Ezetimibe
Encyclopedia
Ezetimibe is a drug that lowers cholesterol
. It acts by decreasing cholesterol absorption in the intestine
. It may be used alone (marketed as Zetia or Ezetrol), when other cholesterol-lowering medications are not tolerated, or together with statin
s (e.g., ezetimibe/simvastatin
, marketed as Vytorin and Inegy) when statins alone do not control cholesterol.
Even though ezetimibe decreases cholesterol levels, the results of two major, high-quality clinical trials (in 2008 and 2009) showed that it did not improve clinically significant outcomes, such as major coronary events, and actually made some outcomes, such as artery wall thickness, worse. Indeed, a panel of experts concluded in 2008 that it should "only be used as a last resort". In one of those studies, a head-to-head trial in 2009, a much less expensive medication (extended-release niacin
) was found to be superior. Ezetimibe actually increased the thickness of artery walls (a measurement of atherosclerosis) and caused more major cardiovascular events. However, in combination with simvastatin, a 2010 trial has shown it to be better than atorvastatin and rosuvastatin at lowering lipid levels. A significantly more positive view of the benefits of Ezetimibe is offered by Britain's NICE.
of the small intestine
, where it inhibits the absorption of cholesterol
from the intestine. Specifically, it appears to bind to a critical mediator of cholesterol absorption, the Niemann-Pick C1-Like 1 (NPC1L1) protein on the gastrointestinal tract
epithelial cells as well as in hepatocytes. In addition to this direct effect, decreased cholesterol absorption leads to an upregulation of LDL-receptors on the surface of cells and an increased LDL-cholesterol uptake into cells, thus decreasing levels of LDL in the blood plasma
which contribute to atherosclerosis and cardiovascular events.
On 9 June 2006, US regulators approved the use of ezetimibe in combination with fenofibrate
to treat mixed hyperlipidaemia
.
s (≥1% of patients) associated with ezetimibe therapy include: headache and/or diarrhea (steathorrea). 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.
In 2005, the manufacturer of Ezetrol, Merck Frosst/Schering Pharmaceuticals issued a warning through Health Canada
associating Ezetrol (ezetimibe) with "myalgia
, rhabdomyolysis
, hepatitis
, pancreatitis
, and thrombocytopenia
". Also noted were possible changes in liver function tests
as described above and longer clotting times if the patient is currently on warfarin
while on the cholesterol-lowering medication.
, which combines ezetimibe with a statin
, is also available.
; rarely arthralgia
, hypersensitivity reactions (including rash, angioedema
, and anaphylaxis
), hepatitis
; very rarely pancreatitis
, cholelithiasis, cholecystitis
, thrombocytopenia
, raised creatine kinase
, myopathy
, and rhabdomyolysis
.
and published in the New England Journal of Medicine
suggest that in combination with statin
s, Niaspan, a slow-release form of niacin
, is more effective than ezetimibe at reducing arterial plaque buildup.
Ezetimibe is primarily metabolized in the liver and the small intestine via glucuronide conjugation with subsequent renal and biliary excretion. Both the parent compound and its active metabolite are eliminated from plasma with a half-life of approximately 22 hours allowing for once daily dosing. Ezetimibe lacks significant inhibitor or inducer effects on cytochrome P-450 isoenzymes which explains its limited number of drug interactions (Table 4). No dose adjustment is needed in patients with renal insufficiency 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 approximately 1.7-fold, 3–4 fold, and 5–6 fold respectively, compared to healthy subjects
The ENHANCE trial was not a clinical-outcome trial, but an imaging study of the thickness of plaque in arteries. The American College of Cardiology (ACC) maintains that ezetimibe may be a reasonable option for patients who cannot tolerate a statin or cannot be controlled on a high dose statin. The primary outcome in the treatment of hypercholesterolemia is prevention of cardiovascular events such as death from cardiovascular disease. While the ENHANCE trial did not have the power to detect significant differences in death, it measured the difference in artery thickness (in the carotid and femoral intima-media) to detect reductions in atherosclerotic plaque. At the end of two years, there was no significant difference in artery thickness between patients taking simvastatin and ezetimibe versus patients taking simvastatin alone.
