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Ezetimibe is a medication used in the management and treatment of hypercholesterolemia. It is among a novel class of selective cholesterol-absorption inhibitors. It is indicated to reduce total cholesterol, low-density lipoprotein (LDL), apolipoprotein B (apo B), and non-high-density lipoprotein (HDL) in patients with primary hyperlipidemia, mixed hyperlipidemia, familial hypercholesterolemia (HoFH), and homozygous sitosterolemia (phytosterolemia). This activity describes the indications, actions, and contraindications for ezetimibe as a valuable agent in treating hypercholesterolemia. In addition, this activity highlights the administration and monitoring principles that the interprofessional team should employ to manage patients with hypercholesterolemia using ezetimibe. Objectives: Identify the indications for initiating ezetimibe therapy. Review the contraindications for ezetimibe therapy. Summarize the common and less common adverse effects of ezetimibe therapy. Explain the importance of collaboration and communication amongst the interprofessional team to ensure appropriate monitoring of patients receiving ezetimibe. Access free multiple choice questions on this topic.

According to the manufacturer's product labeling, administration of ezetimibe in doses up to 40-50 mg daily was generally well tolerated in clinical trials. In addition, one patient with homozygous sitosterolemia had an accidental overdose of ezetimibe 120 mg/day for 28 days with no significant clinical or laboratory adverse events. There is no specific antidote to ezetimibe. In an overdose with ezetimibe, clinicians should provide symptomatic and supportive care. In addition, clinicians should obtain LFTs if hepatotoxicity is suspected, as autoimmune hepatitis associated with ezetimibe requires treatment with corticosteroid therapy.[9] The incidence of skeletal muscle toxicity related to ezetimibe and concomitant statin treatment increases with age over 65, hypothyroidism, or renal impairment. Patients taking ezetimibe with cyclosporine are at an increased risk of ezetimibe toxicity as it can result in a 2.3 to 12-fold increase in drug exposure.[14]

The landmark trial for ezetimibe is called the Improved Reductions of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT). It evaluated the effect of ezetimibe and simvastatin compared with simvastatin alone in patients with acute coronary syndrome. This double-blinded study published in 2015 followed over 18,000 hospitalized patients with acute coronary syndrome randomized to simvastatin monotherapy or simvastatin combined with ezetimibe. The study found that adding ezetimibe to statin therapy lowered LDL cholesterol by 24%. The combination also lowered the risk of cardiovascular events by 2%. This trial has been a watershed moment in lipid management. Based on the trial, a target LDL cholesterol of less than 70 mg per deciliter is recommended for patients after acute coronary syndrome.[6] Other studies found that reducing LDL levels to less than 50 mg per deciliter reduced all-cause mortality, ischemic events, and myocardial infarctions. These studies include FOURIER and ODYSSEY trials using PCSK9 inhibitors, alirocumab, and evolocumab.[16] Clinicians need to understand the importance and the efficacy of additional agents in lowering LDL cholesterol in addition to dietary and lifestyle modifications. Another trial, known as the SHARP (Study of Heart and Renal Protection), published in 2011, found that patients with chronic kidney disease receiving simvastatin and ezetimibe had reduced atherosclerotic events.[17] With this publication, the Kidney Disease: Improving Global Outcomes (KDIGO) organization updated its practical guidelines in 2013, stating that all adults over 50 years with chronic kidney disease should receive treatment with a statin. Moreover, ezetimibe and statin are recommended in patients with chronic kidney disease stages 3 through 5. People with chronic kidney disease demonstrate an increased risk of cardiovascular disease, so lipid assessment and treatment are essential in this patient population.

Another trial, known as the SHARP (Study of Heart and Renal Protection), published in 2011, found that patients with chronic kidney disease receiving simvastatin and ezetimibe had reduced atherosclerotic events.[17] With this publication, the Kidney Disease: Improving Global Outcomes (KDIGO) organization updated its practical guidelines in 2013, stating that all adults over 50 years with chronic kidney disease should receive treatment with a statin. Moreover, ezetimibe and statin are recommended in patients with chronic kidney disease stages 3 through 5. People with chronic kidney disease demonstrate an increased risk of cardiovascular disease, so lipid assessment and treatment are essential in this patient population. According to AHA(American Heart Association)/ACC (American College of Cardiology)/NLA (National Lipid Association) joint guidelines, patients with clinical ASCVD (atherosclerotic cardiovascular disease) on maximally tolerated statin therapy have a very high risk and have an LDL-C≥70 mg/dL; it is useful to add ezetimibe therapy.[1][6] [Level IIa] In addition, for patients between 20 to 75 years of age with an LDL-C≥190 mg/dL and a 50% reduction in LDL-C while receiving maximally tolerated statin therapy or having an LDL-C≥100 mg/dL, clinicians should consider ezetimibe therapy.[18][6] [Level IIa] Ezetimibe therapy is most effective when the entire interprofessional healthcare team is involved. The prescribing clinician can work with the pharmacist to ensure that dosing is appropriate and that there are no medications that will interact and result in adverse events, particularly rhabdomyolysis. Nursing involvement will include verifying compliance, monitoring for adverse events, and providing counsel regarding administration and what to look for as potential side effects. Both pharmacy and nursing will report any concerns to the prescriber promptly. This interprofessional team approach will maximize treatment effectiveness and minimize adverse events, resulting in better patient outcomes. [Level 5]