Ezetimibe

Introduction

Ezetimibe is currently the only drug in the class of intestinal cholesterol reuptake inhibitors. Ezetimibe blocks intestinal cholesterol uptake and lowers low-density lipoprotein cholesterol (LDL-C) 15% to 20% when used with a statin or as monotherapy. Ezetimibe was the first nonstatin to clearly reduce atherosclerotic cardiovascular disease (ASCVD) event risk when added to background statin therapy, shown in the IMPROVE-IT trial.

Based on the IMPROVE-IT data and a more favorable cost-benefit ratio compared to PCSK9 monoclonal antibodies (which have also been demonstrated to reduce ASCVD events), the 2018 multi-society cholesterol guideline considers ezetimibe the preferred nonstatin option for patients who achieve suboptimal LDL-C lowering on statins alone (see the Appropriate Uses section below).

Clinical Highlight I

• Consider adding ezetimibe to lower LDL-C and further reduce ASCVD risk in patients receiving maximal statin therapy, or who are completely statin intolerant

Appropriate Uses

LDL-C Lowering

The FDA has approved ezetimibe for:

• Patients with primary (heterozygous familial and non-familial) 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, apoB and non-HDL-C
• 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, apoB and non-HDL-C
• Patients with homozygous familial hypercholesterolemia: Ezetimibe, in combination with atorvastatin or simvastatin, is indicated for the reduction of elevated total-C and LDL-C levels, as an adjunct to other lipid-lowering treatments (eg, LDL apheresis) or if such treatments are unavailable
• Patients with homozygous sitosterolemia: Ezetimibe is indicated as adjunctive therapy to diet for the reduction of elevated sitosterol and campesterol levels.

ASCVD Risk Reduction

Ezetimibe further reduced ASCVD events in very high-risk patients with a recent acute coronary syndrome plus an additional high-risk characteristic treated with background moderate-intensity statin therapy.

2018 Multi-Society Cholesterol Guideline Recommendations

Because of affordability and established efficacy in LDL-C lowering and ASCVD risk reduction, the 2018 multi-society guideline considers ezetimibe the preferred nonstatin add-on to maximally-tolerated statin therapy.

The guideline considers addition of ezetimibe to a maximally-tolerated statin regimen in patients with clinical ASCVD (secondary prevention):

• Reasonable (class of recommendation [COR] IIa) in patients whose ASCVD is deemed to be very high risk (Figure 8-2) and whose LDL-C levels are ≥70 mg/dL
• Potentially useful (COR IIb) in patients whose LDL-C levels are ≥70 mg/dL.

Addition of ezetimibe to maximally-tolerated statin therapy in patients 20 to 75 years of age with an LDL-C level of ≥190 mg/dL (primary prevention: hypercholesterolemia) is considered reasonable (COR IIa) if less than 50% LDL-C reduction from baseline is achieved and/or LDL-C level is ≥100 mg/dL.

Addition of ezetimibe to maximally-tolerated statin therapy to reduce LDL-C levels by 50% or more in patients with diabetes (primary prevention: diabetes) may be useful (COR IIb) in patients whose estimated 10-year ASCVD risk is ≥20%.

Addition of ezetimibe to moderate-intensity statin therapy in adult patients 40 to 75 years of age with LDL-C levels of 70-189 mg/dL and an estimated 10-year ASCVD risk of 7.5% to <20% (primary prevention: intermediate risk) may be reasonable (COR IIb) in patients who would benefit from more intensive LDL-C lowering but for whom high-intensity statins are not advisable or tolerable.

Finally, for adult patients 40 to 75 years of age with LDL-C levels of 70-189 mg/dL and chronic kidney disease (CKD) who are at 10-year ASCVD risk of ≥7.5% (primary prevention: intermediate and high risk), ezetimibe in combination with a moderate-intensity statin regimen is considered reasonable (COR IIa) in patients whose CKD is not treated with dialysis or kidney transplantation.

The 2022 American College of Cardiology (ACC) Expert Consensus Decision Pathway on nonstatin therapy generally recapitulates the above recommendations (without assigning a COR), but further suggests that ezetimibe may be considered as an add-on to statin therapy in:

• Secondary prevention patients with very high risk ASCVD who fail to achieve 50% LDL-C reduction on maximally-tolerated statin therapy and whose LDL-C level remains ≥55 mg/dL (compared to ≥70 mg/dL in the 2018 guideline; the threshold of ≥70 mg/dL remains for non-very high risk ASCVD)
• Primary prevention patients with diabetes who fail to achieve 50% LDL-C reduction on maximally tolerated statin therapy and whose LDL-C level remains ≥70 mg/dL (the 2018 guideline does not mention an absolute concentration threshold)
• Primary prevention patients with high estimated 10-year ASCVD risk (≥20%) who do not achieve 50% LDL-C reduction on maximally-tolerated statin therapy and whose LDL-C level remains ≥70 mg/dL (not mentioned in the 2018 guideline).