Since in the ENHANCE trial ezetimibe didn't reduce cardiovascular events, atherosclerosis or death, despite the reduction in LDL, doctors have been trying to figure out whether it has any use. Doctors have also concluded that reducing LDL doesn't always reduce atherosclerosis. Reviewers of the ENHANCE trial have raised the possibility that it did not last long enough for ezetimibe to work. Also, many patients had already been treated on statins for a long time, so their artery thickness was already lower. Perhaps if they had not used statins, ezetimibe might have had a greater effect.
Results from the trial have provoked three large clinical-outcome trials.
The ARBITER 6–HALTS trial enrolled patients with coronary artery disease, or an equivalent risk condition such as diabetes, who were already taking statins. They were randomized to additionally take either extended-release niacin or ezetimibe, and the primary end point was change in artery wall thickness. Both drugs reduced LDL cholesterol levels. Niacin reduced artery wall thickness, but ezetimibe paradoxically increased artery wall thickness. Patients on ezetimibe also had more major cardiovascular events. The trial was terminated early after 208 volunteers had completed the study.
The results from the other trials will be presented in the next 3 years. However even before completion of ARBITER 6–HALTS, a March 30, 2008 meeting of the ACC resulted in negative press for drugs like Zetia as Yale University Cardiologist Harlan Krumholz and concurring colleagues called into question the efficacy of such drugs. Krumholz' statements maintained that such pharmaceuticals should not be the first or even second option for prescribing doctors. Definitive conclusions of the efficacy and safety of Zetia can be made such a time when the results of more substantial and comprehensive trials are released, such as the upcoming SHARP Trial which has an enrollment of 9000 patients and will report in 2010 and IMPROVE-IT Trial which has an enrollment of 18,000 patients and will report in 2012.
Results of the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial (ClinicalTrials.gov number, NCT00092677 [ClinicalTrials.gov] ) showed a potential increase in cancer in association with the use of these drugs together. (www.nejm.org September 2, 2008 (10.1056/NEJMe0807200). The actual significance has yet to be determined.
Trials of ezetimibe in combination with simvastatin have proven more favourable than those for ezetimibe alone, however. A 2010 study found that this combination was more effective at lowering lipid levels than alternative agents rosuvastatin
and atorvastatin
.
In the SHARP study, cardiovascular events were lowered by combining ezetimibe and simvastatin.
Degradation behaviour: HPLC studies on ezetimibe under different stress conditions suggested the following degradation behaviour.
Acidic condition: The drug gradually decreased with time on heating at 80 °C in 1 M HCl by forming degradation products. The rate of hydrolysis in acid was slower as compared to that of alkali or water.
Neutral (water) condition: Upon heating the drug solution in water at 80 °C for 1 h, almost complete degradation of the drug was observed.
Degradation in alkali: The drug was found to be highly labile to alkaline hydrolysis. The reaction in 0.1 M NaOH at 80 °C was so fast that whole of the drug was degraded in 0 min. Subsequently, studies were performed in 0.01 M NaOH at 40 °C and complete degradation of the drug was observed in 4 h.
Oxidative conditions: The drug was stable to hydrogen peroxide (3 and 20%) at room temperature.
Photolytic conditions: No major degradation product was observed after exposure of drug solution in 1 M HCl to sunlight for 2 d, only minor degradation products were formed. The nature of degradation in light and dark was found to be similar, indicating that light had no effect on the degradation of the drug in acid. On the other hand, the samples in water degraded under sunlight for 2 d. Corresponding rate of degradation in dark was much slower.
Solid-state study: The solid-state studies showed that ezetimibe was stable to the effect of temperature. When the drug powder was exposed to dry heat at 50 °C for 45 d and at 60°C for 7 ◦d, no decomposition of the drug was seen.
formation between p-benzyloxybenzaldehyde and p-fluoroaniline provides one of the required reactants. This compound is then treated with the depicted acid chloride in the presence of triethylamine
. In all likelihood, this first dehydrohalogenates under reaction conditions to form the substituted ketene
. The transient intermediate reacts with the imine in a 2 + 2 cycloaddition
to afford a four-membered ring. The reaction proceeds to give the trans isomer almost exclusively. The ester group is then hydrolyzed by means of lithium hydroxide. Condensation with the zinc reagent formed in situ from p-fluoromagnesium bromide and zinc chloride affords the ketone. The carbonyl group is then reduced with diborane to afford the alcohol. Removal of the benzyl protecting group by hydrogenolysis over palladium finally affords ezetimibe.
