When is Zetia (ezetimibe) recommended for lowering Low-Density Lipoprotein (LDL) cholesterol?

Ezetimibe (Zetia) Recommendations for Lowering LDL Cholesterol

Ezetimibe is recommended as a second-line therapy after maximally tolerated statin therapy when LDL-C targets are not achieved, particularly in high-risk and very high-risk patients with atherosclerotic cardiovascular disease (ASCVD). 1

Primary Indications for Ezetimibe

• Ezetimibe is indicated in combination with a statin, or alone when additional LDL-C lowering therapy is not possible, as an adjunct to diet to reduce elevated LDL-C in adults with primary hyperlipidemia, including heterozygous familial hypercholesterolemia (HeFH) 2
• For patients with clinical ASCVD who are receiving maximally tolerated statin therapy and whose LDL-C level remains ≥70 mg/dL, adding ezetimibe is reasonable 1
• In patients 20-75 years with LDL-C ≥190 mg/dL who achieve <50% reduction in LDL-C while receiving maximally tolerated statin therapy and/or have LDL-C ≥100 mg/dL, ezetimibe therapy is reasonable 1
• For patients with diabetes who have <50% reduction in LDL-C on maximally tolerated statin therapy (and LDL-C ≥100 mg/dL or non-HDL-C ≥130 mg/dL), ezetimibe may be considered as the initial non-statin agent 1

Risk Stratification and Treatment Algorithm

Very High-Risk Patients:

• Patients with clinical ASCVD who are on maximally tolerated statin therapy and have LDL-C ≥70 mg/dL 1
• Add ezetimibe as second-line therapy before considering PCSK9 inhibitors 1
• Ezetimibe typically provides an additional 15-20% reduction in LDL-C when added to statin therapy 3, 4

High-Risk Patients:

• Patients with severe hypercholesterolemia (LDL-C ≥190 mg/dL) 1
• Patients with diabetes and 10-year ASCVD risk ≥7.5% or high-risk features 1
• Add ezetimibe when <50% reduction in LDL-C is achieved with maximally tolerated statin therapy 1

Moderate to Low-Risk Patients:

• The 2022 BMJ guideline recommends against adding ezetimibe in people at low cardiovascular risk 1
• For patients with diabetes and <7.5% 10-year ASCVD risk, ezetimibe may be considered if LDL-C reduction is <50% on maximally tolerated statin therapy 1

Special Considerations

• Ezetimibe is preferred as the initial non-statin therapy due to demonstrated safety, tolerability, convenience, and single-tablet daily dosing 1
• Ezetimibe can be used as monotherapy in patients who are statin-intolerant 2, 5
• When used in combination with statins, ezetimibe provides an additional 25% LDL-C lowering effect, with total LDL-C reductions of 34-61% 4
• Administer ezetimibe either ≥2 hours before or ≥4 hours after administration of a bile acid sequestrant if used together 2

Monitoring and Safety

• Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating ezetimibe 2
• Monitor liver enzymes as clinically indicated; consider withdrawal if ALT or AST ≥3 times upper limit of normal persist 2
• The safety profile of ezetimibe monotherapy is similar to placebo, with common adverse events including upper respiratory tract infection, diarrhea, arthralgia, and fatigue 2, 3
• When adding ezetimibe to statin therapy, the safety profile is generally comparable to statin monotherapy 5, 6

Common Pitfalls and Caveats

• Ezetimibe primarily causes quantitative rather than qualitative changes in LDL, with small net effects on LDL subclass distribution 7
• Bile acid sequestrants may be considered as an alternative if patients have an inadequate response to ezetimibe or are ezetimibe-intolerant, but only if fasting triglycerides are <300 mg/dL 1
• In the absence of ASCVD or baseline LDL-C ≥190 mg/dL, PCSK9 inhibitors do not have an established role for primary prevention in patients with diabetes 1
• Referral to a lipid specialist is recommended for patients with statin intolerance, baseline LDL-C ≥190 mg/dL not due to secondary causes, complex mixed dyslipidemias, or severe hypertriglyceridemia 1