Dr. Paul D. Thompson, MD, explains how bempedoic acid lowers LDL cholesterol for people who cannot tolerate statins, why it should spare skeletal muscle, which laboratory changes doctors should anticipate, and where PCSK9-blocking medications fit as further options.
Cholesterol Lowering Without Statins: Bempedoic Acid, Kidney Laboratory Tests, and PCSK9 Blockers
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- LDL reduction with bempedoic acid
- Activation in the liver, not in muscle
- Heart attack and stroke risk in statin intolerance
- Uric acid and gout
- Creatinine measurements during treatment
- PCSK9 blockers and other options
- Full Transcript
LDL reduction with bempedoic acid
Bempedoic acid is a cholesterol-lowering medication that cardiologist Dr. Paul D. Thompson, MD, has researched. Dr. Anton Titov, MD, asks when a patient with statin side effects should consider it and when an injectable cholesterol medication is needed. Dr. Thompson says he wrote one of the first clinical research articles on bempedoic acid, in 2015.
In that work, bempedoic acid at 180 mg daily reduced LDL cholesterol by about 31%, a figure he then revises to 29 to 30%. He calls it a good reduction. He notes that the compound was developed by a friend of his, Roger Newton, whom he describes as a very smart pharmacist trained at the University of Connecticut.
Activation in the liver, not in muscle
Activation in the liver is one of the interesting things Dr. Thompson points out about bempedoic acid. He places its action much higher up in the cholesterol pathway than the statins. It is not given in its active form: it is absorbed from the gut and converted into the active medication in the liver by a specific enzyme, very-long-chain acyl-CoA synthetase 1.
According to Dr. Thompson, only two places in the body have much of this enzyme: the liver, which has a lot, and the kidney, which has a little. The liver takes up bempedoic acid and cholesterol production is blocked. If some escapes the liver and reaches skeletal muscle, nothing should happen, because muscle cannot convert it into the active form.
Heart attack and stroke risk in statin intolerance
Statin intolerance was the focus of a big study Dr. Thompson took part in. He cannot remember the exact number of participants and thinks it was 10,000. All of them could not tolerate statins and received bempedoic acid or placebo, and bempedoic acid reduced their risk of heart attack, stroke, or sudden cardiac death. On that basis, he thinks bempedoic acid should be used in patients who cannot tolerate statins.
Uric acid and gout
Uric acid is the first of two kidney effects Dr. Thompson asks patients and doctors to be careful about. A small amount of bempedoic acid reaches the kidney, where it blocks the excretion of uric acid, and uric acid can cause gout. He says gout goes up a little in people taking bempedoic acid in the studies.
In his practice, he does not start bempedoic acid in a patient whose uric acid level is very high at the outset, because he does not want to push it higher and cause gout.
Creatinine measurements during treatment
Creatinine is the second laboratory effect Dr. Thompson discusses. He explains that bempedoic acid can reduce creatinine excretion, affecting a measurement used to assess kidney function. In his example, a doctor who sees creatinine go from 0.5 to 1 might decide to refer the patient for a kidney evaluation.
Dr. Thompson describes creatinine coming back down when bempedoic acid is stopped. In that example, he attributes the change to altered creatinine excretion rather than worsening kidney function. He also mentions a similar effect with fenofibrate. His explanation concerns the medication-related effect he describes, rather than a general interpretation of every rise in creatinine.
PCSK9 blockers and other options
PCSK9 blockers are another option Dr. Thompson describes for people who cannot tolerate statins. He runs a clinic for people with statin problems, and bempedoic acid is one of the options he uses there. He explains that PCSK9 grabs the LDL receptor and causes it to be broken down. Medications that block this are given by injection or infusion, and he mentions that there is now also a new oral medication, which he names in connection with Merck. He suggests discussing these options with a clinician when statins cannot be tolerated.
Full Transcript
Dr. Anton Titov, MD: Statin intolerance, cholesterol medication for patients who cannot take statins. You were first author of a clinical trial of bempedoic acid in patients with statin intolerance. Muscle complaints were about as frequent as with placebo. Professor Thompson, when should a patient with statin side effects consider bempedoic acid? When does a patient need an injectable cholesterol medication?
Dr. Paul D. Thompson, MD: So, bempedoic acid is an interesting drug. I wrote one of the first clinical papers on it in 2015. And what we did is we gave bempedoic acid to patients, and we were able to show that bempedoic acid, 180 mg daily, reduced LDL cholesterol about, let me see, it was about 31%, 29-30%.
