Ezetimibe Topic Review

Ezetimibe is a nonstatin low-density lipoprotein cholesterol-lowering small molecule drug.

Ezetimibe is the only currently FDA-approved approved member of the of intestinal cholesterol reuptake inhibitors drug class. [Robinson JG. Clinical Lipid Management;443a; Zetia package insert;1a]

Ezetimibe acts by inhibiting the Niemann-Pick C1-Like 1 (NPC1L1) receptor, which mediates the absorption of cholesterol from the small intestine. This reduces a reduction in the liver cholesterol level, which in turn upregulates low-density lipoprotein (LDL) receptors, lowering LDL cholesterol (LDL-C) levels in the blood. [Robinson JG. Clinical Lipid Management;444a] Ezetimibe also lowers non-HDL-C, and, to a more modest degree, triglycerides. Levels of HDL-C are not significantly affected. [Robinson JG. Clinical Lipid Management;444a-445a]

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Source: commons.wikimedia.org/wiki/File:Ezetimibe.svg. Created by Harbin. Released to public domain.

Indications

Ezetimibe is currently FDA-approved for the following indications:

• Patients with primary (heterozygous familial and nonfamilial) hyperlipidemia: Ezetimibe, alone or in combination with a statin, is indicated as adjunctive therapy to diet for the reduction of elevated total cholesterol, LDL-C, apolipoprotein B (Apo B) and non-HDL-C [Zetia package insert;2a-b]
• Adult patients with mixed hyperlipidemia: Ezetimibe, in combination with a fenofibrate, is indicated as adjunctive therapy to diet for the reduction of elevated total cholesterol, LDL-C, Apo B, and non-HDL-C [Zetia package insert;2c]
• Patients with homozygous familial hypercholesterolemia: Ezetimibe, in combination with atorvastatin or simvastatin, is indicated for the reduction of elevated total cholesterol and LDL-C levels, as an adjunct to other lipid-lowering treatments (eg, LDL apheresis) or if such treatments are unavailable. [Zetia package insert;2d]
• Patients with homozygous sitosterolemia: Ezetimibe is indicated as adjunctive therapy to diet for the reduction of elevated sitosterol and campesterol levels. [Zetia package insert;2e]

Dosage and Administration

The recommended dosage of ezetimibe is 10 mg once per day, taken with or without food. [Zetia package insert;2g] When taken as part of a combination regimen with a statin or fenofibrate, ezetimibe may be taken at the same time as the other drug. [Zetia package insert;2h] No dosage adjustment is necessary in patients with hepatic or renal impairment. [Zetia package insert;2i-j]

Guideline Recommendations

The 2018 American College of Cardiology/American Heart Association/Multisociety Guideline on the Management of Blood Cholesterol considers ezetimibe an efficacious add-on to statin therapy with a favorable safety profile. [Grundy SM, et al. Circulation. 2018;10a] Specific recommendations on ezetimibe use from the guideline are presented below, organized by patient population.

For secondary prevention in patients with clinical atherosclerotic cardiovascular disease (ASCVD), the guideline contains the following recommendations:

• Addition of ezetimibe to a maximally tolerated statin regimen is reasonable (class of recommendation [COR] IIa) in patients whose ASCVD is deemed to be very high risk and whose LDL-C levels are ≥ 70 mg/dL (≥ 1.8 mmol/L) [Grundy SM, et al. Circulation. 2018;10b]
• Addition of ezetimibe to a maximally tolerated statin regimen may be reasonable (COR IIb) in patients whose LDL-C levels are ≥ 70 mg/dL (≥ 1.8 mmol/L) [Grundy SM, et al. Circulation. 2018;11a]
• Before addition of a PCSK9 inhibitor in patients with very high risk ASCVD is considered, their maximally tolerated LDL-C-lowering therapy should (COR I) include ezetimibe and a statin [Grundy SM, et al. Circulation. 2018;10c]

For primary prevention in patients with primary severe hypercholesterolemia, the guideline recommends:

• Addition of ezetimibe is reasonable (COR IIa) in patients 20 to 75 years of age with an LDL-C level of ≥ 190 mg/dL (≥ 4.8 mmol/L) who achieve a < 50% LDL-C reduction and/or whose LDL-C level is ≥ 100 mg/dL (≥ 2.6 mmol/L) while on a maximally tolerated statin therapy [Grundy SM, et al. Circulation. 2018;14a]

