A community-based, randomized trial of ezetimibe added to statin therapy to attain NCEP ATP III goals for LDL cholesterol in hypercholesterolemic patients: the ezetimibe add-on to statin for effectiveness (EASE) trial

OBJECTIVE: To determine the extent of reduction in low-density lipoprotein cholesterol (LDL-C) level and improvement in National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) LDL-C goal attainment when ezetimibe was added to ongoing statin therapy in a diverse population of community-based patients. PATIENTS AND METHODS: In this multicenter, double-blind, placebo-controlled trial (from January 2003 to August 2003), hypercholesterolemic patients (from 299 US primary care and specialty practices) with LDL-C levels exceeding NCEP ATP III goals were randomized (2:1) to receive ezetimibe (10 mg/d) or placebo in addition to their ongoing statin therapy for 6 weeks. RESULTS: In a study of 3030 randomized patients, ezetimibe added to statin therapy significantly reduced the LDL-C level by an additional 25.8% in the total population, compared with an additional 2.7% reduction with placebo plus statin (treatment difference, -23.1%; P<.001); the treatment difference ranged from -19.9% to -24.0% (P<.001) in each NCEP ATP III risk category subgroup. Significantly (P<.001) more patients (71.0%) treated with ezetimibe added to statin reached their NCEP ATP III target LDL-C level compared with those treated with placebo plus statin (20.6%). The addition of ezetimibe also resulted in improvement in other lipid parameters and high-sensitivity C-reactive protein levels. These benefits were consistent across sex, race, age, statin brand, and dose subgroups. Ezetimibe plus statin therapy was well tolerated, with a safety profile similar to placebo plus statin. CONCLUSION: Across multiple subgroups, ezetimibe added to statin therapy consistently produced significant additional improvements in LDL-C levels and goal attainment, as well as in other lipoproteins, compared with addition of placebo. The addition of ezetimibe to statin therapy should be considered for patients not achieving their NCEP ATP III LDL-C goals while receiving statin therapy alone.     

Efficacy and safety of ezetimibe coadministered with statins: randomised, placebo-controlled, blinded experience in 2382 patients with primary hypercholesterolemia

We assessed pooled safety and lipid-regulating efficacy data from four similarly designed trials of ezetimibe coadministered with statins in 2382 patients with primary hypercholesterolemia. Patients were randomised to one of the following double-blind treatments for 12 weeks: placebo; ezetimibe 10 mg; statin; or statin + ezetimibe. Statin doses tested were 10, 20, 40 mg/day (atorvastatin, simvastatin, pravastatin or lovastatin) or 80 mg/day (atorvastatin, simvastatin). Treatment with ezetimibe + statin led to significantly greater reductions in low-density lipoprotein cholesterol (LDL-C), total cholesterol, triglycerides, non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B and increases in HDL-C, compared to statin alone. At each statin dose, treatment with ezetimibe + statin led to a greater LDL-C reduction compared to the next highest statin monotherapy dose. Ezetimibe + statin had a safety profile similar to statin monotherapy. Coadministration of ezetimibe + statin offers a well-tolerated, highly efficacious new treatment strategy for patients with hypercholesterolemia.     

Type of preexisting lipid therapy predicts LDL-C response to ezetimibe

BACKGROUND: Ezetimibe as monotherapy or in combination with statins effectively lowers low-density lipoprotein cholesterol (LDL-C). However, there are few reports of ezetimibe's effect when added to ongoing non-statin lipid-lowering drugs or combination lipid-lowering therapy. OBJECTIVE: To evaluate the impact of preexisting lipid therapy on LDL-C response to ezetimibe. METHODS: We performed a retrospective review of all patients started on ezetimibe therapy at the Veterans Affairs Long Beach Healthcare System between March 1, 2003, and March 1, 2005. We calculated the ezetimibe-induced percent change in LDL-C in patients without concomitant changes in other lipid-lowering medications. We then stratified the population according to the type and number of preexisting lipid therapies and compared the LDL-C-lowering efficacy of ezetimibe among these groups. RESULTS: Overall, ezetimibe was associated with a 23.0% reduction in LDL-C. Patients with preexisting statin monotherapy had significantly greater LDL-C reduction with ezetimibe than did those with preexisting non-statin drugs (-26.1% vs -9.3%; p = 0.0138). In patients with no preexisting lipid therapy (n = 58), monotherapy (n = 115), double therapy (n = 36), or triple therapy (n = 9), ezetimibe decreased LDL-C by 17.3%, 21.4%, 33.5%, and 38.1%, respectively. This stepwise trend in increased ezetimibe efficacy was statistically significant, even with adjustments for baseline LDL-C. CONCLUSIONS: Ezetimibe's LDL-C-lowering effects are most pronounced when added to preexisting combination lipid therapy. It appears to be more effective when added to statin therapy compared with other lipid-lowering therapies.     

