Bempedoic acid + Ezetimibe

• Approved Indications:
• As an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular disease (ASCVD) who require additional lowering of low-density lipoprotein cholesterol (LDL-C).
• For patients who are statin-intolerant or for whom statins are contraindicated, as an adjunct to diet for LDL-C reduction.
• Off-label Uses:
• May be used in selected patients with hyperlipidemia who require further LDL-C lowering beyond statins and ezetimibe alone, under physician guidance.

• Route: Oral administration.
• Usual Adult Dose: One fixed-dose combination tablet containing 180 mg bempedoic acid + 10 mg ezetimibe once daily, with or without food.
• Pediatrics: Safety and efficacy not established.
• Elderly: No dose adjustment necessary, but monitor for tolerability.
• Renal Impairment: No dose adjustment required for mild to moderate impairment; limited data in severe impairment—use with caution.
• Hepatic Impairment: Not recommended in severe hepatic impairment; caution advised in mild to moderate cases.
• Administration Notes:
• Take at the same time daily.
• Adherence to lifestyle and dietary recommendations should continue alongside therapy.

Bempedoic acid is a prodrug activated primarily in the liver to inhibit ATP citrate lyase (ACL), an enzyme upstream of HMG-CoA reductase in the cholesterol biosynthesis pathway. This inhibition reduces cholesterol synthesis, leading to upregulation of LDL receptors and increased clearance of LDL cholesterol from the bloodstream. Ezetimibe selectively inhibits the Niemann-Pick C1-like 1 (NPC1L1) transporter in the small intestine, reducing intestinal absorption of cholesterol. The combination of these complementary mechanisms results in additive LDL-C lowering effects.

• Absorption:
• Bempedoic acid: Peak plasma concentration approximately 3.5 hours after oral dosing.
• Ezetimibe: Rapid absorption with peak plasma levels in 1–2 hours.
• Distribution:
• Bempedoic acid is highly protein bound (>99%).
• Ezetimibe is extensively bound to plasma proteins.
• Metabolism:
• Bempedoic acid is converted in the liver to its active CoA form; undergoes glucuronidation.
• Ezetimibe is metabolized via glucuronidation to an active metabolite.
• Elimination:
• Bempedoic acid: Primarily excreted via urine and feces.
• Ezetimibe and its metabolites are eliminated mainly in the feces.
• Half-life:
• Bempedoic acid: Approximately 21 hours.
• Ezetimibe: Approximately 22 hours.

• Pregnancy: No adequate human studies; animal studies showed no fetal harm. Use only if clearly needed.
• Lactation: Unknown if excreted in human milk; caution advised. Breastfeeding is generally not recommended during treatment.

• Primary Therapeutic Class: Lipid-lowering agent
• Subclass: Combination of ATP citrate lyase inhibitor (bempedoic acid) and cholesterol absorption inhibitor (ezetimibe)

• Known hypersensitivity to bempedoic acid, ezetimibe, or any excipients.
• Active liver disease or unexplained persistent elevations in hepatic transaminases.
• Pregnancy and lactation unless benefits outweigh risks.

• Monitor liver function tests periodically; discontinue if significant elevations occur.
• Use cautiously in patients with a history of tendon disorders; rare cases of tendon rupture reported with bempedoic acid.
• May increase uric acid levels; monitor in patients with gout or hyperuricemia.
• Monitor for muscle symptoms, especially when used with statins.
• Not studied in severe renal impairment; use with caution.
• Avoid concomitant use with strong OATP1B1 inhibitors.

• Common:
• Upper respiratory tract infections, muscle spasms, hyperuricemia, abdominal pain, constipation, bronchitis.
• Serious but Rare:
• Tendon rupture, increased liver enzymes, hypersensitivity reactions including rash and angioedema, myopathy.

• May interact with statins increasing risk of myopathy.
• Bempedoic acid is an inhibitor of OATP1B1 and OATP1B3 transporters; may increase plasma levels of drugs such as statins.
• Concomitant use with cyclosporine not recommended.
• No significant CYP450 involvement; fewer CYP-mediated interactions expected.
• Avoid grapefruit products due to ezetimibe component caution.

• Recent guidelines endorse the use of bempedoic acid + ezetimibe as an effective LDL-C lowering option especially in statin-intolerant patients or those needing additional lipid control.
• FDA approvals have expanded indications to include patients with ASCVD or HeFH requiring further LDL-C lowering.
• Ongoing studies evaluating cardiovascular outcomes are in progress.

• Store at controlled room temperature 20°C to 25°C (68°F to 77°F).
• Protect from moisture and light.
• Keep tablets in original packaging until use.
• Do not freeze.
• Keep out of reach of children.