Ezetimibe

Ezetimibe (an azetidinone) is a lipid-lowering substance for the treatment of hypercholesterolemia and the rare hereditary siterostemia (phytosterolemia).

Significance:

Ezetimibe is the first and only cholesterolabsorption inhibitor to date. It inhibits cholesterol absorption in the small intestine and thus limits the exogenous food-dependent and biliary cholesterol intake.

After the introduction of statins/HMG-CoA reductase inhibitors,ezetimibe was the first lipid-lowering drug with a novel mechanism of action that is not comparable to statins, as it does not inhibit endogenous cholesterol synthesis but limits exogenous cholesterol intake and is therefore the first 'non-statin' that can be used for lipid lowering.

Due to the advantages (greater LDL-C reduction, faster achievement of target values) that have been shown through different and synergistic effects together with statins, ezetimibe has since established itself essentially in combination therapy with statins and is an essential component of individualized therapy to achieve LDL-C target values according to 2019 ESC/EAS guidelines (Mach F et al 2020). A combination preparation with bempedoic acid, which also inhibits endogenous cholesterol synthesis and can also be used in cases of statin intolerance, has also been approved since 2020.

Ezetimibe attaches to the brush border of the small intestine and selectively inhibits the intestinal absorption of cholesterol and otherrelated phytosterols. Ezetimibe acts on the sterol transporter , the so-calledNiemann-Pick-C1-Like-1(NPC1L1) protein, which is responsible for the intestinal absorption of cholesterol and phytosterols and is localized in the brush border of the small intestine (Altmann et al 2004). This leads to a reduced absorption of exogenously supplied and biliary cholesterol from the intestine into the bloodstream (Davis HR and Veltri EP 2007).

Ezetimibe can therefore be combined well with statins or bempedoic acid, which inhibit endogenous cholesterol synthesis in the liver, and an additional greater reduction in cholesterol levels can be achieved through a complementary effect of both substances than through monotherapy (Ballantyne CM et al 2004). The cholesterol reduction in monotherapy with ezetimibe is reported to be approx. 17% (Dujovne CA et al 2002) and in combination with statins approx. 25% (Gagno C et al 2002). In addition, there is a slight reduction in triglygerides (approx. 8%) and a slight increase in HDL cholesterol (approx. 5%).

Preclinical and clinical studies have shown that ezetimibe inhibits the absorption of cholesterol, but has no effect on the absorption of triglycerides, fatty acids, bile acids, progesterone, ethinylestradiol or the fat-soluble vitamins A and D (Knoop RH et al 2003).

Ezetimibe given either in monotherapy or together with a statin leads to significant reductions in elevated levels of total cholesterol, LDL cholesterol, apolipoprotein B and triglycerides and improves HDL cholesterol in patients with hypercholesterolemia (Ballantyne CM et al 2004).

Combination therapy with statins is more effective than increasing the dose of statinmonotherapy. The LDL-C values are lowered more and LDL-C target values can be achieved more quickly than with monotherapy with statins. This allows statins to be 'saved' and dose-dependent side effects of statins to be limited.

The effect of ezetimibe in combination with bempedoic acid is even greater than when combined with statins, with a reduction in LDL-C of approx. 47% ( ).

After initially unclear results with regard to an improvement in cardiovascular risk and endpoints, the IMPROVE study in over 18,000 patients showed that the combination of statins with ezetimibe (40 mg simvastatin/10 mg ezetimibe) can effectively reduce cardiovascular risk after an acute coronarysyndrome (ACS) compared to monotherapy with statins (40 mg) (Cannon CP et al 2015).

Recent meta-analyses confirm combination therapy ezetimibe with statins improves LDL-C lowering with comparable side effect profile, and lower risk of mortality, major cardiovascular events and stroke compared to monotherapy with statins (Banach M et al 2025).

For patients with type 2DM with extremely increased atherosclerotic risk, there is a comparable result in terms of cardiovascular risk and outcome for monotherapy with high-dose statins and combination therapy statins/ezetimibe (Kao Y-C et al 2021).

(For cardiovascular risk, morbidity and mortality, see also Ludwig WD Hsg. guideline AkdÄ 2023).

Ezetimibe also shows efficacy in rare homozygous sitosterolemia. A significant reduction in sitosterol and campesterol was demonstrated in a study with 50 patients.

For additional information, see the Information for healthcare professionals

In addition to lifestyle changes, i.e. dietary changes, exercise and, if necessary, smoking cessation as basic therapy

• as combination therapy together with statins or as an add-on to existing statin therapy if target values are not achieved in the case of primary heterozygous hypercholesterolemia
• as combination therapy with bempedoic acid or as an add-on to existing therapy with bempedoic acid
• as monotherapy if statins are unsuitable or not tolerated
• in rare forms of homozygous familial hypercholesterolemia
• in rare homozygous siterostemia (phytosterolemia)
• for the prevention of cardiovascular events in addition to statins or initially in combination with statins to reduce the risk of further cardiovascular events following acute coronary syndrome and a history of myocardial infarction

Ezetimibe should not be used during pregnancy. There are insufficient data on this. Ezetimibe is placental in animal studies. Preclinical studies have not shown any harmful effects of ezetimibe monotherapy in animal experiments. Harmful effects were observed with combination therapy with statins.

Ezetimibe must not be used during breastfeeding. Animal studies have shown that ezetimibe passes into breast milk. Sufficient data are not available in humans.

Effects of ezetimibe on fertility have not been studied in humans. Ezetimibe had no effects on fertility in animal studies.

