- Ezetimibe (Zetia)
- How Drug That Blocks Cholesterol Absorption From The Diet Works
- Ezetimibe: The Lower the LDL-C, the Better (Even for Total Cardiovascular Events)
- CLINICAL PHARMACOLOGY
- Mechanism Of Action
- Specific Populations
- Drug Interactions
- Animal Toxicology And/Or Pharmacology
- Clinical Studies
- Primary Hyperlipidemia
- Homozygous Familial Hypercholesterolemia (HoFH)
- Homozygous Sitosterolemia (Phytosterolemia)
- CLINICAL PHARMACOLOGY
- FDA Cautions On Memory, Diabetes Side Effects In Cholesterol-Lowering Drugs
- Patent Expirations Of Crestor And Zetia And The Impact On Other Cholesterol Drugs
Volume VI, Number 2 | March/April 2003
Bernadette A. Clark, Pharm. D. Candidate
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A new lipid lowering agent, ezetimibe (Zetia; Merck/Schering Plough Pharmaceuticals), was recently approved by the Food and Drug Administration (FDA). It is indicated as 1) monotherapy or in combination with HMG-CoA Reductase Inhibitors (statins) for primary hypercholesterolemia, 2) for homozygous sitosterolemia, and 3) in combination with atorvastatin (Lipitor®) or simvastatin (Zocor®) for homozygous familial hypercholesterolemia. Ezetimibe has a unique mechanism of action compared to other classes of lipid-lowering agents. It inhibits the absorption of dietary and biliary cholesterol decreasing the intestinal absorption by 54%. Ezetimibe does not, however, affect triglyceride absorption.
The recent cholesterol lowering guidelines, published by the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III), have low-density lipoprotein (LDL) goals lower than previously recommended (See Table 1). Reaching these new goals may be difficult in some patients when using the existing lipid-lowering agents; therefore, combination therapy may be needed.
Statins are currently recommended as part of the management for hypercholesterolemia. Combining statins with other available lipid-lowering drugs (e.g., fibrates, niacin, and bile acid sequestrants) to reach target goals, may lead to an increase in adverse effects or intolerable side effects. Now, however, ezetimibe is a safe and effective alternative that may be used alone or in combination with statins to reduce LDL levels to the recommended goal.
Table 1. NCEP ATP III Guidelines
Adapted from: Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001: 285(19); 2486-2536
CHD= Coronary Heart Disease
* Risk factors are described in the NCEP ATP III guidelines and consider age, smoking status, family history and HDL level.
Therapeutic Lifestyle Changes (TLC) as described in the NCEP ATP-III guidelines
Risk determined by Framingham scoring
Pharmacology and Pharmacokinetics
Bile acid sequestrants (e.g., cholestyramine) bind bile acids inhibiting their reabsorbtion. In turn, to produce more bile acids, the liver breaks down cholesterol. Similar to bile acid sequestrants, ezetimibe also acts in the small intestine. After oral administration, it is glucuronidated to an active metabolite (ezetimibe glucuronide), travels through the portal vessels to the bile, and is then brought back to the small intestine via enterohepatic recycling. When food is ingested, ezetimibe is excreted with the bile and acts at the brush border of the small intestine to inhibit the uptake of dietary and biliary cholesterol into the enterocytes. Furthermore, there is no inhibition of cholesterol synthesis in the liver or increase in bile acid secretion.
The exact half-life of ezetimibe has yet to be determined; however, in the product labeling, the half-life of both ezetimibe and its active metabolite is listed as approximately 22 hours. It is excreted primarily in the feces (78%). Due to unknown effects of increased exposure, ezetimibe is not recommended in patients with moderate-to-severe hepatic insufficiency. Currently, no dosage adjustment is necessary in renal insufficiency.
Selected Clinical Trials
Sudhop and colleagues conducted a randomized, double-blind, placebo-controlled, 2-period, crossover trial evaluating ezetimibe monotherapy (Circulation 2002;106:1943-8). Clinic patients (n=18) with mild-to-moderate hypercholesterolemia were administered placebo for a 2-week run-in period. Then, the patients were randomized to treatment group 1 or 2. Treatment group 1 received ezetimibe 10 mg daily for 2 weeks, followed by a 2-week washout period, and then received placebo for 2 weeks. Treatment group 2 received placebo for 2 weeks, followed by a 2-week washout period, and then received ezetimibe 10 mg daily for 2 weeks. The primary efficacy endpoint was the effect of ezetimibe on the intestinal absorption of cholesterol. Secondary endpoints included cholesterol synthesis, sterol excretion, and plasma concentrations of cholesterol and non-cholesterol sterols. Inclusion criteria for the trial were the following: 18 to 55 years of age, body mass index (BMI) between 19 and 30 kg/m2, LDL cholesterol concentrations > 130 mg/dL but < 180mg/dL, triglyceride (TG) concentrations below 250 mg/dL, and dietary cholesterol intake between 200 and 500 mg/day. Patients were excluded from the study if they received lipid-lowering drugs within 6 weeks of study entry, had a history of excessive alcohol intake, had diabetes or other endocrine disorders, had a history of hepatic disease, or gastrointestinal tract dysfunction or renal dysfunction.
Of the 18 patients enrolled, all participants were male with a mean age of 25.8 years (range: 24 to 58 years) and a mean body weight of 85 kg (range: 66 to 105 kg). For the primary efficacy endpoint, ezetimibe decreased intestinal cholesterol absorption by 54% (p<0.001). A compensatory increase in cholesterol synthesis of 89% was found to be significant with ezetimibe (1763 mg/day ± 1098) compared to placebo (931 mg/day ± 1027; p<0.001). After 2 weeks of receiving ezetimibe, the mean percent change from baseline in all patients for LDL (baseline mean: 142 mg/dL) and total cholesterol (baseline mean: 220 mg/dL) was -20.4% and -15.1%, respectively (p<0.001). Comparing ezetimibe to placebo after the 2-week period, there was a -22.3% change in LDL as well as a -13.2% change in total cholesterol (p<0.001). However, there was not a significant change in high-density lipoprotein (HDL) or triglycerides for ezetimibe as compared to placebo at the end of the 2-week period. Ezetimibe therapy was well tolerated with no serious adverse effects or critical laboratory elevations during treatment. In addition, there were no elevations of aspartate or alanine aminotranferase (AST and ALT) of three times greater than the upper limit of normal, and there were no elevations of creatinine phosphokinase (CPK) 10 times the upper limit of normal. The authors concluded that ezetimibe monotherapy in patients with mild-to-moderate hypercholesteremia is effective in reducing the intestinal absorption of cholesterol by 54%. Reductions in the total cholesterol and LDL concentrations were also associated with ezetimibe treatment.
In the Journal of the American College of Cardiology, Davidson and colleagues published a multicenter, placebo-controlled study evaluating the use of ezetimibe in combination with simvastatin in patients (n= 668) with primary hypercholesterolemia. The design of the trial was a 2 X 5 factorial which consisted of a 2- to 12-week pre-treatment washout phase, a 4-week lead-in placebo phase, and a 12-week treatment phase.
