Nexletol (Bempedoic Acid)
bempedoic acid
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| CV risk reduction — established CVD | Adults unable to take recommended statin therapy | Alone or add-on to other LLT | FDA Approved |
| CV risk reduction — high risk without established CVD | Adults unable to take recommended statin therapy, at high risk for CVD event | Alone or add-on to other LLT | FDA Approved |
| Primary hyperlipidemia (including HeFH) — LDL-C lowering | Adults | Adjunct to diet; alone or combined with other LDL-C lowering therapies including statins | FDA Approved |
Bempedoic acid is a first-in-class oral ACL inhibitor initially approved in February 2020 for LDL-C lowering in patients with HeFH or established ASCVD on maximally tolerated statins. In March 2024, the FDA approved a major label expansion based on the CLEAR Outcomes trial, adding CV risk reduction indications for both primary and secondary prevention patients unable to take recommended statin therapy, and removing the statin co-administration requirement. Bempedoic acid is the only oral non-statin LDL-C-lowering drug with an FDA indication for both primary prevention of CV events and LDL-C reduction.
Statin-associated muscle symptoms (SAMS) without complete intolerance: While the CLEAR Outcomes trial enrolled patients who were statin-intolerant or unable to take recommended doses, bempedoic acid is increasingly used in patients with partial statin intolerance who can tolerate low-dose statins combined with bempedoic acid. Evidence quality: Moderate (subgroup analyses of CLEAR Outcomes).
Combination with PCSK9 inhibitors: PCSK9 inhibitor users were excluded from the primary hyperlipidemia trials. Combination use has limited data but is mechanistically rational. Evidence quality: Low.
Dosing
Adult Dosing by Clinical Scenario
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| ASCVD with LDL-C above goal — statin-intolerant | 180 mg PO daily | 180 mg PO daily | 180 mg/day | Can be taken with or without food. Single fixed dose; no titration. CLEAR Outcomes showed 13% MACE-4 reduction (HR 0.87). Assess lipids within 8–12 weeks of initiation |
| High CV risk, primary prevention — unable to take recommended statin doses | 180 mg PO daily | 180 mg PO daily | 180 mg/day | March 2024 label expansion. Only non-statin oral LDL-C-lowering agent indicated for primary prevention. May be used alone or with low-dose statin. |
| HeFH or primary hyperlipidemia — adjunct to maximally tolerated statin | 180 mg PO daily | 180 mg PO daily | 180 mg/day | Expected LDL-C reduction 17–18% vs placebo at Week 12 when added to background statin (Trials 2 & 3). Avoid simvastatin >20 mg and pravastatin >40 mg when co-prescribed |
| Monotherapy for primary hyperlipidemia — statin not possible | 180 mg PO daily | 180 mg PO daily | 180 mg/day | 2024 label supports use alone when concomitant LDL-C lowering therapy is not possible. Consider adding ezetimibe for greater LDL-C reduction (Nexlizet combination available). |
Special Populations
| Population | Dose Adjustment | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Renal impairment (mild through renal failure) | None required | 180 mg/day | 180 mg/day | No clinically significant PK differences across renal function categories (FDA PI). Monitor uric acid and creatinine as bempedoic acid inhibits renal OAT2. |
| Hepatic impairment (mild to moderate; Child-Pugh A or B) | None required | 180 mg/day | 180 mg/day | Not studied in severe hepatic impairment (Child-Pugh C). Use with caution given hepatic activation of the prodrug. |
| Elderly (≥65 years) | None required | 180 mg/day | 180 mg/day | 58–59% of participants in clinical trials were ≥65 years. No differences in safety or efficacy observed (FDA PI). Monitor for tendon rupture risk, which increases with age. |
Bempedoic acid is a prodrug activated in the liver by ACSVL1 (very long-chain acyl-CoA synthetase 1), an enzyme not expressed in skeletal muscle. This liver-selective activation is the mechanistic basis for the low incidence of myalgia and muscle-related adverse events relative to statins, making it particularly suitable for statin-intolerant patients. In the CLEAR Outcomes trial, muscle-related complaints were not significantly different between bempedoic acid and placebo.
