Cholesterol – Cardiovascular Pharmacology

00:00 In fact, it’s only in the last 20 years that we have really had effective therapy... pharmacological therapy and I am going to show you some information about that in a moment.

00:11 Let’s just talk a little bit more about the different components of hyperlipidemia.

00:16 Here’s the evil enemy. You will notice the little cartoon, the little devil with the tail? So, low density lipoprotein cholesterol is the one that gets itself into the wall of the artery, sets off an inflammatory reaction that eventually leads to atherosclerosis, which is progressive. The lesions continue to enlarge, they become often fragile and friable. They can even crack and open and a blood clot can form leading to a heart attack or a stroke depending upon whether the broken artery with the blood clot is in the heart or whether it’s in the arteries leading to the brain.

00:54 And again, we are going to go into this in much more detail in the lecture on… on coronary artery disease and atherosclerosis. In any case, this is often referred to as the bad cholesterol. The number that we like to see is in milligrams percent. In the United States, it… the number we usually like to see it below 100 and ideally, somewhere down around 60 to 70 milligram percent or milligram per deciliter.

01:23 Even that number is actually elevated compared to what people living in a state of nature might have. It’s been measured - LDL cholesterol, that is, has been measured in patients who live in the highlands of New Guinea or the headwaters of the Amazon. There they have a very healthy diet because it’s a tropical area, lots of fruits and vegetables and fish and so forth, but these people do not eat a western diet. They have LDL cholesterols that are only 20 to 30 milligrams percent. So, you can see that all of us living here with a western lifestyle actually have at least moderately elevated LDL cholesterol.

02:03 High density lipoprotein works in the opposite direction. You will see it has little angel wings here. High density lipoprotein helps to remove cholesterol from the arterial wall.

02:15 In pharmacology, there have been great attempt to come up with a drug to increase HDL and work against the atherosclerotic process. Unfortunately, so far, that research has not been successful. A number of agents have been tried, they did indeed increase the HDL level, but in fact, they did not decrease the heart attack rate and in some instances, actually were associated with a worse outcome than in the placebo group. So, we are still searching for a way to raise HDL cholesterol safely. The only way to raise it safely and to retard the development of atherosclerosis is number one, with regular exercise and number two, with modest use of alcohol. For example, a glass or two of wine per day.

03:03 Now, what we do in cardiovascular pharmacology, as I pointed out in the first lecture, is we look to large clinical trials in which an agent is compared to placebo. The trials are conducted in a double-blind fashion so that neither the doctors who are administering the drugs nor the patients know whether the patient is getting the placebo or whether they are getting the drug that’s being tested. The drugs that were tested and shown to be very, very effective in these, what I call gold standard clinical trials - the double-blind clinical trials were the drugs known as Statins. And they have become widely, they... used throughout the world. They are now one of the most widely used drugs throughout the world. Why? Because they very effectively lower LDL cholesterol and they very modestly elevate HDL cholesterol. So, you can see they really work in the perfect direction. They lower the bad cholesterol and they increase the good cholesterol a little bit, but their major effect is in lowering LDL cholesterol. By the way, they have some other pharmacological actions - they are also anti-oxidant that is they reduce so called ‘rust’ in the… in the cells of the body and in the arterial cells so that they decrease injury to those arterial cells. And by the way, there’s a lot of research going on in this area in basic science and in clinical science trying to come up with new drugs to reduce this oxidation, this rusting, if you will, of our bodies. So far, we don’t have any drugs that are really effective long term, but it’s an area of intense investigation.

04:50 Now, Statins also decrease inflammation, and as I am going to point out to you in this talk and also later on when we talk in more in depth about atherosclerosis, the atherosclerotic process begins with oxidation and also injury and inflammation within the vessel wall. And if there were ways to retard that, we might markedly decrease the atherosclerosis. So far, the best thing we have going forth are the Statin drugs.

05:23 How do the Statin drugs work? The Statin drugs work in the liver. And the way they work in the liver is that they are able to block the production of cholesterol within the liver cell. They block an enzyme called HMA co-enzyme reductase and what this does inside the liver cell, is it slows the production of cholesterol in the liver cell. When the liver cell looks around and says, “Hey, I don’t see enough cholesterol, I am going to put some more LDL receptors up on my surface and pull some out of the blood stream.” And when they do that, of course, the level of LDL cholesterol in the blood goes down and that decreases, as you will see in a moment on the slide, markedly the risk for heart attacks and strokes.

06:15 There are fortunately very few side effects from Statins. They are very, very well tolerated.

06:21 Which is good because that means we can give them to large number of people without having too many very unpleasant adverse events, as they are called in the pharmacology literature.

06:32 In the lay term, we call them side effects. There is an occasional patient that has significant liver injury from that and obviously, can’t continue to take the drug and a fair number of people have occasional muscle cramps or muscle aches, but rarely there is also serious muscle damage and consequently, those people can’t take it. But, we are talking about one or two people in many thousands. Many thousands can take the drug without major side effects and it is very, very effective at lowering LDL cholesterol.

