What is the role of Ezetimibe (EZETIMIBE) in treatment?

From the Guidelines

Ezetimibe should be considered as an adjunct therapy to statins for patients with hypercholesterolemia who cannot achieve target LDL levels with statins alone, or as monotherapy for those who cannot tolerate statins, due to its ability to provide an additional 15-25% reduction in LDL cholesterol beyond what statins alone can achieve, as demonstrated in the IMPROVE-IT trial 1.

Key Points

• Ezetimibe works by blocking the Niemann-Pick C1-Like 1 (NPC1L1) protein in the intestinal lining, which is responsible for cholesterol absorption.
• The standard dose is 10 mg once daily, taken with or without food, and it can be administered at any time of day.
• Ezetimibe has minimal side effects compared to statins, with the most common being mild gastrointestinal symptoms, such as upper respiratory tract infection, diarrhea, arthralgia, sinusitis, and pain in extremities 1.
• For patients with chronic kidney disease or mild to moderate hepatic impairment, no dose adjustment is necessary, making it a versatile option for various patient populations requiring cholesterol management.

Clinical Considerations

• Ezetimibe can be used in combination with statin therapy to achieve greater LDL-C reduction, with a mean % reduction in LDL-C of 25% when used in combination with statin therapy 1.
• The addition of ezetimibe to maximally tolerated statin therapy can be considered for patients with clinical ASCVD at very high risk who require additional LDL-C lowering, as recommended in the 2022 ACC expert consensus decision pathway on the role of nonstatin therapies for LDL-cholesterol lowering 1.
• Ezetimibe is generally well tolerated, with a low risk of myopathy and rhabdomyolysis, and can be used in patients who are intolerant to statins or require additional LDL-C reduction beyond what statins alone can achieve.

From the FDA Drug Label

Ezetimibe reduces blood cholesterol by inhibiting the absorption of cholesterol by the small intestine. The molecular target of ezetimibe has been shown to be the sterol transporter, Niemann-Pick C1-Like 1 (NPC1L1), which is involved in the intestinal uptake of cholesterol and phytosterols Ezetimibe localizes at the brush border of the small intestine and inhibits the absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver. Ezetimibe Tablet reduces total cholesterol (total-C), LDL-C, apolipoprotein (Apo) B, and non-high-density lipoprotein cholesterol (non-HDL-C) in patients with hyperlipidemia.

The role of ezetimibe is to reduce blood cholesterol levels by inhibiting the absorption of cholesterol in the small intestine. It works by targeting the sterol transporter Niemann-Pick C1-Like 1 (NPC1L1) and localizing at the brush border of the small intestine to inhibit cholesterol absorption. This leads to a decrease in the delivery of intestinal cholesterol to the liver, resulting in a reduction of hepatic cholesterol stores and an increase in LDL receptors, which helps to clear cholesterol from the blood. Ezetimibe is used to lower elevated low-density lipoprotein cholesterol (LDL-C) or bad cholesterol in adults with primary hyperlipidemia, including heterozygous familial hypercholesterolemia (HeFH) 2.

From the Research

Role of Ezetimibe in Lowering Low-Density Lipoprotein Cholesterol

• Ezetimibe is typically administered at a dose of 10 mg daily, but studies have shown that increasing the dose to 20 mg daily can further reduce total and LDL cholesterol in patients receiving concomitant statin therapy 3.
• The use of ezetimibe as monotherapy has been compared to proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) in patients not receiving statins, with PCSK9i showing significantly greater reduction in LDL-C levels 4.
• Ezetimibe has been shown to lower LDL-C by reducing intestinal absorption of cholesterol, and can be used in combination with other agents, such as PCSK9i and bempedoic acid, to synergistically lower LDL-C and reduce risk of major adverse cardiovascular events (MACE) 5.

Comparison with Other Therapies

• Ezetimibe has been compared to PCSK9 inhibitors in terms of LDL-C reduction, with PCSK9 inhibitors showing greater efficacy in patients not receiving statins 4.
• The combination of ezetimibe with statin therapy has been shown to be effective in reducing LDL-C and improving clinical outcomes, even in patients with baseline LDL-C <70 mg/dL 6.
• Ezetimibe can be used as an alternative to statins in patients who are intolerant of statins, and can be combined with other non-statin therapies, such as PCSK9i and bempedoic acid, to achieve greater LDL-C reduction 5, 7.

Clinical Outcomes

• The use of ezetimibe in combination with statin therapy has been shown to reduce the risk of cardiovascular events in post-acute coronary syndrome (ACS) patients, regardless of baseline LDL-C values 6.
• Ezetimibe has been shown to be well-tolerated and safe, with no significant differences in safety endpoints compared to placebo 6.
• The addition of ezetimibe to statin therapy has been recommended for secondary prevention in very high-risk patients with LDL-C ≥70 mg/dL despite maximally tolerated statin 6.