Pharmacology
Mechanism of Action
Bempedoic acid inhibits adenosine triphosphate-citrate lyase (ACL), an enzyme that operates upstream of HMG-CoA reductase in the hepatic cholesterol biosynthesis pathway. It is a prodrug requiring activation via coenzyme A conjugation by ACSVL1 to form ETC-1002-CoA, the active inhibitory species. Since ACSVL1 is expressed predominantly in the liver and is absent from skeletal muscle, bempedoic acid achieves liver-selective cholesterol synthesis inhibition without the muscle toxicity associated with HMG-CoA reductase inhibitors. Inhibition of ACL reduces intrahepatic cholesterol pools, triggering compensatory upregulation of LDL receptor expression on hepatocyte surfaces and thereby increasing clearance of circulating LDL-C. Bempedoic acid also has a reversible active metabolite (ESP15228) that contributes modestly to the overall pharmacological effect. In the CLEAR Outcomes trial, bempedoic acid reduced LDL-C by 20% more than placebo at 6 months (95% CI: 19–21%; FDA PI) and reduced high-sensitivity C-reactive protein by 22%, suggesting additional anti-inflammatory properties (NEJM 2023).
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Oral; median Tmax 3.5 h; food has no effect on bioavailability; Cmax 20.6 ± 6.1 µg/mL at steady state | Convenient once-daily dosing with or without meals. Maximum LDL-C-lowering effect occurs by Week 4. |
| Distribution | V/F 18 L; protein binding 99.3%; does not partition into blood cells | Small volume of distribution indicates primarily intravascular and hepatic distribution. High protein binding may be relevant for drug displacement interactions, though none have been identified clinically. |
| Metabolism | Primary: acyl glucuronide conjugation (UGT2B7). Also converted to active metabolite ESP15228 (AUC ratio ~18%). Not a CYP450 substrate, inhibitor, or inducer. Weakly inhibits OATP1B1, OATP1B3, and OAT2. | CYP450-independent metabolism avoids most traditional DDIs. OAT2 inhibition explains elevations in serum uric acid and creatinine. OATP1B1/1B3 inhibition accounts for increased statin levels (simvastatin, pravastatin). |
| Elimination | t½ 21 ± 11 h; CL/F 11.2 mL/min; ~70% urine (mainly as glucuronide), ~30% feces; <2% unchanged in urine; <5% unchanged in feces + urine combined | Once-daily dosing appropriate given the ~21-hour half-life. Steady state achieved by Day 7 with ~2.3-fold accumulation. Minimal renal excretion of parent drug supports use across renal function categories. |
Side Effects
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Hyperuricemia | 16% (vs 8% placebo) | Due to OAT2 inhibition in renal tubules. Onset within first 4 weeks; persists during treatment; reversible on discontinuation. Mean placebo-adjusted uric acid increase ~0.8 mg/dL. Higher risk in patients with prior gout history. |
| Renal impairment (lab-based) | 11% (vs 9% placebo) | Includes eGFR decrease, creatinine increase, and hematuria. Mean creatinine increase 0.05 mg/dL at Week 12 (hyperlipidemia trials); in CLEAR, creatinine increased ≥0.5 mg/dL in 7.1% vs 5.5% placebo. Mechanistic (OAT2-mediated), not structural nephrotoxicity. Generally reversible on discontinuation. |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Upper respiratory tract infection | 4.5% (vs 4.0% placebo) | Marginal excess; unlikely to be causally related |
| Muscle spasms | 3.6% (vs 2.3% placebo) | Distinct from statin-induced myalgia; not associated with CK elevation. May reflect electrolyte shifts or local effects. |
| Hyperuricemia | 3.5% (vs 1.1% placebo) | Lower rate in the shorter hyperlipidemia trials than in the longer CLEAR Outcomes trial (16%). 26% of patients with normal baseline uric acid experienced at least one hyperuricemia event. |
| Back pain | 3.3% (vs 2.2% placebo) | Small excess over placebo; monitor for tendon-related symptoms |
| Abdominal pain or discomfort | 3.1% (vs 2.2% placebo) | Includes upper and lower abdominal pain. Generally mild and self-limiting. |
| Bronchitis | 3.0% (vs 2.5% placebo) | Minimal difference from placebo |
| Pain in extremity | 3.0% (vs 1.7% placebo) | Not associated with CK elevations; assess for tendon pathology if persistent |
| Anemia | 2.8% (vs 1.9% placebo) | 5.1% had hemoglobin decrease ≥2 g/dL below LLN (vs 2.3%); generally asymptomatic. Long-term CLEAR data: 4.7% vs 3.9%. |
