver says I got all the cholesterol I need now. But what if I block the absorption of cholesterol in the gut? And there are a few ways of doing that. Nowadays the most potent way is to prescribe a drug that inhibits cholesterol absorption. Ezetimibe, brand name Zetia. People who have loss of function of the transporter that pulls cholesterol into the gut have hypocholesterolemia, hypobata Lipoproteinemia, they get far less heart disease. So we know reducing cholesterol absorption reduces heart disease. Proven by Mendelian Studies of the neem and pixi1 like protein also now. So, okay, I can now deplete cholesterol synthesis in the liver. I can reduce absorption of cholesterol from the gut, depleting the cholesterol pool. We do have a backup way to inhibit cholesterol synthesis nowadays. It's called bempedoic acid. Nexletol. It inhibits a different step in the cholesterol synthesis chain. Not quite as potent as the statins which inhibit the rate limiting enzyme. But nonetheless, I can further reduce cholesterol synthesis. If I combine bempedoic acid in the statin, I can really shut off cholesterol synthesis. But even by itself, bempedoic acid shuts off enough cholesterol synthesis that the liver will have to get cholesterol elsewhere. Upregulate LDL receptors, pulling in your particles. So ezetimibe statins and bempedoic acid all lower apob. The statin, it's dependent on the dose you use. Ezetimibe. There's one dose, you can even use less of the one dose. Intermittent dosing and you pretty much get the same efficacy. Bempedoic acid, there's only one dose. You never have to titrate anything. So. And by the way, the amount of LDL receptor upregulation you get with a statin, 80% of it occurs with the lowest baby dose of the statin. As you double, triple, quadruple the dose of the statin, you get 6 to 8% more. Far less efficacious. I say all you get is side effects by doubling and tripling the dose of a statin. So we should all. Whatever your favorite statin is, you should be using the lowest dose. If you're a zoo or satin fan like I am for a variety of reasons, 5 milligrams of rosuvastatin, you get almost like a 38% lowering of APOB. That's as much as higher doses of other statins, for God's sakes. So of course, adding ezetimibe to a statin or bempidoic acid to a statin, if need be, you can get a lot more APOB load by itself. Ezetimibe or will lower 15 if you're lucky. 20% of APOB. Bempedoic acid a little bit higher. 20 to 30. 23%. So now the howitzer that we can Take out, if needed, is our last drug, which, as you know, are PCSK9 inhibitors. And we have two types. Now, one is monoclonal antibodies that bind to PCSK9. And the other is a small interfering RNA drug that goes into the nucleus, interferes with RNA. You can't translate the RNA. The messenger RNA that comes out your liver stops making PCSK9. So then you obviously have less PCSK9 through that mechanism. So what the PCSK9 does is remember I told you LDL receptors recycle. The PCSK9 does not let the LDL receptor get by inhibiting PCSK9. The LDL receptor will not be catabolized as readily in that lysosome. PCSK9 tells the lysosome destroy the LDL receptor. So if we can inhibit PCSK9, the LDL receptor gets to recycle many times the more you recycle your LDL receptors. People be. Now think of this. What If I upregulated LDL receptors with the first three drugs I mentioned and then I draw a PCSK9 on top of them? Goodbye, Apob. Remember, all of the PCSK9 studies have been done on top of at least statin or Ezetimibe monotherapy. There's small ones on top of benfedoic acid that didn't work. I haven't seen a triple therapy yet, statin, ezetimibe and pcsk9. But I can tell you in practice I've seen it used many times for the apob Nightmares of the world. So that's it, doctors. And here's what I will tell you. When Ezetimibe is like next to zero side effects, you have to know one you should inform the patient you're affecting the makeup of sterols in your biliary tree and gallstones are due to both bile acids and cholesterol in the bile. So there's this minuscule, trivial evidence that has maybe been seen in the trials of Ezetimibe and suggested even in Mendelian studs gallstones. So you'll learn in person too. We'll deal with that should they occur. A minuscule number of people might get mild transient hemanosemia. We don't even know if that means anything. Very rarely will you triple the transaminases, which is where guidelines tell you to back off any drug tripling aminases, even though nobody's proved that that's harmful even at that level. But most would stop it. So you're going to measure transaminase periodically after ezetimibe benpedoic acid. Look, there's a trivial chance that given to the wrong patient you could elevate uric acid. So you never give it to a patient who's had a lot of gout or if they have had hyperuricemia, you've controlled it through other mechanisms, then it's probably safe. The uric acid excursion is small, but you wouldn't want to precipitate gout. But if I had a gout propensity patient where for some reason I couldn't tolerate everything else and how to use bet, I would warn them. Gout, pedagro delto, swelling the knee. Call me up and we'll deal with that if it occurs. I don't know of any other side effects of bempedoic acid. I can tell you a lot of maybe benefits that are going to come, including the elimination or de escalation of insulin resistance and diabetes. But that's again a lecture for another day. And then you have the PCSK9 inhibitors and I don't know of any side effects of them right now. Now you know we've got at least 5, 6 years worth of data. Now we don't have 30 years of data like we do on the statins, but so far very safe drug. We have more data on the monoclonal antibodies than the sirnas. Sirnas? For those who don't know, they're much longer acting. So the monoclonal antibodies, alirocumab, evolucumab, pralate, repatha that people use every two weeks, it's a minor injection, whereas the SIRNA drugs, baseline injection, three month injection, then every six months thereafter because it really interferes with the RNA through a complex mechanism for a long time. It's very hepatoselective. By the way, Bempedoic acid only works in the liver, can't affect any other cell in your body. So the last thing is the statins. If you're going to be a statin writer, there are things you have to know about. So yes, you can get APOB control and you will drastically reduce mace. That is not even arguable that I really do will reduce the number one killer cause of morbidity mortality in the world. But at what price? So we will look at the amnases on statins again. An extreme minority will have elevations of transaminase at a certain level that you might cut back or stop the statin. 2 We have this. Oh my God, you'll cause diabetes with a statin now at a Molecular level statins in some people, mostly those genetically prone to insulin resistance can. If you're measuring very complex markers of insulin resistance, you will see statins do aggravate insulin resistance in some people. And ultimately if you aggravate insulin resistance and type 2 diabetes is a loss of insulin sensitivity, you will get a glycemic excursion. It might put you into the pre diabetes level of glucose of 100, might cross the barrier of 126 where I can say you're a type 2 diabetic. So certain people on statins have gone into oh my God, you're now a prediabete. They were mostly people who had a sugar of 96 or 94 as opposed to 76 for people who don't have who have great insulin sensitivity. And ultimately if you must continue to statin because that's the only way you get APOB to control they may actually cross the 126 threshold. It's almost always in obese insulin lost people who have already loss of insulin sensitivity who you probably are going to get that with a statin. So you watch for it. But we also know that even though I may cross some barrier that changes the definition of what is diabetes or not to me diabetes is a glucose of 8890 where I know you're on your way to insulin most of the time. So I don't need a sugar of 126. And the bad all the microvascular complications of glucose can occur long before a glucose of 100 or 126. So Bob, I'm still reducing mace in these diabetics, the leading killer of diabetics. So I can deal. And if I really do put you in a diabetic threshold, obviously easiest thing would be crack the lifestyle a little bit improve their insulin sensitivity. Well God, the list of pharmacology. We can reduce insulin sensitivity if you feel you have to with a standard. Why are they not all on coping or zip down nowadays if that's what's causing their insulin resistance and they're not going to do lifestyle or it doesn't work in them. So we have solutions to that too. That's pharmacology in a nutshell. It's so easy and the statins are the only ones you almost have to maybe worry about.