The treatment groups were the following: 1) ezetimibe 10 mg monotherapy, 2) ezetimibe 10 mg in combination with simvastatin 10-, 20-, 40- or 80-mg, 3) simvastatin 10-, 20-, 40- or 80-mg monotherapy, and 4) placebo. The objective of the trial was to determine if the co-administration of ezetimibe and simvastatin (pooled doses, n= 274) produced incremental reductions in LDL while maintaining a safety profile similar to simvastatin monotherapy (pooled doses, n=263). Secondary objectives were to evaluate changes in other lipid profile variables. Patients were included if they were at least 18 years of age and had primary hypercholesterolemia (defined as LDL > 145 mg/dL but £250 mg/dL) as well as TG < 350 mg/dL. Patients were excluded if they exhibited congestive heart failure, uncontrolled cardiac arrhythmias, history of unstable or severe peripheral artery disease within 3 months of study entry, unstable angina pectoris, myocardial infarction, coronary bypass surgery or angioplasty within six months of study entry, uncontrolled or newly diagnosed diabetes mellitus, active or chronic hepatic or hepatobiliary disease, known impairment of renal function, known coagulopathy or unstable endocrine disease. Study results were based on an intent-to-treat analysis. For the primary objective, when added to simvastatin, ezetimibe improved LDL significantly compared to simvastatin monotherapy. More specifically, the co-administration of ezetimibe and simvastatin (mean baseline direct LDL: 176.3 mg/dL) and the use of simvastatin monotherapy (mean baseline in direct LDL: 178.5 mg/dL) had a mean change in direct LDL of -49.9% and -36.1%, respectively (p<0.01). Furthermore, the co-administration was more effective than ezetimibe monotherapy, with the mean change in direct LDL from baseline of -49.9% and -18.1%, respectively (p<0.01). At the treatment endpoint, 77% (207/268) of the ezetimibe/simvastatin-treated patients were below the NCEP ATP III Guidelines target LDL levels as compared to 64% (167/261) of the simvastatin monotherapy-treated patients. Overall, when ezetimibe was added to simvastatin, there was an additional 13.8% decrease in LDL. Ezetimibe was also well tolerated. There was no incidence of elevated AST, ALT, or CPK reported. Two patients in the simvastatin monotherapy-treated group (on 20- and 40-mg doses) had elevations in CPK > 10 times the upper limit of normal (n=1 with associated muscle symptoms). Asymptomatic elevations of AST and ALT were seen in eight patients (n=6 co-administration arm and n=2 simvastatin monotherapy). The authors concluded that ezetimibe was well tolerated and possesses a safety profile similar to simvastatin and placebo.
Adverse Drug Reactions
Overall, ezetimibe is well tolerated. When used as monotherapy, the most commonly reported adverse effect is back pain (4.1%). In the majority of the studies, the adverse effects associated with ezetimibe were similar to placebo. Additionally, when it is used in combination with a statin, ezetimibe has a side effect profile similar to statin monotherapy. When ezetimibe was administered with a statin, there was a slight increase in the incidence of elevated transaminases compared to statin monotherapy.
Ezetimibe does not appear to affect the absorption of triglycerides or fat-soluble vitamins. It is not a substrate for the cytochrome (CY) P450 1A2, 2D6, 2C8/9, or 3A4, and has not been shown to induce or inhibit any of the CYP450 enzymes. Additionally, ezetimibe has no interaction with common medications that are metabolized via the CYP450 system . It also does not have an effect on the statin bioavailability. Since cholestyramine (Questran®) decreases the area-under-the-curve (AUC) of ezetimibe by 80%, it is recommended to administer ezetimibe 2 hours before or 4 hours after the bile-acid binding resin. Finally, cyclosporine (Neoral®; Sandimmune®) and gemfibrozil (Lopid®)) may increase ezetimibe concentrations and close monitoring is recommended.
Pregnancy and Lactation
Ezetimibe is classified as pregnancy-risk category C which is defined as either studies in animals have revealed adverse effects on the fetus (teratogenic or embryocidal effects or other) and there are no controlled studies in women, or studies in women and animals are not available. Therefore, drugs should be given only if the potential benefits justify the potential risk to the fetus. Ezetimibe has been studied in pregnant rabbits and rats, but there is no adequate data for use in pregnant women. It has also been studied in nursing rats, but it is not known whether ezetimibe is excreted into human breast milk. Therefore, ezetimibe should not be used in nursing mothers unless the benefit clearly outweighs the risk.
As stated previously, the adverse effects associated with ezetimibe are minimal. However, when used in combination with a statin, the incidence of elevated liver function tests (LFTs) may increase slightly. Therefore, when using ezetimibe with a statin, LFTs should be performed at the initiation of therapy and then as recommended for the statins. According to the NCEP ATP III Guidelines for monitoring statins, 1) baseline measurements should include LFTs (e.g., AST and ALT) and a CPK, 2) follow-up appointments should evaluate muscle symptoms and CPK, and 3) AST and ALT should be evaluated 12 weeks after initiation of therapy and then, annually, or more frequently, if needed. A cholesterol panel should be drawn to monitor the effectiveness of ezetimibe therapy.
Dosage and Administration
Ezetimibe is commercially available as 10 mg tablets. The recommended dose of ezetimibe is 10 mg administered by mouth once daily. It may be taken with or without food, and when using ezetimibe as an adjunct to statin therapy, it may be taken at the same time as the statin. The Average Wholesale Price (AWP) for 10 mg ezetimibe is $2.35 for each tablet, while 30 tablets is $70.64.
Ezetimibe is a therapeutically beneficial drug that works by a unique mechanism and differs from traditional lipid lowering therapies. Ezetimibe may be used alone or in combination with statins for lowering lipids. However, statins as monotherapy are more effective in lowering lipid levels than ezetimibe monotherapy. As monotherapy, ezetimibe is well tolerated having adverse effects similar to those seen with placebo. It is well known that the adverse effects associated with statins, such as myopathy, rhabdomyolysis and elevated LFTs are dose dependent. Ezetimibe may be used with a statin to increase lipid lowering without increasing the chance for adverse effects.
References Available Upon Request
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How Drug That Blocks Cholesterol Absorption From The Diet Works
Earlier studies had suggested that ezetimibe acts on an intestinal and liver protein recently found to play a critical role in cholesterol absorption. Now, the researchers reveal how that protein known as Niemann-Pick C1-like 1 (NPC1L1) carries cholesterol into the cell. They also show that ezetimibe bars NPC1L1’s entry into the cell, thereby keeping cholesterol at bay.
” This is a breakthrough in terms of understanding how cholesterol is absorbed,” said Bao-Liang Song of Shanghai Institutes for Biological Sciences. “Now we see how NPC1L1 is recycled between the cell surface and vesicles and how it takes in cholesterol.”
The findings might also have important implications for the search for new cholesterol absorption inhibitors, he added. “If we can uncover the players, we can try to identify new small molecules to interfere with the process.”
Despite its bad reputation as a major risk factor for coronary heart disease, cholesterol is an essential component of most biological membranes and is the precursor for synthesis of steroid hormones and bile acids produced by the liver to break down fat. Almost every kind of mammalian cell can synthesize cholesterol, but the process is an energy-intensive one. Therefore, mammals including humans obtain significant amounts of cholesterol from their diets.
Four years ago, scientists identified NPC1L1 as a critical player in cholesterol’s absorption. Researchers also found that mice lacking NPC1L1 stop responding to ezetimibe. While there were clues that the drug interacts directly with the cholesterol absorption protein, the details remained unclear.
Song’s group now finds that cholesterol specifically encourages cells to engulf and internalize NPC1L1 in a process known as endocytosis. In that process, part of the cell membrane pinches off to form a vesicle containing the protein.
By preventing NPC1L1’s entry into the cell, the researchers showed they could dramatically reduce the amount of cholesterol taken up by cells. Ezetimibe accomplishes that by preventing NPC1L1 from incorporating into vesicles.
Although ezetimibe can dramatically decrease blood cholesterol concentrations in some people, it is barely effective in others, the researchers said.
” Therefore,” Song said, “there is an urgent need for more cholesterol uptake inhibitory drugs. Our work provides the molecular basis for developing additional cholesterol absorption inhibitors. Moreover, the cell-based assay that we have established can potentially be used to screen for novel inhibitors of NPC1L1 endocytosis, which will block cholesterol uptake eventually.”
The researchers include Liang Ge, Jing Wang, Wei Qi, Hong-Hua Miao, Jian Cao, Yu-Xiu Qu, Bo-Liang Li, and Bao-Liang Song, of the Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
This work was supported by grants from the Ministry of Science and Technology of China, the National Natural Science Foundation of China, the Chinese Academy of Sciences, and the Shanghai Science and Technology Committee.
Ezetimibe: The Lower the LDL-C, the Better (Even for Total Cardiovascular Events)
Ezetimibe: Safety and Efficacy
Ezetimibe is a non-statin lipid-lowering medication that inhibits absorption of dietary cholesterol by blocking the Niemann-Pick C1-Like 1 protein (NPC1L1). It has a half-life of approximately 22 hours due to enterohepatic circulation; it is metabolized in the small intestine and the liver not via the cytochrome P450 system and excreted back in bile as means of elimination.1
Ezetimibe lowers low-density lipoprotein cholesterol (LDL-C) by 15-20% when used alone2 as compared to 5-10% from doubling the dose of statin.3 A recent pooled analysis3 of 17 double-blind trials of patients who were already on a statin showed that the largest percent reductions in LDL-C were seen with adding ezetimibe.