Ezetimibe: a novel option for lowering cholesterol

Elevated low-density lipoprotein (LDL)-cholesterol is associated with a significantly increased risk of coronary heart disease but lowering LDL-cholesterol to levels established in current National Cholesterol Education Program (NCEP) guidelines provides significant risk reduction. Nevertheless, many patients receiving lipid-lowering therapy, particularly those at highest coronary heart disease risk, do not reach LDL-cholesterol goals with their current medications. Ezetimibe (Zetia^®, Merck Schering-Plough) is the first of a new class of lipid-lowering drugs known as cholesterol absorption inhibitors. Ezetimibe has a favorable pharmacokinetic profile, which allows it to be administered once daily and to be given in conjunction with statins. In a series of randomized, controlled, multicenter studies, ezetimibe produced significant improvements in levels of LDL-cholesterol and other lipid parameters when used as monotherapy, with a safety profile comparable with that of placebo. Furthermore, coadministration of ezetimibe with a statin (simvastatin, atorvastatin, lovastatin, or pravastatin) was more effective than statin monotherapy in lowering LDL-cholesterol and improving other lipid parameters. Moreover, coadministration of ezetimibe with a statin allowed a greater percentage of patients to achieve treatment goals established in NCEP guidelines. The safety and side-effect profile of ezetimibe plus statin coadministration therapy was generally comparable with that of statin monotherapy. These studies establish ezetimibe as an effective lipid-lowering agent, which will likely be useful in the management of a broad range of patients with hypercholesterolemia. Ezetimibe can be used in conjunction with a statin at the beginning of therapy, or it can be added if patients do not achieve their LDL-cholesterol goal with statins alone.     

Ezetimibe: a novel option for lowering cholesterol

Elevated low-density lipoprotein (LDL)-cholesterol is associated with a significantly increased risk of coronary heart disease but lowering LDL-cholesterol to levels established in current National Cholesterol Education Program (NCEP) guidelines provides significant risk reduction. Nevertheless, many patients receiving lipid-lowering therapy, particularly those at highest coronary heart disease risk, do not reach LDL-cholesterol goals with their current medications. Ezetimibe (Zetia, Merck Schering-Plough) is the first of a new class of lipid-lowering drugs known as cholesterol absorption inhibitors. Ezetimibe has a favorable pharmacokinetic profile, which allows it to be administered once daily and to be given in conjunction with statins. In a series of randomized, controlled, multicenter studies, ezetimibe produced significant improvements in levels of LDL-cholesterol and other lipid parameters when used as monotherapy, with a safety profile comparable with that of placebo. Furthermore, coadministration of ezetimibe with a statin (simvastatin, atorvastatin, lovastatin, or pravastatin) was more effective than statin monotherapy in lowering LDL-cholesterol and improving other lipid parameters. Moreover, coadministration of ezetimibe with a statin allowed a greater percentage of patients to achieve treatment goals established in NCEP guidelines. The safety and side-effect profile of ezetimibe plus statin coadministration therapy was generally comparable with that of statin monotherapy. These studies establish ezetimibe as an effective lipid-lowering agent, which will likely be useful in the management of a broad range of patients with hypercholesterolemia. Ezetimibe can be used in conjunction with a statin at the beginning of therapy, or it can be added if patients do not achieve their LDL-cholesterol goal with statins alone.     

