#8 Bempedoic Acid for Cholesterol-Lowering in Statin Intolerant Patients

Overview

High cholesterol is a major concern for nearly 40 percent of American adults. Although high cholesterol is extremely common, affected individuals exhibit no symptoms. If left untreated, high cholesterol can lead to devastating health problems like heart attack, stroke or sudden cardiac death.

Cholesterol is a waxy, fat-like substance that the body needs to function normally. It is used as a building block for many structures within the body including some hormones. But when the “bad” LDL cholesterol (the type of cholesterol associated with atherosclerosis) is present in excess, this substance can be deposited within the lining of artery walls, decreasing the amount of blood flow to various areas of the body or promoting devastating blood clots.

Several medications exist for the treatment of high cholesterol – statins being the most popular. This class of medication functions by way of inhibiting HMG-CoA reductase, the rate-limiting enzyme of the mevalonate pathway. By inhibiting HMG-CoA, the liver is unable to produce the molecule melvalonate that is eventually converted to cholesterol. In response to cholesterol deprivation, the liver cells remove more LDL cholesterol from the blood stream.

But the prescription of statins comes with some unpleasant, adverse side effects in some patients. Statins can accumulate in muscles, resulting in muscle pain in approximately 5-10% of people. In clinical practice, muscle symptoms occur at higher rates than seen in randomized clinical trials. In the absence of these side effects, statins are very effective in lowering low-density lipoprotein (LDL) cholesterol. In recent studies, very low levels of LDl-cholesterol have been associated with a reduction in heart attack and stroke. The opportunity for further reduction and protection against heart attack and stroke opens doors to development of additional therapies.

New agents like bempedoic acid have the potential to fill complimentary role. Bempedoic acid has been designed as a once-daily, oral therapy that significantly lowers LDL levels when added to other lipid-lowering therapies (including statins). The compound is a targeted therapy designed to work in the liver. Converted to its active moiety, bempedoic acid inhibits adenosine triphosphate citrate lyase (ACL) – an enzyme two steps upstream from HMC-CoA reductase (the target of statins). Unlike statins, bempedoic acid cannot be converted to its active form in the skeletal muscle, thus reducing cholesterol levels in the blood without the side effect of muscle pain.

In clinical trials of the therapy, bempedoic acid reduced LDL about 25% in patients unable to tolerate full dosages of statins. These findings were the centerpiece of a submission for approval for the FDA in February 2019. If approved, the therapy provides a method for further, well tolerated, cholesterol reduction in patients whose levels need to be reduced.

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