- ACRONYMS AND DEFINITIONS
- ASCVD - Atherosclerotic cardiovascular disease
- AHA - American Heart Association
- BUN - Blood urea nitrogen
- CVD - Cardiovascular disease
- HeFH - Heterozygous familial hypercholesterolemia
- ULN - Upper limits of normal
- DRUGS IN CLASS
- Adenosine triphosphate-citrate lyase (ACL) inhibitor
- Bempedoic acid (Nexletol®)
- Combination products with ezetimibe
- Nexlizet® (ezetimibe + bempedoic acid)
- FDA-APPROVED INDICATIONS
- Bempedoic acid is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease who require additional lowering of LDL-C
- MECHANISM OF ACTION
- Adenosine triphosphate-citrate lyase (ACL) inhibitor
- Bempedoic acid is an adenosine triphosphate-citrate lyase (ACL) inhibitor that lowers LDL-C by inhibition of cholesterol synthesis in the liver. ACL is an enzyme upstream of HMG-CoA reductase in the cholesterol biosynthesis pathway.
- Inhibition of ACL by bempedoic acid results in decreased cholesterol synthesis in the liver and lowers LDL-C in blood via upregulation of low-density lipoprotein receptors
- CHOLESTEROL EFFECTS
Effects of Bempedoic Acid on Lipid Parameters in Patients with HeFH and/or ASCVD on Maximally Tolerated Statin Therapy at 12 weeks | ||
---|---|---|
Bempedoic acid 180 mg (N=1488) |
Placebo (N=742) |
|
Total | -10% | +1% |
LDL | -17% | +2% |
Non-HDL cholesterol | -12% | +2% |
Apo B | -9% | +3% |
- CARDIOVASCULAR DISEASE PREVENTION
- Overview
- The CLEAR study detailed below evaluated the effects of bempedoic acid on CVD outcomes in statin-intolerant patients
- The CLEAR study enrolled 13,970 patients with or at high risk for CVD who were unable or unwilling to receive statins owing to adverse effects
Main inclusion criteria
- Adults 18 - 85 years old
- Previous CVD event or high risk for CVD
- Unable or unwilling to receive statins (low-dose statins were allowed)
Main exclusion criteria
- Triglycerides > 500 mg/dl
- GFR < 30 ml/min
- CVD event within 90 days
- NYHA class IV heart failure
- Uncontrolled hypertension
Baseline characteristics
- Average age 65 years
- Previous CVD event - 70%
- Average LDL - 139 mg/dl
- Diabetes - 46%
- Using low-dose statin - 23%
Randomized treatment groups
- Group 1 (6992 patients): Bempedoic acid 180 mg once daily
- Group 2 (6978 patients): Placebo
- Other lipid-lowering therapies, including low-dose statins (e.g. atorvastatin < 10 mg), ezetimibe, niacin, bile acid sequestrants, fibrates, and PCSK9 inhibitors were allowed
- If LDL levels rose above 25% of baseline after 6 months, other lipid-lowering therapies could be adjusted
Primary outcome: Composite of major adverse cardiovascular events, defined as death from cardiovascular causes,
nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization, as assessed in a time-to-first-event analysis
Results
Duration: Median 40.6 months | |||
Outcome | Bempedoic acid | Placebo | Comparisons |
---|---|---|---|
Primary outcome | 11.7% | 13.3% | p=0.004 |
Myocardial infarction | 3.7% | 4.8% | p=0.002 |
Stroke | 1.9% | 2.3% | p=0.16 |
Coronary revascularazation | 6.2% | 7.6% | p=0.001 |
Death from CV causes | 3.8% | 3.7% | Diff 1.04 95%CI [0.88 to 1.24] |
Overall mortality | 6.2% | 6.0% | Diff 1.03 95%CI [0.90 to 1.18] |
Change in LDL at 6 months | -21.1% | -0.8% | Diff -20.3 95%CI [-21.1 to -19.5] |
Renal impairment | 11.5% | 8.6% | N/A |
Elevated liver enzymes | 4.5% | 3.0% | N/A |
|
Findings: Among statin-intolerant patients, treatment with bempedoic acid was associated with a lower risk of major adverse cardiovascular events (death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization).
- Professional recommendations
- Bempedoic acid was FDA-approved in 2020 and has not been incorporated into any guidelines yet
- See cholesterol treatment guidelines
- Summary
- In the CLEAR study, bempedoic acid lowered LDL cholesterol by 21% and improved CVD outcomes, however, it had no effect on overall mortality (6.2% vs 6.0%) or death from cardiovascular causes (3.8% vs 3.7%). It was well-tolerated, making it a possible alternative to patients who refuse statins.