Ezetimibe in hypercholesterolaemia

Ezetimibe is the first member of a new class of selective cholesterol absorption inhibitors, compounds that effectively block intestinal absorption of dietary and biliary cholesterol, without affecting absorption of fat soluble vitamins or triglycerides. Ezetimibe underwent glucuronidation to a single metabolite and localised at the intestinal wall, where it prevented luminal cholesterol absorption. Pre-clinical studies demonstrated the lipid-lowering and antiatherosclerotic properties of ezetimibe. The efficacy and safety of ezetimibe monotherapy have been determined in phase II/III studies: in phase II studies, the optimal efficacy was reached with ezetimibe 10 mg per day and the pooled efficacy data have shown that ezetimibe 10 mg has a positive effect on the lipoprotein profile with a significant reduction in LDL-cholesterol of 18.5%, an increase in HDL-cholesterol of 3.5% and a trend towards lowering in triglyceride concentrations (-4.9%). The monotherapy phase III studies have confirmed the efficacy with a decrease in LDL-C of 17.4% and have demonstrated an excellent safety and tolerability profile. The potential for a pharmacokinetic and/or pharmacodynamic interaction between ezetimibe and various statins and the efficacy and safety or the co-administration of ezetimibe and statins have been evaluated in different phase I/II studies: ezetimibe had no significant effect on the pharmacokinetics of simvastatin or atorvastatin. Ezetimibe 10 mg co-administrated with the starting dose of any statin induced a mean 18% additive LDL-C lowering effect. This additive 18% reduction in LDL-C is achieved in one step compared with the three steps necessary with statin monotherapy.     

Effectiveness and tolerability of ezetimibe in patients with primary hypercholesterolemia: pooled analysis of two phase II studies

BACKGROUND: Ezetimibe (SCH 58235) is a novel cholesterol absorption inhibitor that selectively and potently blocks intestinal absorption of dietary and biliary cholesterol. OBJECTIVE: Data from 2 multicenter, placebo-controlled, double-blind, randomized, parallel-group, 12-week studies of ezetimibe were pooled to evaluate the drug's effect on lipid parameters in patients with primary hypercholesterolemia. METHODS: After dietary stabilization (National Cholesterol Education Program Step I diet or a stricter diet), washout of lipid-altering drugs, and a 6-week placebo lead-in period, patients with baseline plasma low-density lipoprotein cholesterol (LDL-C) levels > or = 130 and < or = 250 mg/dL and plasma triglyceride (TG) levels < or = 300 mg/dL were randomized to receive either ezetimibe 0.25, 1, 5, or 10 mg, or placebo administered once daily before the morning meal in study A (dose-response study) or ezetimibe 5 or 10 mg or placebo administered once daily before the morning meal or at bedtime in study B (dose-regimen study). RESULTS: A total of 432 patients were included in this pooled analysis, 243 in study A and 189 in study B. The 5- and 10-mg doses of ezetimibe significantly reduced LDL-C levels by 15.7% and 18.5%, respectively (P < 0.01 vs placebo) and significantly increased high-density lipoprotein cholesterol (hDL-C) levels by 2.9% and 3.5%, respectively (P < 0.05 vs placebo). A reduction in plasma TG levels was observed (P = NS). With the 10-mg dose of ezetimibe, 67.8% of patients achieved > or = 15% reduction in plasma LDL-C levels, and 22.0% achieved > or = 25% reduction. With the 5-mg dose, 54.0% of patients achieved > or = 15% reduction in plasma LDL-C levels, and 15.3% achieved > or = 25% reduction. The decrease in plasma LDL-C levels was significantly greater with ezetimibe 10 mg compared with ezetimibe 5 mg (P < 0.05). Ezetimibe was well tolerated, with an adverse event profile similar to that of placebo. Conclusions: In these two 12-week studies, ezetimibe significantly decreased plasma LDL-C levels and increased plasma HDL-C levels, with a tolerability profile similar to that of placebo.     