Two previous outcomes trials, Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) and Study of Heart and Renal Protection (SHARP), studied ezetimibe-statin combination therapy versus placebo treatment. Lowering LDL-C levels by about 75 mg/dl and 32 mg/dl, they showed a relative reduction in major cardiovascular events of 22% and 17%, respectively. The IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) is the first study powered for atherosclerotic cardiovascular disease (ASCVD) outcomes to show a benefit of a non-statin agent (ezetimibe) when added to a statin in patients post-acute coronary syndrome (ACS).4 Now clinicians have a clinically proven second-line agent that can be added to the highest-tolerated dose of a statin.
This option was notably safe in IMPROVE-IT over a median of 6 years with lower LDL-C levels among the ezetimibe-simvastatin group as opposed to the simvastatin alone group (median LDL-C values of ~54 vs. 70 mg/dL). Previous National Cholesterol Education Program-Adult Treatment Panel III guidelines and other landmark studies, such as the Pravastatin or Atorvastatin Evaluation and Infection TherapyThrombolysis in Myocardial Infarction 22 (PROVE ITTIMI 22) trial, have supported an LDL-C target of < 70 mg/dl for maximal CVD risk reduction.
The most recent IMPROVE-IT trial results reinforce the LDL-C hypothesis rather than the statin intensity hypothesis and suggest that an LDL-C closer to 50 mg/dl is even better. Ongoing outcomes trials are studying the effect of adding a PCSK-9 monoclonal antibody to statin therapy (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab , Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk , The Evaluation of Bococizumab in Reducing the Occurrence of Major Cardiovascular Events in High Risk Subjects , SPIRE-2) to attain similar or lower LDL-C levels.
Despite growing evidence supporting a lower-is-better approach for LDL-C, treatment with statin therapy alone may not be sufficient to achieve optimal LDL-C targets or percent reductions; IMPROVE-IT demonstrates that adding ezetimibe to a statin is safe and efficacious. Moreover, based on a recent unique analysis of the IMPROVE-IT trial, ezetimibe reduced additional and total cardiovascular events over the course of the study, not only the first occurring event as trials are traditionally designed to assess.5 This provides clinicians with more data to assuredly utilize ezetimibe in their clinical practice whenever applicable.
Ezetimibe Reduces Total Cardiovascular Events: Does It Matter?
The 2013 American Heart Association and American College of Cardiology (AHA/ACC) cholesterol treatment guideline focused on lowering ASCVD risk through LDL-C lowering.6 The guideline emphasized the importance of lifestyle modification and maximizing statin therapy, with attention to adherence, prior to adding non-statin therapy. The expert panel stated that non-statin therapies were an important consideration in high-risk patients when a less-than-anticipated LDL-C lowering was observed.
Priority was placed on agents shown to provide net clinical benefit; however, questions lingered. How low can we go with LDL-C? Is ezetimibe safe? Does adding ezetimibe help protect patients against recurring or additional ASCVD events? These questions have now been addressed by the IMPROVE-IT trial.
The IMPROVE-IT trial investigators adopted a novel and clinically relevant analytic approach to further understand ezetimibe’s impact on clinical events. The analysis addresses the fact that patients with a nonfatal, first cardiovascular event are at risk of developing additional events. Due to the long duration of follow-up in IMPROVE-IT, 13% of the participants had recurrent cardiovascular events. The investigators now report that adding ezetimibe to simvastatin reduces not only first cardiovascular events, but also additional and total cardiovascular events during the entire study period (relative risk reductions of 6%, 11%, and 8%, respectively) correlating with persistent lower LDL-C levels throughout the study period.5
In other words, approximately 11 total cardiovascular events (MI, stroke and revascularizations) can be prevented for every 100 patients treated for 10 years with ezetimibe and simvastatin, which is essentially double the number of first cardiovascular events prevented. Therefore, providing this data on recurrent and total events helps clinicians, insurers, and patients better understand long-term benefits.
There are costs linked to recurrent events, including costs of the hospitalization itself, new medications, any follow-up testing and additional physician follow-up appointments. As such, understanding ezetimibe’s impact on recurrent events helps derive better estimates of the costs associated with a patient’s morbidity and mortality risk over the next decade. The IMPROVE-IT trial investigators are in the process of studying the health economics of the ezetimibe-simvastatin strategy, which will provide us with more insight into its cost-effectiveness at the population level. Importantly, generic ezetimibe is expected later this year.
As for now, clinicians can consider ezetimibe in the management of high-risk patients who are already on a maximally tolerated dose of a statin.
Ezetimibe is a safe and efficacious non-statin LDL-C-lowering agent particularly in high-risk patients, such as those post-ACS. Clinicians now have randomized clinical trial evidence to support the prescription of ezetimibe as an add-on agent or alternative therapy in statin intolerant patients or among those with suboptimal LDL-C reductions on a statin monotherapy, incremental to lifestyle modifications. Furthermore, until further evidence is available, targeting at least 50% reduction in LDL-C levels and down to about an LDL-C of 50mg/dl seems to be an efficacious and safe strategy for utilizing ezetimibe in our clinical practice for better ASCVD outcomes in persons with recent ACS.
The distinctive analysis of total cardiovascular events conducted by Murphy et al. in the IMPROVE-IT trial presents a model for ongoing and future outcomes studies, such as the PCSK-9 inhibitors trials, that will help clinicians make more informed decisions on potentially efficacious emerging medications.
- Phan BAP, Dayspring TD, Toth PP. Ezetimibe therapy: mechanism of action and clinical update. Vasc Health Risk Manag 2012;8:415-27.
- Battagia A, Alberto D, Font M, Molteni D, Galvano A. Clinical efficacy and safety of Ezetimibe on major cardiovascular endpoint: systematic review and meta-analysis of randomized controlled trials. PLoS One 2015;10:e0124587.
- Ambegaonkar BM, Tipping D, Polis AB, Tomassini JE, Tershakovec AM. Achieving goal lipid levels with ezetimibe plus statin add-on or switch therapy compared with doubling the statin dose. A pooled analysis. Atherosclerosis 2014;237:829-37.
- Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015;372:2387-97.
- Murphy SA, Cannon CP, Blazing MA, et al. Reduction in total cardiovascular events with Ezetimibe/Simvastatin post-acute coronary syndrome. J Am Coll Cardiol 2016;67:353-61.
- Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;65(25 Pt B):2889-934.
Clinical Topics: Acute Coronary Syndromes, Diabetes and Cardiometabolic Disease, Dyslipidemia, Valvular Heart Disease, Lipid Metabolism, Nonstatins, Novel Agents, Statins
Keywords: Acute Coronary Syndrome, Aortic Valve Stenosis, Atherosclerosis, Azetidines, Bile, Cholesterol, Cholesterol, Dietary, Cholesterol, LDL, Cytochrome P-450 Enzyme System, Enterohepatic Circulation, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Intestine, Small, Liver, Myocardial Infarction, Pravastatin, Risk, Risk Reduction Behavior, Simvastatin, Stroke
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Mechanism Of Action
Ezetimibe reduces blood cholesterol by inhibiting the absorption of cholesterol by the small intestine. In a 2-week clinical study in 18 hypercholesterolemic patients, ZETIA inhibited intestinal cholesterol absorption by 54%, compared with placebo. ZETIA had no clinically meaningful effect on the plasma concentrations of the fat-soluble vitamins A, D, and E (in a study of 113 patients), and did not impair adrenocortical steroid hormone production (in a study of 118 patients).
The cholesterol content of the liver is derived predominantly from three sources. The liver can synthesize cholesterol, take up cholesterol from the blood from circulating lipoproteins, or take up cholesterol absorbed by the small intestine. Intestinal cholesterol is derived primarily from cholesterol secreted in the bile and from dietary cholesterol.