| Elevated liver enzymes | 2.1% (vs 0.8% placebo) | AST >3× ULN in 1.4% vs 0.4%; mostly transient and resolved with continued therapy. No cases of drug-induced liver injury with Hy’s law criteria met. |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Tendon rupture | 0.5% (vs 0% placebo in hyperlipidemia trials; 1.2% vs 0.9% in CLEAR) | Weeks to months after initiation | Discontinue immediately. Sites include rotator cuff, biceps tendon, and Achilles tendon. Higher risk in patients >60 years, on corticosteroids or fluoroquinolones, renal failure, or prior tendon disorders. |
| Gout | 1.5% (vs 0.4% placebo in hyperlipidemia trials; 3.2% vs 2.2% in CLEAR) | Within weeks; elevated risk in patients with prior gout history (11.2% vs 1.7% placebo) | Initiate urate-lowering therapy as appropriate. Consider risk-benefit in patients with gout history before prescribing. In patients without prior gout: 1.0% vs 0.3% placebo. |
| Hepatotoxicity (AST >3× ULN) | 1.4% (vs 0.4% placebo) | Variable; usually within first months | Monitor LFTs. Most elevations transient and resolve with continued therapy or discontinuation. No Hy’s law cases in pivotal trials. CLEAR Outcomes: confirmed ALT/AST >3× ULN in 1.6% vs 1.0%. |
| Angioedema (post-marketing) | Rare | Variable | Discontinue permanently. Reported in post-marketing surveillance along with wheezing, rash, and urticaria. |
| Cholelithiasis | 2% (vs 1% placebo in CLEAR) | Months to years | Assess for biliary symptoms. Manage surgically if symptomatic. Likely related to altered cholesterol metabolism in bile. |
Hyperuricemia is the most clinically significant adverse effect unique to bempedoic acid. The mechanism is pharmacological (OAT2 inhibition in renal tubules), not structural kidney injury. Before initiation, check baseline uric acid and gout history. Patients with prior gout face an 11.2% risk of gout events (vs 1.7% on placebo) and require careful risk-benefit assessment. Uric acid elevations typically appear within 4 weeks, persist throughout treatment, and normalize after discontinuation. If gout develops, initiate standard urate-lowering therapy; bempedoic acid does not necessarily need to be discontinued if gout is adequately managed.
Drug Interactions
Bempedoic acid is not metabolized by CYP450 enzymes and is not a CYP substrate, inhibitor, or inducer. However, it weakly inhibits hepatic uptake transporters OATP1B1 and OATP1B3, which are involved in the hepatic clearance of several statins. This transporter-mediated interaction results in clinically significant increases in simvastatin and pravastatin exposure, and modest increases in atorvastatin and rosuvastatin exposure. Bempedoic acid also inhibits renal OAT2, which explains the increases in serum uric acid and creatinine (FDA PI).
Monitoring
-
Lipid Panel
8–12 weeks after initiation; then per clinical need
Routine FDA PI specifies analyzing lipid levels within 8–12 weeks. Maximum LDL-C lowering effect occurs by Week 4. Reassess at 6–12 months to confirm sustained response. -
Serum Uric Acid
Baseline, then periodically as clinically indicated
Routine Elevations typically appear within first 4 weeks. Mean placebo-adjusted increase ~0.8 mg/dL. In CLEAR Outcomes, 16% developed hyperuricemia. Particularly important in patients with prior gout history (gout risk 11.2% in this subgroup). Monitor for signs/symptoms of gout. -
Hepatic Function
Baseline; if clinically indicated
Trigger-based AST >3× ULN occurred in 1.4% vs 0.4% placebo. Most elevations transient. In CLEAR Outcomes, confirmed ALT/AST >3× ULN in 1.6% vs 1.0%. No hepatic failure reported. Assess if symptoms of hepatotoxicity arise. -
Renal Function
Baseline; periodically
Routine Mean creatinine increase of 0.05 mg/dL at Week 12 (OAT2-mediated). BUN doubled in 3.8% (vs 1.5%). CLEAR: creatinine increase ≥0.5 mg/dL in 7.1% vs 5.5%. Changes are functional, not structural, and reverse on discontinuation. -
CBC / Hemoglobin
Baseline; if symptoms develop
Trigger-based Hemoglobin decrease ≥2 g/dL below LLN in 5.1% vs 2.3% (hyperlipidemia trials). Leukocyte decrease below LLN in 9.0% vs 6.7%. Generally asymptomatic. Platelet increase ≥100×10&sup9;/L in 10.1% vs 4.7% (asymptomatic, no thromboembolic excess). -
Tendon Symptoms
At each visit; ongoing clinical vigilance
Trigger-based Ask about shoulder, upper arm, and heel pain. Tendon rupture 0.5% in hyperlipidemia trials (0% placebo); 1.2% vs 0.9% in CLEAR. Discontinue at first sign of rupture. Higher risk with age >60, concurrent corticosteroids or fluoroquinolones, renal failure, or prior tendon disorders. -
Creatine Kinase
If muscle symptoms develop
Trigger-based CK >5× ULN in 1.0% vs 0.6% placebo. Not routinely required, but check if patients develop unexplained muscle pain, especially when combined with simvastatin or pravastatin.