Ezetimibe for management of hypercholesterolemia

OBJECTIVE: To review the primary literature describing the pharmacology of ezetimibe and clinical trials investigating its use in the management of hypercholesterolemia. DATA SOURCES: A MEDLINE search (1966-December 2002) was performed using SCH 48461, SCH 58235, ezetimibe, and 2-azetidinone as key words. English-language articles were identified and the references of these articles were used to further identify pertinent articles and abstracts. Given the paucity of published articles available on ezetimibe, many of the references cited are abstracts. STUDY SELECTION: All acquired articles that discussed the pharmacology, pharmacokinetics, chemistry, and clinical efficacy of ezetimibe were reviewed. DATA EXTRACTION: Articles were selected based on content regarding the medicinal chemistry, pharmacology, and clinical use of ezetimibe. DATA SYNTHESIS: Ezetimibe, approved for use in October 2002, belongs to a new class of antihyperlipidemic agents that uniquely inhibit the absorption of cholesterol by inhibiting the cholesterol transport system located within intestinal cell walls. In humans, ezetimibe reduced cholesterol absorption by >50%. In clinical trials, ezetimibe 10 mg/d reduced low-density lipoprotein cholesterol (LDL-C) by approximately 18% and further enhanced the LDL-C-lowering effect of statin medications by an additional 15-20%. In addition, ezetimibe lowered triglycerides about 5% and increased high-density lipoprotein cholesterol (HDL-C) approximately 3%. Ezetimibe is well tolerated. At present, no serious adverse effects have been directly attributable to ezetimibe. CONCLUSIONS: Based on the data currently available, it appears that ezetimibe has a potential role in the treatment of primary hypercholesterolemia; however further data are needed to determine its long-term tolerability and efficacy. The potential roles for ezetimibe include its concurrent use with a statin to further enhance the lowering of LDL-C. Other possible roles for ezetimibe include its concurrent use with a statin to permit a lowering of statin dosage to avoid statin-related complications or its use as monotherapy to treat hypercholesterolemia when statin use cannot be tolerated or is contraindicated. Outcome data demonstrating that cardiovascular morbidity and/or mortality are reduced by ezetimibe therapy have yet to be generated.     

Ezetimibe/simvastatin (INEGY) in the treatment of hyperlipidaemia

Ezetimibe/simvastatin (INEGY), a dual inhibitor of both cholesterol production and absorption, is a new approach to the management of hyperlipidaemia. Recent studies have shown that it produces greater reductions in low-density lipoprotein (LDL) cholesterol than the single inhibition of statin therapy, enabling many more patients to achieve their LDL cholesterol treatment goals. With ezetimibe/simvastatin therapy, reductions of up to 61% from baseline have been seen in LDL cholesterol, with clear improvements in other associated lipid fractions. It has been well tolerated across all studies, with a safety profile similar to that of statin therapy. This article will review clinical experience to date with ezetimibe/simvastatin, commenting upon its place and potential value in the prevention of cardiovascular disease.     

Cross-Sectional Survey to Assess the Status of Lipid Management in High-Risk Patients With Dyslipidemia: Clinical Impact of Combination Therapy With Ezetimibe

BackgroundPrevious retrospective surveys have shown that lipid management goals are well achieved in patients with dyslipidemia at relatively low risk for atherosclerotic diseases. However, more than half of patients in high-risk groups have not achieved the management goals. Since these surveys, newer medications, including rosuvastatin and ezetimibe, have emerged in clinical practice that may influence lipid management.ObjectiveTo assess the current status of lipid management in high-risk patients, we conducted a cross-sectional study between January and March 2010.MethodsEligible patients were those with dyslipidemia who were classified into the primary prevention high-risk or secondary prevention groups according to the Japan Atherosclerosis Society guideline for diagnosis and prevention of atherosclerotic cardiovascular diseases. Patient data were collected from 300 randomly selected physicians at hospitals and clinics across Japan if patients had been receiving the same statin with or without other lipid-lowering agents for ≥3 months. The main outcome was the percentage of patients who achieved the serum LDL-C goal according to the guideline.ResultsData were collected from 1720 patients. The LDL-C goal was achieved in 56.5% of patients (447 of 791) in the primary prevention high-risk group and in 24.5% (103 of 420) in the secondary prevention group by statin monotherapy. For patients who had not reached the LDL-C goal with statin therapy alone, 53.8% (113 of 210) in the primary prevention high-risk group and 63.8% (111 of 174) in the secondary prevention group achieved their lipid management goal with the addition of ezetimibe. Ezetimibe significantly lowered mean serum LDL-C levels by 17.9% to 34.6% when added to various statins (P < 0.001).ConclusionsAlthough strong statins are available, lipid management in high-risk patients remains unsatisfactory. More aggressive treatment is needed for these patients.     

