Bempedoic acid

Introduction

Bempedoic acid is an inhibitor of adenosine triphosphate-citrate lyase (ACL), an enzyme that plays a role in lipid synthesis by converting citrate to acetyl coenzyme A (CoA). Adenosine triphosphate-citrate lyase is upstream in the same biosynthetic pathway as 3-hydroxy-3-methyl-glutaryl-CoA (HMG CoA) reductase (the target enzyme for statins). Inhibition of ACL slows lipid production and thus lowers low-density lipoprotein cholesterol (LDL-C) levels in blood. Bempedoic acid received Food and Drug Administration (FDA) approval in 2020, following several other attempts to develop a safe and effective ACL inhibitor.

Appropriate Uses

In the United States, the FDA has approved bempedoic acid for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular disease (ASCVD), as an adjunct to diet and maximally tolerated statin therapy, for patients who require additional lowering of LDL-C. Bempedoic acid is available in two tablet formulations: one containing only bempedoic acid as the active ingredient (Nexletol), and another containing bempedoic acid in combination with ezetimibe (Nexlizet), a cholesterol absorption inhibitor. Administration of bempedoic acid in combination with a maximally-tolerated statin regimen, with or without other lipid modifying agents, decreases LDL-C, non-high density lipoprotein cholesterol (HDL-C), apolipoprotein B (apoB) and total cholesterol (TC) in patients with hyperlipidemia.

The 2018 multi-society cholesterol guideline was published before bempedoic acid was approved and therefore does not contain recommendations on its use. The 2022 American College of Cardiology (ACC) Expert Consensus Decision Pathway on the use of nonstatins, however, states that bempedoic acid may be considered in the following cases:

• Patients with very high risk ASCVD (secondary prevention) who do not achieve ≥50% reduction in LDL-C levels and an absolute LDL-C level of <55 mg/dL on maximally-tolerated statin therapy
• Patients with non-very high risk ASCVD (secondary prevention) who do not achieve ≥50% reduction in LDL-C levels and an absolute LDL-C level of <70 mg/dL on maximally-tolerated statin therapy
• Patients without clinical ASCVD with a baseline LDL-C level of ≥190 mg/dL (primary prevention) who do not achieve ≥50% reduction in LDL-C levels and an absolute LDL-C level of <100 mg/dL on maximally-tolerated statin therapy
• Select patients with statin-associated side effects, after ezetimibe and/or PCSK9 monoclonal antibodies (for secondary prevention and primary prevention in patients with LDL-C ≥190 mg/dL) and ezetimibe followed by bile acid sequestrants (for primary prevention in patients with diabetes or in patients with LDL-C 70-189 mg/dL) have been tried.

Mechanism of Action

Bempedoic acid is a prodrug that is converted to the active form, bempedoyl CoA, by the enzyme very long-chain acyl-CoA synthease-1 (ACSVL1) that inhibits ACL in the liver (Figure 24-1). This decreases the conversion of mitochondrial-derived citrate to cytosolic acetyl-CoA, creating less substrate for cholesterol and fatty acid synthesis. As a result, LDL receptors are upregulated, which eventually reduces hepatic cholesterol synthesis and lowers blood LDL-C levels. Additionally, bempedoic acid activates adenosine monophosphate-activated protein kinase, an enzyme which has been shown to inhibit acetyl-CoA carboxylase and hydroxymethylglutaryl-CoA reductase in mice. This results in reduced production of fatty acids and cholesterol.

In order to have therapeutic effect, bempedoic acid and its active metabolite need to be activated by ACSVL1, which is expressed in the liver, but not in skeletal muscle. This reduces the risk for muscle-related adverse effects.

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LDL-C Lowering Efficacy

The CLEAR Wisdom trial randomized (2:1) 779 adults at high cardiovascular risk because of ASCVD (coronary artery disease [CAD] or CAD risk equivalents), HeFH, or both, to bempedoic acid 180 mg once daily or a matching placebo for 52 weeks. Documented CAD included acute myocardial infarction (MI), silent MI, unstable angina, coronary revascularization, or clinically significant CAD. Cerebrovascular atherosclerotic disease (CBVD) and symptomatic peripheral arterial disease (PAD), but not type 2 diabetes mellitus, were considered CAD risk equivalents. Eligible patients were on a stable, maximally tolerated lipid-lowering therapy and had a fasting LDL-C level of 100 mg/dL or higher at the first screening visit and 70 mg/dL or higher 1 week before randomization. Exclusion criteria included: a total fasting triglyceride level of 500 mg/dL or higher, body mass index 50 or greater, severe renal impairment (estimated glomerular filtration rate <30 mL/min/1.73 m²), CAD event within 3 months of screening, and clinically significant disease that could interfere with study participation. Assessment of fasting LDL-C levels was done at week 4, week 12, week 24 and week 52.