Ezetimibe has a mechanism of action that differs from those of other classes of cholesterol-reducing compounds (statins, bile acid sequestrants , fibric acid derivatives, and plant stanols). 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 does not inhibit cholesterol synthesis in the liver, or increase bile acid excretion. Instead, 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. This causes a reduction of hepatic cholesterol stores and an increase in clearance of cholesterol from the blood; this distinct mechanism is complementary to that of statins and of fenofibrate .
Clinical studies have demonstrated that elevated levels of total-C, LDL-C and Apo B, the major protein constituent of LDL, promote human atherosclerosis. In addition, decreased levels of HDL-C are associated with the development of atherosclerosis. Epidemiologic studies have established that cardiovascular morbidity and mortality vary directly with the level of total-C and LDL-C and inversely with the level of HDL-C. Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including very-low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), and remnants, can also promote atherosclerosis. The independent effect of raising HDL-C or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined.
ZETIA reduces total-C, LDL-C, Apo B, non-HDL-C, and TG, and increases HDL-C in patients with hyperlipidemia. Administration of ZETIA with a statin is effective in improving serum total-C, LDL-C, Apo B, non-HDL-C, TG, and HDL-C beyond either treatment alone. Administration of ZETIA with fenofibrate is effective in improving serum total-C, LDL-C, Apo B, and non-HDL-C in patients with mixed hyperlipidemia as compared to either treatment alone. The effects of ezetimibe given either alone or in addition to a statin or fenofibrate on cardiovascular morbidity and mortality have not been established.
After oral administration, ezetimibe is absorbed and extensively conjugated to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide). After a single 10-mg dose of ZETIA to fasted adults, mean ezetimibe peak plasma concentrations (Cmax) of 3.4 to 5.5 ng/mL were attained within 4 to 12 hours (Tmax ). Ezetimibe-glucuronide mean Cmax values of 45 to 71 ng/mL were achieved between 1 and 2 hours (Tmax). There was no substantial deviation from dose proportionality between 5 and 20 mg. Â The absolute bioavailability of ezetimibe cannot be determined, as the compound is virtually insoluble in aqueous media suitable for injection.
Effect Of Food On Oral Absorption
Concomitant food administration (high-fat or non-fat meals) had no effect on the extent of absorption of ezetimibe when administered as ZETIA 10-mg tablets. The C value of ezetimibe was increased by 38% with consumption of high-fat meals. ZETIA can be administered with or without food.
Ezetimibe and ezetimibe-glucuronide are highly bound ( > 90%) to human plasma proteins.
Metabolism And Excretion
Ezetimibe is primarily metabolized in the small intestine and liver via glucuronide conjugation (a phase II reaction) with subsequent biliary and renal excretion. Minimal oxidative metabolism (a phase I reaction) has been observed in all species evaluated.
In humans, ezetimibe is rapidly metabolized to ezetimibe-glucuronide. Ezetimibe and ezetimibeglucuronide are the major drug-derived compounds detected in plasma, constituting approximately 10 to 20% and 80 to 90% of the total drug in plasma, respectively. Both ezetimibe and ezetimibe-glucuronide are eliminated from plasma with a half-life of approximately 22 hours for both ezetimibe and ezetimibeglucuronide. Plasma concentration-time profiles exhibit multiple peaks, suggesting enterohepatic recycling.
Following oral administration of 14C-ezetimibe (20 mg) to human subjects, total ezetimibe (ezetimibe + ezetimibe-glucuronide) accounted for approximately 93% of the total radioactivity in plasma. After 48 hours, there were no detectable levels of radioactivity in the plasma.
Approximately 78% and 11% of the administered radioactivity were recovered in the feces and urine, respectively, over a 10-day collection period. Ezetimibe was the major component in feces and accounted for 69% of the administered dose, while ezetimibe-glucuronide was the major component in urine and accounted for 9% of the administered dose.
Geriatric Patients: In a multiple-dose study with ezetimibe given 10 mg once daily for 10 days, plasma concentrations for total ezetimibe were about 2-fold higher in older (≥65 years) healthy subjects compared to younger subjects.
Gender: In a multiple-dose study with ezetimibe given 10 mg once daily for 10 days, plasma concentrations for total ezetimibe were slightly higher ( < 20%) in women than in men.
Race: Based on a meta-analysis of multiple-dose pharmacokinetic studies, there were no pharmacokinetic differences between Black and Caucasian subjects. Studies in Asian subjects indicated that the pharmacokinetics of ezetimibe were similar to those seen in Caucasian subjects.
Hepatic Impairment: After a single 10-mg dose of ezetimibe, the mean AUC for total ezetimibe was increased approximately 1.7-fold in patients with mild hepatic impairment (Child-Pugh score 5 to 6), compared to healthy subjects. The mean AUC values for total ezetimibe and ezetimibe were increased approximately 3- to 4-fold and 5- to 6-fold, respectively, in patients with moderate (Child-Pugh score 7 to 9) or severe hepatic impairment (Child-Pugh score 10 to 15). In a 14-day, multiple-dose study (10 mg daily) in patients with moderate hepatic impairment, the mean AUC values for total ezetimibe and ezetimibe were increased approximately 4-fold on Day 1 and Day 14 compared to healthy subjects. Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe hepatic impairment, ZETIA is not recommended in these patients .
Renal Impairment: After a single 10-mg dose of ezetimibe in patients with severe renal disease (n=8; mean CrCl ≥ 30 mL/min/1.73 m²), the mean AUC values for total ezetimibe, ezetimibe-glucuronide, and ezetimibe were increased approximately 1.5-fold, compared to healthy subjects (n=9).
ZETIA had no significant effect on a series of probe drugs (caffeine, dextromethorphan, tolbutamide, and IV midazolam) known to be metabolized by cytochrome P450 (1A2, 2D6, 2C8/9 and 3A4) in a “cocktail” study of twelve healthy adult males. This indicates that ezetimibe is neither an inhibitor nor an inducer of these cytochrome P450 isozymes, and it is unlikely that ezetimibe will affect the metabolism of drugs that are metabolized by these enzymes.
TABLE 4: Effect of Coadministered Drugs on Total Ezetimibe
|Coadministered Drug and Dosing Regimen||Total Ezetimibe *|
|Change in AUC||Change in Cmax|
|Cyclosporine-stable dose required (75-150 mg BID)†,‡||240%||290%|
|Fenofibrate, 200 mg QD, 14 days‡||48%||64%|
|Gemfibrozil, 600 mg BID, 7 days‡||64%||91%|
|Cholestyramine, 4 g BID, 14 days‡||↓55%||↓4%|
|Aluminum & magnesium hydroxide combination antacid, single dose§||↓4%||↓30%|
|Cimetidine, 400 mg BID, 7 days||6%||↓30%|
|Glipizide, 10 mg, single dose||4%||↓8%|
|Lovastatin 20 mg QD, 7 days||9%||3%|
|Pravastatin 20 mg QD, 14 days||7%||23%|
|Atorvastatin 10 mg QD, 14 days||↓2%||12%|
|Rosuvastatin 10 mg QD, 14 days||13%||18%|
|Fluvastatin 20 mg QD, 14 days||↓19%||7%|
|*Based on 10-mg dose of ezetimibe.
† Post-renal transplant patients with mild impaired or normal renal function. In a different study, a renal transplant patient with severe renal insufficiency (creatinine clearance of 13.2 mL/min/1.73 m²) who was receiving multiple medications, including cyclosporine, demonstrated a 12-fold greater exposure to total ezetimibe compared to healthy subjects.
‡ See DRUG INTERACTIONS.
§ Supralox, 20 mL.
