Safety Of Ezetimibe Research Articles

The role of ezetimibe in the prevention of cardiovascular disease: Where do we stand after ARBITER 6-HALTS

Ezetimibe, a selective inhibitor of intestinal cholesterol absorption, rapidly became one of the most widely drugs in the US following its approval by the FDA in 2002. Due to its capacity to significantly lower LDL-C with few side effects, ezetimibe has been very useful in enabling patients who were statin intolerant to reach their recommended therapeutic goal for LDL-C. In addition, ezetimibe also reduces non-HDL-C and raises HDL-C, further enhancing its effectiveness in clinical practice. A significant preponderance of evidence supports the reduction of LDL-C and non-HDL-C as the most effective therapy to prevent or reverse atherosclerotic cardiovascular disease (ASCVD). However 3 recent clinical trials, ENHANCE, SEAS, and ARBITER 6-HALTS have raised questions about the efficacy and safety of ezetimibe and have led to a re-examination of its clinical use as a drug for managing lipid risk factors to prevent or manage ASCVD. An in-depth analysis of these three trials reveals methodological deficiencies and concerns with the statistical methods used which significantly diminish their indictment of the clinical utility of ezetimibe. In contrast, The SANDS trial has confirmed the effectiveness of ezetimibe in managing both LDL-C and non-HDL-C, and also demonstrated this drug’s ability to improve carotid atherosclerosis by producing regression of CIMT. One of the important conclusions of the SANDS Trail is that ezetimibe remains an effective adjunctive medication for use in patients who do not reach their LDL-C goals on statin monotherapy. However, as a significant residual risk for ASCVD remains even after aggressive goals for LDL-C and non-HDL-C are reached, current treatment strategies should emphasize managing of all cardiac risk factors and increasing HDL in addition to the attainment and maintenance of recommended goals for LDL-C and non-HDL-C. Hence, ezetimibe should be considered as an important component of broad-spectrum management of lipid risk factors with therapy that includes statins, niacin, bile acid sequestrants, fibrates and Omega 3 fatty acids in appropriate combinations in addition to therapeutic life change.

Retrospective, Observation Study: Quantitative and Qualitative Effect of Ezetimibe and HMG-CoA Reductase Inhibitors on LDL-Cholesterol: Are There Disappearance Thresholds for Small, Dense LDL and IDL?

Lipid profiles were evaluated for 281 dyslipidemia patients treated with HMG-CoA reductase inhibitors (statins) for 2 years. The efficacy and safety of ezetimibe 10 mg/day one-year add-on therapy were also retrospectively evaluated. The results show that in 281 dyslipidemia patients with a mean low-density lipoprotein-cholesterol (LDL-C) level of 120 mg/dl or greater, ezetimibe 10 mg/day administration reduced LDL-C levels to 90 mg/dl or below. Patients who had been treated with one of six statins (pravastatin, simvastatin, fluvastatin, pitavastatin, atorvastatin, and rosuvastatin) for one year were given ezetimibe add-on therapy for one year, which reduced their LDL-C levels by 18% (pravastatin), 25% (simvastatin), 27% (fluvastatin), 30% (pitavastatin), 29% (atorvastatin), and 31% (rosuvastatin). Also, during the one-year add-on therapy, no severe adverse event was detected. An analysis of associations among lipids during a two-year lipid-lowering pharmacotherapy revealed correlations in a single patient. The correlation was between LDL-C and small, dense LDL as well as mid-band lipoprotein cholesterol. In conclusion, ezetimibe 10mg/day add-on therapy may be safe and effective for treating dislipidemia patients who have been treated with a statin. Moreover, this article discusses the disappearance thresholds for small, dense LDL and intermediate-density lipoprotein (IDL) by using the quantitative analysis of densitometric pattern based on genetic algorithm, which indicated that the major eight subspecies of lipoprotein (VLDL1, VLDL2, IDL1, IDL2, LDL1, LDL2, LDL3, HDL). The thershold for small dense LDL indicates the IDL1 plus IDL2 when LDL2 and LDL3 were not detectable, while the thershold for IDL indicates the LDL1 when IDL1, IDL2 and LDL3 were not detectable.

