Ezetimibe

Ezetimibe belongs to a class of lipid-lowering compounds that are cholesterol absorption inhibitors. It selectively inhibits the intestinal absorption of cholesterol and related plant sterols. Some features of this agent are described:

• ezetimibe localizes at the brush border of the small intestine and inhibits the absorption of cholesterol and thus results in reduced delivery of intestinal cholesterol to the liver. Ezetimibe does not increase bile acid secretion (like bile acid sequestrants) and does not inhibit synthesis of cholesterol by the liver (as do statins)
• unlike bile acid sequestrants and orlistat, ezetimibe selectively inhibits absorption of both dietary and biliary cholesterol without interfering with absorption of fatty acids and fat-soluble vitamins
  • the Niemann-Pick C1 like 1 protein (NPC1L1) appears to play a critical role in the intestinal absorption. The complete insensitivity of NPC1L1-null mice to ezetimibe suggests that NPC1L1 or an associated protein may be the molecular target of this drug (1)
• ezetimibe undergoes glucuronidation in the intestinal wall and is delivered back to the intestinal site of action via enterohepatic circulation. Glucuronidation appears to increase residence time in the intestine, minimising systemic exposure
• ezetimibe is not metabolised by the cytochrome P450 system and therefore does not interact with drugs that are metabolised by this system
• as monotherapy ezetimibe treatment resulted in LDL-cholesterol reductions, beyond those achieved with diet alone (2):
  • a pooled analysis of two phase II studies
    • a total of 432 patients were included in this pooled analysis, 243 in study A and 189 in study B
    • The 5- and 10-mg doses of ezetimibe significantly reduced LDL-C levels by 15.7% and 18.5%, respectively (P < 0.01 vs placebo) and significantly increased high-density lipoprotein cholesterol (hDL-C) levels by 2.9% and 3.5%, respectively (P < 0.05 vs placebo). A reduction in plasma TG levels was observed (P = NS)
• combination therapy with a statin
  • there is evidence that combination therapy with 10mg ezetimibe plus 10 mg simvastatin led to a reduction LDL-cholesterol levels by an additional 17% compared with treatment with simvastatin 10mg alone (3) (note that generally the doubling of a statin dose only results in an additional 6% lowering of LDL-cholesterol (4))
    • in the NICE review (5), the Assessment Group conducted a meta-analysis of the five studies identified (6 to 8 weeks in duration) and reported the mean percentage change in lipid profiles from the time ezetimibe was added to the statin, expressed as a proportion of post-statin cholesterol
      • results showed that the addition of ezetimibe to statin therapy reduced LDL cholesterol concentrations by 23.2% (95% CI, 24.3 to 22.1) more than statin therapy alone
• combination therapy with statin and ezetimibe post myocardial infarction (MI) (6):
  • analysis (n=35,826) found late or no ezetimibe initiation, vs early initiation, increased 3-yr MACE risk by 0.7% (95% CI −0.2% to 1.3%;P=0.18) and 1.9% (0.8%-3.1%;P<0.01), respectively
  • study authors conclude early combination therapy with statins and ezetimibe should be standard care

Notes:

• NICE have issued guidance on the use of ezetimibe (5).
  • summary points from the guidance:
    • ezetimibe monotherapy is recommended as an option for the treatment of adults with primary (heterozygous-familial or non-familial) hypercholesterolaemia who would otherwise be initiated on statin therapy but who are unable to do so because of contraindications to initial statin therapy
    • ezetimibe monotherapy is recommended as an option for the treatment of adults with primary (heterozygous-familial or non-familial) hypercholesterolaemia who are intolerant to statin therapy
    • ezetimibe, coadministered with initial statin therapy, is recommended as an option for the treatment of adults with primary (heterozygous-familial or non-familial) hypercholesterolaemia who have been initiated on statin therapy when:
      • serum total or low-density lipoprotein (LDL) cholesterol concentration is not appropriately controlled either after appropriate dose titration of initial statin therapy or because dose titration is limited by intolerance to the initial statin therapy and
      • consideration is being given to changing from initial statin therapy to an alternative statin
    • when the decision has been made to treat with ezetimibe coadministered with a statin, ezetimibe should be prescribed on the basis of lowest acquisition cost
    • for the purposes of this guidance, appropriate control of cholesterol concentrations should be based on individualised risk assessment in accordance with national guidance on the management of cardiovascular disease for the relevant populations
    • for the purposes of this guidance, intolerance to initial statin therapy should be defined as the presence of clinically significant adverse effects from statin therapy that are considered to represent an unacceptable risk to the patient or that may result in compliance with therapy being compromised. Adverse effects include evidence of new-onset muscle pain (often associated with levels of muscle enzymes in the blood indicative of muscle damage), significant gastrointestinal disturbance or alterations of liver function tests
• a MeReC extra has reviewed the use of ezetimibe and has stated (7):
  • ezetimibe is licensed for use in primary (heterozygous-familial and non-familial) hypercholesterolaemia i.e. patients with high (undefined) cholesterol concentrations not due to an underlying cause
  • clinical trial data have shown that ezetimibe reduces cholesterol levels, but there are no published outcome studies which examine whether it reduces morbidity or mortality outcomes, such as heart attacks or cardiovascular deaths
  • ezetimibe is not licensed for the primary or secondary prevention of cardiovascular events
  • results from the ENHANCE study did not show benefit for the combination of ezetimibe 10mg plus simvastatin 80mg compared with simvastatin 80mg alone on carotid artery intima media thickness

The summary of product characteristics should be consulted before prescribing this drug.

References:

1. Altman SW et al. Niemann-Pick C1 Like 1 protein is critical for intestinal cholesterol absorption. Science. 2004 Feb 20;303(5661):1201-4.
2. Effectiveness and tolerability of ezetimibe in patients with primary hypercholesterolemia: pooled analysis of two phase II studies. Clin Ther. 2001 Aug;23(8):1209-30.
3. Pharmacodynamic interaction between the new selective cholesterol absorption inhibitor ezetimibe and simvastatin. Br J Clin Pharmacol. 2002 Sep;54(3):309-19.
4. Knopp RH. Drug treatment of lipid disorders. N Engl J Med 1999;341:498-511.
5. NICE (November 2007). Ezetimibe for the treatment of primary (heterozygous-familial and non-familial) hypercholesterolaemia.
6. Leosdottir M et al. Early Ezetimibe Initiation After Myocardial Infarction Protects Against Later Cardiovascular Outcomes in the SWEDEHEART Registry. JACC April 22nd 2025.
7. MeReC Extra (2008);32.