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.     

The effects of atorvastatin and rosuvastatin on oxidative stress in diabetic patients

Aim

Diabetes is associated with abnormalities in lipid profile and increased oxidative stress. Statins are preferred agents in diabetic patients due to their antioxidant and LDL-C lowering effects. This study is designed to compare the effects of atorvastatin and rosuvastatin on low density lipoprotein cholesterol (LDL-C), lipid hydroperoxide (LOOH), total oxidant status (TOS) and total antioxidant capacity (TAC) in diabetic patients with hyperlipidemia.

Materials and methods

Sixty two patients who have type 2 diabetes mellitus with serum LDL levels more than 100 mg/dL were randomly assigned to receive atorvastatin 20 mg (n = 31) or rosuvastatin 10 mg (n = 31). Blood tests were performed at the beginning of the study and after three months.

Results

There were no statistically significant differences in the pre- and after treatment levels of the LDL-C between groups. TAC values were increased in both groups and statistically significant in the former group (p = 0.007). There was no diferrence between the change percentages ((after treatment TAC − pretreatment TAC) / pretreatment level) of TAC between two treatment groups. The effects of two drugs on the other oxidative parameters were not significantly different.

Conclusion

Both atorvastatin and rosuvastatin may be helpful in reducing increased oxidative stress in diabetic patients with hyperlipidemia.     

Ezetimibe added to atorvastatin compared with doubling the atorvastatin dose in patients at high risk for coronary heart disease with diabetes mellitus,metabolic syndrome or neither

Aim: Type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS) are both associated with increased risk for atherosclerotic coronary heart disease (CHD). Thus, it is useful to know the relative efficacy of lipid‐altering drugs in these patient populations. Methods: A double‐blind, parallel group trial of adult patients with hypercholesterolaemia at high‐CHD risk receiving atorvastatin 40 mg/day compared atorvastatin 40 mg plus ezetimibe 10 mg (ezetimibe) vs. doubling atorvastatin to 80 mg. This post hoc analysis reports lipid efficacy results in patients grouped by diagnosis of T2DM, MetS without T2DM or neither. Per cent change from baseline at week 6 was assessed for LDL‐C, total cholesterol, HDL‐C , non‐HDL‐C , Apo A‐I, Apo B and triglycerides. Safety was monitored through clinical and laboratory adverse events (AEs). Results: Compared with doubling atorvastatin, atorvastatin plus ezetimibe resulted in greater reductions in LDL‐C, triglycerides, Apo B, non‐HDL‐C, total cholesterol and lipid ratios in the T2DM, MetS and neither groups. Treatment effects were of similar magnitude across patient groups with both treatments, except triglycerides, which were slightly greater in the T2DM and MetS groups vs. neither group. Changes in HDL‐C , Apo A‐I and high sensitivity C‐reactive protein (hs‐CRP) were comparable for both treatments in all three groups. Safety and tolerability profiles were generally similar between treatments and across patient groups, as were the incidence of liver and muscle AEs. Conclusions: Compared with doubling atorvastatin to 80 mg, addition of ezetimibe to atorvastatin 40 mg produced greater improvements in multiple lipid parameters in high‐CHD risk patients with T2DM, MetS or neither, consistent with the significantly greater changes observed in the full study cohort (clinical trial # NCT00276484).     

Efficacy and safety of ezetimibe coadministered with atorvastatin or simvastatin in patients with homozygous familial hypercholesterolemia