Dr. Paul D. Thompson, MD: So it got a good reduction. Bempedoic acid is an interesting compound developed by a friend of mine, a guy named Roger Newton, who is a pharmacist who trained at the University of Connecticut, a very smart guy. So, bempedoic acid works in the cholesterol pathway.
Dr. Paul D. Thompson, MD: So, here is the cholesterol pathway. Right down here are the statins. Bempedoic acid works way up top.
Dr. Paul D. Thompson, MD: And here is the interesting thing about bempedoic acid. When you give it to a patient, you do not give it as the active drug. It is actually given as a prodrug.
Dr. Paul D. Thompson, MD: It has to get absorbed in the gut. It has to go to the liver, and the liver has a very specific enzyme to make bempedoic acid, the pre-drug, into bempedoic acid, the active drug. Now, there are only two places in the body that have much of this special very-long-chain acyl-CoA synthetase 1, and that is the kidney, where there is a little bit of it, and the liver, which has a lot of it.
Dr. Paul D. Thompson, MD: So if you take bempedoic acid, it goes in the gut, the gut delivers blood to the liver, and the liver picks up the bempedoic acid and blocks the production of cholesterol. But suppose the bempedoic acid escapes the liver; it does not all get picked up by the cell, and it escapes. So the bempedoic acid goes out and it gets to your skeletal muscle.
Dr. Paul D. Thompson, MD: Nothing should happen, because the skeletal muscle cannot take the prodrug and make it into the active drug. So it has been shown to be useful in people who cannot take statins. I was part of a big study.
Dr. Paul D. Thompson, MD: I cannot remember how many people, I think 10,000 people, who got bempedoic acid or a placebo. All these people could not tolerate statins, and the bempedoic acid reduced their risk of having a heart attack, stroke or sudden cardiac death. So I think bempedoic acid should be used in patients who cannot tolerate statins.
Dr. Paul D. Thompson, MD: Now, there are two groups you want to be careful of, or two things you want to be careful of. A small amount of bempedoic acid can get to the kidney. And in the kidney it does two things.
Dr. Paul D. Thompson, MD: One of them is potentially bad; one of them is just neutral. It blocks the excretion of uric acid. Now, uric acid can cause gout.
Dr. Paul D. Thompson, MD: So if a patient has a very high uric acid level at the start, I do not put them on bempedoic acid, because I do not want to push the uric acid level higher and give them gout. And in the studies, gout goes up a little bit in people on bempedoic acid. The other thing about bempedoic acid is that because it gets to the kidney and blocks the excretion of the uric acid, it also blocks the excretion of creatinine.
Dr. Paul D. Thompson, MD: And creatinine is something we use to measure kidney function. So it looks like your kidney has gotten worse. Now, your kidney has not gotten worse.
Dr. Paul D. Thompson, MD: You stop the bempedoic acid, and your creatinine comes back down. But if your doctor does not know about this, your doctor will look at your creatinine level and say, I have got to send you to somebody to evaluate your kidney function. It went from 0.5 to 1; your kidney is getting worse.
Dr. Paul D. Thompson, MD: No, the kidney is not getting worse. It is just the excretion of the creatinine that is getting worse. You stop the bempedoic acid, and it shows that the kidney is functioning fine.
Dr. Paul D. Thompson, MD: Now, this happens with other cholesterol-lowering drugs. One of the older cholesterol drugs, fenofibrate, also blocks the excretion of creatinine. It is important to know these things, for your doctors to know these things, because sometimes we can think, whew, kidney function is getting worse, this person is in trouble, when really all it is is that the drug is blocking the excretion. There are no side effects of that, there is no problem; it is just a measurement error.
Dr. Paul D. Thompson, MD: So I use bempedoic acid for a while, because I run a clinic that sees people with statin problems, and one of the things you can do is bempedoic acid. Now, there are these injectable drugs that work differently as well. And now an oral drug.
Dr. Paul D. Thompson, MD: There is something called PCSK9. PCSK9 grabs the LDL receptor, and when the LDL receptor goes into the liver, it causes it to be broken down. There are drugs that can block this PCSK9 grabbing, that can block the grabbing before the PCSK9 can grab the LDL receptor.
Dr. Paul D. Thompson, MD: Those are injectable drugs and infusion drugs, and there is also now a new oral drug for Merck. So this can be discussed with your clinician again, on one of those, if you cannot tolerate statins.