- SIDE EFFECTS
Side effect | Bempedoic acid + statin (N=2009) |
Placebo + statin (N=999) |
---|---|---|
Upper respiratory tract infection | 4.5% | 4.0% |
Muscle spasms | 3.6% | 2.3% |
Hyperuricemia | 3.5% | 1.1% |
Back pain | 3.3% | 2.2% |
Abdominal pain or discomfort | 3.1% | 2.2% |
Bronchitis | 3.0% | 2.5% |
Pain in extremity | 3.0% | 1.7% |
Anemia | 2.8% | 1.9% |
Elevated liver enzymes | 2.1% | 0.8% |
Atrial fibrillation | 1.7% | 1.1% |
New-onset BPH in men | 1.3% | 0.1% |
- Lab effects
- Increase in serum creatinine and BUN
- In trials, approximately 3.8% of patients treated with bempedoic acid had BUN values that doubled (versus 1.5% placebo), and about 2.2% of patients had serum creatinine values that increased by 0.5 mg/dL (versus 1.1% with placebo)
- Decrease in hemoglobin
- In trials, approximately 5.1% of patients (versus 2.3% placebo) had decreases in hemoglobin levels of ≥ 2 g/dL and below the lower limit of normal on one or more occasions. Anemia was reported in 2.8% of bempedoic acid-treated patients and 1.9% of placebo-treated patients. Hemoglobin decreases were generally asymptomatic and did not require medical intervention.
- Decrease in leukocytes
- In trials, approximately 9.0% of bempedoic acid-treated patients and 6.7% of placebo-treated patients with normal baseline leukocyte count had a decrease to less than the lower limit of normal on one or more occasions. Leukocyte decrease was generally asymptomatic and did not require medical intervention
- Increase in platelet count
- In trials, approximately 10.1% of bempedoic acid-treated patients (versus 4.7% with placebo) had increases in platelet counts of ≥ 100×109/L on one or more occasions. Platelet count increases were asymptomatic, did not result in increased risk for thromboembolic events, and did not require medical intervention.
- Elevated liver enzymes
- In trials, increases of > 3 X ULN in AST occurred in 1.4% of bempedoic acid-treated patients and 0.4% of placebo-treated patients, and increases > 5 X ULN occurred in 0.4% and 0.2%, respectively. In most cases, the elevations were transient and resolved or improved with continued therapy or after discontinuation of therapy.
- Increase in Creatine Kinase (CK)
- In trials, approximately 1.0% of bempedoic acid-treated patients and 0.6% of placebo-treated patients had elevations of CK levels of ≥ 5 X normal on one or more occasions, and elevations ≥ 10 X normal were seen in 0.4% and 0.2% of patients, respectively.
- CONTRAINDICATIONS
- None
- PRECAUTIONS
- Kidney disease
- CrCl ≥ 30 ml/min: no dose adjustment necessary
- CrCl < 30 ml/min: has not been studied. Manufacturer makes no recommendation.
- Liver disease
- Child-Pugh A/B: no dose adjustment necessary
- Child-Pugh C: has not been studied. Manufacturer makes no recommendation.
- Hyperuricemia / Gout
- Bempedoic acid inhibits renal OAT2 which may increase uric acid levels. In trials, the average placebo-adjusted increase in uric acid levels among bempedoic acid-treated patients was 0.8 mg/dl. Uric acid increases occurred during the first 4 weeks of treatment and persisted throughout therapy. Gout was reported in 1.5% of bempedoic acid-treated patients and 0.4% of placebo-treated patients. Patients with a history of gout were at higher risk with 11.2% of bempedoic acid-treated patients reporting gout events compared to 1.7% of placebo-treated patients.
- Use caution when prescribing bempedoic acid to patients with gout, and assess uric acid levels when clinically indicated
- Tendon rupture
- In trials, tendon rupture occurred in 0.5% of bempedoic acid-treated patients and 0% of placebo-treated patients. Ruptures were seen in the rotator cuff, biceps tendon, and Achilles tendon.
- Patients with any of the following may be at greater risk: ≥ 60 years old; taking corticosteroid or fluoroquinolone drugs; renal failure; previous tendon disorders
- Discontinue bempedoic acid if tendon rupture occurs and consider discontinuing if patient experiences joint pain, swelling, or inflammation. Consider alternative therapy in patients with a history of tendon rupture.
- DRUG INTERACTIONS
- NOTE: Drug interactions presented here are NOT all-inclusive. Other interactions may exist. The interactions presented here are meant to encompass commonly prescribed medications and/or interactions that are well-documented. Always consult your physician or pharmacist before taking medications concurrently. CLICK HERE for more information on drug interactions.
- Pravastatin (Pravachol®) - bempedoic acid increases pravastatin exposure. Doses of pravastatin should not exceed 40 mg when combining.
- Simvastatin (Zocor®) - bempedoic acid increases simvastatin exposure. Doses of simvastatin should not exceed 20 mg when combining.
- Metabolism and clearance
- The primary route of elimination for bempedoic acid is through metabolism of the acyl glucuronide
- Bempedoic acid (Nexletol®)
- Dosage forms (tablet)
- 180 mg
- No generic | Cost > $150 for 30 tablets
- Dosing (High cholesterol)
- 180 mg once daily
- May take without regard to food
- Check lipids 8 - 12 weeks after starting
- Bempedoic acid should be taken with maximally-tolerated statin therapy
- Bempedoic acid + Ezetimibe (Nexlizet®)
- Dosage forms (tablet)
- Bempedoic acid - Ezetimibe
- 180 mg - 10 mg
- No generic | Cost > $150 for 30 tablets
- Dosing (High cholesterol)
- 180/10 mg once daily
- May take without regard to food
- Swallow tablet whole
- Check lipids 8 - 12 weeks after starting
- Nexlizet should be taken with maximally-tolerated statin therapy
- LONG-TERM SAFETY
- Bempedoic acid was FDA-approved in 2020. There is no long-term safety data available.
- BIBLIOGRAPHY
- 1 - Nexletol PI