At week 12, LDL-C change from baseline (the primary endpoint of the trial) was significantly lower with bempedoic acid than with placebo (–15.1% vs 2.4%, respectively; P <.001; see Figure 24-2). At week 24, the change in LDL-C level from baseline was –12.1% in the bempedoic acid group, compared to 2.7% in the placebo group (difference, -14.8% [95% CI, -19.5% to -10.0%]; P <.001).

The CLEAR Harmony trial randomized (2:1) 2,230 patients with ASCVD, HeFH, or both, to bempedoic acid 180 mg once daily or a matching placebo for 52 weeks. Participants were required to be receiving stable, maximally tolerated lipid-lowering therapy and to have a fasting LDL-C level of 70 mg/dL or higher during a 2-week screening period. The use of gemfibrozil or simvastatin at doses above 40 mg per day was the key exclusion criterion (by contrast, high-intensity atorvastatin and rosuvastatin regimens were allowed). The use PCSK9 inhibitors was prohibited in the 4 weeks before trial entry; however, PCSK9 inhibitors were allowed after trial week 24 in patients whose LDL-C levels were greater than 170 mg/dL and had increased from baseline by 25% or more. Assessment of LDL-C levels was done at week 4, week 8, week 12, week 24, week 36 and week 52.

Bempedoic acid reduced LDL-C levels significantly more than placebo both at week 12 (difference, -18.1%; 95% CI, -20.0% to -16.1; P <0.001; see Figure 24-3) and at week 24 (difference, -16.1%; 95% CI, -18.2% to -14.0%; P <.001).

The efficacy of bempedoic acid in combination with ezetimibe was tested in a trial which randomized (2:2:2:1) 382 adults at high CVD risk due to the presence of ASCVD, HeFH, or multiple CVD risk factors to one of: 1) a fixed-dose combination of bempedoic acid 180 mg and ezetimibe 10 mg (BA+EZE FDC); 2) bempedoic acid 180 mg; 3) ezetimibe 10 mg; or 4) placebo, for a treatment duration of 12 weeks. In the context of this trial, documented ASCVD was defined as a history of acute MI, silent MI, unstable angina, coronary revascularization procedures, clinically significant CAD, symptomatic PAD, CBVD. The presence of multiple CVD risk factors was defined as a combination of diabetes and one other CVD risk factor, or any three of the following CVD risk factors: age ≥45 years (men) or ≥55 years (women), family history of CAD, smoking, hypertension, low HDL-C, and coronary calcium score above the 95^th percentile for the patient’s age, sex and race or ethnicity. For patients with ASCVD and/or HeFH, fasting LDL-C levels were required to be at least 100 mg/dL while on a stable maximally-tolerated statin regimen. For patients with multiple CVD risk factors, fasting LDL-C levels on stable maximally-tolerated statin therapy were required to be 130 mg/dL or higher. Assessment of LDL-C levels was done at the screening visit and before dosing on day 1 and weeks 4, 8 and 12.

At week 12, LDL-C lowering with BA+EZE FDC was significantly greater than that for the placebo, ezetimibe, or bempedoic acid groups (P <.001 for all comparisons; Figure 24-4). BA+EZ FDC provided a reduction of 38.0% compared with placebo. A significantly greater proportion of patients achieved LDL-C levels of <100 mg/dL and <70 mg/dL at week 12 in the BA+EZE FDC treatment group (67.5% and 31.3%, respectively) compared to the placebo (17.5% and 0%; P <.001), ezetimibe alone (42.5% and 10.0%; P ≤.002), and bempedoic acid alone (43.9% and 6.1%; P ≤0.003) groups. A significantly higher proportion of patients had an LDL-C reduction from baseline of at least 50% in the BA+EZE FDC group (33.7%) compared to the placebo (0%), ezetimibe alone (5.0%) and bempedoic acid alone (3.7%) groups (P <.001 for all comparisons).

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Patients Who Cannot Tolerate Statins

In the combination regimen (BA+EZE FDC) trial, the study population included 31–38% of patients who were not receiving a statin due to SASE. The BA+EZE FDC regimen lowered LDL-C in this subgroup by 38.8%. The combination regimen thus has potential to lower LDL-C levels regardless of baseline statin use.

ASCVD and Mortality Outcomes

The effects of bempedoic acid (alone on in combination) on cardiovascular morbidity and mortality has not yet been determined. In CLEAR Harmony, a major adverse cardiac event (MACE) was reported in 68 (4.6%) patients in the bempedoic acid group and 42 (5.7%) patients in the placebo group. Those MACE included six deaths from cardiovascular causes in the bempedoic acid group (0.4%) and to 1 death from cardiovascular causes in placebo group (0.1%), nonfatal myocardial infarction in 19 patients in the bempedoic acid group (1.3%) and 13 patients in placebo group (1.8%), nonfatal stroke in 5 patients in the bempedoic acid group (0.3%) and 2 patients in placebo group (0.3%), coronary revascularization in 38 patients in the bempedoic acid group (2.6%) and 24 patients in placebo group (3.2%) and hospitalization for unstable angina in 14 patients in the bempedoic acid group (0.9%) and 11 patients in placebo group (1.5%). A valid statistical analysis of these adverse event data has not been performed.