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
. It acts by decreasing cholesterol absorption in the intestine
Intestine
In human anatomy, the intestine is the segment of the alimentary canal extending from the pyloric sphincter of the stomach to the anus and, in humans and other mammals, consists of two segments, the small intestine and the large intestine...
. It may be used alone (marketed as Zetia or Ezetrol), when other cholesterol-lowering medications are not tolerated, or together with statin
Statin
Statins are a class of drugs used to lower cholesterol levels by inhibiting the enzyme HMG-CoA reductase, which plays a central role in the production of cholesterol in the liver. Increased cholesterol levels have been associated with cardiovascular diseases, and statins are therefore used in the...
s (e.g., ezetimibe/simvastatin
Ezetimibe/simvastatin
Ezetimibe/simvastatin is a drug combination used for the treatment of dyslipidemia. It is a combination of ezetimibe and the statin drug simvastatin...
, marketed as Vytorin and Inegy) when statins alone do not control cholesterol.
Even though ezetimibe decreases cholesterol levels, the results of two major, high-quality clinical trials (in 2008 and 2009) showed that it did not improve clinically significant outcomes, such as major coronary events, and actually made some outcomes, such as artery wall thickness, worse. Indeed, a panel of experts concluded in 2008 that it should "only be used as a last resort". In one of those studies, a head-to-head trial in 2009, a much less expensive medication (extended-release niacin
Niacin
"Niacin" redirects here. For the neo-fusion band, see Niacin .Niacin is an organic compound with the formula and, depending on the definition used, one of the forty to eighty essential human nutrients.Niacin is one of five vitamins associated with a pandemic deficiency disease: niacin deficiency...
) was found to be superior. Ezetimibe actually increased the thickness of artery walls (a measurement of atherosclerosis) and caused more major cardiovascular events. However, in combination with simvastatin, a 2010 trial has shown it to be better than atorvastatin and rosuvastatin at lowering lipid levels. A significantly more positive view of the benefits of Ezetimibe is offered by Britain's NICE.
Pharmacology
Ezetimibe localises at the brush borderBrush border
A brush border is the name for the microvilli-covered surface of simple cuboidal epithelium and simple columnar epithelium cells found in certain locations of the body. Microvilli are approximately 100 nanometers in diameter and their length varies from approximately 100 to 2,000 nanometers in...
of the small intestine
Small intestine
The small intestine is the part of the gastrointestinal tract following the stomach and followed by the large intestine, and is where much of the digestion and absorption of food takes place. In invertebrates such as worms, the terms "gastrointestinal tract" and "large intestine" are often used to...
, where it inhibits the absorption of cholesterol
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
from the intestine. Specifically, it appears to bind to a critical mediator of cholesterol absorption, the Niemann-Pick C1-Like 1 (NPC1L1) protein on the gastrointestinal tract
Gastrointestinal tract
The human gastrointestinal tract refers to the stomach and intestine, and sometimes to all the structures from the mouth to the anus. ....
epithelial cells as well as in hepatocytes. In addition to this direct effect, decreased cholesterol absorption leads to an upregulation of LDL-receptors on the surface of cells and an increased LDL-cholesterol uptake into cells, thus decreasing levels of LDL in the blood plasma
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
which contribute to atherosclerosis and cardiovascular events.
Indications
Ezetimibe is indicated as an adjunct to dietary measures in the management of:- Hypercholesterolaemia
- Homozygous sitosterolemiaSitosterolemiaSitosterolemia is a rare autosomal recessively inherited lipid metabolic disorder. It is characterized by hyperabsorption and decreased biliary excretion of dietary sterols leading to hypercholesterolemia, tendon and tuberous xanthomas, premature development of atherosclerosis, and abnormal...
(phytosterolemia)
On 9 June 2006, US regulators approved the use of ezetimibe in combination with fenofibrate
Fenofibrate
Fenofibrate is a drug of the fibrate class. Fenofibrate was developed by Groupe Fournier SA, before it was acquired in 2005 by Solvay Pharmaceutical, a business unit owned by the Belgian corporation, Solvay S.A. In 2009 Solvay Pharmaceutical was acquired by Abbott Laboratories. It is mainly used to...
to treat mixed hyperlipidaemia
Hyperlipidemia
Hyperlipidemia, hyperlipoproteinemia, or hyperlipidaemia is the condition of abnormally elevated levels of any or all lipids and/or lipoproteins in the blood...