Lipid-Altering Efficacy and Safety of Ezetimibe/ Simvastatin Versus Atorvastatin in Patients With Hypercholesterolemia and the Metabolic Syndrome (from the VYMET Study)

Patients with the metabolic syndrome are at an increased risk of cardiovascular disease and might require intensive lipid therapy. Many patients remain at the starting dose of lipid therapy and might not be titrated up to a higher dose. The present double-blind, randomized, 6-week study assessed the lipid-lowering efficacy of ezetimibe/simvastatin 10/20 mg versus atorvastatin 10 or 20 mg, and ezetimibe/simvastatin 10/40 mg versus atorvastatin 40 mg in 1,128 patients with hypercholesterolemia and the metabolic syndrome. The primary end point was the percentage of change from baseline in low-density lipoprotein (LDL) cholesterol. Additional end points included changes in other lipids, lipoprotein ratios, high-sensitivity C-reactive protein, and attainment of prespecified lipid levels. Significantly greater improvements in the levels of LDL cholesterol, non-high-density lipoprotein cholesterol, apolipoprotein B, and lipid/lipoprotein ratios resulted with ezetimibe/simvastatin compared with atorvastatin at all specified dose comparisons (p <0.001). The attainment of prespecified LDL cholesterol and non-high-density lipoprotein cholesterol levels was also significantly greater with ezetimibe/simvastatin than with atorvastatin at all dose comparisons (p <0.05). High-density lipoprotein cholesterol increases were significantly greater with ezetimibe/simvastatin 10/20 mg than with atorvastatin 10 mg (p <0.05) and ezetimibe/simvastatin 10/40 mg than with atorvastatin 40 mg (p <0.01). The changes in triglycerides, very low-density lipoprotein cholesterol, and high-sensitivity C-reactive protein were similar for both treatments. The incidence of liver, muscle, and gastrointestinal-, hepatitis- and allergic reaction/rash-related adverse events were low and generally similar to those in previous studies of ezetimibe/simvastatin and/or atorvastatin. In conclusion, ezetimibe/simvastatin was more likely to result in lipid treatment end points than atorvastatin and was generally well tolerated at the doses compared in our patients.

Safety and effectiveness of ezetimibe in liver transplant recipients with hypercholesterolemia

Hypercholesterolemia is a common problem among transplant recipients. Despite package-insert warnings about the potential side effects of the use of statins in patients with chronic liver disease, they are often prescribed for liver transplant recipients. Unlike statins, ezetimibe acts through inhibition of enterohepatic recirculation of lipids. We report the effectiveness and safety of ezetimibe among liver transplant recipients because this has been evaluated previously only in kidney and heart transplant patients. A consecutive cohort of 25 liver graft recipients with serum low-density lipoprotein (LDL) levels > 100 mg/dL (2.5 mmol/L) after a mean (+/-standard deviation) of 55 +/- 21 months following liver transplantation received ezetimibe (10 mg orally every day) for at least 6 months. Serum lipid profiles, liver and renal function tests, and dosages and blood levels of the immunosuppression drugs at baseline, 3 months, and 6 months were prospectively collected. The overall mean age was 58 +/- 12 years, and 56% were males. Statin therapy and fibrates were already being used in 32% and 20% of recipients for elevated LDL and/or triglycerides, respectively. The immunosuppression regimen included cyclosporine in 48% of subjects, tacrolimus in 32%, sirolimus in 48%, and mycophenolate mofetil in 44%; only 12% were on oral prednisone with a maximum daily dose of 5 mg. After ezetimibe was started, an 18% reduction in LDL values was observed [at baseline, 147 +/- 35 mg/dL (3.8 +/- 0.9 mmol/L), and at 6 months, 120 +/- 31 mg/dL (3.1 +/- 0.8 mmol/L); P = 0.010]. After 6 months, an additional 32% achieved the target LDL level of <100 mg/dL. None of the remaining variables, including immunosuppression drug levels, varied significantly during ezetimibe therapy. None of the subjects required adjustments in their pharmacological dosages. One discontinued ezetimibe 3 months later because of cost, 2 subjects had minimal nausea, 1 subject had myalgias without a rise in creatine phosphokinase, and 1 subject had a transient elevation (3-5 times) in liver enzymes from baseline with increases in the total and indirect bilirubin levels. In conclusion, among liver transplant recipients, hypercholesterolemia can be effectively treated with ezetimibe with few side effects and no interaction with immunosuppressive regimens.