Evaluation of the efficacy,safety, and tolerability of ezetimibe in primary hypercholesterolaemia: a pooled analysis from two controlled phase III clinical studies

Ezetimibe is a novel cholesterol absorption inhibitor that blocks intestinal absorption of dietary and biliary cholesterol. Data from 1719 patients who participated in two multicentre, double-blind studies of ezetimibe were pooled to evaluate the drug's efficacy and safety in patients with primary hypercholesterolaemia. Following dietary stabilisation, a two- to 12-week washout period, and a four-week, single-blind, placebo lead-in period, patients were randomised to ezetimibe 10 mg or placebo once daily in the morning for 12 consecutive weeks. The primary efficacy endpoint was percent reduction in plasma low-density lipoprotein (LDL)-cholesterol from baseline at endpoint. Ezetimibe reduced LDL-cholesterol by a mean of 18.2% compared with an increase of 0.9% with placebo (p<0.01) and resulted in favourable, statistically significant changes in HDL-cholesterol, triglycerides and apo B. The response to ezetimibe was consistent across all subgroups analysed. Ezetimibe was well tolerated, with a safety profile similar to placebo.     

Estimating the health benefits and costs associated with ezetimibe coadministered with statin therapy compared with higher dose statin monotherapy in patients with established cardiovascular disease: results of a Markov model for UK costs using data registries

BACKGROUND: Ezetimibe has been reported to improve lipid control in patients with established cardiovascular disease (CVD). OBJECTIVE: The aim of this study was to estimate the potential long-term impact on health status of prescribing ezetimibe in combination with statin therapy in patients with established CVD and evaluate its cost-effectiveness in a health economic model. METHODS: A Markov model was used to compare ezetimibe and statin combination therapy with statin monotherapy. A published relationship linking changes in low-density lipoprotein cholesterol and cardiovascular events was used to estimate the cardiovascular events avoided through lipid-lowering therapies. The model was populated using results of extensive literature searches and a meta-analysis of clinical evidence. An adjustment was applied to model second-line lipid-lowering benefits. Conservative assumptions were used to extend the patient pathway beyond the clinical evidence. The analysis took the perspective of the UK Department of Health; therefore, only direct costs were included. Costs were calculated as year-2006 British pounds. RESULTS: For a cohort of 1,000 hypothetical male patients aged 55 years, ezetimibe coadministered with current statin therapy was estimated to prevent a mean of 43 nonfatal myocardial infarctions, 7 nonfatal strokes, and 26 cardiovascular deaths over a lifetime, compared with doubling the current statin dose. The events avoided would provide a mean of 134 additional quality-adjusted life-years (QALYs). With a mean incremental cost of pound 3,693,000, the lifetime discounted cost per QALY gained would be pound 27,475 (95% CI, pound 27,331- pound 27,620) and would rise to pound 32,000 for men aged 75 years. CONCLUSIONS: The results suggest that, in some instances, ezetimibe coadministration may be cost-effective compared with statin monotherapy, but there are several limitations with this model. The economic effects of ezetimibe must be revisited when long-term effectiveness and safety data become available.     

Supratherapeutic response to ezetimibe administered with cyclosporine

OBJECTIVE: To report the case of a patient who underwent orthotopic heart transplant (OHT) and demonstrated a supratherapeutic response to ezetimibe when administered with cyclosporine. CASE SUMMARY: Ezetimibe 10 mg/day was added to the lipid-lowering regimen (atorvastatin 40 mg/day) of a 64-year-old male patient after OHT to achieve a target low-density lipoprotein cholesterol (LDL-C) level < or = 97 mg/dL, as recommended by national guidelines. After 2 months of ezetimibe, the patient's LDL-C level had decreased by 60% to 51 mg/dL. Subsequently, the dose of ezetimibe was reduced to 5 mg/day and, after another 2 months, a repeat lipid panel revealed LDL-C 57 mg/dL. DISCUSSION: Hyperlipidemia is a common problem among heart transplant recipients. Combination therapy using a statin plus ezetimibe appears to be an attractive option to achieve target lipid levels in this population. However, the manufacturer warns that ezetimibe should be administered cautiously in patients concomitantly receiving cyclosporine. Unpublished data suggest a pharmacokinetic interaction between ezetimibe and cyclosporine that results in a significant 2.3- to 12-fold increase in exposure to total ezetimibe. An objective causality assessment in this case revealed that this supratherapeutic LDL-C reduction was probably related to coadministration of ezetimibe and cyclosporine. A potential mechanism to explain this interaction might be an alteration in glucuronidation induced by cyclosporine. CONCLUSIONS: When ezetimibe is prescribed for patients concomitantly receiving cyclosporine, it should be initiated at a lower than recommended dose (> or = 5 mg/day) and titrated upward. Careful and consistent monitoring of patients on this combination is also advised.     

