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CLINICAL PHARMACOLOGY UPDATE

Bempedoic Acid: A Novel LDL –Lowering Agent Kylee Shriver

Hypercholesterolemia is commonly associated with di- of bempedoic acid/ combination products. A abetes. In combination with diabetes, it puts patients at cardiovascular outcomes trial of bempedoic acid is an increased risk for premature coronary heart disease ongoing (NCT02993406). This agent is the first oral and (1). adenosine triphosphate citrate lyase (ACL) inhibitor for LDL cholesterol–lowering. Lipoproteins are developed in one of two ways, via the exogenous or endogenous pathways. LDL cholesterol is a product of VLDL metabolism via the endogenous pathway. Indication Levels of LDL in the plasma are determined by the rate of Bempedoic acid is to be used as adjunctive therapy to LDL production and clearance. The LDL production rate diet and maximally controlled therapy for the from VLDL depends on LDL receptor activity. High re- treatment of heterozygous familial ceptor activity leads to a decrease in LDL production. or established atherosclerotic in Alternatively, low LDL receptor activity leads to an in- adults who require additional LDL cholesterol–lowering crease in LDL production. These levels of receptors in the therapies (4). The effect of bempedoic acid on are regulated by the cholesterol content of the cardiovascular morbidity and mortality has not hepatocytes. If the content is low, LDL receptor activity been determined. increases to allow for the increased uptake of cholesterol. If the content is higher, LDL receptor activity is decreased, and the LDL uptake is diminished (2). Mechanism of Action

Many medications are available today to manage hy- Bempedoic acid inhibits ACL, an enzyme that is upstream percholesterolemia. The most commonly used are , from HMG-CoA reductase in the cholesterol synthesis fibrates, bile acid sequestrants, , and dietary cho- pathway. Bempedoic acid and its active metabolite, lesterol uptake inhibitors. Less commonly used therapies ESP15228, require CoA activation via very-long-chain for cholesterol management include PCSK9 (proprotein acyl-CoA synthetase 1 (ACSVL1) to ETC-1002-CoA and convertase subtilisin/kexin type 9) inhibitors, MTP ESP15528-CoA. ASCVL1 is primarily expressed in the liver (microsomal triglyceride transfer protein) inhibitors, and is not activated in the skeletal muscle (5). Inhibition of CETP (cholesteryl ester transfer protein) inhibitors, and ACL by ETC-1002-CoA results in decreased cholesterol synthesis in the liver and decreases LDL cholesterol in apolipoprotein B-100 antisense oligonucleotides. None of plasma via upregulation of LDL receptors (4,5). these therapies have the same mechanism of action as the novel therapy bempedoic acid (Esperion Therapeutics).

Bempedoic acid has been shown to significantly lower LDL Potential Advantages cholesterol levels when added to maximally tolerated The main advantage of bempedoic acid is its novel statin therapies compared with placebo (3). Recently, mechanism. As the first drug of its kind, it allows patients bempedoic acid has been approved by the U.S. Food and the opportunity to try to optimize their therapy via a novel Drug Administration (FDA). The manufacturer has also mechanism before transitioning to the more invasive, submitted new drug applications (NDAs) and marketing injectable agents such as PCSK9 inhibitors. During the authorization applications (MMAs) seeking FDA approval CLEAR Wisdom (Evaluation of Long-Term Efficacy of

Washington State University Corresponding author: Kylee Shriver, [email protected] https://doi.org/10.2337/cd20-0038 ©2020 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at https://www.diabetesjournals.org/content/license.

1 Clinical Diabetes Online Ahead of Print, published online August 7, 2020 CLINICAL PHARMACOLOGY UPDATE

Bempedoic Acid (ETC-1002) in Patients With Hyperlip- . levels should be monitored and urate- idemia at High Cardiovascular Risk) and CLEAR lowering therapies should be initiated as appropriate. Harmony (Evaluation of Long-Term Safety and Tolera- Tendon rupture was also observed during trials (in 0.5% bility of ETC-1002 in High-Risk Patients With Hyper- of patients); thus, bempedoic acid should be avoided in lipidemia and High CV Risk) trials (6), the LDL those with a known history of tendon disorders or cholesterol–lowering capability of bempedoic acid was ruptures (4). significant. At week 12, bempedoic acid decreased levels Some other side effects noticed with bempedoic acid by 15.1% compared with a 2.4% increase with placebo. In during trials were upper respiratory tract infections (in participants not on statin therapy, bempedoic acid low- 4.5%), muscle spasms (in 3.6%), and back pain (in 3.3%), ered LDL cholesterol by 24.6% compared with 2.6% in the as well as abdominal pain, bronchitis, pain in extremities, placebo group; when used in combination with high- anemia, and elevated liver enzymes in smaller fractions of intensity statin therapy, bempedoic acid reduced trial participants (4). LDL levels by 14.4% compared with a 2.8% decrease in placebo. These effects were sustained for at least 52 weeks, making long-term therapy a possible option. Cost In addition to lowering LDL cholesterol levels, bempedoic It is estimated that bempedoic acid will cost ~ $300/ fi acid was shown to signi cantly decrease total cholesterol month ($10/day) for 180 mg tablets taken once daily as by 9.9% compared with an increase of 1.3% with placebo. directed. Although this can be considered a hefty price for This treatment could be a more attractive options for most patients, there is a manufacturer’s coupon available ’ prescribers if the goal is to lower a patient s total and LDL offering some cost savings (7). Although it is a newly ’ – cholesterol levels. Although it s LDL cholesterol lowering approved drug, its price is lower than expected for a capability is not as good as that of PCSK9 inhibitors, novel agent. it is cheaper and is an oral option, so no injections are necessary.

