Ezetimibe

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Ezetimibe
Ezetimibe.svg
Clinical data
Pronunciation /ɛˈzɛtɪmɪb,-maɪb/
Trade names Zetia, Ezetrol, others
AHFS/Drugs.com Monograph
MedlinePlus a603015
License data
Pregnancy
category
Routes of
administration 		By mouth
Drug class Cholesterol absorption inhibitor
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 35% to 65%
Protein binding >90%
Metabolism Intestinal wall, liver
Elimination half-life 19 h to 30 h
Excretion Kidney 11%, fecal 78%
Identifiers
  • (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.207.996 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C24H21F2NO3
Molar mass 409.433 g·mol−1
3D model (JSmol)
Melting point 164 to 166 °C (327 to 331 °F)
  • Fc1ccc(cc1)[C@@H](O)CC[C@H]4C(=O)N(c2ccc(F)cc2)[C@@H]4c3ccc(O)cc3
  • InChI=1S/C24H21F2NO3/c25-17-5-1-15(2-6-17)22(29)14-13-21-23(16-3-11-20(28)12-4-16)27(24(21)30)19-9-7-18(26)8-10-19/h1-12,21-23,28-29H,13-14H2/t21-,22+,23-/m1/s1 Yes check.svgY
  • Key:OLNTVTPDXPETLC-XPWALMASSA-N Yes check.svgY
   (verify)

Ezetimibe is a medication used to treat high blood cholesterol and certain other lipid abnormalities. [3] [4] Generally it is used together with dietary changes and a statin. [5] Alone, it is less preferred than a statin. [4] It is taken by mouth. [4] It is also available in the fixed combinations ezetimibe/simvastatin, [6] ezetimibe/atorvastatin, [7] ezetimibe/rosuvastatin, [4] [8] and ezetimibe/bempedoic acid. [9]

Contents

The most commonly reported adverse events include upper respiratory tract infections, joint pain, diarrhea, and tiredness. [4] Serious side effects may include anaphylaxis, liver problems, depression, and muscle breakdown. [4] [5] Use in pregnancy and breastfeeding is of unclear safety. [10] Ezetimibe works by decreasing cholesterol absorption in the intestines. [5]

Ezetimibe was approved for medical use in the United States in 2002. [4] It is available as a generic medication. [5] In 2021, it was the 92nd most commonly prescribed medication in the United States, with more than 7 million prescriptions. [11] [12]

Medical uses

A 2015 review found that adding ezetimibe to statin treatment of high blood cholesterol had no effect on overall mortality or cardiovascular mortality, although it significantly reduced the risk of myocardial infarction and stroke. [13] A 2015 trial found that adding ezetimibe to simvastatin had no effect on overall mortality but did lower the risk of heart attack or stroke in people with prior heart attack. [14] [15] Several treatment guidelines recommend adding ezetimibe in select high risk persons in whom LDL goals cannot be achieved by maximally tolerated statin alone. [16] [17] [18] [19] [20]

In a systematic review and meta-analysis involving data from 11 different studies (20,291 patients), Dutta et. al. demonstrated that initiation of ezetimibe along with high-intensity statin therapy at the time of an acute coronary syndrome (ACS) event was associated with significantly better cholesterol reduction at day-7, 1-month, 3-months and 1-year post ACS event; which translated into significantly lower recurrent cardiovascular events (death from any cause, major ACS, non-fatal stroke, non-fatal myocardial infarction, and ischemic stroke) post the index event of ACS. [21]

Ezetimibe is indicated in the United States as an add-on to dietary measures to reduce levels of certain lipids in people with: [3]

A 2018 review found that ezetimibe used as sole treatment slightly lowered plasma levels of lipoprotein(a), but the effect was not large enough to be important. [22]

Ezetimibe improves the non-alcoholic fatty liver disease activity score but the available evidence indicates it does not improve outcomes of hepatic steatosis. [23]

