Dr. Paul D. Thompson, MD, explains why doubling a statin dose adds little LDL lowering, what his group found with rosuvastatin given twice weekly, and why he often prefers adding ezetimibe. He also discusses why such dosing strategies are absent from clinical guidelines.
Low-Dose Statin Treatment: Diminishing Returns, Intermittent Dosing, and Ezetimibe
Jump To Section
- LDL reduction per milligram at low doses
- The statin rule of six
- Rosuvastatin taken a few days a week
- Adding ezetimibe instead of doubling the dose
- Why these approaches are not in guidelines
- Each patient as an experiment of one
- Full Transcript
LDL reduction per milligram at low doses
Low-dose statin treatment is one of the favorite topics of cardiologist Dr. Paul D. Thompson, MD. Dr. Anton Titov, MD, asks how a patient can lower cholesterol with the smallest statin dose and when ezetimibe makes more sense than a higher statin dose. Dr. Thompson's starting point is that the most LDL cholesterol reduction per milligram of medication comes at very low doses, and that doubling the dose does not add much.
The statin rule of six
The statin rule of six is his name for this pattern. Dr. Thompson illustrates it with an example: with an LDL level of 200, pravastatin 20 milligrams should give about a 25% reduction, to about 150. Doubling to pravastatin 40 does not bring another 50-point fall. It adds only 6% of the baseline, or 12 points, taking LDL from 150 to 138 on average.
He adds that the returns are even smaller at the top of the dose range. In his account, going from 40 to 80 milligrams of atorvastatin, the highest dose, gives only about a 4% further reduction, and going from 20 to 40 milligrams of rosuvastatin, its highest dose, only about 3%.
Rosuvastatin taken a few days a week
Intermittent dosing of longer-acting statins is something his group has studied. Dr. Thompson describes giving 5 milligrams of rosuvastatin on Monday and on Thursday. After seven doses, measured on Thursday morning before the eighth dose, patients had a 27 percent reduction in LDL cholesterol, which he calls a big reduction.
He also mentions studies showing that 5 milligrams of rosuvastatin once a week produced roughly a 15% LDL reduction. His conclusion is that there is room to adjust these schedules.
Adding ezetimibe instead of doubling the dose
Ezetimibe is what Dr. Thompson often adds instead of doubling the statin dose. He explains that statins block cholesterol production in the liver by acting on the rate-limiting enzyme, hydroxymethylglutaryl CoA reductase. When production falls, the body responds by absorbing more cholesterol from the gut. Ezetimibe blocks that absorption.
In his figures, ezetimibe alone gives about a 20% average LDL reduction, and ezetimibe added to a statin about 24%. Because ezetimibe has a long half-life, he says he will often give it on Monday, Wednesday, and Friday.
Why these approaches are not in guidelines
Clinical guidelines do not include these approaches, and Dr. Thompson explains why. Guidelines have to be based on science and on completed studies. In his view, no pharmaceutical company wants patients to take its daily medication twice a week, so nobody studies it. Studies like his show a reduction in LDL cholesterol, but there are no big outcome studies showing a reduction in heart attacks, so this kind of approach does not get into the guidelines.
Each patient as an experiment of one
Individual response is the theme of his closing remarks. Dr. Thompson tells every patient that they are an experiment of one: he never knows exactly what will happen until treatment starts and both doctor and patient pay attention. He says patients can help their doctor a lot by observing along with them, while asking them, with some humor, not to drive their doctor nuts with their observations.
Full Transcript
Dr. Anton Titov, MD: Low-dose statin treatment, the statin rule of six. On your blog you wrote that doubling a statin dose lowers cholesterol only a little more. You were senior author of an article on rosuvastatin taken twice a week by statin-intolerant patients. Cholesterol fell, and most patients tolerated the schedule. Professor Thompson, how can a patient lower cholesterol with the smallest statin dose? When does ezetimibe make more sense than a higher statin dose?