TABLE 5: Effect of Ezetimibe Coadministration on Systemic Exposure to Other Drugs
|Coadministered Drug and its Dosage Regimen||Ezetimibe Dosage Regimen||Change in AUC of Coadministered Drug||Change in Cmax of Coadministered Drug|
|Warfarin. 25-mg single dose on Day 7||10 mg QD, 11 days||↓2% (R-warfarin)||3% (R-warfarin)|
|↓4% (S-warfarin)||1% (S-warfarin)|
|Digoxin. 0.5-mg single dose||10 mg QD, 8 days||2%||↓7%|
|Gemfibrozil, 600 mg BID, 7 days*||10 mg QD, 7 days||↓1%||↓11%|
|Ethinyl estradiol & Levonorgestrel, QD, 21 days||10 mg QD, days 8-14 of 21d oral contraceptive cycle||Ethinyl estradiol 0%||Ethinyl estradiol ↓9%|
|Levonorgesnel 0%||Levonorgesirel ↓5%|
|Glipizide, 10 mg on Days 1 and 9||10 mg QD, days 2-9||↓3%||↓5%|
|Fenofibrate, 200 mg QD, 14 days*||10 mg QD, 14 days||11%||7%|
|Cyclosporine, 100-mg single dose Day 7*||20 mg QD, 8 days||15%||10%|
|Lovastatin 20 mg QD, 7 days||10 mg QD, 7 days||19%||3%|
|Pravastatin 20 mg QD, 14 days||10 mg QD, 14 days||↓20%||↓24%|
|Atorvastatin 10 mg QD, 14 days||10 mg QD, 14 days||↓4%||7%|
|Rosuvastatin 10 mg QD, 14 days||10 mg QD, 14 days||19%||17%|
|Fluvastatin 20 mg QD, 14 days||10 mg QD, 14 days||↓39%||↓27%|
|* See DRUG INTERACTIONS|
Animal Toxicology And/Or Pharmacology
The hypocholesterolemic effect of ezetimibe was evaluated in cholesterol-fed Rhesus monkeys, dogs, rats, and mouse models of human cholesterol metabolism. Ezetimibe was found to have an ED50 value of 0.5 μg/kg/day for inhibiting the rise in plasma cholesterol levels in monkeys. The ED50 values in dogs, rats, and mice were 7, 30, and 700 μg/kg/day, respectively. These results are consistent with ZETIA being a potent cholesterol absorption inhibitor.
In a rat model, where the glucuronide metabolite of ezetimibe (SCH 60663) was administered intraduodenally, the metabolite was as potent as the parent compound (SCH 58235) in inhibiting the absorption of cholesterol, suggesting that the glucuronide metabolite had activity similar to the parent drug.
In 1-month studies in dogs given ezetimibe (0.03 to 300 mg/kg/day), the concentration of cholesterol in gallbladder bile increased ~2- to 4-fold. However, a dose of 300 mg/kg/day administered to dogs for one year did not result in gallstone formation or any other adverse hepatobiliary effects. In a 14-day study in mice given ezetimibe (0.3 to 5 mg/kg/day) and fed a low-fat or cholesterol-rich diet, the concentration of cholesterol in gallbladder bile was either unaffected or reduced to normal levels, respectively.
A series of acute preclinical studies was performed to determine the selectivity of ZETIA for inhibiting cholesterol absorption. Ezetimibe inhibited the absorption of 14C-cholesterol with no effect on the absorption of triglycerides, fatty acids, bile acids, progesterone, ethinyl estradiol, or the fatsoluble vitamins A and D.
In 4- to 12-week toxicity studies in mice, ezetimibe did not induce cytochrome P450 drug metabolizing enzymes. In toxicity studies, a pharmacokinetic interaction of ezetimibe with statins (parents or their active hydroxy acid metabolites) was seen in rats, dogs, and rabbits.
ZETIA reduces total-C, LDL-C, Apo B, non-HDL-C, and TG, and increases HDL-C in patients with hyperlipidemia. Maximal to near maximal response is generally achieved within 2 weeks and maintained during chronic therapy.
TABLE 6: Response to ZETIA in Patients with Primary Hyperlipidemia (Mean % Change from Untreated Baseline†)
Combination with Statins
ZETIA Added to On-going Statin Therapy
In a multicenter, double-blind, placebo-controlled, 8-week study, 769 patients with primary hyperlipidemia, known coronary heart disease or multiple cardiovascular risk factors who were already receiving statin monotherapy, but who had not met their NCEP ATP II target LDL-C goal were randomized to receive either ZETIA or placebo in addition to their on-going statin.
ZETIA, added to on-going statin therapy, significantly lowered total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared with a statin administered alone (see Table 7). LDL-C reductions induced by ZETIA were generally consistent across all statins.
TABLE 7: Response to Addition of ZETIA to On-Going Statin Therapy in Patients with Hyperlipidemia (Mean % Change from Treated Baseline‡)
ZETIA Initiated Concurrently with a Statin
In four multicenter, double-blind, placebo-controlled, 12-week trials, in 2382 hyperlipidemic patients, ZETIA or placebo was administered alone or with various doses of atorvastatin, simvastatin, pravastatin, or lovastatin.
When all patients receiving ZETIA with a statin were compared to all those receiving the corresponding statin alone, ZETIA significantly lowered total-C, LDL-C, Apo B, non-HDL-C, and TG, and, with the exception of pravastatin, increased HDL-C compared to the statin administered alone. LDL-C reductions induced by ZETIA were generally consistent across all statins. (See footnote , Tables 8 to 11.)
TABLE 8: Response to ZETIA and Atorvastatin Initiated Concurrently in Patients with Primary Hyperlipidemia (Mean % Change from Untreated Baseline†)
TABLE 9: Response to ZETIA and Simvastatin Initiated Concurrently in Patients with Primary Hyperlipidemia (Mean % Change from Untreated Baseline†)
TABLE 10: Response to ZETIA and Pravastatin Initiated Concurrently in Patients with Primary Hyperlipidemia (Mean % Change from Untreated Baseline†)
TABLE 11: Response to ZETIA and Lovastatin Initiated Concurrently in Patients with Primary Hyperlipidemia (Mean % Change from Untreated Baseline†)
Combination with Fenofibrate
In a multicenter, double-blind, placebo-controlled, clinical study in patients with mixed hyperlipidemia, 625 patients were treated for up to 12 weeks and 576 for up to an additional 48 weeks. Patients were randomized to receive placebo, ZETIA alone, 160-mg fenofibrate alone, or ZETIA and 160-mg fenofibrate in the 12-week study. After completing the 12-week study, eligible patients were assigned to ZETIA coadministered with fenofibrate or fenofibrate monotherapy for an additional 48 weeks.
ZETIA coadministered with fenofibrate significantly lowered total-C, LDL-C, Apo B, and non-HDL-C compared to fenofibrate administered alone. The percent decrease in TG and percent increase in HDLC for ZETIA coadministered with fenofibrate were comparable to those for fenofibrate administered alone (see Table 12).
TABLE 12: Response to ZETIA and Fenofibrate Initiated Concurrently in Patients with Mixed Hyperlipidemia (Mean % Change from Untreated Baseline† at 12 weeks†)
The changes in lipid endpoints after an additional 48 weeks of treatment with ZETIA coadministered with fenofibrate or with fenofibrate alone were consistent with the 12-week data displayed above.
Homozygous Familial Hypercholesterolemia (HoFH)
A study was conducted to assess the efficacy of ZETIA in the treatment of HoFH. This double-blind, randomized, 12-week study enrolled 50 patients with a clinical and/or genotypic diagnosis of HoFH, with or without concomitant LDL apheresis, already receiving atorvastatin or simvastatin (40 mg). Patients were randomized to one of three treatment groups, atorvastatin or simvastatin (80 mg), ZETIA administered with atorvastatin or simvastatin (40 mg), or ZETIA administered with atorvastatin or simvastatin (80 mg). Due to decreased bioavailability of ezetimibe in patients concomitantly receiving cholestyramine , ezetimibe was dosed at least 4 hours before or after administration of resins. Mean baseline LDL-C was 341 mg/dL in those patients randomized to atorvastatin 80 mg or simvastatin 80 mg alone and 316 mg/dL in the group randomized to ZETIA plus atorvastatin 40 or 80 mg or simvastatin 40 or 80 mg. ZETIA, administered with atorvastatin or simvastatin (40- and 80-mg statin groups, pooled), significantly reduced LDL-C (21%) compared with increasing the dose of simvastatin or atorvastatin monotherapy from 40 to 80 mg (7%). In those treated with ZETIA plus 80-mg atorvastatin or with ZETIA plus 80-mg simvastatin, LDL-C was reduced by 27%.