Contraindications

The two contraindications to taking ezetimibe are a previous allergic reaction to it, including symptoms of rash, angioedema, and anaphylaxis, and severe liver disease, especially when taken with a statin. [24]

Ezetimibe may have significant medication interactions with ciclosporin and with fibrates other than fenofibrate. [3]

Adverse effects

Common adverse drug reactions (≥1% of patients) associated with ezetimibe therapy include headache and/or diarrhea (steatorrhea). Infrequent adverse effects (0.1–1% of patients) include myalgia and/or raised liver function test (ALT/AST) results. Rarely (<0.1% of patients), hypersensitivity reactions (rash, angioedema) or myopathy may occur. [3] Cases of muscle problems (myalgia and rhabdomyolysis) have been reported and are included as warnings on the label for ezetimibe. [3]

Since NPC1L1 also regulates vitamin K uptake, the use of ezetimibe can lead to side effects in warfarin therapy. [25]

Overdose

The incidence of overdose with ezetimibe is rare; subsequently, few data exist on the effects of overdose. However, an acute overdose of ezetimibe is expected to produce an exaggeration of its usual effects, leading to loose stools, abdominal pain, and fatigue. [26]

Pharmacology

Mechanism of action

Ezetimibe inhibits the absorption of cholesterol from the small intestine and decreases the amount of cholesterol normally available to liver cells. The lower levels of cholesterol in the liver cells leads them to absorb more cholesterol from circulation and thus lowering the levels of circulating cholesterol. It blocks the critical mediator of cholesterol absorption, the Niemann-Pick C1-like 1 (NPC1L1) protein on the gastrointestinal tract epithelial cells, as well as in hepatocytes; it blocks aminopeptidase N and interrupts a caveolin 1–annexin A2 complex involved in trafficking cholesterol. [14]

Pharmacokinetics

Within 4–12 hours of the oral administration of a 10-mg dose to fasting adults, the attained mean ezetimibe peak plasma concentration (Cmax) was 3.4–5.5 ng/ml. Following oral administration, ezetimibe is absorbed and extensively conjugated to a phenolic glucuronide (active metabolite). Mean Cmax (45–71 ng/ml) of ezetimibe-glucuronide is attained within 1–2 hours. The concomitant administration of food (high-fat vs. nonfat meals) has no effect on the extent of absorption of ezetimibe. However, coadministration with a high-fat meal increases its Cmax by 38%. The absolute bioavailability cannot be determined, since ezetimibe is insoluble in aqueous media suitable for injection. Ezetimibe and its active metabolites are highly bound to human plasma proteins (90%). [3]

Ezetimibe is primarily metabolized in the liver and the small intestine via glucuronide conjugation with subsequent renal and biliary excretion. [27] Both the parent compound and its active metabolite are eliminated from plasma with a half-life around 22 hours, allowing for once-daily dosing. Ezetimibe lacks significant inhibitor or inducer effects on cytochrome P450 isoenzymes, which explains its limited number of drug interactions. No dose adjustment is needed in patients with chronic kidney disease or mild hepatic dysfunction (Child-Pugh score 5–6). Due to insufficient data, the manufacturer does not recommend ezetimibe for patients with moderate to severe hepatic impairment (Child-Pugh score 7–15). In patients with mild, moderate, or severe hepatic impairment, the mean AUC values for total ezetimibe are increased about 1.7-fold, 3-to-4-fold, and 5-to-6-fold, respectively, compared to healthy subjects. [3]

Related Research Articles

<span class="mw-page-title-main">Low-density lipoprotein</span> One of the five major groups of lipoprotein

Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein that transport all fat molecules around the body in extracellular water. These groups, from least dense to most dense, are chylomicrons, very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL) and high-density lipoprotein (HDL). LDL delivers fat molecules to cells. LDL is involved in atherosclerosis, a process in which it is oxidized within the walls of arteries.

<span class="mw-page-title-main">Statin</span> Class of drugs used to lower cholesterol levels

Statins are a class of medications that reduce illness and mortality in people who are at high risk of cardiovascular disease. They are the most commonly prescribed cholesterol-lowering drugs.

