What are cholesterol absorption inhibitors?

From the Guidelines

Ezetimibe, a cholesterol absorption inhibitor, is recommended as an adjunct to statin therapy to further reduce LDL cholesterol levels and cardiovascular risk, as evidenced by the IMPROVE-IT trial 1.

Mechanism of Action

Ezetimibe works by blocking the Niemann-Pick C1-Like 1 (NPC1L1) protein in the intestinal lining, which is responsible for cholesterol absorption. This medication can lower LDL cholesterol by approximately 20% when used in combination with statins.

Clinical Evidence

The IMPROVE-IT trial, a large randomized controlled trial, demonstrated that the addition of ezetimibe to simvastatin resulted in a significant 2% absolute reduction in the composite of cardiovascular death, major coronary event, or stroke compared with placebo after 7 years 1. This study provides strong evidence for the use of ezetimibe as an adjunct to statin therapy in patients with acute coronary syndrome.

Safety and Tolerability

Ezetimibe is generally well-tolerated with minimal side effects, which may include mild gastrointestinal symptoms, headache, and rarely, muscle pain. It's particularly useful for patients who cannot tolerate statins or need additional cholesterol lowering beyond what statins provide.

Dosage and Administration

The recommended dose of ezetimibe is 10 mg once daily, which can be taken with or without food at any time of day. Unlike statins, ezetimibe doesn't affect liver enzyme production of cholesterol but instead targets the intestinal absorption pathway, offering a complementary approach to cholesterol management.

Key Points

• Ezetimibe is a cholesterol absorption inhibitor that can lower LDL cholesterol levels by approximately 20% when used in combination with statins.
• The IMPROVE-IT trial provides strong evidence for the use of ezetimibe as an adjunct to statin therapy in patients with acute coronary syndrome.
• Ezetimibe is generally well-tolerated with minimal side effects and can be taken with or without food at any time of day.
• The recommended dose of ezetimibe is 10 mg once daily.

From the FDA Drug Label

Ezetimibe, USP is in a class of lipid-lowering compounds that selectively inhibits the intestinal absorption of cholesterol and related phytosterols. 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.

Cholesterol Absorption Inhibitors work by inhibiting the absorption of cholesterol in the small intestine.

• Ezetimibe is an example of a cholesterol absorption inhibitor.
• It selectively inhibits the intestinal absorption of cholesterol and related phytosterols.
• The molecular target of ezetimibe is the sterol transporter, Niemann-Pick C1-Like 1 (NPC1L1).
• Ezetimibe localizes at the brush border of the small intestine and inhibits the absorption of cholesterol.
• This leads to a decrease in the delivery of intestinal cholesterol to the liver, causing a reduction of hepatic cholesterol stores and an increase in LDL receptors, resulting in clearance of cholesterol from the blood 2.

From the Research

Cholesterol Absorption Inhibitors

• Cholesterol absorption inhibitors, such as ezetimibe, are a new class of antihyperlipidemic agents that inhibit the absorption of biliary and dietary cholesterol from the small intestine 3, 4.
• Ezetimibe has been shown to reduce intestinal cholesterol absorption by 54% from baseline in association with a compensatory increase in endogenous cholesterol synthesis 3.
• Ezetimibe monotherapy has been reported to produce a 17% to 20% reduction from baseline in low-density lipoprotein cholesterol (LDL-C), while combination therapy with statins has produced a reduction in LDL-C of up to 40% 3, 4.

Efficacy and Safety

• Ezetimibe has been evaluated in several clinical trials, including a randomized, double-blind, placebo-controlled trial of 892 patients with primary hypercholesterolemia, which showed that ezetimibe significantly reduced direct LDL cholesterol by a mean of 16.9% compared with an increase of 0.4% with placebo 5.
• Ezetimibe has been shown to be well tolerated, with a safety profile similar to that of placebo, and minimal drug interactions involving the CYP enzyme system 3, 4.
• The addition of ezetimibe to a statin has been shown to produce additional LDL-C reduction, allowing many patients to reach LDL-C targets 6.

Combination Therapy

• Combination therapy with a statin and another lipid-modifying agent, such as ezetimibe, has been compared with intensified statin monotherapy in a systematic review of 36 trials 7.
• The review found that mid-intensity statin plus ezetimibe decreased LDL cholesterol level 5% to 15% and 3% to 21% more than high-intensity monotherapy among patients with ASCVD and diabetes mellitus, respectively 7.
• However, the evidence was insufficient to evaluate long-term clinical outcomes, adherence, and harms for all regimens, and many trials had short durations and high attrition rates, lacked blinding, and did not assess long-term clinical benefits or harms 7.