The Efficacy and Safety of Ezetimibe and Low-Dose Simvastatin as a Primary Treatment for Dyslipidemia in Renal Transplant Recipients

Background/AimsThe efficacy and safety of a combination of ezetimibe and low-dose statin as primary treatment for dyslipidemia in renal transplant patients were evaluated prospectively.MethodsThe study enrolled 77 renal transplant recipients with dyslipidemia. They were given ezetimibe (10 mg) and simvastatin (10 mg) for 6 months as the initial treatment for dyslipidemia. Efficacy and safety were evaluated using lipid profiles, trough calcineurin inhibitor levels, allograft function, and adverse effects. The effects on proteinuria and high sensitivity C-reactive protein (hsCRP) levels were also evaluated.ResultsEzetimibe and low-dose simvastatin significantly decreased the levels of total cholesterol (34.6%), triglyceride (16.0%), and low-density lipoprotein cholesterol (LDL-C) (47.6%), and 82.5% of the patients reached the target LDL-C level of <100 mg/dL. No significant change in the trough calcineurin inhibitor levels or allograft function occurred, and no serious adverse effects were observed. Fourteen patients (18.2%) discontinued treatment; eight patients (11.7%) developed muscle pain or weakness without an increase in creatinine kinase levels, and two patients (2.6%) developed elevated liver transaminase levels. The proteinuria and hsCRP levels did not change significantly.ConclusionsEzetimibe and low-dose statin treatment is safe and effective as a primary treatment for dyslipidemia in renal transplant patients.

A randomised trial of three counselling strategies for lifestyle changes in patients with hypercholesterolemia treated with ezetimibe on top of statin therapy (TWICE)

To compare the impact of three patient counselling strategies for lifestyle changes and to assess the safety and efficacy of ezetimibe on top of statin therapy in hypercholesterolemic high risk patients. Open, cluster randomized 3-parallel group trial. Physicians were randomized between patient motivation on: diet or physical exercise or both. Counselling was adapted to the patient's baseline Prochaska stage of change. High cardiovascular risk patients, with LDL-C above or equal to 3 mmol/L despite statin therapy for at least 3 months, were enrolled. Ezetimibe (10mg/day) and patient counselling were started at the same time. Target goal was defined as total cholesterol less than 5 mmol/L and LDL-C above 3 mmol/L. Overall 428 physicians enrolled 1,496 patients. At baseline, LDL-C was 3.9+/-0.9 mmol/L and total cholesterol was 6.1+/-1.1 mmol/L. LDL-C decreased by -30.4+/-19.3% and 869 (62%) patients achieved target goal. No difference was shown between randomisation groups. However, improvements in diet consumption patterns were more easily obtained than improvement in physical activity stage of change in non-active patient at baseline. The marked short-term impact (-30%) on LDL-C, although similar between the three groups, slightly exceeds usual LDL-C reductions achieved by this dose of ezetimibe. Decreasing fat consumption seems easier than increasing physical activity. This study confirms the good efficacy, short-term tolerability and safety of ezetimibe on top of statins.

Long-term (48-week) safety of ezetimibe 10 mg/day coadministered with simvastatin compared to simvastatin alone in patients with primary hypercholesterolemia

