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Bempedoic Acid

Bempedoic Acid

Last Updated: October 1, 2023 | Dr Reza Moazzeni

Bempedoic Acid | Introduction and Video

Video: Bempedoic Acid mechanism of action

Bempedoic acid is a novel treatment against hypercholesterolemia. It offers hope to patients struggling to control their cholesterol levels, mainly when traditional therapies fall short or cause undesirable side effects.

High LDL cholesterol levels can increase the risk of heart-related problems. Numerous studies have shown that the more we reduce the LDL cholesterol levels, the more we can lower the risk of heart disease. Statins have been the cornerstone drugs for treating high cholesterol for over two decades. They work by reducing the internal production of cholesterol, which in turn promotes the liver drawing more cholesterol out of the blood by increasing the receptors for LDL cholesterol. These effects reduce cardiovascular morbidity and mortality. There is clear evidence that this effect is proportional to the absolute reduction of LDL cholesterol, independent of the type of treatment.

However, no drug is perfect, and statins are no exception. Firstly, there are occasional patients’ whose LDL cholesterol levels don’t drop to the recommended levels with statins. Secondly, 5-10% of the patients who could benefit from statins are incapable or reluctant to use them, mainly citing muscle-related symptoms as the cause. However, most of these complaints can be attributed to the nocebo effect. Because of these challenges, new “non-statin” medications, such as Bempedoic acid, have emerged as potential alternatives to statins.

What is Bempedoic Acid, and how does it work?

Bempedoic acid is a new drug that reduces LDL cholesterol differently from statins. It works by blocking a different step in the cholesterol production process. While this is not a critical step in cholesterol production, it’s at an important crossroads where fats and carbohydrates are metabolized in the body.

Bempedoic acid works by reducing the body’s natural production of cholesterol. This decrease in cholesterol triggers an increase in a particular receptor (LDLR) on the surface of the liver cells that helps to further lower LDL particles in our blood. Interestingly, in experiments using models that don’t have LDLR, bempedoic acid still managed to reduce LDL cholesterol levels and prevent the build-up of fats and inflammation in the aorta. This suggests that bempedoic acid might have additional ways of lowering cholesterol that doesn’t rely on LDL receptors.

Furthermore, bempedoic acid significantly reduces other harmful lipids in the blood, such as very-low-density lipoprotein cholesterol (VLDL-C) and triglycerides. This suggests that bempedoic acid might reduce the liver’s production of VLDL, but more studies are needed to confirm this theory.

Fig-1: How does bempedoic acid work? (Click on the image for a larger view)

Once Bempedoic acid in the body, it’s activated primarily in the liver by an enzyme called ACSVL1. Once activated, Bempedoic acid inhibits an enzyme called ATP citrate lyase (ACL), blocking an early step in the body’s cholesterol synthesis pathway known as the “mevalonate pathway”. By inhibiting this process, the drug reduces the liver’s natural production of cholesterol. This decrease in cholesterol production triggers an increase in the number of LDL receptors on the surface of the liver cells, promoting the liver to draw more LDL cholesterol out of the bloodstream and reduce overall LDL cholesterol levels.

Furthermore, bempedoic acid significantly reduces other harmful lipids in the blood, such as very-low-density lipoprotein cholesterol (VLDL-C) and triglycerides. This suggests that bempedoic acid might reduce the liver’s production of VLDL, but more studies are needed to confirm this theory.

What is unique about Bempedoic acid?

Bempedoic acid is what’s known as a prodrug, which means it needs to be activated in the body to do its job. This activation happens primarily in the liver by an enzyme called ACSVL1. ACSVL1 is found mainly in the liver and, to a lesser extent, in the kidneys. However, it’s not present in muscle or fat tissues. As a result, bempedoic acid remains “inactive” in the skeletal muscle tissue, significantly lowering the chance of muscle-related side effects often associated with statins. This characteristic makes it a desirable option for those who struggle with side effects from statin therapy or are unwilling to take them.

Fig-2: Why bempedoic acid causes less muscle pain, compared to statins? (Click on the image for a larger view)

Bempedoic acid requires activation by an enzyme called ACSVL1, which is present in liver cells (hepatocytes). This image illustrates how bempedoic acid is selectively activated in the liver, where it exerts its cholesterol-lowering effect. Muscle cells lack the ACSVL1 enzyme, meaning bempedoic acid stays inactive in these cells.

What is the evidence for Bempedoic acid?

