What is ezetimibe?

What is Ezetimibe?

Ezetimibe is a cholesterol absorption inhibitor that works by blocking the NPC1L1 (Niemann-Pick C1-like 1) protein in the small intestine, thereby reducing the absorption of both dietary and biliary cholesterol without affecting fat-soluble vitamins, triglycerides, or bile acids. 1, 2

Mechanism of Action

• Ezetimibe selectively inhibits intestinal cholesterol absorption by binding to the NPC1L1 sterol transporter located at the brush border of enterocytes in the small intestine, preventing cholesterol from entering the bloodstream 1, 2

• The drug undergoes extensive glucuronidation (>80%) to form ezetimibe-glucuronide, which is the pharmacologically active metabolite that binds with even higher affinity to NPC1L1 than the parent compound 3, 4

• Enterohepatic recirculation ensures repeated delivery to the intestinal site of action with limited peripheral exposure, contributing to its favorable safety profile 3

• The mechanism is complementary to statins: ezetimibe blocks intestinal cholesterol absorption while statins inhibit hepatic cholesterol synthesis, making combination therapy particularly effective 1

Clinical Efficacy

As monotherapy, ezetimibe reduces LDL cholesterol by approximately 18-20%, with modest increases in HDL cholesterol of 2.5-5% 5, 1

• When added to statin therapy, ezetimibe provides an additional 24-25% reduction in LDL cholesterol beyond what the statin achieves alone 5

• The IMPROVE-IT trial demonstrated that adding ezetimibe to moderate-intensity statin therapy significantly reduced major cardiovascular events by approximately 7% (2% absolute reduction, HR 0.936) in patients with recent acute coronary syndrome after 7 years 5, 1

• Ezetimibe inhibits cholesterol absorption by an average of 54% in hypercholesterolemic individuals 3

FDA-Approved Indications

The FDA has approved ezetimibe for multiple specific conditions 2:

• Primary hyperlipidemia: Used with diet and either a statin or alone (when additional treatments are not possible) to lower LDL-C in adults

• Heterozygous familial hypercholesterolemia (HeFH): With a statin in adults and children ≥10 years of age

• Homozygous familial hypercholesterolemia (HoFH): With a statin and other treatments in adults and patients ≥10 years of age

• Mixed hyperlipidemia: With fenofibrate to lower LDL-C in adults

• Homozygous familial sitosterolemia: To lower sitosterol and campesterol levels in adults and children ≥9 years of age

Dosing and Administration

• The standard dose is 10 mg orally once daily, which can be taken with or without food 2

• The terminal half-life is approximately 22 hours, with about 2-fold accumulation upon repeated once-daily dosing 4

• No dosage adjustment is necessary based on age, sex, race, or in patients with mild hepatic impairment or mild-to-severe renal insufficiency 4

Safety Profile

Ezetimibe has a favorable safety profile with adverse effects similar to placebo when used as monotherapy 6, 7

• The most common adverse effects with monotherapy include upper respiratory tract infection, diarrhea, arthralgia, sinusitis, and pain in extremities 6

• When combined with statins, reported adverse effects include nasopharyngitis, myalgia, upper respiratory tract infection, arthralgia, and diarrhea 6

• Ezetimibe should not be used in patients with moderate to severe hepatic impairment 6, 2

• Persistent elevations in hepatic transaminases may occur with concomitant statin therapy, and rare cases of myopathy and rhabdomyolysis have been reported 6

• Clinical trials demonstrated no increased risk of hemorrhagic stroke, cancer, bleeding-related adverse events, or noncardiovascular mortality 6

Drug Interactions

Ezetimibe has minimal drug interactions due to its limited systemic absorption and lack of effect on major CYP450 enzymes 7, 4

• Cholestyramine (bile acid sequestrant) significantly decreases ezetimibe bioavailability; these agents should be administered several hours apart 4

• Cyclosporine increases ezetimibe exposure and ezetimibe causes small increases in cyclosporine levels; careful monitoring is advised with concomitant use 6, 4

• Gemfibrozil and fenofibrate increase ezetimibe bioavailability, but this is not considered clinically significant given the flat dose-response curve 4

• No significant interactions occur with statins, digoxin, glipizide, warfarin, or oral contraceptives 4

Special Populations

Ezetimibe should be discontinued 1-2 months before attempting pregnancy, or immediately if pregnancy is unplanned 5

• It is unknown if ezetimibe passes into breast milk; the decision to breastfeed while taking ezetimibe should be discussed with a healthcare provider 2

• Safety and effectiveness have not been established in children <10 years of age with HeFH or HoFH, or <9 years of age with sitosterolemia 2