Lipid-lowering agents, also sometimes referred to as hypolipidemic agents, cholesterol-lowering drugs, or antihyperlipidemic agents are a diverse group of pharmaceuticals that are used to lower the level of lipids and lipoproteins such as cholesterol, in the blood (hyperlipidemia). The American Heart Association recommends the descriptor 'lipid lowering agent' be used for this class of drugs rather than the term 'hypolipidemic'.

Dyslipidemia is a metabolic disorder characterized by abnormally high or low amounts of any or all lipids or lipoproteins in the blood. Dyslipidemia is a risk factor for the development of atherosclerotic cardiovascular diseases (ASCVD), which include coronary artery disease, cerebrovascular disease, and peripheral artery disease. Although dyslipidemia is a risk factor for ASCVD, abnormal levels don't mean that lipid lowering agents need to be started. Other factors, such as comorbid conditions and lifestyle in addition to dyslipidemia, is considered in a cardiovascular risk assessment. In developed countries, most dyslipidemias are hyperlipidemias; that is, an elevation of lipids in the blood. This is often due to diet and lifestyle. Prolonged elevation of insulin resistance can also lead to dyslipidemia. Likewise, increased levels of O-GlcNAc transferase (OGT) may cause dyslipidemia.

<span class="mw-page-title-main">Atorvastatin</span> Cholesterol-lowering medication

Atorvastatin is a statin medication used to prevent cardiovascular disease in those at high risk and to treat abnormal lipid levels. For the prevention of cardiovascular disease, statins are a first-line treatment. It is taken by mouth.

<span class="mw-page-title-main">Simvastatin</span> Lipid-lowering medication

Simvastatin, sold under the brand name Zocor among others, is a statin, a type of lipid-lowering medication. It is used along with exercise, diet, and weight loss to decrease elevated lipid levels. It is also used to decrease the risk of heart problems in those at high risk. It is taken by mouth.

<span class="mw-page-title-main">Rosuvastatin</span> Statin medication

Rosuvastatin, sold under the brand name Crestor among others, is a statin medication, used to prevent cardiovascular disease in those at high risk and treat abnormal lipids. It is recommended to be used together with dietary changes, exercise, and weight loss. It is taken orally.

<span class="mw-page-title-main">Pravastatin</span> Cholesterol lowering medication in the statin class

Pravastatin, sold under the brand name Pravachol among others, is a statin medication, used for preventing cardiovascular disease in those at high risk and treating abnormal lipids. It is suggested to be used together with diet changes, exercise, and weight loss. It is taken by mouth.

<span class="mw-page-title-main">Cerivastatin</span> Chemical compound

Cerivastatin is a synthetic member of the class of statins used to lower cholesterol and prevent cardiovascular disease. It was marketed by the pharmaceutical company Bayer A.G. in the late 1990s, competing with Pfizer's highly successful atorvastatin (Lipitor). Cerivastatin was voluntarily withdrawn from the market worldwide in 2001, due to reports of fatal rhabdomyolysis.

<span class="mw-page-title-main">HMG-CoA reductase</span> Mammalian protein found in Homo sapiens

HMG-CoA reductase is the rate-controlling enzyme of the mevalonate pathway, the metabolic pathway that produces cholesterol and other isoprenoids. HMGCR catalyzes the conversion of HMG-CoA to mevalonic acid, a necessary step in the biosynthesis of cholesterol. Normally in mammalian cells this enzyme is competitively suppressed so that its effect is controlled. This enzyme is the target of the widely available cholesterol-lowering drugs known collectively as the statins, which help treat dyslipidemia.

<span class="mw-page-title-main">Ezetimibe/simvastatin</span> Drug combination used for the treatment of dyslipidemia

Ezetimibe/simvastatin is a drug combination used for the treatment of dyslipidemia. It is a combination of ezetimibe and the statin drug simvastatin.