.
Adverse effects
Common adverse drug reactionAdverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...
s (≥1% of patients) associated with ezetimibe therapy include: headache and/or diarrhea (steathorrea). Infrequent adverse effects (0.1–1% of patients) include: myalgia
Myalgia
Myalgia means "muscle pain" and is a symptom of many diseases and disorders. The most common causes are the overuse or over-stretching of a muscle or group of muscles. Myalgia without a traumatic history is often due to viral infections...
and/or raised liver function test (ALT/AST) results. Rarely (<0.1% of patients), hypersensitivity
Hypersensitivity
Hypersensitivity refers to undesirable reactions produced by the normal immune system, including allergies and autoimmunity. These reactions may be damaging, uncomfortable, or occasionally fatal. Hypersensitivity reactions require a pre-sensitized state of the host. The four-group classification...
reactions (rash, angioedema
Angioedema
Angioedema or Quincke's edema is the rapid swelling of the dermis, subcutaneous tissue, mucosa and submucosal tissues. It is very similar to urticaria, but urticaria, commonly known as hives, occurs in the upper dermis...
) or myopathy
Myopathy
In medicine, a myopathy is a muscular disease in which the muscle fibers do not function for any one of many reasons, resulting in muscular weakness. "Myopathy" simply means muscle disease...
may occur.
In 2005, the manufacturer of Ezetrol, Merck Frosst/Schering Pharmaceuticals issued a warning through Health Canada
Health Canada
Health Canada is the department of the government of Canada with responsibility for national public health.The current Minister of Health is Leona Aglukkaq, a Conservative Member of Parliament appointed to the position by Prime Minister Stephen Harper.-Branches, regions and agencies:Health Canada...
associating Ezetrol (ezetimibe) with "myalgia
Myalgia
Myalgia means "muscle pain" and is a symptom of many diseases and disorders. The most common causes are the overuse or over-stretching of a muscle or group of muscles. Myalgia without a traumatic history is often due to viral infections...
, rhabdomyolysis
Rhabdomyolysis
Rhabdomyolysis is a condition in which damaged skeletal muscle tissue breaks down rapidly. Breakdown products of damaged muscle cells are released into the bloodstream; some of these, such as the protein myoglobin, are harmful to the kidneys and may lead to kidney failure...
, hepatitis
Hepatitis
Hepatitis is a medical condition defined by the inflammation of the liver and characterized by the presence of inflammatory cells in the tissue of the organ. The name is from the Greek hepar , the root being hepat- , meaning liver, and suffix -itis, meaning "inflammation"...
, pancreatitis
Pancreatitis
Pancreatitis is inflammation of the pancreas. It occurs when pancreatic enzymes that digest food are activated in the pancreas instead of the small intestine. It may be acute – beginning suddenly and lasting a few days, or chronic – occurring over many years...
, and thrombocytopenia
Thrombocytopenia
Thrombocytopenia is a relative decrease of platelets in blood.A normal human platelet count ranges from 150,000 to 450,000 platelets per microliter of blood. These limits are determined by the 2.5th lower and upper percentile, so values outside this range do not necessarily indicate disease...
". Also noted were possible changes in liver function tests
Liver function tests
Liver function tests , are groups of clinical biochemistry laboratory blood assays designed to give information about the state of a patient's liver. The parameters measured include PT/INR, aPTT, albumin, billirubin and others...
as described above and longer clotting times if the patient is currently on warfarin
Warfarin
Warfarin is an anticoagulant. It is most likely to be the drug popularly referred to as a "blood thinner," yet this is a misnomer, since it does not affect the thickness or viscosity of blood...
while on the cholesterol-lowering medication.
Dosage forms
Ezetimibe is available as 10 mg tablets in most markets. A combination preparation ezetimibe/simvastatinEzetimibe/simvastatin
Ezetimibe/simvastatin is a drug combination used for the treatment of dyslipidemia. It is a combination of ezetimibe and the statin drug simvastatin...
