Usage
Bempedoic acid + Rosuvastatin is prescribed to lower low-density lipoprotein cholesterol (LDL-C) levels in adults with primary hypercholesterolemia (including heterozygous familial hypercholesterolemia) or mixed dyslipidemia. It is used as an adjunct to diet and other lipid-lowering therapies, especially in patients who cannot tolerate statins or cannot achieve LDL-C goals with statins alone. It also reduces the risk of heart attack and heart procedures. Rosuvastatin is additionally indicated for homozygous familial hypercholesterolemia and isolated hypertriglyceridemia.
This combination falls under the pharmacological classification of lipid-lowering agents, specifically HMG-CoA reductase inhibitors (statins) for rosuvastatin and ATP citrate lyase (ACL) inhibitors for bempedoic acid.
Bempedoic acid inhibits ACL, an enzyme upstream of HMG-CoA reductase in the cholesterol synthesis pathway. This reduces cholesterol synthesis in the liver. Rosuvastatin competitively inhibits HMG-CoA reductase, further decreasing cholesterol production and increasing LDL receptor expression, leading to enhanced LDL clearance.
Alternate Names
Bempedoic acid is also known as Nexletol. Rosuvastatin is also known as Crestor. The combination is sometimes referred to as bempedoic acid/rosuvastatin. There might be other brand names depending on the region and manufacturer.
How It Works
Pharmacodynamics: Bempedoic acid reduces LDL-C by inhibiting hepatic cholesterol synthesis. This, in turn, increases LDL receptor expression, which leads to increased LDL clearance. Rosuvastatin inhibits HMG-CoA reductase, a key enzyme in cholesterol synthesis. Its action leads to increased hepatic LDL receptor expression and enhanced LDL clearance.
Pharmacokinetics: Bempedoic acid is a prodrug activated in the liver to bempedoic acid-CoA. It is extensively metabolized via glucuronidation and eliminated mainly in the urine and feces. Rosuvastatin is primarily metabolized by CYP2C9, with minor contributions from CYP2C19 and CYP3A4. It’s mainly excreted in the feces.
Mode of Action: Bempedoic acid inhibits ACL, an enzyme involved in cholesterol biosynthesis. It is a prodrug requiring activation by very long-chain acyl-CoA synthetase 1 (ACSVL1), an enzyme not found in skeletal muscle, thereby reducing the risk of statin-associated muscle side effects. Rosuvastatin competitively inhibits HMG-CoA reductase, blocking the conversion of HMG-CoA to mevalonate, a key precursor of cholesterol. This reduces cholesterol synthesis in the liver. The combination works synergistically to reduce cholesterol levels by acting at two different points in the cholesterol biosynthesis pathway. Elimination pathways for Bempedoic acid are primarily via renal excretion, while Rosuvastatin is eliminated mostly via the liver, with minimal renal excretion.
Dosage
Standard Dosage
Adults:
- Bempedoic acid: 180 mg orally once daily.
- Rosuvastatin: Initial dose: 5-10 mg orally once a day. Dosage can be titrated up to 40 mg/day based on individual response and treatment goals. When combined with Bempedoic acid, Rosuvastatin dose should not exceed 20 mg unless absolutely necessary for patients with severe hypercholesterolaemia and high cardiovascular risk.
- Bempedoic acid/ezetimibe fixed-dose combination: One tablet (180 mg bempedoic acid/10 mg ezetimibe) orally once a day.
Children: The safety and efficacy of bempedoic acid haven’t been established in children. Rosuvastatin is approved for children aged 8 and above for specific indications and dosages. Specific pediatric dosing guidelines for rosuvastatin vary by age and indication.
Special Cases:
- Elderly Patients: No dose adjustment is generally necessary for Bempedoic acid. Rosuvastatin dosage initiation should be conservative, with close monitoring.
- Patients with Renal Impairment: No dose adjustment is necessary for mild to moderate renal impairment for both. For severe renal impairment, the rosuvastatin dose should not exceed 10 mg daily. Bempedoic acid has limited data with severe renal impairment, and caution is advised.
- Patients with Hepatic Dysfunction: No dose adjustment is required for mild to moderate hepatic impairment for bempedoic acid. Rosuvastatin should be used with caution in mild hepatic impairment. It should be avoided with moderate to severe hepatic impairment.
- Patients with Comorbid Conditions: Individualized dosing is crucial.
Clinical Use Cases
The combination isn’t typically used in settings such as intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations. Its primary role is chronic LDL-C lowering.
Dosage Adjustments
Dose adjustments are mainly based on LDL-C response, tolerance, and hepatic/renal function. Monitor liver function tests and creatine kinase levels periodically.