Homozygous Sitosterolemia (Phytosterolemia)
A study was conducted to assess the efficacy of ZETIA in the treatment of homozygous sitosterolemia. In this multicenter, double-blind, placebo-controlled, 8-week trial, 37 patients with homozygoussitosterolemia with elevated plasma sitosterol levels ( > 5 mg/dL) on their current therapeutic regimenÂ (diet, bile-acid-binding resins, statins, ileal bypass surgery and/or LDL apheresis), were randomized to receive ZETIA (n=30) or placebo (n=7). Due to decreased bioavailability of ezetimibe in patients concomitantly receiving cholestyramine , ezetimibe was dosed at least 2 hours before or 4 hours after resins were administered. Excluding the one subject receiving LDL apheresis, ZETIA significantly lowered plasma sitosterol and campesterol, by 21% and 24% from baseline, respectively. In contrast, patients who received placebo had increases in sitosterol and campesterol of 4% and 3% from baseline, respectively. For patients treated with ZETIA, mean plasma levels of plant sterols were reduced progressively over the course of the study. The effects of reducing plasma sitosterol and campesterol on reducing the risks of cardiovascular morbidity and mortality have not been established.
Reductions in sitosterol and campesterol were consistent between patients taking ZETIA concomitantly with bile acid sequestrants (n=8) and patients not on concomitant bile acid sequestrant therapy (n=21).
Limitations Of Use
The effect of ZETIA on cardiovascular morbidity and mortality has not been determined.
One of the key messages coming from the IMPROVE-IT trial, published this week in the New England Journal of Medicine, is that “lower is better” for LDL cholesterol regardless of the specific agent used to get there.
We contacted cardiologists and a variety of healthcare professionals and asked:
Should this trial be enough to change the American Heart Association/American College of Cardiology guidelines back to using a treatment target?
If so, should the former 70 mg/dL target become a 50 to 55 mg/dL target as achieved in the IMPROVE-IT intervention group?
Should IMPROVE-IT shift the statin-centric emphasis of the guidelines?
The participants this week are:
Donald M. Lloyd-Jones, MD/ScM, senior associate dean for Clinical and Translational Research, chair, Department of Preventive Medicine, director, Northwestern University Clinical and Translational Sciences Institute (NUCATS) and professor of epidemiology and cardiology at the Northwestern University Feinberg School of Medicine
Randall Mark Zusman, MD, director, division of hypertension at Massachusetts General Hospital in Boston
Stephen L. Kopecky, MD, professor, medicine at the Mayo Clinic in Rochester, Minn. (Dr. Kopecky discloses he is on the Atherosclerosis advisory board for Merck)
Jennifer G. Robinson, MD, MPH, professor, Departments of Epidemiology and Medicine, director, Prevention Intervention Center at the University of Iowa in Iowa City
Merle Myerson, MD, EdD, cardiologist and expert in cardiovascular disease prevention and lipids in New York City
Michael Hudson, MD, FACC, director, Inpatient Cardiology Services at Henry Ford Hospital, and clinical associate professor of medicine at Wayne State University School of Medicine in Detroit
No Evidence to Change Guidelines
Donald Lloyd-Jones, MD: “The short answer is no. This finding was anticipated by the guidelines panel and fits well within the current recommendations. The guideline stated:
Clinicians treating high-risk patients who have a less than anticipated response to statins, who are unable to tolerate a less than recommended intensity of a statin, or who are completely statin intolerant, may consider the addition of non-statin cholesterol lowering therapy…. In this situation, this guideline recommends clinicians preferentially prescribe drugs that have been shown in RCTs to provide ASCVD risk-reduction benefits that outweigh the potential for adverse effects and drug-drug interactions and consider patient preferences.
The findings of IMPROVE-IT, which revealed an excellent safety profile for ezetimibe and significant (though very modest) additional benefit when added to moderate-dose statin in a very-high-risk group of patients, fit well within this framework. That said, it would be useful to have a focused update of the 2013 guidelines with specific recommendations on ezetimibe and long-acting niacin now that IMPROVE-IT and HPS2-THRIVE have been published.”
Randall Mark Zusman, MD: “The guidelines, although also controversial, really focus on supporting the clinical trials conducted to date that have emphasized the use of maximal lipid-lowering therapies. And this trial doesn’t really address that question, because it’s a study of submaximal statin therapy versus submaximal statin therapy with an augmented cholesterol-lowering drug. I think that my major concern or criticism of this study was it wasn’t maximal statin therapy versus maximal statin therapy plus ezetimibe. Given that the guidelines currently recommend maximal statin dosages or maximum lipid-lowering dosages, they’re not talking about 40 mg of simvastatin, a modest dose of a modestly effective statin. This study emphasizes the importance of lowering LDL cholesterol further than modest cholesterol lowering therapies, but doesn’t address the question that has been reviewed and recommendations from the AHA/ACC panel.”
“Lower is Better, But It Matters How You Get There”
Stephen Kopecky, MD: “We all believed, I think, that the lower the LDL, the better off it is for a patient, especially if they have disease. Now if you look at the guidelines, they said the trials haven’t been done to get to a certain goal. IMPROVE-IT is no different — it didn’t get to a goal, it just said it was a dose versus a dose. So if you take the strict Institute of Medicine rules, which is what they used to put the guidelines together, IMPROVE-IT doesn’t change it. It doesn’t say ‘Let’s get to a goal,’ but just like all the other studies, they have the dose of group A versus group B — it was just a different dosing and they didn’t say get to a different goal. So I do think that we ought to rethink that, although based on IMPROVE-IT, it doesn’t really give us evidence that we should.”
Jennifer Robinson, MD: “IMPROVE-IT still does not provide evidence that titration to a specific LDL-C goal improves CV outcomes. Half the participants in the ezetimibe arm had LDL-C levels >54 mg/dL. The number-needed-to-treat to prevent one CV event (NNT) is about 67 for the average very-high-risk IMPROVE-IT patient with about a 15% 5-year hard CV event rate. The average statin-treated chronic CHD patient without diabetes has a 5-year CV event rate of about 10% and would have an NNT of about 100 for ezetimibe added to lower LDL-C from 70 to 54 mg/dL. Therefore, it not only matters how you lower LDL-C but whether the patient is likely to experience a meaningful net benefit based on their baseline level of CV risk.”
Merle Myerson, MD: “The IMPROVE-IT trial provides important information showing that “lower is better” for LDL-C which supports continuation of targets as an integral part of lipid management. The ACC/AHA guidelines focused on statins stating the randomized clinical trials used to write the guidelines only provided evidence for statin use. While there is data in support of using other classes of medication from a variety of studies, the IMPROVE-IT study supports the use of nonstatins to lower LDL and reduce cardiac events.”
Michael Hudson, MD: ” IMPROVE-IT does not contradict the 2013 AHA/ACC Cholesterol Treatment Guidelines or support the renewed use of cholesterol treatment targets. Consistent with these guidelines and prior studies, IMPROVE-IT shows that patients are likely to benefit from maximally tolerated LDL lowering, regardless of initial or on-treatment LDL levels. IMPROVE-IT should appropriately but modestly stimulate ezetimibe use in statin-intolerant patients and in combination with high-dose (intensity) statin agents such as atorvastatin and rosuvastatin. Indirectly, but more importantly, these findings are likely to increase cardiologist and patient enthusiasm for the more potent PCSK9 inhibitors as the preferred adjunctive agents to high-dose statin therapy.”
Debate Over Target-Driven Therapy
Zusman: “I think that instead of thinking about a target LDL, we should think about maximum LDL-reducing therapies, since we know that lowering LDL cholesterol is cardioprotective. All those people on modest doses of statins, 10 and 20 mg, would do better if they were on 80 mg of a more potent statin, for example, and I think that the reason the AHA/ACC guidelines came out that way is because those are the doses that were, in fact, studied in the major clinical trials as opposed to a titration protocol; they used a fixed dose – a maximal dose, so at least in theory, they would maximize the clinical benefit. It’s really very difficult to compare this study to other studies of untreated patients with baseline LDL cholesterol values and other lipids in the absence of concomitant therapy.”