BACKGROUND: Patients with homozygous familial hypercholesterolemia (HoFH) have a high incidence of cardiovascular morbidity and mortality from premature atherosclerosis, and the efficacy of pharmacological therapy has been limited. We evaluated the efficacy, safety, and tolerability of ezetimibe, a novel cholesterol absorption inhibitor, in a multicenter, double-blind, randomized trial of HoFH patients receiving atorvastatin or simvastatin. Methods and Results- Fifty patients with a diagnosis of HoFH on the National Cholesterol Education Program Step 1 or stricter diet and taking open-label atorvastatin 40 mg/d or simvastatin 40 mg/d (statin-40) with (n=25) or without (n=25) concomitant LDL apheresis were randomized to 1 of 3 double-blind treatments: atorvastatin or simvastatin 80 mg/d (statin-80, n=17); ezetimibe 10 mg/d plus atorvastatin or simvastatin 40 mg/d (n=16); or ezetimibe 10 mg/d plus atorvastatin or simvastatin 80 mg/d (n=17) for 12 weeks. The primary end point was mean percentage change in LDL cholesterol (LDL-C) from statin-40 baseline to the end point for patients receiving statins alone (statin-80) versus patients receiving ezetimibe plus atorvastatin or simvastatin at either dose (ezetimibe plus statin-40/80). Ezetimibe plus statin-40/80 significantly reduced LDL-C levels compared with statin-80 (-20.7% versus -6.7%, P=0.007). In the high-dose statin cohorts, ezetimibe plus statin-80 reduced LDL-C by an additional 20.5% (P=0.0001) versus statin-80. Similar significant reductions in LDL-C concentrations were observed for patients with genotype-confirmed HoFH (n=35). Ezetimibe was safe and well tolerated. CONCLUSIONS: Ezetimibe coadministered with atorvastatin or simvastatin in patients with HoFH produced clinically important LDL-C reductions compared with best current therapy. Ezetimibe provides a new, complementary pharmacological approach for this high-risk population.     

The achievement of target cholesterol level differs between coronary heart disease and diabetic patients

Background

Guidelines recommend that LDL-C level should be < 100 mg/dl among diabetes mellitus (DM) and coronary heart disease (CHD) patients.

Objective

To evaluate how patients with DM and CHD differ in attaining the target level and to examine the association between goal achievement, demographic and clinical parameters.

Methods

The study was conducted in Maccabi Healthcare Services, the second largest health maintenance organization in Israel. All patients with DM (n = 54,261), CHD (n = 24,083) or DM and CHD (n = 15,370) who were listed in the computerized database and had at least one LDL-C level measurement between January 1, 2007 and July 15, 2008 were eligible. The percentage of patients who attained LDL-C level < 100 mg/dl and its association with demographic and clinical parameters were analyzed.

Results

The rate of reaching the LDL-C target level was higher among the CHD and CHD and DM patients than DM ones (67% vs. 57% vs. 50%, p < 0.001, respectively). Male gender; 5th socioeconomic status quintile; underlying disease i.e. CHD, CHD and DM; high statins compliance; and revascularization by percutaneous coronary intervention predicted for reaching target level. DM; absence of renal function evaluation; hospitalizations; HbA1C > 7% or missing its measurements had a negative predictive value.

Conclusions

The rate of reaching LDL-C target level should be increased in all high risk patients, mainly diabetic ones. Efforts should include educational programs to physicians and patients regarding the importance, the need to adhere and to intensify the cholesterol lowering treatment.     

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 > or =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 < or =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.     

Treatment of high-risk patients with ezetimibe plus simvastatin co-administration versus simvastatin alone to attain National Cholesterol Education Program Adult Treatment Panel III low-density lipoprotein cholesterol goals

This study assessed whether the co-administration of ezetimibe and simvastatin would be more effective than simvastatin monotherapy in allowing high-risk patients to achieve a low-density lipoprotein (LDL) cholesterol goal of <100 mg/dl. Men and women with LDL cholesterol ≥130 mg/dl and meeting National Cholesterol Education Program Adult Treatment Panel III criteria for coronary heart disease (CHD) or CHD risk equivalent were randomized to 1 of 4 daily treatments for 23 weeks: simvastatin 20 mg (n = 253), ezetimibe 10 mg plus simvastatin 10 mg (n = 251), ezetimibe 10 mg plus simvastatin 20 mg (n = 109), and ezetimibe 10 mg plus simvastatin 40 mg (n = 97). In all groups, patients not at goal had their simvastatin doses doubled at weeks 6, 12, and/or 18, up to a maximum of 80 mg. The primary efficacy objective was LDL cholesterol goal attainment (<100 mg/dl) after 5 weeks of treatment. Ezetimibe plus any dose of simvastatin produced greater reductions in LDL cholesterol and allowed more patients to achieve goal after 5 weeks (p <0.001) and at the end of the study (p <0.001) than simvastatin 20 mg alone. At 5 weeks, 75%, 83%, and 87% of patients receiving ezetimibe plus simvastatin 10, 20, and 40 mg had LDL cholesterol <100 mg/dl compared with 46% of patients receiving simvastatin 20 mg. In patients who started on ezetimibe plus simvastatin 10, 20 and 40 mg, 33%, 22%, and 12%, respectively, required simvastatin titration during the study compared with 68% of patients who started on simvastatin 20 mg. The corresponding median simvastatin doses used were 10, 20, 40, and 40 mg, respectively. Ezetimibe plus simvastatin was well tolerated, with an overall safety profile similar to that of simvastatin monotherapy. Thus, through the dual inhibition of cholesterol absorption and synthesis, ezetimibe plus simvastatin allowed more patients to reach LDL cholesterol <100 mg/dl at a lower simvastatin dose and with fewer dose titrations than simvastatin monotherapy.     