, which combines ezetimibe with a statin
Statin
Statins are a class of drugs used to lower cholesterol levels by inhibiting the enzyme HMG-CoA reductase, which plays a central role in the production of cholesterol in the liver. Increased cholesterol levels have been associated with cardiovascular diseases, and statins are therefore used in the...
, is also available.
Side effects
Side-effects include gastro-intestinal disturbances; headache, fatigue; myalgiaMyalgia
Myalgia means "muscle pain" and is a symptom of many diseases and disorders. The most common causes are the overuse or over-stretching of a muscle or group of muscles. Myalgia without a traumatic history is often due to viral infections...
; rarely arthralgia
Arthralgia
Arthralgia literally means joint pain; it is a symptom of injury, infection, illnesses or an allergic reaction to medication....
, hypersensitivity reactions (including rash, angioedema
Angioedema
Angioedema or Quincke's edema is the rapid swelling of the dermis, subcutaneous tissue, mucosa and submucosal tissues. It is very similar to urticaria, but urticaria, commonly known as hives, occurs in the upper dermis...
, and anaphylaxis
Anaphylaxis
Anaphylaxis is defined as "a serious allergic reaction that is rapid in onset and may cause death". It typically results in a number of symptoms including throat swelling, an itchy rash, and low blood pressure...
), hepatitis
Hepatitis
Hepatitis is a medical condition defined by the inflammation of the liver and characterized by the presence of inflammatory cells in the tissue of the organ. The name is from the Greek hepar , the root being hepat- , meaning liver, and suffix -itis, meaning "inflammation"...
; very rarely pancreatitis
Pancreatitis
Pancreatitis is inflammation of the pancreas. It occurs when pancreatic enzymes that digest food are activated in the pancreas instead of the small intestine. It may be acute – beginning suddenly and lasting a few days, or chronic – occurring over many years...
, cholelithiasis, cholecystitis
Cholecystitis
-Signs and symptoms:Cholecystitis usually presents as a pain in the right upper quadrant. This is known as biliary colic. This is initially intermittent, but later usually presents as a constant, severe pain. During the initial stages, the pain may be felt in an area totally separate from the site...
, thrombocytopenia
Thrombocytopenia
Thrombocytopenia is a relative decrease of platelets in blood.A normal human platelet count ranges from 150,000 to 450,000 platelets per microliter of blood. These limits are determined by the 2.5th lower and upper percentile, so values outside this range do not necessarily indicate disease...
, raised creatine kinase
Creatine kinase
Creatine kinase , also known as creatine phosphokinase or phospho-creatine kinase , is an enzyme expressed by various tissues and cell types. CK catalyses the conversion of creatine and consumes adenosine triphosphate to create phosphocreatine and adenosine diphosphate...
, myopathy
Myopathy
In medicine, a myopathy is a muscular disease in which the muscle fibers do not function for any one of many reasons, resulting in muscular weakness. "Myopathy" simply means muscle disease...
, and rhabdomyolysis
Rhabdomyolysis
Rhabdomyolysis is a condition in which damaged skeletal muscle tissue breaks down rapidly. Breakdown products of damaged muscle cells are released into the bloodstream; some of these, such as the protein myoglobin, are harmful to the kidneys and may lead to kidney failure...
.
Efficacy
A clinical study, results of which were presented at the 2009 annual meeting of the American Heart AssociationAmerican Heart Association
The American Heart Association is a non-profit organization in the United States that fosters appropriate cardiac care in an effort to reduce disability and deaths caused by cardiovascular disease and stroke. It is headquartered in Dallas, Texas...
and published in the New England Journal of Medicine
New England Journal of Medicine
The New England Journal of Medicine is an English-language peer-reviewed medical journal published by the Massachusetts Medical Society. It describes itself as the oldest continuously published medical journal in the world.-History:...
suggest that in combination with statin
Statin
Statins are a class of drugs used to lower cholesterol levels by inhibiting the enzyme HMG-CoA reductase, which plays a central role in the production of cholesterol in the liver. Increased cholesterol levels have been associated with cardiovascular diseases, and statins are therefore used in the...
s, Niaspan, a slow-release form of niacin
Niacin
"Niacin" redirects here. For the neo-fusion band, see Niacin .Niacin is an organic compound with the formula and, depending on the definition used, one of the forty to eighty essential human nutrients.Niacin is one of five vitamins associated with a pandemic deficiency disease: niacin deficiency...