Another advantage of bempedoic acid is that it was Commentary designed specifically to avoid myalgias, one of the side Bempedoic acid is the first ACL inhibitor for use as an LDL effects of statin use. Many patients requiring dual therapy cholesterol–lowering therapy. Many trials, most notably for hypercholesterolemia are on agents in combinations the CLEAR Wisdom and CLEAR Harmony trials, have with statins that can increase the risk for myalgias and proven the efficacy of bempedoic acid in lowering LDL rhabdomyolysis. Although it works on the same choles- cholesterol levels when used in conjunction with maxi- terol pathway as statins, its active metabolite is not mized statin therapy. This novel treatment offers a new present in skeletal muscles; therefore, the myalgia risk is option for patients and providers when trying to optimize eliminated (6). cholesterol-lowering therapy. Pending NDAs and MAAs for combinations of bempedoic acid and ezetimibe could provide even more options. Potential Disadvantages Although its primary use will be in conjunction with statin therapy, bempedoic acid cannot be administered with Bottom Line doses of .20 mg or doses .40 mg. Bempedoic acid is an attractive adjunctive therapy for LDL Exceeding these doses can result in higher concentrations cholesterol–lowering in adults. Additionally, its design of statin and increase the risk of myopathies. Also, it helps to avoid myalgia risk, and its oral administration has been shown that the LDL cholesterol–lowering makes it potentially easier to use than injectable capability of bempedoic acid decreases as statin intensity PSCK9 inhibitors. Finally, it can potentially offer a is increased (6). cost advantage when compared with other injectable During trials, bempedoic acid was associated with ele- options when additional LDL cholesterol control vations in serum uric acid (in 1.5% of patients), causing is needed. new-onset gout or precipitating gout flares in patients with preexisting gout. Because of this potential DUALITY OF INTEREST adverse effect, bempedoic acid should be used with No potential conflicts of interest relevant to this article were caution in patients with known or reported.

2 CLINICAL.DIABETESJOURNALS.ORG Clinical Diabetes Online Ahead of Print, published online August 7, 2020 SHRIVER

GUARANTOR AUTHOR 4. Nexletol [package insert]. Ann Arbor, MI, Esperion Thera- As the sole author, K.S. is the guarantor of this work and, as such, peutics Inc., 2020 had full access to all of the references cited and takes re- 5. Esperion Therapeutics. Bempedoic acid: a novel agent. sponsibility for the accuracy of the content. Available from https://www.esperion.com/science/bempedoic- acid. Accessed 10 April 2020

REFERENCES 6. Mao J, Blumenthal R, Martin SS. Bempedoic acid, the next LDL cholesterol-lowering medication to join the 1. American Heart Association. Cholesterol abnormalities and arsenal? Insights from the CLEAR Wisdom trial. Available diabetes. Available from https://www.heart.org/en/health-topics/ from https://www.acc.org/latest-in-cardiology/articles/ – diabetes/why-diabetes-matters/cholesterol-abnormalities 2019/05/03/10/20/bempedoic-acid-the-next-ldl-cholesterol- diabetes. Accessed 10 April 2020 lowering-medication-to-join-the-arsenal. Accessed 10 2. Feingold KR, Grunfeld C. Introduction to lipids and lioproteins. April 2020 Available from https://www.endotext.org. Accessed 10 April 7. Vinluan F. Esperion’s FDA-approved cholesterol drug 2020 priced even lower than expected. Available from https:// 3. Ray KK, Bays HE, Catapano AL, et al.; CLEAR Harmony xconomy.com/detroit-ann-arbor/2020/02/24/esperions-fda- Trial. Safety and efficacy of bempedoic acid to reduce LDL approved-cholesterol-drug-priced-even-lower-than-expected. cholesterol. N Engl J Med 2019;380:1022–1032 Accessed 10 April 2020

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