Comparison of effects of ezetimibe/simvastatin versus simvastatin versus atorvastatin in reducing C-reactive protein and low-density lipoprotein cholesterol levels

The lowering effects of ezetimibe/simvastatin combination therapy on low-density lipoprotein (LDL) cholesterol and high-sensitivity C-reactive protein (CRP) were compared with those of simvastatin or atorvastatin monotherapy in a large cohort of patients with primary hypercholesterolemia. To compare ezetimibe/simvastatin with simvastatin, data were combined from 3 identical, prospective 12-week trials in which patients were randomized to receive placebo; ezetimibe 10 mg; ezetimibe 10 mg added to simvastatin 10, 20, 40, or 80 mg; or simvastatin 10, 20, 40, or 80 mg. To compare ezetimibe/simvastatin with atorvastatin, data were analyzed from a phase III double-blind, active-controlled study in which patients were randomized equally to receive ezetimibe/simvastatin 10/10, 10/20, 10/40, or 10/80 mg or atorvastatin 10, 20, 40, or 80 mg for 6 weeks. When averaged across doses, ezetimibe/simvastatin produced significantly greater reductions compared with simvastatin alone in LDL cholesterol (52.5% vs 38.0%, respectively) and CRP levels (31.0% vs 14.3%, respectively). At each individual simvastatin dose, co-administration with ezetimibe produced significant further CRP reductions versus simvastatin alone. Ezetimibe/simvastatin was significantly more effective at lowering LDL cholesterol than atorvastatin when pooled across doses (53.4% vs 45.3%, respectively) and in each milligram-equivalent dose comparison. Reductions in CRP of similar magnitude were observed with ezetimibe/simvastatin and atorvastatin when averaged across doses and at each milligram-equivalent statin dose comparison. In conclusion, the lipid-modulating and anti-inflammatory effects of ezetimibe/simvastatin provide additional benefits not realized by statin monotherapy alone.     

Vascular basis for the treatment of myocardial ischemia study: trial design and baseline characteristics

Background

Increased low-density lipoprotein (LDL) and oxidized LDL cholesterol levels adversely affect endothelial function in patients with stable coronary artery disease (CAD). Statin drugs are efficacious in primary and secondary prevention of clinical CAD events, but they have not been extensively studied as a treatment for ischemia during routine daily activities or during exercise, indicators of high-risk in patients with stable CAD. The purpose of the Vascular Basis for the Treatment of Myocardial Ischemia study is to determine whether aggressive lowering of LDL cholesterol level with atorvastatin, with or without supplemental antioxidant vitamins C and E, can improve endothelial function and ischemia during ambulatory electrocardiogram (AECG) monitoring and exercise treadmill testing (ETT).

Methods

Patients are eligible when they have ischemia during an ETT and AECG monitoring and when their fasting total cholesterol level is ≤250 mg/dL. Eligible patients are randomized to receive 1 of 3 treatments: intensive atorvastatin to reduce LDL cholesterol level to ≤80 mg/dL, intensive atorvastatin to reduce LDL cholesterol level to ≤80 mg/dL plus antioxidant vitamins C and E, and control of diet and low-dose lovastatin, when needed, to reduce LDL cholesterol level ≤ to 130 mg/dL. Patients undergo endothelial function testing, 48-hour AECG monitoring, and ETT at randomization and at 6 and 12 months.

Results

A total of 300 patients have been randomized: 101 to receive atorvastatin alone, 103 to receive atorvastatin plus antioxidant vitamins, and 96 to receive placebo. Baseline characteristics are similar across treatment groups.

Conclusions

The Vascular Basis study will provide important insight on the effects of aggressive management of dyslipidemia with statin drugs and antioxidant vitamins in patients with stable but high-risk CAD.     