Dosage of ezetimibe is always 10 mg orally in tablet form for monotherapy as well as in combination (with variable concentration for statins; for combination bempedoic acid 180mg/10mg; for the corresponding combined substance see also the technical information of the respective substance or the respective combination preparation).

It can be taken independently of food; high-fat food has essentially no influence on biotransformation.

If an anion exchanger is used at the same time, ezetimibe must be administered at least 2 hours before or 4 hours after taking the anion exchanger.

Dose adjustment for elderly patients is not necessary.

Treatment of children and adolescents only by a specialist if necessary (off-label, as there are usually no RCTs available). There are some special features and restrictions (see contraindications)!

Dose adjustment for renal impairment not necessary.

Dose adjustment not necessary for mild hepatic impairment; use is not indicated for moderate and severe hepatic impairment (see contraindications).

Ezetimibe is generally well tolerated. Gastrointestinal complaints, headache, paraesthesia, fatigue, myopathy, joint complaints, skin rash, urticaria are frequently reported and described as mild and reversible.

Increase in serum transaminases ALT and/or AST, more frequent; gamma GT occasionally; CK more frequently elevated (laboratory checks, discontinue if transaminases increase above 3 times the upper normal value, especially persistent or signs of liver dysfunction).

Serious side effects are very rare: anaphylaxis (contraindicated in case of known hypersensitivity or a history of angioedema).

Increased risk of myopathies with risk of rhabdomyolysis, especially in combination with statins (incidence according to manufacturer's instructions 0.1% in combination with simvastatin, 0.2% with statin monotherapy). Patients should be informed about symptoms and instructed to report them.

If CK is severely elevated (≥10 times the norm or several times ≥ 5 - 10 times the norm), discontinue medication immediately.

In the case of combination therapy, always observe the side effect profile of the combined substance!

Ciclosporin: with caution, the effect can be significantly enhanced, control ciclosporin levels, dose adjustment.

Anticoagulants: Vit K uptake is also regulated via Niemann-Pick-C1-Like-1(NPC1L1) protein (Takada T et al 2015), therefore WW (increased effect of Vit K antagonists) may occur with the effect of Vit K antagonists (warfarin) (laboratory controls, dose adjustment or Vit K substitution).

Fibrates: the combination of ezetimibe and fibrates can lead to increased excretion of cholesterol in the bile and there is a risk of increased occurrence of cholelithiasis and cholecystitis.

1. Altmann SW et al (2004). Niemann-Pick C1 Like 1 Protein Is Critical for Intestinal Cholesterol Absorption. Science 303;5661:1201-1204. DOI: 10.1126/science.1093131
2. Ballantyne CM et. al. (2003). Effect of Ezetimibe Coadministered With Atorvastatin in 628 Patients With Primary Hypercholesterolemia: A Prospective, Randomized, Double-Blind Trial. Circulation 107, 19: 2409-2415. https://doi.org/10.1161/01.CIR.0000068312.21969.C8
3. Banach M et. al.(2025) Impact of Lipid-Lowering Combination Therapy With Statins and Ezetimibe vs Statin Monotherapy on the Reduction of Cardiovascular Outcomes: A Meta-analysis. Mayo Clin Proc. n XXX 2025;nn(n):1-20 n https://doi.org/10.1016/j.mayocp.2025.01.018.
4. Cannon CP et. al. for the IMPROVE-IT Investigators (2015). Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med 372:2387-2397 DOI: 10.1056/NEJMoa1410489.
5. Davis HR and Velti EP. (2007) Zetia: Inhibition of Niemann-Pick C1 Like 1 (NPC1L1) to Reduce Intestinal Cholesterol Absorption and Treat Hyperlipidemia (Review). J Atheroscler Thromb 14:99-108.
6. Dujovne CA et al (2002). Efficacy and safety of a potent new selective cholesterol absorption inhibitor, ezetimibe, in patients with primary hypercholesterolemia. Am J Cardiol 90:1092-1097.
7. Gagno C et al (2002). Efficacy and safety of ezetimibe added to ongoing statin therapy for treatment of patients with primary hypercholesterolemia. Am J Cardiol 90:1084-1091.
8. Kao Y-C et al (2021). Similar major cardiovascular outcomes between pure statin and ezetimibe-statin in comparable intensity for type 2 diabetes with extremely atherosclerotic risks. Scientifc Reports 11:6697 https://doi.org/10.1038/s41598-021-86090-9.
9. Knoop RH, et. al. for Ezetimibe Study Group. (2003). Effects of ezetimibe, a new cholesterol absorption inhibitor, on plasma lipids in patients with primary hypercholesterolemia. Eur Heart J 24(8):729-41. doi: 10.1016/s0195-668x(02)00807-2
10. Ludwig WD (Ed.) (2023). Guideline of the Drug Commission of the German Medical Association (AkdÄ). Drug-based cholesterol lowering for the prevention of cardiovascular events 1st edition, version 2.0 July 2023.
11. Mach F et al (2020). 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. European Heart Journal (2020) 41, 111-188. doi:10.1093/eurheartj/ehz455.
12. Takada T et al (2015). NPC1L1 is a key regulator of intestinal vitamin K absorption and a modulator of warfarin therapy. Science Translational Medicine 7(275): 275ra23. doi:10.1126/scitranslmed.3010329.

Figure credits:

Altmann SW et al. (2004). Niemann-Pick C1 Like 1 Protein Is Critical for Intestinal Cholesterol Absorption. Science 303;5661:1201-1204.
DOI: 10.1126/science.1093131