, is more effective than ezetimibe at reducing arterial plaque buildup.
Pharmacokinetics
Ezetimibe is available as 10 mg tablets. The recommended dose of ezetimibe is 10 mg once daily without regard to meals for all its approved indications. 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 are attained within 1–2 hours. The concomitant administration of food (high-fat vs. non-fat meals) has no effect on the extent of absorption of ezetimibe. However, co-administration with a high fat meal increases the Cmax of ezetimibe by 38%.5 The absolute bioavailability cannot be determined since ezetimibe is insoluble in aqueous media suitable for injection. Ezetimibe and its active metabolite are highly bound to human plasma proteins (90%).Ezetimibe is primarily metabolized in the liver and the small intestine via glucuronide conjugation with subsequent renal and biliary excretion. Both the parent compound and its active metabolite are eliminated from plasma with a half-life of approximately 22 hours allowing for once daily dosing. Ezetimibe lacks significant inhibitor or inducer effects on cytochrome P-450 isoenzymes which explains its limited number of drug interactions (Table 4). No dose adjustment is needed in patients with renal insufficiency 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 approximately 1.7-fold, 3–4 fold, and 5–6 fold respectively, compared to healthy subjects
Clinical trial controversy
The ENHANCE trial of Vytorin (ezetimibe and simvastatin) was designed to show that ezetimibe could reduce the growth of fatty plaques in arteries. Instead, it reported in 2008 that ezetimibe resulted in growth of plaque.The ENHANCE trial was not a clinical-outcome trial, but an imaging study of the thickness of plaque in arteries. The American College of Cardiology (ACC) maintains that ezetimibe may be a reasonable option for patients who cannot tolerate a statin or cannot be controlled on a high dose statin. The primary outcome in the treatment of hypercholesterolemia is prevention of cardiovascular events such as death from cardiovascular disease. While the ENHANCE trial did not have the power to detect significant differences in death, it measured the difference in artery thickness (in the carotid and femoral intima-media) to detect reductions in atherosclerotic plaque. At the end of two years, there was no significant difference in artery thickness between patients taking simvastatin and ezetimibe versus patients taking simvastatin alone.
Since in the ENHANCE trial ezetimibe didn't reduce cardiovascular events, atherosclerosis or death, despite the reduction in LDL, doctors have been trying to figure out whether it has any use. Doctors have also concluded that reducing LDL doesn't always reduce atherosclerosis. Reviewers of the ENHANCE trial have raised the possibility that it did not last long enough for ezetimibe to work. Also, many patients had already been treated on statins for a long time, so their artery thickness was already lower. Perhaps if they had not used statins, ezetimibe might have had a greater effect.
Results from the trial have provoked three large clinical-outcome trials.
The ARBITER 6–HALTS trial enrolled patients with coronary artery disease, or an equivalent risk condition such as diabetes, who were already taking statins. They were randomized to additionally take either extended-release niacin or ezetimibe, and the primary end point was change in artery wall thickness. Both drugs reduced LDL cholesterol levels. Niacin reduced artery wall thickness, but ezetimibe paradoxically increased artery wall thickness. Patients on ezetimibe also had more major cardiovascular events. The trial was terminated early after 208 volunteers had completed the study.
The results from the other trials will be presented in the next 3 years. However even before completion of ARBITER 6–HALTS, a March 30, 2008 meeting of the ACC resulted in negative press for drugs like Zetia as Yale University Cardiologist Harlan Krumholz and concurring colleagues called into question the efficacy of such drugs. Krumholz' statements maintained that such pharmaceuticals should not be the first or even second option for prescribing doctors. Definitive conclusions of the efficacy and safety of Zetia can be made such a time when the results of more substantial and comprehensive trials are released, such as the upcoming SHARP Trial which has an enrollment of 9000 patients and will report in 2010 and IMPROVE-IT Trial which has an enrollment of 18,000 patients and will report in 2012.
Results of the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial (ClinicalTrials.gov number, NCT00092677 [ClinicalTrials.gov] ) showed a potential increase in cancer in association with the use of these drugs together. (www.nejm.org September 2, 2008 (10.1056/NEJMe0807200). The actual significance has yet to be determined.