Effects of ezetimibe/simvastatin on lipoprotein subfractions in patients with primary hypercholesterolemia: an exploratory analysis of archived samples using two commercially available techniques

BACKGROUND: Cholesterol-rich lipoproteins, including low-density lipoprotein cholesterol (LDL-C), intermediate-density lipoprotein cholesterol (IDL-C), and very-low-density lipoprotein cholesterol (VLDL-C), are known to promote atherosclerosis. Ezetimibe/simvastatin (E/S) is an efficacious lipid-lowering treatment that inhibits both the intestinal absorption and biosynthesis of cholesterol. OBJECTIVE: The aim of the current analysis was to compare the effects of ezetimibe and simvastatin monotherapy and E/S treatment on lipoprotein subfractions and LDL particle size in patients with primary hypercholesterolemia. METHODS: This was an exploratory (hypothesis generating) analysis of archived plasma samples drawn from patients in a multicenter, randomized, double-blind, placebo-controlled, parallel-arm study. After a washout and diet/placebo run-in, patients with hypercholesterolemia (LDL-C, > or =145- < or =250 mg/dL; triglycerides, < or =350 mg/dL) were randomized equally to 1 of 10 daily treatments for 12 weeks: E/S (10/10, 10/20, 10/40, or 10/80 mg), simvastatin monotherapy (10, 20, 40, or 80 mg), ezetimibe monotherapy (10 mg), or placebo. A subset of patients had lipid subfraction measurements taken at baseline (week 0) and postrandomization (week 12). Plasma samples were used to quantify cholesterol associated with VLDL subfractions (VLDLI+2 and VLDL3), IDL, and 4 LDL subfractions (LDL1-4) via the Vertical Auto Profile II method. LDL-C particle size was determined using segmented gradient gel electrophoresis. The primary end point was median percent change in subfraction cholesterol for E/S versus ezetimibe or simvastatin monotherapy, pooled across doses. RESULTS: Of the 1528 patients randomized in the original study, 1397 (91%) had lipid subfraction measurements taken. E/S was associated with significant reductions in VLDL-CI+2, VLDL-C3, IDL-C, LDL-C1, LDL-C2, and LDL-C3 versus ezetimibe, simvastatin, and placebo. E/S resulted in near-additive reductions in VLDL-CI+2, VLDL-C3, IDL-C, LDL-C1, LDL-C2, and LDL-C3 versus ezetimibe and simvastatin monotherapy. Of the subfractions examined, with regard to E/S, the greatest reductions were observed in IDL-C and LDL-C1, LDL-C2, and LDL-C3. When compared with placebo, ezetimibe, simvastatin, and E/S did not shift the distribution of LDL particles toward a larger, more buoyant LDL subclass pattern. CONCLUSION: E/S was more effective than ezetimibe and simvastatin monotherapy in reducing atherogenic lipoprotein subfractions in these patients with primary hypercholesterolemia.     

Pharmacology and therapeutics of ezetimibe (SCH 58235), a cholesterol-absorption inhibitor