Side Effects
Common Side Effects
- Bempedoic Acid: Hyperuricemia, back pain, pain in extremity, anemia, upper respiratory tract infections, bronchitis, muscle spasms
- Rosuvastatin: Headache, myalgia, asthenia, abdominal pain, nausea, constipation, dizziness.
Rare but Serious Side Effects
- Bempedoic Acid: Gout, tendon rupture
- Rosuvastatin: Myopathy, rhabdomyolysis, hepatotoxicity, pancreatitis
Long-Term Effects
Long-term use of rosuvastatin may increase the risk of new-onset diabetes. Regular monitoring of HbA1c is recommended. Long-term effects for bempedoic acid are still being studied.
Adverse Drug Reactions (ADR)
Severe muscle pain or weakness, signs of liver injury (jaundice, dark urine), and allergic reactions (rash, itching, swelling) require immediate medical attention.
Contraindications
- Bempedoic Acid: Hypersensitivity to bempedoic acid, pregnancy and breast-feeding.
- Rosuvastatin: Active liver disease, unexplained persistent transaminase elevation, pregnancy, breastfeeding, women of child-bearing potential not using contraception.
Drug Interactions
- Bempedoic Acid: Concomitant use with simvastatin should be limited to 20 mg/day (40 mg/day in specific cases). It may increase exposure to other statins and some medications that are OATP1B1/OATP1B3 substrates.
- Rosuvastatin: Interacts with several medications, including cyclosporine, gemfibrozil, and certain HIV protease inhibitors. Monitor carefully when co-administered.
Pregnancy and Breastfeeding
Bempedoic acid is contraindicated in pregnancy and breastfeeding. Rosuvastatin is also contraindicated in pregnancy and should not be used during breastfeeding.
Drug Profile Summary
- Mechanism of Action: Bempedoic acid: ACL inhibitor; Rosuvastatin: HMG-CoA reductase inhibitor.
- Side Effects: See above.
- Contraindications: See above.
- Drug Interactions: See above.
- Pregnancy & Breastfeeding: Contraindicated.
- Dosage: See above.
- Monitoring Parameters: LDL-C, liver function tests, creatine kinase, uric acid levels, HbA1c.
Popular Combinations
Bempedoic acid is commonly used with ezetimibe, another cholesterol absorption inhibitor, often along with statin therapy, to reduce LDL levels. Rosuvastatin can be used with other lipid-lowering therapies such as ezetimibe.
Precautions
See Side Effects and Contraindications sections. Monitor carefully. Caution in patients with hepatic or renal impairment.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Bempedoic acid + Rosuvastatin?
A: Bempedoic acid is taken as 180mg once daily. Rosuvastatin’s initial dose is typically 5-10 mg once daily, titratable up to 40mg depending on response and patient tolerance. When used concurrently, rosuvastatin should not exceed 20 mg daily unless the benefits outweigh the risks in patients with severe hypercholesterolemia and high cardiovascular risk.
Q2: What are the main side effects of this combination?
A: Common side effects include hyperuricemia, muscle aches, back pain, joint pain, and gastrointestinal issues like nausea and constipation. Rare but serious side effects are rhabdomyolysis, hepatotoxicity, and gout.
Q3: Can this combination be used during pregnancy or breastfeeding?
A: No, both bempedoic acid and rosuvastatin are contraindicated during pregnancy and breastfeeding.
Q4: How do these medications interact with other drugs?
A: Bempedoic acid can interact with simvastatin and medications metabolized by OATP1B1/OATP1B3. Rosuvastatin can interact with several drugs, including cyclosporine, gemfibrozil, and certain HIV protease inhibitors.
Q5: How often should monitoring parameters be checked?
A: Monitor LDL-C, liver function tests, creatine kinase, and uric acid levels regularly. Frequency depends on the patient’s individual risk factors and clinical picture. HbA1c should be monitored periodically for long-term statin users.
Q6: What is the mechanism of action of this drug combination?
A: Bempedoic acid inhibits ACL, and rosuvastatin inhibits HMG-CoA reductase, both enzymes in the cholesterol synthesis pathway. They work synergistically at different points in the pathway to reduce cholesterol production.
Q7: Who should not take this combination?
A: Patients with active liver disease, pregnant or breastfeeding women, and those with a hypersensitivity to either drug should not take this combination.
Q8: Are there any specific precautions for elderly patients?
A: Start rosuvastatin at a lower dose and monitor closely. Bempedoic acid typically doesn’t require dose adjustment. Monitor for muscle related side effects.
Q9: How long does it take for this combination to work?
A: Significant LDL-C reduction can typically be observed within a few weeks of starting treatment.
Q10: What should patients do if they experience muscle pain while on this medication?
A: They should immediately contact their doctor, as muscle pain can be a sign of a serious side effect.