Contraindications & Cautions
Absolute Contraindications
- Prior serious hypersensitivity reaction to bempedoic acid or any excipient in Nexletol — post-marketing reports include angioedema, wheezing, rash, and urticaria.
Relative Contraindications (Specialist Input Recommended)
- Active gout or history of recurrent gout: Risk of gout was 11.2% in patients with prior gout history receiving bempedoic acid (vs 1.7% placebo). If prescribing, ensure urate-lowering therapy is optimized and discuss elevated risk with the patient.
- History of tendon disorders or tendon rupture: FDA PI recommends avoiding bempedoic acid in patients with prior tendon disorders. If prescribed, advise rest at first sign of tendinitis and monitor closely.
- Severe hepatic impairment (Child-Pugh C): Not studied. Bempedoic acid requires hepatic activation; impaired liver function could alter both efficacy and safety.
Use with Caution
- Concurrent simvastatin (>20 mg) or pravastatin (>40 mg): Increased myopathy risk due to ~2-fold increase in statin exposure. Must cap doses when co-prescribing.
- Patients >60 years on corticosteroids or fluoroquinolones: Additive tendon rupture risk factors.
- Pregnancy: Discontinue when recognized. Mechanism-based fetal harm possible (cholesterol biosynthesis inhibition). Not teratogenic in animal studies at up to 11–12× MRHD, but adverse effects on fetal development observed at maternally toxic doses.
- Breastfeeding: Detected in human breast milk (RID ~0.5%). Breastfeeding is not recommended during treatment.
Bempedoic acid carries two specific FDA warnings: (1) Hyperuricemia due to inhibition of renal OAT2, which can lead to gout (3.2% in CLEAR Outcomes vs 2.2% placebo); and (2) Tendon rupture (0.5–1.2% in trials), involving the rotator cuff, biceps, or Achilles tendons. Patients should be advised to report signs of gout (acute joint pain, swelling, redness) and tendon symptoms (pain, swelling, snapping sensation) immediately. Bempedoic acid should be discontinued at the first sign of tendon rupture.
Unlike statins, bempedoic acid was not associated with increased new-onset type 2 diabetes in the CLEAR Outcomes trial. In fact, Mendelian randomization studies of the ACLY gene locus predict that ACL inhibition may be associated with lower weight and no increased diabetes risk. In CLEAR Outcomes, HbA1c and fasting glucose were not adversely affected, and bempedoic acid reduced hsCRP by 22%, suggesting potential cardiometabolic benefits beyond LDL-C lowering.
Patient Counselling
Purpose of Therapy
Bempedoic acid is a once-daily tablet that lowers LDL cholesterol by blocking cholesterol production in the liver through a different mechanism than statins. It has been proven in a large clinical trial (CLEAR Outcomes, nearly 14,000 patients) to reduce the risk of heart attacks and procedures to open blocked heart arteries. It is particularly useful for patients who cannot tolerate statins or cannot take the recommended statin dose.
How to Take
Take one 180 mg tablet by mouth once daily, with or without food. Your healthcare provider will check your cholesterol levels 8–12 weeks after starting the medication to assess your response. Continue taking the tablet even if you feel well, as high cholesterol does not cause symptoms.
Sources
- Esperion Therapeutics, Inc. Nexletol (bempedoic acid) tablets, for oral use. Full Prescribing Information. Ann Arbor, MI: Esperion; revised July 2025. FDA Label (2025) Primary source for all dosing, adverse reactions, PK data, drug interactions, and warnings in this monograph.
- Esperion Therapeutics, Inc. Nexletol (bempedoic acid) tablets. Full Prescribing Information. Ann Arbor, MI: Esperion; revised March 2024. FDA Label (2024) Label version incorporating the March 2024 CV risk reduction indication and primary prevention expansion based on CLEAR Outcomes.