Efficacy and safety of ezetimibe coadministered with lovastatin in primary hypercholesterolemia

This multicenter, randomized, double-blind, placebo-controlled clinical study assessed the efficacy and safety of ezetimibe administered with lovastatin in primary hypercholesterolemia. After dietary stabilization, a 2- to 12-week washout period, and a 4-week single-blind placebo lead-in period, 548 patients with low-density lipoprotein (LDL) cholesterol > or =145 mg/dl (3.75 mmol/L) and < or =250 mg/dl (6.47 mmol/L) and triglycerides < or =350 mg/dl (3.99 mmol/L) were randomized to one of the following, administered daily for 12 weeks: ezetimibe 10 mg; lovastatin 10, 20, or 40 mg; ezetimibe 10 mg plus lovastatin 10, 20, or 40 mg; or placebo. The primary efficacy variable was percentage decrease in direct LDL cholesterol from baseline to end point for pooled ezetimibe plus lovastatin versus pooled lovastatin alone. Ezetimibe plus lovastatin significantly improved concentrations of LDL cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides compared with lovastatin alone (p <0.01). The coadministration of ezetimibe provided an incremental 14% LDL cholesterol decrease, a 5% HDL cholesterol increase, and a 10% decrease in triglycerides compared with pooled lovastatin alone. Ezetimibe plus lovastatin provided mean LDL cholesterol decreases of 33% to 45%, median triglyceride decreases of 19% to 27%, and mean HDL cholesterol increases of 8% to 9%, depending on the statin dose. The coadministration of ezetimibe 10 mg plus the starting dose of lovastatin (10 mg) provided comparable efficacy to high-dose lovastatin (40 mg) across the lipid profile (LDL cholesterol, HDL cholesterol, and triglycerides). Ezetimibe plus lovastatin was well tolerated, with a safety profile similar to both lovastatin alone and placebo. The coadministration of ezetimibe and lovastatin may offer a new treatment option in lipid management of patients with hypercholesterolemia.     

Efficacy and safety of ezetimibe co-administered with simvastatin compared with atorvastatin in adults with hypercholesterolemia

This study compared the efficacy and safety of co-administered ezetimibe + simvastatin with atorvastatin monotherapy in adults with hypercholesterolemia. Seven hundred eighty-eight patients were randomized 1:1:1 to 3 treatment groups; each group was force-titrated over four 6-week treatment periods: (1) 10 mg of atorvastatin as the initial dose was titrated to 20, 40, and 80 mg; (2) co-administration of 10 mg of ezetimibe and 10 mg of simvastatin (10/10 mg) was titrated to 10/20, 10/40, and 10/80 mg of ezetimibe + simvastatin; and (3) co-administration of 10/20 mg of ezetimibe + simvastatin was titrated to 10/40 mg (for 2 treatment periods) and 10/80 mg of ezetimibe + simvastatin. Key efficacy measures included percent changes in low-density lipoprotein cholesterol (LDL) and high-density lipoprotein cholesterol (HDL) from baseline to the ends of (1) treatment periods 1 and 2 (for LDL cholesterol) comparing co-administration of 10/20 mg and 10/10 mg of ezetimibe + simvastatin with 10 mg of atorvastatin and (2) treatment period 4 (for LDL cholesterol and HDL cholesterol) comparing co-administration of 10/80 mg of ezetimibe + simvastatin with 80 mg of atorvastatin. Baseline LDL and HDL cholesterol levels were comparable between treatment groups. At the end of treatment period 1, the mean decrease of LDL cholesterol was significantly (p ≤0.001) greater for co-administration of 10/10 mg and 10/20 mg of ezetimibe + simvastatin than for 10 mg of atorvastatin. At the end of treatment period 4 and after comparing maximum doses, co-administration of 10/80 mg of ezetimibe + simvastatin was superior to 80 mg of atorvastatin in the percent LDL cholesterol decrease (−59.4% vs −52.5%, p <0.001) and HDL cholesterol increase (12.3% vs 6.5%; p <0.001). All treatments were well tolerated. Thus, a greater LDL cholesterol decrease and HDL cholesterol increase were attained by treating patients with co-administration of ezetimibe and simvastatin than with atorvastatin.     