Trials of ezetimibe in combination with simvastatin have proven more favourable than those for ezetimibe alone, however. A 2010 study found that this combination was more effective at lowering lipid levels than alternative agents rosuvastatin
Rosuvastatin
Rosuvastatin is a member of the drug class of statins, used to treat high cholesterol and related conditions, and to prevent cardiovascular disease. It was developed by Shionogi.-Medical uses:The primary uses of rosuvastatin is for the treatment of dyslipidemia...
and atorvastatin
Atorvastatin
Atorvastatin , sold by Pfizer under the trade name Lipitor, is a member of the drug class known as statins, used for lowering blood cholesterol. It also stabilizes plaque and prevents strokes through anti-inflammatory and other mechanisms...
.
In the SHARP study, cardiovascular events were lowered by combining ezetimibe and simvastatin.
Chemical properties
Ezetimibe is highly soluble in alcohols (methanol, ethanol, 1-propanol, 2-propanol, etc.) and insoluble in water.Degradation behaviour: HPLC studies on ezetimibe under different stress conditions suggested the following degradation behaviour.
Acidic condition: The drug gradually decreased with time on heating at 80 °C in 1 M HCl by forming degradation products. The rate of hydrolysis in acid was slower as compared to that of alkali or water.
Neutral (water) condition: Upon heating the drug solution in water at 80 °C for 1 h, almost complete degradation of the drug was observed.
Degradation in alkali: The drug was found to be highly labile to alkaline hydrolysis. The reaction in 0.1 M NaOH at 80 °C was so fast that whole of the drug was degraded in 0 min. Subsequently, studies were performed in 0.01 M NaOH at 40 °C and complete degradation of the drug was observed in 4 h.
Oxidative conditions: The drug was stable to hydrogen peroxide (3 and 20%) at room temperature.
Photolytic conditions: No major degradation product was observed after exposure of drug solution in 1 M HCl to sunlight for 2 d, only minor degradation products were formed. The nature of degradation in light and dark was found to be similar, indicating that light had no effect on the degradation of the drug in acid. On the other hand, the samples in water degraded under sunlight for 2 d. Corresponding rate of degradation in dark was much slower.
Solid-state study: The solid-state studies showed that ezetimibe was stable to the effect of temperature. When the drug powder was exposed to dry heat at 50 °C for 45 d and at 60°C for 7 ◦d, no decomposition of the drug was seen.
Synthesis
The key to the construction of this compound involves formation of an azetidone. ImineImine
An imine is a functional group or chemical compound containing a carbon–nitrogen double bond, with the nitrogen attached to a hydrogen atom or an organic group. If this group is not a hydrogen atom, then the compound is known as a Schiff base...
formation between p-benzyloxybenzaldehyde and p-fluoroaniline provides one of the required reactants. This compound is then treated with the depicted acid chloride in the presence of triethylamine
Triethylamine
Triethylamine is the chemical compound with the formula N3, commonly abbreviated Et3N. It is also abbreviated TEA, yet this abbreviation must be used carefully to avoid confusion with triethanolamine, for which TEA is also a common abbreviation....
. In all likelihood, this first dehydrohalogenates under reaction conditions to form the substituted ketene
Ketene
A ketene is an organic compound of the form R'RC=C=O. The term is also used specifically to mean ethenone, the simplest ketene, where R' and R are hydrogen atoms.Ketenes were first studied as a class by Hermann Staudinger.-Formation:...
. The transient intermediate reacts with the imine in a 2 + 2 cycloaddition
Cycloaddition
A cycloaddition is a pericyclic chemical reaction, in which "two or more unsaturated molecules combine with the formation of a cyclic adduct in which there is a net reduction of the bond multiplicity." The resulting reaction is a cyclization reaction.Cycloadditions are usually described by the...
to afford a four-membered ring. The reaction proceeds to give the trans isomer almost exclusively. The ester group is then hydrolyzed by means of lithium hydroxide. Condensation with the zinc reagent formed in situ from p-fluoromagnesium bromide and zinc chloride affords the ketone. The carbonyl group is then reduced with diborane to afford the alcohol. Removal of the benzyl protecting group by hydrogenolysis over palladium finally affords ezetimibe.