HMG-CoA Reductase Inhibitors – Lipid Control

by Pravin Shukle, MD

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    00:01 Let's move to the HMG-CoA reductase. Now, HMG-CoA reductase block a step in the conversion of HMG-CoA to cholesterol.

    00:12 So competitive inhibition of the HMG-CoA reductase enzyme is how we get the name statins, because it stops this enzyme.

    00:22 Now most of the effects are due to LDL receptor expression. What do I mean by that? Well, let's think of it this way.

    00:29 Everytime you want to catch a LDL particle from the blood to be used internally by the hepatocyte, you have to have a little baseball glove on the surface of the cell. That baseball glove catches the baseball which is the LDL particle.

    00:46 Now the baseball glove which is the LDL receptor and the baseball which is the LDL, get internalized into the cell and get broken down in the cell. Normally the LDL receptor is protected from being broken down and it goes back up to the surface, but every now and then one of them are clipped together with the baseball and they all get broken down.

    01:09 So, that means that the cell has this intrinsic way of making sure that the LDL receptors aren't to old. Now when you have HMG-CoA reductase inhibitors, you're blocking intracellular cholesterol production. So the cell, now has to rely on external cholesterol in the LDL particles. So it starts making more and more LDL receptors or more and more baseball gloves to catch more and more baseballs because it's not making it's own cholesterol. And that's how you get a reduction of LDL cholesterol with an HMG-CoA reductase inhibitor. Now there is a couple of secondary beneficial effects of the statins.

    01:50 We call this pleotrophic effects. Pleo means multi-coloured. So, there is some wonderful things that happened because of the statins.

    01:59 First of all, it actually may prevent bone loss suprisingly. We know that it has some anti-inflammatory effects both systemically and with respect to the generation of sclerotic lesions in the vasculature. Now, this is above and beyond it's effect on LDL. So we think there might be a direct anti-inflammatory effect as well as the anti-cholesterol effect in terms of atherosclerosis. We think that statins may even be protective against contrast nephropathy, which is a bit of a suprise.

    02:31 Now, the toxicity behind these agents include a mild elevation of the CK values. You might get a mild transaminitis.

    02:40 How mild is mild? Anything under 8 times the upper limit of normal is acceptable. Anything above that is concerning.

    02:48 Anything that shows more than 2 times the upper limmit of normal is enough for me to be monitoring them at least once a month. Now here is where we become a little bit concerned and here's is where all the press around statins occur.

    03:01 There is a potentially fatal reaction on patients who take both statins and fibrates. Now this was first discovered on a statin called cerivastatin also called Baycol. And another fibrate called gemfibrozil. We noted that people were getting very bad rhabdomyolysis and very bad tissue muscle necrosis because of these combination drugs. Now, as time has gone by, we've discovered that the newer generation of statins are far less likely to cause this reaction and fenofibrate is less likely to cause it than gemfibrozil. Right now if you are taking a look at rosuvastatin and fenofibrate together, the risk is in the 1 in 1000000 range. Now, you may also get some kind of reactions like this with niacin as well. Remember that statins are broken down by the 3A4 isoenzyme of cytochrome P450. So that means that it's gonna have a lot of drug interactions including grapefruit juice and bitter oranges on marmalade. So going back to cerivastatin, it was withdrawn from the market due to that rhabdomyolysis that I had been talking about. The first generation of statins are lovastatin and simvastatin, and these are introduced into the body in their drugs as prodrugs and then they are metabolized into active agents.

    04:29 There is an increased number of drug reactions with these medications. You can see that those first agents have a relatively poor reduction in LDL. In terms of fluvastatin which is Lescol, atorvastatin which is known as Lipitor, and rosuvastatin which is known as Crestor they are far more effective in terms of cholesterol reduction and they have fewer drug reactions. Now if you look at this graph carefully, please note that the 60% reduction is at the bottom of the y-axis, and the 0% reduction is at the top of the y-axis. So the lower the graph line, the better the drug is. And you can see that atorvastatin and rosuvastatin are probably the most potent and most effective drugs on the market today. The important points about statins. First of all, statin effects is mostly due to increased LDL receptor expression. It is not because of the reduction of internal cholesterol synthesis on it's own, it's because of LDL receptor expression that we see the changes. Normal LDL receptors are required for statins to work. So if you have a theoretical disease where the LDL receptor is defective, the statins not going to work. And that's what happens with some types of homozygous familial hypercholesterolemia because it is often a disease of dysfunctional LDL receptors. And so we see that in this specific disease, the statins don't work that well. So that's why it's important to understand the mechanism of why it's working, as opposed to just the mechanism itself. Let's move on to ezetimibe. Ezetimibe is a prodrug and it undergoes glucuronidation in the liver to become active. It inhibits cholesterol transport or the cholesterol transporter. It prevents absorption of dietary cholesterol into the hepatocyte. There is a reactive increase in the LDL receptors which also helps reduce the cholesterol. So on it's own ezetimibe isn't that incredibly powerful. You're only gonna get about a 20% reduction in cholesterol values but it is remarkably free of side effects. It is very well tolerated. And it works beautifully in combination with statins to give us a huge cholesterol reduction when we use statin and ezetimibe together. In fact, there are some products available in different countries that combine ezetimibe and one of the statins in one pill.