- Nissen SE, Lincoff AM, Brennan D, et al. Bempedoic acid and cardiovascular outcomes in statin-intolerant patients. N Engl J Med. 2023;388(15):1353–1364. doi:10.1056/NEJMoa2215024 CLEAR Outcomes: landmark CV outcomes trial (N=13,970) demonstrating 13% MACE-4 reduction with bempedoic acid in statin-intolerant patients over median 40.6 months.
- Nicholls SJ, Lincoff AM, Garcia D, et al. Impact of bempedoic acid on total cardiovascular events: a prespecified analysis of the CLEAR Outcomes randomized clinical trial. JAMA Cardiol. 2024;9(4):385–392. doi:10.1001/jamacardio.2023.5618 Pre-specified analysis showing bempedoic acid reduced total MACE-4 events by 20% (HR 0.80) and total MI events by 31% (HR 0.69).
- Goldberg AC, Leiter LA, Stroes ESG, et al. Effect of bempedoic acid vs placebo added to maximally tolerated statins on low-density lipoprotein cholesterol in patients at high cardiovascular risk: the CLEAR Wisdom randomized clinical trial. JAMA. 2019;322(18):1780–1788. doi:10.1001/jama.2019.16585 Trial 2 (CLEAR Wisdom): 18% placebo-corrected LDL-C reduction at Week 12 in 2,230 patients with CVD or HeFH on maximally tolerated statin.
- Ray KK, Bays HE, Catapano AL, et al. Safety and efficacy of bempedoic acid to reduce LDL cholesterol. N Engl J Med. 2019;380(11):1022–1032. doi:10.1056/NEJMoa1803917 CLEAR Harmony trial demonstrating the safety and LDL-C-lowering efficacy of bempedoic acid added to maximally tolerated statin therapy over 52 weeks.
- Laufs U, Banach M, Mancini GBJ, et al. Efficacy and safety of bempedoic acid in patients with hypercholesterolemia and statin intolerance. J Am Heart Assoc. 2019;8(7):e011662. doi:10.1161/JAHA.118.011662 CLEAR Serenity trial in statin-intolerant patients showing 21% LDL-C reduction with bempedoic acid; muscle-related AE rates similar to placebo.
- Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol. Circulation. 2019;139(25):e1082–e1143. doi:10.1161/CIR.0000000000000625 Foundation guideline establishing LDL-C targets and criteria for adding non-statin therapies in high-risk patients.
- Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS guidelines for the management of dyslipidaemias. Eur Heart J. 2020;41(1):111–188. doi:10.1093/eurheartj/ehz455 European guidelines placing bempedoic acid in the stepwise lipid-lowering treatment algorithm for patients unable to reach LDL-C goals.
- Pinkosky SL, Newton RS, Day EA, et al. Liver-specific ATP-citrate lyase inhibition by bempedoic acid decreases LDL-C and attenuates atherosclerosis. Nat Commun. 2016;7:13457. doi:10.1038/ncomms13457 Preclinical study establishing the liver-selective mechanism of bempedoic acid via ACSVL1-dependent activation and ACL inhibition.
- Lalwani ND, Hanselman JC, MacDougall DE, et al. Complementary low-density lipoprotein-cholesterol lowering and pharmacokinetics of adding bempedoic acid (ETC-1002) or ezetimibe to high-dose statin therapy. Atherosclerosis. 2019;284:93–98. doi:10.1016/j.atherosclerosis.2019.02.024 PK study evaluating bempedoic acid interactions with high-dose statins; supports mechanistic basis for simvastatin and pravastatin dose restrictions.
- Nissen SE, Lincoff AM, Brennan D, et al. Bempedoic acid for primary prevention of cardiovascular events in statin-intolerant patients. JAMA. 2023;330(2):131–140. doi:10.1001/jama.2023.9696 Pre-specified CLEAR Outcomes subgroup analysis demonstrating CV event reduction in primary prevention patients without established CVD.
- Nicholls SJ, Lincoff AM, Bays HE, et al. Efficacy and safety of bempedoic acid among patients with and without diabetes. Lancet Diabetes Endocrinol. 2023;11(12):956–966. doi:10.1016/S2213-8587(23)00316-9 Pre-specified analysis confirming bempedoic acid does not increase new-onset diabetes risk and may lower HbA1c; consistent CV benefit in diabetic and non-diabetic patients.