ABSTRACTObjective: This study evaluated the long-term safety and tolerability of ezetimibe/simvastatin coadministration therapy compared to simvastatin monotherapy in patients with primary hypercholesterolemia.Research design and methods: After completing a 12-week randomized, double-blind, placebo-controlled, factorial, 10-armed study comparing ezetimibe 10 mg/simvastatin 10, 20, 40, or 80 mg; simvastatin 10, 20, 40, or 80 mg; ezetimibe 10 mg; or placebo, 768 patients entered a 48-week extension, with randomized, blinded, reassignment of the simvastatin 10 mg, ezetimibe, and placebo groups to one of the ezetimibe/simvastatin groups. Patients previously receiving ezetimibe/simvastatin combination therapy, or simvastatin 20, 40, and 80 mg monotherapy continued the same therapies in this 7-arm extension study. During the extension study, investigators assessed adverse events (AEs).Main outcome measures and results: Ezetimibe/simvastatin (n = 539) and simvastatin monotherapy (n = 229) groups generally had a similar incidence of all clinical AEs (73 vs. 69%), treatment-related AEs (14 vs. 11%), clinical serious AEs (SAE) (5.2 vs. 2.6%), treatment-related SAEs (0.2 vs. 0%), discontinuations due to all clinical AEs (4.5 vs. 2.6%) and discontinuations due to treatment-related AEs (2.8 vs. 2.2%), respectively. The incidence of total laboratory-related AEs for the ezetimibe/simvastatin and simvastatin monotherapy groups was also similar (12.2 vs. 11.9%), as was treatment-related laboratory AEs (6.2 vs. 5.3%), laboratory SAEs (0 vs. 0%), treatment-related laboratory SAEs (0 vs. 0%), discontinuations due to laboratory AEs (3.0 vs. 0.9%) and discontinuations due to treatment-related laboratory AEs (3.0 vs. 0.4%), respectively. There were no cases of myopathy, rhabdomyolysis, or serious hepatotoxicity observed in any group during this extension study.Conclusions: During this 48-week extension study, the coadministration of ezetimibe/simvastatin was generally as well tolerated as simvastatin monotherapy. The direct application of study observations to clinical practice is limited by patient selection criteria and dosage regime, which randomly applied relatively high doses rather than titration which often occurs in clinical practice.

Efficacy and Safety of Ezetimibe and Ezetimibe Plus Statin Therapy in Patients Aged Under 65, 65–74 and 75 Years and Older

Although the greatest burden of cardiovascular disease occurs after age 65 years, limited efficacy and safety data are available for cholesterol-lowering drugs in elderly patients. We undertook a pooled analysis of individual data from 13,282 patients aged 18–93 years in 16 published trials of ezetimibe and ezetimibe added on to or coadministered with a statin (ezetimibe/statin). Overall, ezetimibe reduced low-density lipoprotein cholesterol by 20% compared with placebo and ezetimibe/statin reduced low-density lipoprotein cholesterol by 17% compared with a statin alone, with consistent treatment effects across age groups (&lt;65, 65–74 and ≥75 years). Rates of any adverse or drug-related adverse events were also similar across age groups. We conclude that the lipid efficacy and safety of ezetimibe and ezetimibe/statin in those aged 65–74 and 75 years and older are similar to those observed in patients aged under 65 years.

Th-P16:277 Efficacy and safety of ezetimibe added to current therapy with statins in molecularly characterized Fh patients

Th-P16:277 Efficacy and safety of ezetimibe added to current therapy with statins in molecularly characterized Fh patients

Efficacy and safety of ezetimibe co-administered with ongoing atorvastatin therapy in achieving low-density lipoprotein goal in patients with hypercholesterolemia and coronary heart disease

This randomised, double-blind, placebo (PBO)-controlled study evaluated the efficacy and safety of ezetimibe (EZE) co-administered with ongoing atorvastatin (ATV) therapy in 450 hypercholesterolemic patients with coronary heart disease (CHD) who had not achieved their low-density lipoprotein cholesterol (LDL-C) goal < or =2.60 mmol/l while on a stable dose of ATV 10 or 20 mg/day for > or =6 weeks. After a 4-week diet/baseline active run-in period, patients with LDL-C >2.60 mmol/l and < or =4.20 mmol/l were stratified by ATV dose and randomised (1 : 1) to EZE 10 mg or PBO for 6 weeks while continuing open-label ATV. Significantly more patients achieved an LDL-C goal < or =2.6 mmol/l with EZE than PBO (81.3 vs. 21.8%; p < or = 0.001). Compared to PBO, co-administration of EZE with ongoing ATV led to significantly (p < or = 0.001) greater reductions in LDL-C, total cholesterol, triglycerides, non-high-density lipoprotein cholesterol (non-HDL-C), and apolipoprotein B; HDL-C was significantly (p < or = 0.05) increased. Co-administration of EZE and ATV was well tolerated, with an overall safety profile similar to ATV alone.