Effects on Other Lipids and Lipoproteins

Bempedoic acid has effects on other lipids and lipoproteins, such as HDL-C, non-HDL-C, total cholesterol, apoB, amd high-sensitivity C-reactive protein (hs-CRP).

In CLEAR Wisdom, the assessment of fasting lipids (HDL-C, non-HDL-C, total cholesterol and triglycerides) was done at week 4, week 12, week 24 and week 52. Levels of apoB and hs-CRP were measured at baseline and at weeks 12, 24 and 52. Significantly greater reductions in non–HDL-C (P <.001), total cholesterol (P <0.001), apoB (P <.001), and hs-CRP (P=.04) levels from baseline were observed with bempedoic acid treatment compared to the placebo.

In CLEAR Harmony, the assessment of fasting lipids was done at week 4, week 8, week 12, week 24, week 36 and week 52. At week 12, bempedoic acid treatment resulted in a significant differences, compared to placebo, in the change from baseline of non-HDL-C (-13.3% [95% CI, -15.1% to -11.6%]), total cholesterol (-11.1% [95% CI, -12.5% to -9.8%]), apoB (-11.9% [95% CI, -13.6% to -10.2%]) and hs-CRP (-21.5% [95% CI, -27.0% to -16.0%]) (P <.001 for all comparisons).

The assessment of fasting lipids in the combination regimen (BA+EZE FDC) trial was done at the screening visit and before dosing on day 1 and weeks 4, 8 and 12. Assessment of apoB and hsCRP was done before dosing on day 1 and at week 12. The BA+EZE FDC regimen reduced hs-CRP by 35.1% from baseline; by contrast, hs-CRP levels increased by 21.6% in the placebo group (P <.001) and were reduced by 8.2% in the ezetimibe group (P=0.002). The BA+EZE FDC regimen also reduced non-HDL-C, total cholesterol and apoB (-31.9%, -26.4% and -24.6%, respectively) more than placebo (1.8%, 0.7% and 5.5%, respectively; P <.001 for all), ezetimibe alone (-19.9%, -16.0%, and -15.3%, respectively; P <.001 for non-HDL-C and total cholesterol and P=.003 for apoB), or bempedoic acid alone (-14.1%, -12.1%, and -11.8%, respectively; P <.001 for all).

Dosing

Bempedoic acid is administered orally, with or without food, alone (Nexletol) or in a fixed-dose combination with ezetimibe (Nexlizet). The recommended dosage is 1 tablet containing 180 mg of bempedoic acid alone once daily or 1 fixed-dose combination tablet containing 180 mg of bempedoic acid and 10 mg of ezetimibe once a day, in combination with maximally tolerated statin therapy.

After initiation of the regimen, lipid levels should be analyzed within 8 to 12 weeks.

See the manufacturer’s package insert for managing missed doses and administration and storage instructions.

Contraindications

Bempedoic acid alone has no contraindications. In patients taking the BA+EZE FDC tablet, hypersensitivity to ezetimibe tablets is the only contraindication. Hypersensitivity reactions (including anaphylaxis, angioedema, rash and urticaria) have been reported with ezetimibe.

Safety

Warnings and Precautions

Hyperuricemia and tendon rupture have been reported in patients receiving bempedoic acid treatment both in combination with ezetimibe and alone.

In clinical trials, 26% of patients with normal baseline uric acid values treated with bempedoic acid experienced hyperuricemia at least once, compared to 9.5% of patients who received placebo. Clinically significant hyperuricemia was reported in 3.5% of patients who received bempedoic acid and 1.1% of those who received the placebo. Gout, which may result from hyperuricemia, was observed in 1.5% of bempedoic acid-treated patients and 0.4% of placebo-receiving patients. Patients should be monitored for signs and symptoms of hyperuricemia and treatment with urate-lowering drugs should be initiated as appropriate.

Tendon rupture involving the rotator cuff, biceps tendon, or Achilles tendon occurred in 0.5% of bempedoic acid-treated patients in clinical trials, compared to 0% of patients who received the placebo. Patients over 60 years of age, taking corticosteroid or fluoroquinolone drugs, with renal failure and patients with previous tendon disorders may experience tendon rupture more frequently. The treatment should be discontinued immediately if the patient experiences rupture of a tendon, while discontinuation should be considered if the patient experiences joint pain, swelling, or inflammation. Alternative therapy should be considered in patients with a history of tendon disorders or tendon rupture.

