Hypercholesterolemia is commonly associated with diabetes. In combination with diabetes, it puts patients at an increased risk for premature coronary heart disease and atherosclerosis (1).

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. Levels of LDL in the plasma are determined by the rate of LDL production and clearance. The LDL production rate from VLDL depends on LDL receptor activity. High receptor activity leads to a decrease in LDL production. Alternatively, low LDL receptor activity leads to an increase in LDL production. These levels of receptors in the liver are regulated by the cholesterol content of the hepatocytes. If the content is low, LDL receptor activity 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).

Many medications are available today to manage hypercholesterolemia. The most commonly used are statins, fibrates, bile acid sequestrants, niacin, and dietary cholesterol uptake inhibitors. Less commonly used therapies for cholesterol management include PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors, MTP (microsomal triglyceride transfer protein) inhibitors, CETP (cholesteryl ester transfer protein) inhibitors, and apolipoprotein B-100 antisense oligonucleotides. None of 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 cholesterol levels when added to maximally tolerated statin therapies compared with placebo (3). Recently, bempedoic acid has been approved by the U.S. Food and Drug Administration (FDA). The manufacturer has also submitted new drug applications (NDAs) and marketing authorization applications (MMAs) seeking FDA approval of bempedoic acid/ezetimibe combination products. A cardiovascular outcomes trial of bempedoic acid is ongoing (NCT02993406). This agent is the first oral adenosine triphosphate citrate lyase (ACL) inhibitor for lowering LDL cholesterol.

Bempedoic acid is to be used as adjunctive therapy to diet and maximally controlled statin therapy for the treatment of heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease in adults who require additional LDL cholesterol–lowering therapies (4). The effect of bempedoic acid on cardiovascular morbidity and mortality has not been determined.

Bempedoic acid inhibits ACL, an enzyme that is upstream from HMG-CoA reductase in the cholesterol synthesis pathway. Bempedoic acid and its active metabolite, ESP15228, require CoA activation via very-long-chain acyl-CoA synthetase 1 (ACSVL1) to ETC-1002-CoA and ESP15528-CoA. ASCVL1 is primarily expressed in the liver and is not activated in the skeletal muscle (5). Inhibition of ACL by ETC-1002-CoA results in decreased cholesterol synthesis in the liver and decreases LDL cholesterol in plasma via upregulation of LDL receptors (4,5).

The main advantage of bempedoic acid is its novel mechanism. As the first drug of its kind, it allows patients the opportunity to try to optimize their therapy via a novel mechanism before transitioning to the more invasive, injectable agents such as PCSK9 inhibitors. During the CLEAR Wisdom (Evaluation of Long-Term Efficacy of Bempedoic Acid [ETC-1002] in Patients With Hyperlipidemia at High Cardiovascular Risk) and CLEAR Harmony (Evaluation of Long-Term Safety and Tolerability of ETC-1002 in High-Risk Patients With Hyperlipidemia and High CV Risk) trials (6), the LDL cholesterol–lowering capability of bempedoic acid was significant. At week 12, bempedoic acid decreased levels by 15.1% compared with a 2.4% increase with placebo. In participants not on statin therapy, bempedoic acid lowered LDL cholesterol by 24.6% compared with 2.6% in the placebo group; when used in combination with high-intensity statin therapy, bempedoic acid reduced 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.

In addition to lowering LDL cholesterol levels, bempedoic acid was shown to significantly decrease total cholesterol by 9.9% compared with an increase of 1.3% with placebo. This treatment could be a more attractive options for prescribers if the goal is to lower a patient’s total and LDL cholesterol levels. Although its LDL cholesterol–lowering capability is not as good as that of PCSK9 inhibitors, it is cheaper and is an oral option, so no injections are necessary.

Another advantage of bempedoic acid is that it was designed specifically to avoid myalgias, one of the side effects of statin use. Many patients requiring dual therapy for hypercholesterolemia are on agents in combinations with statins that can increase the risk for myalgias and rhabdomyolysis. Although it works on the same cholesterol pathway as statins, its active metabolite is not present in skeletal muscles; therefore, the myalgia risk is eliminated (6).

Although its primary use will be in conjunction with statin therapy, bempedoic acid cannot be administered with doses of simvastatin >20 mg or pravastatin doses >40 mg. Exceeding these doses can result in higher concentrations of statin and increase the risk of myopathies. Also, it has been shown that the LDL cholesterol–lowering capability of bempedoic acid decreases as statin intensity is increased (6).

During trials, bempedoic acid was associated with elevations in serum uric acid (in 1.5% of patients), causing new-onset gout or precipitating gout flares in patients with preexisting gout. Because of this potential adverse effect, bempedoic acid should be used with caution in patients with known hyperuricemia or gout. Uric acid levels should be monitored and urate-lowering therapies should be initiated as appropriate. Tendon rupture was also observed during trials (in 0.5% of patients); thus, bempedoic acid should be avoided in those with a known history of tendon disorders or ruptures (4).

Some other side effects noticed with bempedoic acid during trials were upper respiratory tract infections (in 4.5%), muscle spasms (in 3.6%), and back pain (in 3.3%), as well as abdominal pain, bronchitis, pain in extremities, anemia, and elevated liver enzymes in smaller fractions of trial participants (4).

It is estimated that bempedoic acid will cost ∼$300/month ($10/day) for 180-mg tablets taken once daily as directed. Although this can be considered a hefty price for most patients, there is a manufacturer’s coupon available offering some cost savings (7). Although it is a newly approved drug, its price is lower than expected for a novel agent.

Bempedoic acid is the first ACL inhibitor for use as an LDL cholesterol–lowering therapy. Many trials, most notably the CLEAR Wisdom and CLEAR Harmony trials, have proven the efficacy of bempedoic acid in lowering LDL cholesterol levels when used in conjunction with maximized statin therapy. This novel treatment offers a new option for patients and providers when trying to optimize cholesterol-lowering therapy. Pending NDAs and MAAs for combinations of bempedoic acid and ezetimibe could provide even more options.

Bempedoic acid is an attractive adjunctive therapy for LDL cholesterol–lowering in adults. Additionally, its design helps to avoid myalgia risk, and its oral administration makes it potentially easier to use than injectable PSCK9 inhibitors. Finally, it can potentially offer a cost advantage when compared with other injectable options when additional LDL cholesterol control is needed.

Duality of Interest

No potential conflicts of interest relevant to this article were reported.

Guarantor Author

As the sole author, K.S. is the guarantor of this work and, as such, had full access to all of the references cited and takes responsibility for the accuracy of the content.

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Esperion’s FDA-approved cholesterol drug priced even lower than expected
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