Bempedoic acid has been investigated in 5 major trials known as Cholesterol Lowering via Bempedoic acid, an ACL-Inhibiting Regimen (CLEAR) program:

  • CLEAR Wisdom Study: This study had 779 high-risk patients with high cholesterol (LDL-C ≥70 mg/dL) despite maximally tolerated lipid-lowering therapy. At the 12th week, Bempedoic Acid reduced LDL-C cholesterol levels by 15.1% compared to a 2.4% increase in the placebo group. Other markers, including non-HDL-C, total cholesterol, apoB, and hs-CRP, were also significantly reduced. These effects were maintained through the 52nd week of the trial. The study found that Bempedoic Acid worked better in patients not taking statins or any other lipid-lowering therapy.
  • CLEAR Harmony Study: This study involved 2230 patients with cardiovascular disease, familial hypercholesterolemia, or both. These patients had LDL-C > 70 mg/dL while taking the maximum dose of statin they could tolerate. Bempedoic Acid reduced LDL-C levels by 16.5% at week 12 compared to a 1.6% increase in the placebo group. By the 52nd week, the LDL-C levels were still significantly reduced, albeit slightly less than at week 12 (-12.6% vs. -16.5%).
  • CLEAR Serenity Study: This study involved patients who were intolerant to at least two types of statins. Bempedoic Acid significantly reduced LDL-C levels by 23.6% at week 12 compared to a 1.3% reduction with a placebo. It also significantly reduced non–HDL-C, total cholesterol, apoB, and hs-CRP. It was noted that the reduction in LDL-C was different between patients with and without diabetes.
  • CLEAR Tranquility Trial: In this study, Bempedoic Acid was added to a drug called Ezetimibe in patients who could only tolerate the lowest available dose of statin and had LDL-C levels over 100 mg/dL. After 12 weeks, Bempedoic Acid led to a 23.5% reduction in LDL-C levels compared to a 5.0% increase with placebo. The study also noted significant reductions in non–HDL-C, total cholesterol, apoB, and hs-CRP. Interestingly, patients on non-statin drugs (Ezetimibe) as background lipid-lowering therapy had a higher LDL-C reduction than those taking low-dose or very-low-dose statin.
  • CLEAR Outcomes study: In this study, nearly 14,000 high-risk patients who could only tolerate a very low dose of statins, were randomly assigned to Bempedoic acid or placebo. Bempedoic acid lowered LDL cholesterol levels by 21% more than placebo. It also reduced the risk of major cardiovascular events (death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization) by 13% over an average of 3.4 years. The drug was also effective in patients taking concurrent very-low-dose statin and Ezetimibe. Interestingly, it showed more significant benefits for primary prevention patients. While muscle pain was similar between groups, gout, gallstones, and higher levels of certain blood markers, such as creatinine, uric acid and liver enzymes, were more common in those taking the Bempedoic acid.

Who should take bempedoic acid?

Bempedoic acid is primarily for patients at high risk for coronary artery disease who cannot tolerate statins despite multiple attempts with different types of statins. It can also be used concurrently with statins in high-risk patients who still have high LDL cholesterols despite taking maximally tolerated doses of statins. However, the clinical benefit of bempedoic acid added to statins is unknown.

Also, we have observed that bempedoic acid can raise the levels of Pravastatin and Simvastatin in the blood more than other statins. Therefore, switching these medications to a different statin or using them at a minimal dose (less than 20 mg) along with bempedoic acid is recommended.

Should I replace my statin with bempedoic acid?

Bempedoic acid can be a good option for patients who can’t tolerate statins due to side effects, primarily muscle-related symptoms, or who don’t get enough cholesterol reduction from statins alone. Nonetheless, it’s too soon for other patients to see bempedoic acid as a statin alternative. 

Given the robust evidence of statins’ benefits, all possible attempts should be made to initiate statins at the highest tolerated doses for appropriate patients, even those who have discontinued statin use because of presumed side effects.

Amid advanced medical therapies for high cholesterol, what's the role of a healthy lifestyle?

While breakthroughs in medications like Bempedoic acid and traditional statins have significantly advanced managing high LDL cholesterol levels and reducing the risk of heart disease, they are not standalone solutions. It’s essential to remember that these treatments are an adjunct to a healthy lifestyle, not a replacement for one.

A heart-healthy diet, a reasonable amount of exercise, and avoiding harmful habits like smoking are still fundamental to cholesterol management and overall cardiovascular health. It’s a comprehensive approach that brings together lifestyle modifications and medications that offers the most promising results for individuals with high cholesterol.

In essence, while Bempedoic acid and statins are valuable tools in the fight against high LDL cholesterol levels and heart disease, they work best when used in conjunction with a healthy lifestyle.

References and further reading

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