Ezetimibe plus simvastatin lowered lipid levels more than simvastatin monotherapy in primary hypercholesterolemia

Source Citation Goldberg AC, Sapre A, Liu J, Capece R, Mitchel YB. Efficacy and safety of ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia: a randomized, doub...

Efficacy and safety of ezetimibe co‐administered with simvastatin in thiazolidinedione‐treated type 2 diabetic patients

In patients with type 2 diabetes mellitus (T2DM), combination therapy is usually required to optimize glucose metabolism as well as to help patients achieve aggressive targets for low-density lipoprotein cholesterol (LDL-C) and other lipid parameters associated with cardiovascular risk. The thiazolidinediones (TZDs) are increasingly being used for both their blood glucose-lowering properties and their modest beneficial effects on triglycerides (TG) and high-density lipoprotein cholesterol (HDL-C). Ezetimibe, an intestinal cholesterol absorption inhibitor, has a mechanism of action that differs from that of statins, which inhibit hepatic cholesterol synthesis. We compared the lipid-modifying efficacy and safety of adding ezetimibe to simvastatin, vs. doubling the dose of simvastatin, in TZD-treated T2DM patients. This was a randomized, double-blind, parallel group, multicentre study in T2DM patients, 30-75 years of age, who had been on a stable dose of a TZD for at least 3 months and had LDL-C > 2.6 mmol/l (100 mg/dl) prior to study entry. Other antidiabetic medications were also allowed. Following 6 weeks of open-label simvastatin 20 mg/day, patients were randomized to the addition of either blinded ezetimibe 10 mg/day (n = 104) or an additional blinded simvastatin 20 mg/day (total simvastatin 40 mg/day; n = 110) for 24 weeks. Patients were stratified according to TZD type and dose (pioglitazone 15-30 vs. 45 mg/day; rosiglitazone 2-4 vs. 8 mg/day). LDL-C was reduced more (p < 0.001) by adding ezetimibe 10 mg to simvastatin 20 mg (-20.8%) than by doubling the dose of simvastatin to 40 mg (-0.3%). Ezetimibe plus simvastatin 20 mg also produced significant incremental reductions in non-HDL-C (p < 0.001), very low-density lipoprotein cholesterol (p < 0.05) and apolipoprotein B (p < 0.001) relative to simvastatin 40 mg. There were no differences between the groups with respect to changes in TG and HDL-C levels, and both treatments were well tolerated. Co-administration of ezetimibe with simvastatin, a dual inhibition treatment strategy targeting both cholesterol synthesis and absorption, is well tolerated and provides greater LDL-C-lowering efficacy than increasing the dose of simvastatin in T2DM patients taking TZDs.

Achieving lipoprotein goals in patients at high risk with severe hypercholesterolemia: Efficacy and safety of ezetimibe co-administered with atorvastatin