    07:14 In terms of the uses of ezetimibe, we use it to treat hypercholesterolemia which makes sense.

    07:20 As I've said before you're gonna get about a 20% reduction using it on it's own, and a 25-30% additional LDL reduction, when you add it on to a statin. Now listen, that sound like very little but actually it's a lot. Consider this.

    07:36 When you go from 5mg to 10mg of rosuvastatin, you are only going to get a 6% additional reduction.

    07:43 When you go from 10 to 20 of rosuvastatin, you get a 6% additional reduction. And when you go from 20 to 40, 6% additional reduction. So getting a 25 to 30% add-on reduction to a statin, that's huge. That's like quadrupling or sometimes increasing the dose eight-fold to get the same kind of reduction just from statin increases. That's why using low dose statins or single dose ezetrol is actually more effective than doubling or tripling the dose of statin.

    08:17 We also can use ezetimibe in the treatment of phytostrolemia which is an unusual disorder that you can look up on your own.

    08:27 The toxicity is quite well tolerated. In fact it's better tolerated than most medications. It may increase the hepatotoxicity of most statins but that has been more of a theoretical concern than a real concern. It is sold as ezetrol in the United States and it is sold as a combination with simvastatin as Vytorin in the United States.

    08:50 I prefer using ezetrol in combination with rosuvastatin as individual pills because rosuvastatin gives you so much more reduction. Simvastatin is a drug that I no longer use when I can avoid it because simvastatin has 80% of it's breakdown going through cytochrome P450-3A4, whereas rosuvastatin does not use 3A4 and so there is less concern about drug interaction.

    About the Lecture

    The lecture HMG-CoA Reductase Inhibitors – Lipid Control by Pravin Shukle, MD is from the course Cardiovascular Pharmacology. It contains the following chapters:

    • HMG-CoA Reductase Inhibitors
    • HMG-CoA Reductase Inhibitors: Toxicity
    • HMG-CoA Reductase Inhibitors: Important Points
    • Cholesterol Transport Inhibitors: Ezetimibe

    Included Quiz Questions

    1. Protective against contrast nephropathy
    2. Increases LDL receptor expression
    3. Induction of CYP450 3A4 system
    4. Inhibition of cholesterol transporter
    5. Inhibits intracellular production of cholesterol
    1. Rhabdomyolysis risk is increased when combined with Ezitimibe.
    2. They may produce mild elevation of CK levels.
    3. They may produce mild elevations of transaminases.
    4. Drug interactions may occur with inducers of CYP450 3A4 with simvastatin.
    5. Cerivastatin was withdrawn from the market due to risk for rhabdomyolysis.
    1. Pravastatin
    2. Cerivastatin
    3. Rosuvastatin
    4. Atorvastatin
    5. Fluvastatin
    1. Properly functioning LDL receptors are required for statins to produce their effect.
    2. VLDL synthesis is impaired, so these patients have lower LDL levels already.
    3. HMG-CoA reductase binding site is distorted in these patients making statins less effective.
    4. The high risk of drug-induced pancreatitis precludes these patients from being prescribed statins.
    5. These patients are deficient in lipoprotein lipase and rarely have elevated LDL levels.
    1. There is no increase in the risk for hepatoxicity when combined with statins.
    2. It is a prodrug that requires glucuronidation to exert its biological effect.
    3. It is one of the best tolerated drugs in the management of hyperlipidemia.
    4. It acts by inhibiting the cholesterol transporter.
    5. It results in a reactive increase in LDL receptors.

    Author of lecture HMG-CoA Reductase Inhibitors – Lipid Control

     Pravin Shukle, MD

    Pravin Shukle, MD

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