Lloyd-Jones: “I saw nothing in these data to suggest what a target for LDL therapy should be. What is clear, and again is consistent with what the 2013 guidelines said, is that lower LDL is better, but it matters how you get there, and in whom. We should be using proven therapies with net clinical benefit and acceptable safety in the context of the individual patient’s situation. The ezetimibe and niacin stories are perfect object lessons in this regard.”
Kopecky: “It really isn’t fair to give a bunch of people a drug and say the ones that got to a lower LDL did better, and therefore everybody should get there. That doesn’t translate, because not everybody can get there, not everybody responds as well, not everybody can tolerate the medicine as well. So we really do need a study that has a goal of an LDL target because one thing that is not appreciated widely is that when you give a statin to a patient, the average reduction is only the average. Some people’s LDL actually goes up with a statin, and about 15% to 20% of people who are called hyporesponders, they don’t lower their LDL significantly at all and they don’t do well. So not everybody responds the same way and it has to be individualized for patients and we haven’t really done that.”
The Role of Statins
Robinson: “Statins remain the cornerstone of cardiovascular (CV) risk reduction based on an extensive body of evidence from >26 statin trials. IMPROVE-IT fits in with the 2013 ACC/AHA cholesterol guideline recommendation to consider adding a nonstatin for further LDL-C lowering in selected patients, preferably a nonstatin shown to reduce CV events in clinical trials. High-risk patients who might benefit from additional LDL-C lowering include those with clinical atherosclerotic CV disease, genetic hypercholesterolemia, or diabetes who are statin intolerant or who did not achieve at least a 50% LDL-C reduction with the maximally tolerated intensity of statin therapy. Ezetimibe plus moderate intensity statin therapy is now an evidence-based alternative (based on one trial) if a patient does not tolerate high intensity statin therapy (a Class I A recommendation based on three randomized trials).”
Zusman: “I think we should remember that the patients in IMPROVE-IT were being treated with simvastatin, not the most potent statin and also not the most potent dose, and I think it’s interesting that the most potent dose of simvastatin, 80 mg, was not the dose that they chose. It really wasn’t a test of maximal statin therapy versus maximal statin therapy with the theoretical augmented benefit of ezetimibe. I think it addresses the question that was asked: if you use two lipid-lowering drugs, is it more effective than one, and I think the answer here is yes, and that is in sharp contrast to other studies where the combination of a statin with another lipid-lowering drug was not … effective as they’ve cited in their discussion.”
Kopecky: “We need to pay much more attention to lifestyle and that has to be first, second, and third priority, and then after that, then we’ll start talking about medications, because so many patients that we see now say ‘Doc, let me try it my own way — let me do it by changing my diet, my lifestyle, my activity patterns, what I’m eating’ and we need to really emphasize that more to them, because we just haven’t done that, we’ve always just focused on a pill, and patients we know just don’t take the pills that well. Their adherence isn’t as high as we’d like.”
Lloyd-Jones: “Statins are still the best and by far the most cost-effective approach to ASCVD risk reduction on the lipid axis. When they are not enough for higher-risk patients, or when patients are truly statin intolerant, it is nice to have ezetimibe as another arrow in the quiver. But statins should still be first-line therapy for the vast majority of patients.”
From the American Heart Association:
- 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults
- Clinical Practice Guidelines for Prevention
last updated 06.06.2015
FDA Cautions On Memory, Diabetes Side Effects In Cholesterol-Lowering Drugs
Lipitor via Wikipedia
The Food and Drug Administration just added new language telling consumers about potential memory problems and an increased risk of high blood sugar for patients on statin cholesterol-lowering medicines. These medicines, including Lipitor, Zocor, and Crestor, are the most-prescribed class of drug in the country. According to drug data firm IMS Health, 255 million prescriptions for cholesterol-lowering drugs were written in 2010.
According to the FDA, the changes to the statin labels are:
* The drug labels have been revised to remove the need for routine periodic monitoring of liver enzymes in patients taking statins. FDA now recommends that liver enzyme tests should be performed before starting statin therapy, and as clinically indicated thereafter. FDA has concluded that serious liver injury with statins is rare and unpredictable in individual patients, and that routine periodic monitoring of liver enzymes does not appear to be effective in detecting or preventing this rare side effect. Patients should notify their health care professional immediately if they have the following symptoms of liver problems: unusual fatigue or weakness; loss of appetite; upper belly pain; dark-colored urine; yellowing of the skin or the whites of the eyes.
* Certain cognitive (brain-related) effects have been reported with statin use. Statin labels will now include information about some patients experiencing memory loss and confusion. These reports generally have not been serious and the patients’ symptoms were reversed by stopping the statin. However, patients should still alert their health care professional if these symptoms occur.
* Increases in blood sugar levels (hyperglycemia) have been reported with statin use. The FDA is also aware of studies showing that patients being treated with statins may have a small increased risk of increased blood sugar levels and of being diagnosed with type 2 diabetes mellitus. The labels will now warn healthcare professionals and patients of this potential risk.
* Health care professionals should take note of the new recommendations in the lovastatin label. Some medicines may interact with lovastatin, increasing the risk for muscle injury (myopathy/rhabdomyolysis). For example, certain medicines should never be taken (are contraindicated) with Mevacor (lovastatin) including drugs used to treat HIV (protease inhibitors) and drugs used to treat certain bacterial and fungal infections.
via Press Announcements > FDA announces safety changes in labeling for some cholesterol-lowering drugs.
These cholesterol drugs were best-sellers for Pfizer, Bristol-Myers Squibb, and Merck when they were still protected by patents. Lipitor, from Pfizer, was the best-selling drug in the world until it went off patent last year. Despite the loss of patent protection and the availability of generic drugs, Pfizer still has about a third of the market for Lipitor. Merck sells Vytorin, a pill that contains its Zocor and a second drug, Zetia. AstraZeneca’s Crestor is the last major statin-only pill that is not facing generic competition.
The removal of liver monitoring requirements is likely to make doctors and patients more willing to use the drugs. (Blood tests are a nuisance.) And some top cardiologists have already downplayed the importance of the increased blood sugar.
“The diabetes is a very small uptick in blood sugar that makes a few more people cross the threshold we call diabetes,” says Steven Nissen, chairman of cardiology at the Cleveland Clinic. “The reductions in morbidity and mortality are the same in those who get diabetes as those who don’t. It’s very difficult to say it should change our assessment of risk and benefit.” He adds that the removal of the liver warnings is a good thing — because, “to the best of our knowledge, these drugs do not have a toxic effect on the liver.”
But the fact that cognitive issues — even though they appear minor and transient — are finally appearing in statin labels could be a big deal. SmartMoney ran a long feature (The Lipitor Dilemma) on memory problems and statins back in 2003, but doctors have often downplayed the concern. But signs of memory loss and diabetes occurred in the giant JUPITER trial that proved Crestor cuts the risk of death in people who have relatively low cholesterol but other signs of high heart risk including elevated levels of C-reactive protein, a marker for inflammation.
For patients who are at high risk of heart attacks, especially those who have already had a first heart attack and need to prevent a second, the benefits of statins are inarguable. Even for many patients who are trying to prevent a first heart attack, the benefit of taking a statin clearly outweighs the risk. But this new labeling will lead patients and doctors to take memory issues on the drugs more seriously, and it will also lead patients to link normal lapses of memory to their drugs. Nissen cautions that the value of the drug is as good as any other drug. “We don’t want to throw the baby out with the bathwater. These drugs do reduce the risk of heart attack stroke and death.”
Noted cardiologist Sanjay Kaul of Cedars-Sinai Medical Center had this to add:
All of these changes are well informed by emerging evidence from different sources. For example, the periodic monitoring of liver enzymes was originally based on niacin experience. Trial data and clinical experience revealed that liver toxicity was extremely rare with statins, and when it occurred it was not predictable. So trying to capture these rare events via periodic monitoring would understandably be futile. The cognitive effects with statins have been reported for some time, but the data from JUPITER brought additional spotlight on these non-serious adverse event. The glycemic effects were first brought to the public attention by JUPITER and subsequent examinations have shown that they are not unique to rosuvastatin. The drug exposure is significantly increased when statins, especially lovastatin, are co-administered with antiretroviral, antifungal, and some antibacterial therapy.