BACKGROUND: Ezetimibe is the first of a new class of antihyperlipidemic agents, the cholesterol-absorption inhibitors. It is indicated for monotherapy or in combination with 3-hydroxy-3-methylglutaryl coenzyme A-reductase inhibitors (statins) in patients with primary hypercholesterolemia, in combination with simvastatin or atorvastatin in patients with homozygous familial hypercholesterolemia, and as monotherapy in patients with homozygous familial sitosterolemia. OBJECTIVE: This article reviews available data on the clinical pharmacology, clinical efficacy, and tolerability of ezetimibe. METHODS: A literature review was conducted using the search terms ezetimibe and SCH 58235 to identify articles and abstracts indexed in MEDLINE and the Iowa Drug Information Service from 1966 to February 2003. The reference lists of the identified articles were reviewed for additional publications. RESULTS: In adults, ezetimibe 10 mg PO given once daily has been reported to reduce intestinal cholesterol absorption by 54% from baseline in association with a compensatory increase in endogenous cholesterol synthesis. Within 2 weeks of its initiation, ezetimibe monotherapy produced a 17% to 20% reduction from baseline in low-density lipoprotein cholesterol (LDL-C); in combination with statins, ezetimibe produced a reduction in LDL-C of up to 40% over the same period. Based on studies performed to date, ezetimibe appears to be well tolerated, with a safety profile similar to that of placebo. Because ezetimibe is eliminated primarily by glucuronidation and not by cytochrome P450 (CYP) oxidation, it is subject to minimal drug interactions involving the CYP enzyme system. CONCLUSIONS: Ezetimibe is an option for monotherapy in patients with mild hypercholesterolemia or in those requiring adjunctive drug therapy for reduction of LDL-C levels. It may be useful in patients at risk for adverse events (eg, liver toxicity, myopathy) from other hypocholesterolemic agents. Additive LDL-C-lowering effects of ezetimibe may allow use of lower doses of conventional agents (eg, statins, fibric acid derivatives, niacin) to achieve an equivalent effect, thereby reducing the potential for adverse events and drug interactions. However, because trials have lasted no longer than 12 weeks, the long-term effect of ezetimibe on cardiovascular morbidity and mortality remains to be determined.     

Efficacy, safety and LDL-C goal attainment of ezetimibe 10 mg-simvastatin 20 mg vs. placebo-simvastatin 20 mg in UK-based adults with coronary heart disease and hypercholesterolaemia

It is increasingly accepted that more intensive lipid‐lowering treatment is associated with greater cardiovascular risk reductions in patients with coronary heart disease (CHD), thus providing a rationale for more aggressive LDL‐cholesterol (LDL‐C) targets. Ezetimibe in combination with statin therapy provides an additional approach to lipid management by utilising the additive action of two different mechanisms of LDL‐C reduction. In this multicentre, randomised, double‐blind, placebo‐controlled study, a total of 98 men and 55 women with CHD and primary hypercholesterolaemia, naïve to statin therapy, were randomised to receive treatment for 6 weeks with either ezetimibe 10 mg–simvastatin 20 mg (n = 77) or placebo–simvastatin 20 mg (n = 75). At 6 weeks, ezetimibe 10 mg–simvastatin 20 mg provided a mean additional LDL‐C reduction of 14.6% (95% CI 10.1–19.1) compared with simvastatin monotherapy (p < 0.0001). Moreover, a higher proportion of patients on ezetimibe/simvastatin achieved the National Standard Framework LDL‐C standard (<3.0 mmol/l; 93% vs. 75%, p < 0.001) or the new Joint British Societies (JBS 2) goal of LDL‐C < 2.0 mmol/l (49.3% vs. 11.1%, p < 0.001). On logistic regression analysis, the odds ratio of achieving target LDL‐C with ezetimibe 10 mg–simvastatin 20 mg was 5.1 (95% CI 1.8–15.0) times higher than with simvastatin monotherapy (p = 0.003). Clinical chemistry profiles and proportions of adverse events were similar in both groups at baseline and follow‐up. In conclusion, ezetimibe 10 mg–simvastatin 20 mg is a practical, effective and safe option for the treatment of primary hypercholesterolaemia in CHD patients, and brings more patients to new aggressive cholesterol targets compared with simvastatin 20 mg monotherapy.     

Racial bias in patient selection of an obstetrician

OBJECTIVE: The objective of this study was to determine racial bias in patient selection of an obstetrician. METHODS: Obstetrical patients referred for genetic counseling at a community hospital were included. Self-reported patient race/ethnicity were compared with obstetrician's race/ethnicity. RESULTS: The patient population (n = 1,519) was 27.8% white, 25% Hispanic, 22.5% black, 20.5% Asian, and 4.3% other. Physician race/ethnicity was 47.8% white, 28.8% Asian, 14.4% Hispanic, and 9% black. Patient race/ethnicity and physician race/ethnicity were correlated (contingency coefficient = 0.54, P < 0.001). White and Asian patients were more likely to select obstetricians of their own racial background (72.7% and 66.6%) than were Hispanic or black patients (36% and 24.6%, P < 0.001). Patients of all races were more likely to be under the care of a physician of their own race than of a different race. CONCLUSIONS: In an urban community with a racially diverse population, there is a strong racial bias in patient selection of an obstetrician.     