07:06 What we see in this slide is increases or decreases in events with changes in either Statins or placebo therapy. And what you can see is in the lines that are moved to the right, that’s a decrease in events and the one that’s on the left, is actually at the zero point. In other words, nothing has changed. That’s non-cardiovascular events and you can see, they are unaffected by Statins. Everything else, major coronary events, that’s heart attacks and severe angina, strokes and cardiovascular deaths and so forth, all lie to the right and are markedly decreased by 30 to 40%. That’s a huge decrease in cardiovascular events with Statin therapy. All of this data is from the double-blind randomized controlled gold standard trials that we mentioned before in the area of evidence based medicine. That is, do we really have hard data that says that these drugs work when they are tested in that manner? Here we see, actually, this is a composite graph from a number of the Statin trials and what you can see is, as LDL cholesterol on the bottom axis goes up, moving from left to right, you can see that the number of events also goes, the relative risk for... for coronary heart disease, CHD, goes up as well. And conversely, as you move to the left on the bottom line, in other words, the LDL gets lower, you can see that there is a marked drop in the number of cardiovascular coronary heart disease events.

08:55 So, this is actually data brought together. It’s a composite from many of the Statin trials. Essentially every Statin trial showed the same thing, that is a marked reduction in coronary artery disease events such as heart attack, myocardial infarction and strokes.

09:14 Here we see all of the drugs that have been approved, both in the United States by the Food and Drug Administration and in Europe by the European Licensing Agencies for the reduction of LDL cholesterol. In other words, all of the Statin drugs that are currently available in local pharmacies, basically throughout the world.

09:35 The first drug, rosuvastatin at the top, is the most powerful and is given in lower doses.

09:41 The ones below that are less powerful and therefore, are given in higher doses, but you can achieve the same effect regardless of which agent you use as long as you use enough of it. Other agents that are commonly used are atorvastatin, simvastatin and pravastatin. So, the commonly used ones then are rosuvastatin, atorvastatin, simvastatin and pravastatin. Now, other drugs can be used to treat increased cholesterol or hyperlipidemia. Unfortunately, none of them is anywhere near as effective as the Statin drugs. But they have some use in certain individuals who can’t tolerate Statins and sometimes, they have been used in addition to Statins. But unfortunately, the most recent trial data doesn’t show that they add very much. The Statins are really the basis for most of the lowering of LDL cholesterol and for lowering of the coronary heart disease and stroke events. But, these other agents - high dose niacin, fibrates, one can even use a drug that… that grabs bile as it comes into the bowel. Bile is made from cholesterol, so it then passes out in the feces and that also lowers the… the LDL level. But, each of these is a minor league player, as we say in English using the baseball term, as opposed to the major league player which are the Statin drugs.

11:11 Niacin is no longer recommended for raising HDL cholesterol.

11:16 It was shown in a very early trial to reduce number of cardiovascular events, but had a lot of problems with liver toxicity and also flushing and made patients uncomfortable It's used on rare occasions still for patients with elevated lipoprotein little A-levels, but that is an area of current constant investigation.

11:41 Fish oil is still used in high doses for patients with extremely high triglyceride levels, but no longer used to lower cholesterol for primary prevention.

11:50 And most patients who do not tolerate statins prescribing a non statin lipid lowering medication is not routinely recommended except in patients with very high cardiovascular risk, such as homozygous or heterozygous familial hypercholesterolemia.

12:07 However, for secondary prevention in patients with known coronary artery disease, there are a couple of other agents that are used in patients who do not achieve sufficient LDL cholesterol reduction with statin therapy.

12:20 A xylem nib can be added.

12:22 That's called Tzedakah.

12:23 In the United States, this impairs dietary and biliary cholesterol absorption at the brush border.

12:29 Of the intestine, and it may be helpful for avoiding high doses of statins and patients who do not meet LDL cholesterol goals with statins alone.

12:40 A new agent called Bempedoic acid inhibits adenosine triphosphate citrate lyase, which is an upstream enzyme in the HMG--Co-A reductase system.

12:52 Better known that bent the door test is fairly new.

12:54 Even better known and used a lot in the U.S.

12:57 are the PCSK9 inhibitors or probe protein convertase subtilisin/kexin and type nine inhibitors.

13:05 These inhibitors are there are two of them approved in the United States are alirocumab and evolocumab and they are monoclonal antibodies that bind free plasma PCSK9 resulting in lower LDL-cholesterol levels as well as rates of myocardial infarction and stroke They have to be injected into the body.

13:27 Patients have to do the injection themselves.

13:30 Some other newer agents, more of the monoclonal antibodies.

13:34 There's one called evinacumab and also this is a monoclonal antibody against angiopoietin-like protein and it's only currently used in patients with homozygous familial hypercholesterolemia.