So while all of these safety updates are reasonable, the overall benefits of statin trump these safety concerns.
For the full FDA announcement, look here.
Update: On Twitter, Bloomberg News’ Shannon Pettypiece asked what this means for attempts to make statins over-the-counter drugs. It probably helps, because of the removal of liver monitoring. The cognitive side effects appear minor and transient. But I don’t believe any statin is going to be made available as an over-the-counter drug.
For some people, high cholesterol can be passed down through the family, and for others, diet can cause higher than normal cholesterol levels.
Whatever the reason, we have some good news for those of you taking the expensive cholesterol medication Zetia! As of December 12th, 2016 the FDA approved ezetimibe, a less expensive generic to Zetia, and it is in pharmacies now.
What is Zetia (ezetimibe) indicated for?
Zetia (ezetimibe) is prescribed in combination with a proper diet for the treatment of high cholesterol. It works along the edges of the digestive tract in the intestine to block the absorption of cholesterol. Keep in mind that Zetia (ezetimibe) is not a statin, and treats high cholesterol differently than statins.
In fact, Zetia works differently than other cholesterol medications. So, adding it to your current high cholesterol treatment regimen may help reduce your cholesterol even further. You can speak with your doctor to see if Zetia (ezetimibe) will work for you.
What are the most common side effects of ezetimibe?
The most common side effects of ezetimibe include: joint pain, dizziness, upper respiratory tract infection, diarrhea, sinusitis, or pain in extremities.
What strength(s) and dosage form(s) is ezetimibe available in?
Just like the brand name medication, ezetimibe is available as a 10 mg tablet.
Who manufactures ezetimibe?
For the first 180 days (6 months), Glenmark and their partner Endo Pharmaceuticals will be the only company making ezetimibe. After the 180 days of drug exclusivity, other generic drug companies will be permitted to make ezetimibe. When new companies start to manufacture ezetimibe, prices should go down!
Why does high cholesterol matter?
Although you may not feel the direct effects of high cholesterol, it is putting you at higher risk for cardiovascular events such as heart attack or a stroke. Make sure to talk with your doctor if you are worried about your cholesterol levels.
What if I want to continue to use brand Zetia?
If you would like to take brand Zetia, instead of generic ezetimibe, make sure your doctor writes ‘brand medically necessary’ on your prescription. This means that the pharmacy is not permitted to substitute and give you the generic product.
If your doctor does not write ‘brand medically necessary’ on your prescription, you can still request that your pharmacist fills the brand medication for you. Just be sure to inform the pharmacy before having the prescription filled.
Keep in mind that because the generic product is now available, your insurance company may not be willing to cover the cost of the more expensive brand medication. Be sure to check your prescription insurance company to find out if its covered before taking a trip to the pharmacy.
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Patent Expirations Of Crestor And Zetia And The Impact On Other Cholesterol Drugs
The end of 2015 saw a number of stories hailing the productivity of the biopharmaceutical industry for another great year in producing new FDA approved drugs. All drugs, however, have a finite life in terms of exclusivity – the length of time that the innovating company can sell the drug without competition. While 2015 brought us a number of great new medicines, 2016 will see a number of drugs going off patent. The list includes drugs to treat HIV, psychiatric disorders and hypertension. But perhaps most notable are the patent expiries for two major LDL-cholesterol (LDL-c) lowering drugs: the statin, Crestor, from AstraZeneca and the cholesterol absorption inhibitor, Zetia, from Merck.
Anytime a drug becomes generic in the U.S., its price drops dramatically. It is likely that within 12 months, U.S. revenues for both Crestor and Zetia will drop by 90%. That’s to be expected. However, the presence of generic forms for both drugs, rosuvastatin (Crestor) and ezetimibe (Zetia) will have other effects, both commercial and medical. Merck’s Vytorin, a cholesterol lowering drug with sales of over a billion dollars, is actually a combination of ezetimibe and simvastatin (a generic statin originated by Merck’s R&D group). By combining two complementary ways of lowering LDL-c in a single pill, Vytorin offers physicians a simple way of lowering LDL-cholesterol in their heart disease patients. But payers don’t really care about convenience. They are focused on containing costs. Last year, a 30 day prescription of Zetia cost roughly $300, similar to the cost of 30 days of Vytorin. However, it is reasonable to expect that the cost of 30 days of the generic ezetimibe will be less than $10. Given that the 30 day cost of simvastatin, the other component of Vytorin, is even less than that, payers will reject prescription requests for Vytorin and require patients to take each drug individually. This will certainly be less convenient for both patients and physicians. But, by changing from $300 for a 30 day supply of Vytorin to perhaps as low as $10 for 30 days of both ezetimibe and simvastatin, payers will save millions of dollars.
However, the availability of generic ezetimibe and rosuvastatin could have other impacts. There are a number of people who cannot tolerate statins because of side-effects such as muscle pain. Statin intolerance, in fact, is a driver for companies seeking novel LDL-c lowering drugs in order to provide patients with alternatives. But that road has gotten harder. Interestingly, statin intolerance may be able to be overcome in some patients by stopping statin treatment for a brief period, then restarting therapy. Thus, payers will urge that multiple statins be tried before confirming a statin intolerance diagnosis. If all of that doesn’t work, then ezetimibe use will be encouraged as this will be as cheap as statins. These prescribing patterns will shrink the “statin intolerant” patient pool, thus narrowing the heart patient population eyed by Esperion for its novel LDL-c lowering drug, ETC-1002.
But the most compelling new LDL-c drugs are the PCSK-9 inhibitors Praluent (Sanofi/Regeneron ) and Repatha (Amgen). These medicines have the ability to lower LDL-c to levels unattainable by statins alone. Theoretically, the availability of the new generic drugs should have little impact on the sales of PCSK-9 drugs. However, the developers of these drugs have yet to prove that heart patients have better survival with LDL-c levels at 45mg/dL than 70mg/dL., although such data may be available in the next 24 months. The PCSK-9 inhibitors are expensive drugs listing at more than $14,000/year/patient. Payers will seek to have heart patients and their physicians try a variety alternatives, such as combining rosuvastatin and ezetimibe, to lower LDL-c before turning to the PCSK-9s. If a patient can get their LDL-c below 70mg/dL using a combination of drugs costing less than $1 dollar/day, that combination will be used long before allowing access to the more expensive drugs.
There is no doubt that the loss of exclusivity for Crestor and Zetia will impact the bottom lines of AstraZeneca and Merck, respectively. But the availability of the generic forms of these drugs will also have an impact on physician prescribing habits and even drugs not yet on the market. Containing prescription drug costs is a major priority these days, and the use of generics is a key lever in accomplishing this, particularly in the face of high costs alternatives
Patent expiry: December 2016
2012 sales: $2.567 billion
2011 sales: $2.428 billion
Zetia is not the moneymaker it used to be for Merck, but that’s not to say the drug is no longer one of Merck’s ($MRK) top sellers. In 2007, Zetia and sister drug Vytorin had combined sales of $5 billion. Last year it was $4.3 billion.
The drug has struggled in comparison to competitors in clinical trials, with Zetia losing out to AbbVie’s ($ABBV) Niaspan at unclogging arteries. Vytorin, a combo of Zetia and statin Zocor, has proved no more effective at the task than Merck’s Zocor on its own. Vytorin and Zocor are now going head to head once more in Merck’s IMPROVE-IT study, which it hopes will prove the benefits of combining Zocor and Zetia, silencing critics once and for all.
Merck won’t give up on extending the reach of Zetia. The company has won FDA approval for another Zetia/statin tandem drug–this time using a generic form of Lipitor–to be called Liptruzet. The approval, announced earlier this month, immediately faced criticism for Liptruzet’s lack of cardiovascular benefits, including a failure to reduce trial participants’ chances of developing heart disease. But the FDA maintains that proven success at lowering high LDL levels, a risk for the disease, is enough to put the drug to market.
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