Hyperlipidemia is abnormally high levels of any or all lipids or lipoproteins in the blood. The term hyperlipidemia refers to the laboratory finding itself and is also used as an umbrella term covering any of various acquired or genetic disorders that result in that finding. Hyperlipidemia represents a subset of dyslipidemia and a superset of hypercholesterolemia. Hyperlipidemia is usually chronic and requires ongoing medication to control blood lipid levels.

<span class="mw-page-title-main">Pitavastatin</span> Chemical compound

Pitavastatin is a member of the blood cholesterol lowering medication class of statins.

Cholesterol absorption inhibitors are a class of compounds that prevent the uptake of cholesterol from the small intestine into the circulatory system. Most of these molecules are monobactams but show no antibiotic activity. An example is ezetimibe Another example is Sch-48461. The "Sch" is for Schering-Plough, where these compounds were developed. Phytosterols are also cholesterol absorption inhibitors.

<span class="mw-page-title-main">Sitosterolemia</span> Medical condition

Sitosterolemia is a rare autosomal recessively inherited lipid metabolic disorder. It is characterized by hyperabsorption and decreased biliary excretion of dietary sterols. Healthy persons absorb only about 5% of dietary plant sterols, but sitosterolemia patients absorb 15% to 60% of ingested sitosterol without excreting much into the bile. The phytosterol campesterol is more readily absorbed than sitosterol.

<span class="mw-page-title-main">Familial hypercholesterolemia</span> Genetic disorder characterized by high cholesterol levels

Familial hypercholesterolemia (FH) is a genetic disorder characterized by high cholesterol levels, specifically very high levels of low-density lipoprotein cholesterol, in the blood and early cardiovascular diseases. The most common mutations diminish the number of functional LDL receptors in the liver or produce abnormal LDL receptors that never go to the cell surface to function properly. Since the underlying body biochemistry is slightly different in individuals with FH, their high cholesterol levels are less responsive to the kinds of cholesterol control methods which are usually more effective in people without FH. Nevertheless, treatment is usually effective.

<span class="mw-page-title-main">NPC1L1</span> Mammalian protein found in Homo sapiens

Niemann-Pick C1-Like 1 (NPC1L1) is a protein found on the gastrointestinal tract epithelial cells as well as in hepatocytes. Specifically, it appears to bind to a critical mediator of cholesterol absorption.

The discovery of HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) reductase inhibitors, called statins, was a breakthrough in the prevention of hypercholesterolemia and related diseases. Hypercholesterolemia is considered to be one of the major risk factors for atherosclerosis which often leads to cardiovascular, cerebrovascular and peripheral vascular diseases. The statins inhibit cholesterol synthesis in the body and that leads to reduction in blood cholesterol levels, which is thought to reduce the risk of atherosclerosis and diseases caused by it.

Bempedoic acid, sold under the brand name Nexletol among others, is a medication for the treatment of hypercholesterolemia.

Bempedoic acid/ezetimibe, sold under the brand name Nexlizet among others, is a fixed-dose combination medication used for the treatment of high cholesterol. It is a combination of bempedoic acid and ezetimibe.