Ezetimibe-induced hyperlipidaemia

Ezetimibe is intestinally active cholesterol absorption inhibitor used to reduce low-density lipoprotein-cholesterol levels. This case report describes a novel side effect with this agent: ezetimibe-induced hyperlipidaemia in a patient with statin intolerance and familial combined hyperlipidaemia. Ezetimibe therapy induced an asymptomatic 770% increase in triglycerides (TGs) (3.51-27.1 mmol/l) and a 190% increase in total cholesterol (9.8-18.5 mmol/ 1) secondary to an increase (4.6-25.9 micromol/l; 560%) in hepatic cholesterol (lathosterol) synthesis. This lipid profile resolved 9 months after cessation of ezetimibe therapy. This report shows that ezetimibe may have long-lasting effects in man far exceeding its plasma half-life and that ezetimibe monotherapy can induce a large increase in hepatocyte very-low-density lipoprotein synthesis in rare individuals with a consequent mixed hyperlipidaemia or possibly hypercholesterolaemia depending on the metabolism and clearance of TG-rich lipoproteins.     

Colesevelam HCl and ezetimibe combination therapy provides effective lipid-lowering in difficult-to-treat patients with hypercholesterolemia

This study investigated the effects of colesevelam hydrochloride (WelChol; Sankyo Pharma, Parsippany, NJ) and ezetimibe (Zetia; Merck/Schering Plough Pharmaceuticals, North Wales, PA), alone and in combination, for the treatment of hypercholesterolemia in patients who were intolerant to, or refused, HMG-Co-A reductase inhibitor (statin) therapy. Combination therapy with colesevelam HCl/ezetimibe resulted in an additional reduction in low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (HDL-C) levels of approximately 20% (P < 0.005) and 16% (P < 0.01), respectively, compared with monotherapy with either agent. Total cholesterol, LDL-C, and non-HDL-C levels were within National Cholesterol Education Program Adult Treatment Panel III target ranges at the end of the combination therapy regimen in 10 of 12 patients. In conclusion, colesevelam HCl/ezetimibe combination therapy appears to be an efficacious and well-tolerated alternative for patients with hypercholesterolemia.     

Safety profile of statins alone or combined with ezetimibe: a pooled analysis of 27 studies including over 22,000 patients treated for 6-24 weeks

Aims: The aim of this analysis was to assess the overall safety and tolerability profiles of various statins + ezetimibe vs. statin monotherapy and to explore tolerability in sub‐populations grouped by age, race, and sex. Methods: Study‐level data were combined from 27 double‐blind, placebo‐controlled or active‐comparator trials that randomized adult hypercholesterolemic patients to statin or statin + ezetimibe for 6–24 weeks. In the full cohort, % patients with AEs within treatment groups (statin: N = 10,517; statin + ezetimibe: N = 11,714) was assessed by logistic regression with terms for first‐/second‐line therapy (first line = drug‐naïve or rendered drug‐naïve by washout at study entry; second line = ongoing statin at study entry or statin run‐in), trial within first‐/second‐line therapy, and treatment. The same model was fitted for age (< 65, ≥ 65 years), sex, race (white, black, other) and first‐/second‐line subgroups with additional terms for subgroup and subgroup‐by‐treatment interaction. Results: In the full cohort, the only significant difference between treatments was consecutive AST or ALT elevations ≥ 3 × upper limit of normal (ULN) (statin: 0.35%, statin + ezetimibe: 0.56%; p = 0.017). Significantly more subjects reported ≥ 1 AE; drug‐related, hepatitis‐related and gastrointestinal‐related AEs; and CK elevations ≥ 10 × ULN (all p ≤ 0.008) in first‐line vs. second‐line therapy studies with both treatments. AEs were generally similar between treatments in subgroups, and similar rates of AEs were reported within age and race subgroups; however, women reported generally higher AE rates. Conclusions: In conclusion, in second‐line studies, ongoing statin treatment at study entry likely screened out participants for previous statin‐related AEs and tolerability issues. These results describe the safety profiles of widely used lipid‐lowering therapies and encourage their appropriate and judicious use in certain subpopulations.