Adverse Reactions

In CLEAR Wisdom and CLEAR Harmony, the most common adverse reactions for bempedoic acid, occurring in ≥2% of patients and at a greater frequency than in the placebo group, included: upper respiratory tract infections (4.5%), muscle spasms (3.6%), hyperuricemia (including increased blood uric acid; 3.5%), back pain (3.3%), abdominal pain or discomfort (3.1%), bronchitis (3.0%), pain in extremity (3.0%), anemia (2.8%) and liver enzyme elevations (2.1%).

In the combination regimen (BA+EZE FDC) trial, the most common adverse reactions for the BA+EZE FDC regimen, occurring in ≥3% of patients and at a greater frequency than in the placebo group, that were not reported in clinical trials of bempedoic acid or ezetimibe, were urinary tract infection (5.9%), nasopharyngitis (4.7%) and constipation (4.7%).

Pregnancy and Nursing Mothers

The risk of major birth defects, miscarriage and adverse maternal or fetal outcomes associated with bempedoic acid is unknown, owing to a lack of available data in pregnant women. When administered to rats and rabbits at doses resulting in equivalent exposures up to 11-12 times the human exposure at the maximum clinical dose, bempedoic acid was not teratogenic. It is currently not known whether bempedoic acid is present in human or animal milk, what effects it has on the breastfed infant, or whether it affects milk production. Because it decreases synthesis of cholesterol and potentially other biologically active cholesterol derivatives, bempedoic acid may cause harm to the fetus or the breastfed infant. Patients who are pregnant should discontinue bempedoic acid unless the benefit outweigh the risk to the fetus. Patients who are breastfeeding should discontinue the use of bempedoic acid or stop breastfeeding.

Renal Impairment

Patients with mild or moderate renal impairment can take bempedoic acid without dosage adjustment. Clinical trials of bempedoic acid did not include patients with severe renal impairment (estimated glomerular filtration rate <30 mL/min/1.73 m²) or in patients with end-stage renal disease receiving dialysis.

Hepatic Impairment

Patients with mild hepatic impairment do not require dosage adjustment for bempedoic acid, alone or in combination with ezetimibe. Patients with moderate hepatic impairment do not require dosage adjustment for bempedoic acid alone. Bempedoic acid in combination with ezetimibe is not recommended for patients with moderate or severe hepatic impairment because the effects of increased ezetimibe exposure are not known. Bempedoic acid has not been studied in patients with severe hepatic impairment.

Drug-Drug Interactions

Bempedoic acid does not interact with the cytochrome P450 system or other metabolic or transport pathways, with few exceptions. One exception is bempedoic acid glucuronide, which is an OAT3 substrate. Bempedoic acid is a weak inhibitor of OAT3 and exerts this effect only at high multiples of clinically relevant concentrations. Bempedoic acid and its glucuronide also weakly inhibit OATP1B1 and OATP1B3 at concentrations which are clinically relevant. Finally, in vitro data show that bempedoic acid is a weak inhibitor of OAT2; this has been postulated to be the mechanistic basis for minor serum creatinine and uric acid elevations observed in clinical trials.

Clinical trials have evaluated the pharmacokinetic interactions between bempedoic acid and the following statins: simvastatin 20 mg, atorvastatin 10 mg, pravastatin 40 mg and rosuvastatin 10 mg. Concomitant use of bempedoic acid and simvastatin or pravastatin increases the concentration of these statins and may increase the risk of simvastatin/pravastatin-related myopathy. The use of bempedoic acid with simvastatin greater than 20 mg or pravastatin greater than 40 mg should be avoided. Interactions with atorvastatin and rosuvastatin are weak, and do not impact dosing recommendations.

Concomitant use of BA+EZE FDC and cyclosporine increases ezetimibe and cyclosporine concentrations. Cyclosporine concentrations should be monitored in patients receiving BA+EZE FDC. The potential effects of increased ezetimibe exposure from concomitant use of cyclosporine should be carefully weighed against the lipid-lowering benefits of bempedoic acid and ezetimibe.

Since fenofibrate and ezetimibe may increase cholesterol excretion into the bile, their concomitant administration may lead to cholelithiasis. Coadministration of BA+EZE FDC with fibrates other than fenofibrate is not recommended. When cholelithiasis is suspected in a patient receiving BA+EZE FDC and fenofibrate, gallbladder studies should be performed and another form of lipid-lowering therapy considered.

Concomitant use of BA+EZE FDC and cholestyramine decreases the concentration of ezetimibe, potentially resulting in lower efficacy. BA+EZE FDC should be administered either 2 hours or more before or 4 hours or more after bile acid sequestrants.