Background Despite the efficacy of statins in lowering low-density lipoprotein cholesterol (LDL-C) levels, many patients who are at high risk for heart disease with hypercholesterolemia require additional LDL-C level reduction. The cholesterol absorption inhibitor, ezetimibe, has been shown to provide significant incremental reductions in LDL-C levels when co-administered with statins. This study was performed to compare the efficacy and safety of ezetimibe (10 mg) plus response-based atorvastatin titration versus response-based atorvastatin titration alone in the attainment of LDL-C goals in subjects who are at high risk for coronary heart disease (CHD) and are not at their LDL-C goal on the starting dose of atorvastatin. Methods This was a 14-week, multicenter, randomized, double-blind, active-controlled study conducted in 113 clinical research centers in 21 countries. Participants were adults with heterozygous familial hypercholesterolemia (HeFH), CHD, or multiple (≥2) cardiovascular risk factors, and a LDL-C level ≥130 mg/dL after a 6- to10-week dietary stabilization and atorvastatin (10 mg/day) open-label run-in period. Eligible subjects continued to receive atorvastatin (10 mg) and were randomized to receive blinded treatment with ezetimibe (10 mg/day; n = 305) or an additional 10 mg/day of atorvastatin (n = 316). The atorvastatin dose in both groups was doubled after 4 weeks, 9 weeks, or both when the LDL-C level was not at its goal (≤100 mg/dL), so that patients receiving combined therapy could reach 40 mg/day and patients receiving atorvastatin alone could reach 80 mg/day. The primary end point was the proportion of subjects achieving their LDL-C level goal at week 14. A secondary end point was the change in LDL-C level and other lipid parameters at 4 weeks after ezetimibe co-administration with 10 mg/day of atorvastatin versus 20 mg/day of atorvastatin monotherapy. Results The proportion of subjects reaching their target LDL-C level goal of ≤100 mg/dL was significantly higher in the co-administration group than in the atorvastatin monotherapy group (22% vs 7%; P <.01). At 4 weeks, levels of LDL-C, triglycerides, and non-high-density lipoprotein cholesterol were reduced significantly more by combination therapy than by doubling the dose of atorvastatin (LDL-C −22.8% versus −8.6%; P <.01). The combination regimen had a safety and tolerability profile similar to that of atorvastatin alone. Conclusions The addition of ezetimibe to the starting dose of 10 mg/day of atorvastatin followed by response-based atorvastatin dose titration to a maximum of 40 mg/day provides a more effective means for reducing LDL-C levels in patients at high risk for CHD than continued doubling of atorvastatin as high as 80 mg/day alone.

1084-169 Efficacy and safety of ezetimibe coadministered with simvastatin versus simvastatin alone in thiazolidinedione-treated patients with type 2 diabetes mellitus

1084-169 Efficacy and safety of ezetimibe coadministered with simvastatin versus simvastatin alone in thiazolidinedione-treated patients with type 2 diabetes mellitus

Erratum to 'Efficacy and safety of ezetimibe coadministered with pravastatin in patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial' [European Heart Journal 2003; 24(8): 717–728

Erratum to 'Efficacy and safety of ezetimibe coadministered with pravastatin in patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial' [European Heart Journal 2003; 24(8): 717–728

Ezetimibe added to ongoing statin therapy reduced LDL cholesterol in primary hypercholesterolemia

Source Citation Gagne C, Bays HE, Weiss SR, et al. Efficacy and safety of ezetimibe added to ongoing statin therapy for treatment of patients with primary hypercholesterolemia. Am J Cardiol. 2002;9...

Efficacy and safety of a potent new selective cholesterol absorption inhibitor, ezetimibe, in patients with primary hypercholesterolemia

The efficacy and safety of ezetimibe, a new cholesterol absorption inhibitor, was evaluated in this randomized, double-blind, placebo-controlled trial of 892 patients with primary hypercholesterolemia. After ≥2 weeks on the National Cholesterol Education Program (NCEP) Step I or a stricter diet and a 4- to 8-week single-blind placebo lead-in, patients with low-density lipoprotein (LDL) cholesterol 130 to 250 mg/dl and triglycerides ≤350 mg/dl were randomized 3:1 to receive ezetimibe 10 mg or placebo orally each morning for 12 weeks. The primary efficacy end point was the percent reduction in direct plasma LDL cholesterol from baseline to end point. A total of 434 men and 458 women (ages 18 to 85 years) received randomized treatment (666 ezetimibe 10 mg, 226 placebo). Demographics and baseline characteristics were similar between treatment groups. Ezetimibe significantly reduced direct LDL cholesterol by a mean of 16.9%, compared with an increase of 0.4% with placebo (p <0.01). Subgroup analysis indicated that response to ezetimibe was generally consistent across all subgroups, regardless of risk-factor status, gender, age, race, or baseline lipid profile. Ezetimibe effects on LDL cholesterol occurred early (2 weeks) and persisted throughout the 12-week treatment period. Compared with placebo, ezetimibe 10 mg also significantly improved calculated LDL cholesterol, apolipoprotein B, total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, and HDL 3 cholesterol (p <0.01). Ezetimibe was well tolerated. There were no differences in laboratory or clinical safety parameters, or gastrointestinal, liver, or muscle side effects from that of placebo. Ezetimibe 10 mg/day is well tolerated, reduces LDL cholesterol approximately 17%, and improves other key lipid parameters.