References

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  2. ↑ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA . Retrieved 22 October 2023.
  3. 1 2 3 4 5 6 7 8 "Zetia- ezetimibe tablet". DailyMed. 26 January 2011. Archived from the original on 10 May 2021. Retrieved 13 August 2022.
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  5. 1 2 3 4 British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. p. 196. ISBN   9780857113382.
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  8. ↑ "Roszet- rosuvastatin and ezetimibe tablet Roszet (- rosuvastatin and ezetimibe tablet". DailyMed. 15 September 2021. Archived from the original on 14 August 2022. Retrieved 13 August 2022.
  9. ↑ "Nexlizet- bempedoic acid and ezetimibe tablet, film coated". DailyMed. 24 September 2021. Retrieved 13 August 2022.
  10. ↑ "Ezetimibe (Zetia) Use During Pregnancy". Drugs.com. Archived from the original on 13 April 2019. Retrieved 13 April 2019.
  11. ↑ "The Top 300 of 2021". ClinCalc. Archived from the original on 15 January 2024. Retrieved 14 January 2024.
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  14. 1 2 Phan BA, Dayspring TD, Toth PP (2012). "Ezetimibe therapy: mechanism of action and clinical update". Vascular Health and Risk Management. 8: 415–427. doi: 10.2147/VHRM.S33664 . PMC   3402055 . PMID   22910633.
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  16. ↑ Alenghat FJ, Davis AM (February 2019). "Management of Blood Cholesterol". JAMA. 321 (8): 800–801. doi:10.1001/jama.2019.0015. PMC   6679800 . PMID   30715135.
  17. ↑ Catapano AL, Reiner Z, De Backer G, Graham I, Taskinen MR, Wiklund O, et al. (July 2011). "ESC/EAS Guidelines for the management of dyslipidaemias The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS)". Atherosclerosis. 217 (1): 3–46. doi:10.1016/j.atherosclerosis.2011.06.011. PMID   21882396.
  18. ↑ Teramoto T, Sasaki J, Ishibashi S, Birou S, Daida H, Dohi S, et al. (2013). "Executive summary of the Japan Atherosclerosis Society (JAS) guidelines for the diagnosis and prevention of atherosclerotic cardiovascular diseases in Japan -2012 version". Journal of Atherosclerosis and Thrombosis. 20 (6): 517–523. doi: 10.5551/jat.15792 . PMID   23665881.
  19. ↑ "Lipid modification: cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease | Guidance and guidelines | NICE". Archived from the original on 19 November 2014.
  20. ↑ Grundy SM, Arai H, Barter P, Bersot TP, Betteridge DJ, Carmena R, et al. (Expert Dyslipidemia Panel of the International Atherosclerosis Society) (2014). "An International Atherosclerosis Society Position Paper: global recommendations for the management of dyslipidemia--full report". Journal of Clinical Lipidology. 8 (1): 29–60. doi: 10.1016/j.jacl.2013.12.005 . PMID   24528685.
  21. ↑ Mahajan K, Nagendra L, Dhall A, Dutta D (February 2024). "Impact of early initiation of ezetimibe in patients with acute coronary syndrome: A systematic review and meta-analysis". Eur J Intern Med: S0953-6205(24)00049-9. doi: 10.1016/j.ejim.2024.02.004 . PMID   38336550.
  22. ↑ Awad K, Mikhailidis DP, Katsiki N, Muntner P, Banach M (March 2018). "Effect of Ezetimibe Monotherapy on Plasma Lipoprotein(a) Concentrations in Patients with Primary Hypercholesterolemia: A Systematic Review and Meta-Analysis of Randomized Controlled Trials". Drugs. 78 (4): 453–462. doi:10.1007/s40265-018-0870-1. PMID   29396832. S2CID   207489460.
  23. ↑ Lee HY, Jun DW, Kim HJ, Oh H, Saeed WK, Ahn H, et al. (March 2019). "Ezetimibe decreased nonalcoholic fatty liver disease activity score but not hepatic steatosis". The Korean Journal of Internal Medicine. 34 (2): 296–304. doi:10.3904/kjim.2017.194. PMC   6406097 . PMID   29551054.
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  25. ↑ Takada T, Yamanashi Y, Konishi K, Yamamoto T, Toyoda Y, Masuo Y, et al. (February 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. PMID   25696002. S2CID   5951911.
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  27. ↑ Basha SJ, Naveed SA, Tiwari NK, Shashikumar D, Muzeeb S, Kumar TR, et al. (June 2007). "Concurrent determination of ezetimibe and its phase-I and II metabolites by HPLC with UV detection: quantitative application to various in vitro metabolic stability studies and for qualitative estimation in bile". Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences. 853 (1–2): 88–96. doi:10.1016/j.jchromb.2007.02.053. PMID   17442643.
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