For primary prevention in patients with diabetes, the guideline states:

• Addition of ezetimibe to maximally tolerated statin therapy to reduce LDL-C levels by 50% or more may be reasonable (COR IIb) in patients whose 10-year ASCVD risk is ≥ 20% [Grundy SM, et al. Circulation. 2018;16a]

For primary prevention in adult patients 40 to 75 years of age with LDL-C levels 70 to 189 mg/dL, the guideline states:

• Addition of a nonstatin (ezetimibe or a bile acid sequestrant) to moderate-intensity statin therapy may be reasonable (COR IIb) in intermediate-risk (10-year ASCVD risk of 7.5% to < 20%) patients who would benefit from more intensive LDL-C lowering but for whom high-intensity statins are not advisable or tolerable [Grundy SM, et al. Circulation. 2018;22a]

For primary prevention in patients with chronic kidney disease (CKD), the guideline recommends:

• Ezetimibe in combination with a moderate-intensity statin regimen may be useful (COR IIa) in adult patients 40 to 75 years of age with LDL-C levels of 70 to 189 mg/dL who are at 10-year ASCVD risk of ≥ 7.5% and whose CKD is not treated with dialysis or kidney transplantation [Grundy SM, et al. Circulation. 2018;22b;34a]

Efficacy and Safety

The LDL-C-lowering efficacy of ezetimibe is approximately 20% when taken as monotherapy and 15% to 20% when taken with a statin. [Robinson JG. Clinical Lipid Management;444a-445a] In the pivotal IMPROVE-IT clinical trial, researchers randomly assigned 18,144 patients with history of an acute coronary syndrome to receive either simvastatin (40 mg once daily) monotherapy (9,077 patients) or a combination simvastatin (40 mg once daily) and ezetimibe (10 mg once daily) regimen (9,067 patients). [Cannon CP, et al. N Engl J Med. 2015;3b,5a] This trial confirmed the LDL-C-lowering efficacy of ezetimibe, with observed median time-weighted LDL-C levels of 69.5 mg/dL in the simvastatin alone group and 53.7 mg/dL in the simvastatin-ezetimibe group (P < .001). [Cannon CP, et al. N Engl J Med. 2015;1a;5b] The primary efficacy endpoint in IMPROVE-IT was a composite cardiovascular (CV) outcome endpoint which included death from CV disease, a major coronary event (nonfatal myocardial infarction, documented unstable angina requiring hospital admission, or coronary revascularization occurring at least 30 days after randomization), or nonfatal stroke. [Cannon CP, et al. N Engl J Med. 2015;3a] At 7 years, the Kaplan-Meier rates for the primary endpoint were 32.7% in the simvastatin-ezetimibe group and 34.7% in the simvastatin alone group (P = .016), with the benefit of ezetimibe addition emerging after approximately 1 year of treatment. [Cannon CP, et al. N Engl J Med. 2015;6a]

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The Kaplan–Meier curves for the primary efficacy endpoint in the IMPROVE-IT trial. Adapted from Cannon CP, et al. N Engl J Med . 2015;doi:10.1056/NEJMoa1410849.

Ezetimibe has a favorable overall safety profile. In the IMPROVE-IT trial, no significant differences between the simvastatin alone and simvastatin plus ezetimibe groups were observed in any of the prespecified safety endpoints, and adverse event-related discontinuation rates were similar between the two groups. [Cannon CP, et al. N Engl J Med. 2015;6b;8a] A 2022 meta-analysis comprising 48 randomized controlled trials (including a total of 28,444 patients) found no difference in adverse event rates between ezetimibe and placebo or other lipid-lowering medications. [Wang Y, et al. BMJ Med. 2022;1a;8a]

References:

• Cannon CP, et al. N Engl J Med. 2015;doi:10.1056/NEJMoa1410849.
• Grundy SM, et al. Circulation. 2019;doi:10.1161/ CIR.0000000000000625.
• Robinson JG. Clinical Lipid Management. First ed. Montvale NJ: Professional Communications; 2016.
• Wang Y, et al. BMJ Med.2022;doi:10.1136/bmjmed-2022-000134.
• Zetia. Prescribing information. Organon LLC. www.organon.com/product/usa/pi_circulars/z/zetia/zetia_pi.pdf. Revised June 2021. Accessed Nov. 22, 2022.