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Mechanisms of Action

Ezetimibe acts in the small intestine to block uptake of cholesterol via the Niemann-Pick C1-Like 1 receptor, a critical mediator of cholesterol absorption. Ezetimibe reduces absorption of cholesterol from the diet and bile acids. This mechanism is complementary to that of other LDL-lowering medications, including: statins and bempedoic acid, which reduce cholesterol synthesis, as well as PCSK9 inhibitors, which upregulate LDL receptor levels by preventing their intracellular degradation, allowing for more LDL-C uptake from the blood and bile acid sequestrants, which bind and sequester bile acid, thus channeling more cholesterol into bile acid synthesis. Since lower levels of hepatic intracellular cholesterol upregulate expression of LDL receptors, these drugs may have a synergistic effect, resulting in increased removal of LDL-C from the blood.

Ezetimibe undergoes extensive enterohepatic circulation with very little systemic exposure. Although metabolized by the liver, ezetimibe has no effect on the metabolism of statins, fibrates, warfarin, or a number of other drugs. Ezetimibe increases the concentration of cyclosporine.

Efficacy

Lipid-Lowering

Ezetimibe as monotherapy lowers LDL-C and non–HDL-C by about 20%. Used in combination with a statin, ezetimibe lowers LDL-C by 15% to 20% with a lesser effect on non–HDL-C. Ezetimibe 10 mg used in combination with simvastatin 40 mg lowers LDL-C approximately 55% on average, an efficacy similar to that of a high intensity statin. Effects on triglycerides (-9%) are modest with no effects on HDL-C.

Cardiovascular Event Reduction

IMPROVE-IT evaluated very high-risk patients with a recent acute coronary syndrome (within 10 days) and an additional high-risk characteristic such as diabetes (n=18,144). Baseline LDL-C was 50-125 mg/dL if not on lipid-lowering therapy and 50-100 mg/dL if on lipid-lowering therapy. All patients were treated with moderate-intensity statin therapy (simvastatin 40-80 mg) and randomized to ezetimibe 10 mg or placebo daily. LDL-C was reduced to a mean of 54 mg/dL in the ezetimibe-statin group compared with 70 mg/dL in the statin-only group. A 10% reduction in ASCVD events (nonfatal MI, stroke and CVD death) and a 6% reduction in major cardiovascular events (additionally including revascularization and unstable angina requiring rehospitalization) occurred over the average of 6 years of follow-up (Figure 22-1). Ezetimibe appears to reduce major cardiovascular events across prespecified subgroups, with evidence of particular benefit in those with diabetes or who were ≥75 years of age.

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Safety

Pregnancy and Lactation

There are few data regarding the safety of ezetimibe in pregnant women or whether it is secreted in breast milk. Ezetimibe should be used only if the potential benefit justifies the risk for the fetus. Since ezetimibe modestly lowers LDL-C and the reduction in ASCVD risk is correspondingly modest, it is reasonable to discontinue during pregnancy and lactation.

Muscle Symptoms

There does not appear to be a clear signal for increased muscle toxicity with ezetimibe.

Ezetimibe appears to be generally well tolerated, including those with statin-related muscle symptoms. Over the 7 years of the IMPROVE-IT trial, there were similar rates of muscle, gallbladder and hepatic events and cancer in both the ezetimibe and placebo groups.

Liver

Ezetimibe is not recommended for patients with moderate to severe hepatic impairment. Ezetimibe should not be used concomitantly with a statin in patients with unexplained hepatic transaminase elevations or active liver disease.

Ezetimibe monotherapy does not affect hepatic transaminase levels. When used concomitantly with statin therapy, ezetimibe increased the rate of ALT >3 times the upper limit of normal on two or more consecutive occasion at about the same rate as atorvastatin 80 mg (<1.5%). Hepatic transaminase elevations are reversible upon discontinuation of ezetimibe. No serious hepatic toxicity has been reported for ezetimibe.

Renal

No adjustment is needed for renal impairment. In the SHARP trial, ezetimibe 10 mg/simvastatin 20 mg therapy had similar rates of adverse events (muscle, liver enzymes, incident cancer) as placebo. Because renal impairment can increase the risk of myopathy, simvastatin dosage should not exceed 20 mg when administered concomitantly with ezetimibe.

Geriatric

Ezetimibe has similar efficacy and safety in persons ≥75 years.

Drug-Drug Interactions

Ezetimibe is extensively glucuronidated in the liver and does not interact with the cytochrome P450 system. Ezetimibe is excreted in the bile and kidney. Drug interactions are summarized in Table 22-1.

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