Dr. Paul D. Thompson, MD: This whole thing about low-dose statins is one of my favorite topics. Believe it or not, you get the most reduction in LDL cholesterol per milligram of drug. Did you hear that?
Dr. Paul D. Thompson, MD: Per milligram of drug at very low drug levels. You do not get that much more by doubling the dose. So let me give you an example.
Dr. Paul D. Thompson, MD: Suppose my LDL, my ugly cholesterol, is 200 milligrams, and you decide to put me on pravastatin 20 milligrams. Now, that should give me about a 25% reduction. So I was 200, I got a 25% reduction, and I come down to about 150.
Dr. Paul D. Thompson, MD: You say that is not good enough. I am going to double your statin. We are going to go from pravastatin 20 to pravastatin 40.
Dr. Paul D. Thompson, MD: I am not going to get another 50-point reduction. I am only going to get 6% of the baseline, so 6% of 200. I am not going to get another 50-point reduction; I am only going to get a 12-point reduction.
Dr. Paul D. Thompson, MD: So I went from 200 to 150 with 20 milligrams. I go from 150 to 138, on average, with 40 milligrams. That is called the statin rule of six.
Dr. Paul D. Thompson, MD: Doubling the dose of the statin only gives you an additional 6% LDL reduction. And it actually is worse than that, because when you go from the highest dose of atorvastatin, 40 to 80, you only get about a 4% reduction. When you go from 20 milligrams of rosuvastatin to the highest dose, 40, you only get about a 3% reduction, so it is diminishing returns.
Dr. Paul D. Thompson, MD: We have studied giving the longer-acting statins, like rosuvastatin, Monday and Thursday, 5 milligrams. The daily dose should be five milligrams daily. We did five milligrams Monday. We did five milligrams Thursday.
Dr. Paul D. Thompson, MD: What we showed, after seven doses of the drug, on Thursday morning before the eighth dose, was that the patients had a 27 percent reduction in LDL cholesterol. A big reduction. So what do I do instead of doubling the dose?
Dr. Paul D. Thompson, MD: I often add a drug called ezetimibe. Now, what ezetimibe does is it blocks the absorption of cholesterol in your gut. Statins block the production of cholesterol in your liver by affecting the rate-limiting enzyme hydroxymethylglutaryl CoA reductase.
Dr. Paul D. Thompson, MD: So you block the production in the liver and the cholesterol falls down, but your body is not stupid. What the body starts to do is it starts to absorb more cholesterol from the gut. If you are not taking a statin and you take this drug ezetimibe, which blocks cholesterol absorption in the gut, you get about a 20% LDL reduction on average.
Dr. Paul D. Thompson, MD: If you are taking a statin and you take ezetimibe, you get about a 24% LDL reduction. So what I often do is, rather than doubling the statin, I often add ezetimibe. And also, because ezetimibe has a long half-life, oftentimes I will give it Monday, Wednesday, Friday rather than the highest dose.
Dr. Paul D. Thompson, MD: Now, why are these recommendations not in the guidelines? Why is that not the sort of thing that everybody does? The guidelines that we publish and put out have to be based on science.
Dr. Paul D. Thompson, MD: They have to be based on completed studies, and none of the pharmaceutical companies want you to take their daily drug twice a week, so nobody studies it. So there are not big studies with outcomes. You have studies like mine that show a reduction, a reduction in LDL cholesterol, but there are not studies that show a reduction in heart attacks.
Dr. Paul D. Thompson, MD: So that sort of an approach does not get into the guidelines. Believe it or not, there are actually studies that show that taking five milligrams of rosuvastatin once a week produced like a 15% reduction in LDL cholesterol. So you can play around with these things.
Dr. Paul D. Thompson, MD: I tell every patient that they are an experiment of one. They are a single-person experiment. I never know exactly what is going to happen with a patient until we treat them and we pay attention.
Dr. Paul D. Thompson, MD: And you actually help your doctor a lot if you pay attention along with them. So do not be a pain in the butt, driving them nuts with your observations and stuff. But you can be very helpful by seeing what goes on.