Safety and efficacy of ezetimibe added on to rosuvastatin 5 or 10 mg versus up-titration of rosuvastatin in patients with hypercholesterolemia (the ACTE Study)

The present multicenter, 6-week, randomized, double-blind, parallel-group, clinical trial evaluated the safety and efficacy of ezetimibe (10 mg) added to stable rosuvastatin therapy versus up-titration of rosuvastatin from 5 to 10 mg or from 10 to 20 mg. The study population included 440 subjects at moderately high/high risk of coronary heart disease with low-density lipoprotein (LDL) cholesterol levels higher than the National Cholesterol Education Program Adult Treatment Panel III recommendations (<100 mg/dl for moderately high/high-risk subjects without atherosclerotic vascular disease or <70 mg/dl for high-risk subjects with atherosclerotic vascular disease). Pooled data demonstrated that ezetimibe added to stable rosuvastatin 5 mg or 10 mg reduced LDL cholesterol by 21%. In contrast, doubling rosuvastatin to 10 mg or 20 mg reduced LDL cholesterol by 5.7% (between-group difference of 15.2%, p <0.001). Individually, ezetimibe plus rosuvastatin 5 mg reduced LDL cholesterol more than did rosuvastatin 10 mg (12.3% difference, p <0.001), and ezetimibe plus rosuvastatin 10 mg reduced LDL cholesterol more than did rosuvastatin 20 mg (17.5% difference, p <0.001). Compared to rosuvastatin up-titration, ezetimibe add-on achieved significantly greater attainment of LDL cholesterol levels of <70 or <100 mg/dl (59.4% vs 30.9%, p <0.001), and <70 mg/dl in all subjects (43.8% vs 17.5%, p <0.001); produced significantly greater reductions in total cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B (p <0.001); and resulted in similar effects on other lipid parameters. Adverse experiences were generally comparable among the groups. In conclusion, compared to up-titration doubling of the rosuvastatin dose, ezetimibe 10 mg added to stable rosuvastatin 5 mg or 10 mg produced greater improvements in many lipid parameters and achieved greater attainment of the National Cholesterol Education Program Adult Treatment Panel III recommended LDL cholesterol targets in subjects with elevated LDL cholesterol and at moderately high/high coronary heart disease risk.     

Incremental Lowering of Low-Density Lipoprotein Cholesterol With Ezetimibe 20 mg vs 10 mg Daily in Patients Receiving Concomitant Statin Therapy

Background

Ezetimibe is typically administered at a dose of 10 mg daily, with few reports of use at other doses. We compared plasma concentrations of low-density lipoprotein (LDL) cholesterol and other lipid variables in patients with dyslipidemia who were receiving ezetimibe 10 mg and then 20 mg daily.

Methods

A retrospective chart review identified 27 patients who received ezetimibe 10 mg and then 20 mg daily at different times; 15 participants were receiving stable statin therapy and 12 were not receiving concomitant statins. Plasma concentrations of lipids, creatine kinase (CK), and aspartate transaminase (AST) were determined. Plasma concentrations of ezetimibe and ezetimibe glucuronide were measured in a second group of patients.

Results

Patients taking statins and ezetimibe 20 mg had further reductions in total and LDL cholesterol of 7.1% and 10.3%, respectively (both P < 0.05) than did those receiving the 10-mg dose. No difference between 20-mg and 10-mg dosing was seen among patients not receiving statins. Plasma concentrations of ezetimibe and its active metabolite were about 2-fold higher (P < 0.05) in patients taking ezetimibe 20 mg than in those receiving 10 mg daily. All patients tolerated ezetimibe 20 mg without side effects.

Conclusions

Ezetimibe 20 mg daily reduced total and LDL cholesterol further in patients receiving statin therapy compared with 10 mg daily. Prospective studies are required to show whether the higher plasma levels of ezetimibe and its active metabolite in patients taking the 20-mg dose have any detrimental effects. Increasing the ezetimibe dose to 20 mg daily might be an interesting potential approach for patients who fail to reach lipid targets on ezetimibe 10 mg daily along with maximally tolerated doses of statin.     

Diabetes and Coronary Heart Disease as Risk Factors for Mortality in Older Adults

Background

Type 2 diabetes has been described as a coronary heart disease (CHD) “risk equivalent.” We tested whether cardiovascular and all-cause mortality rates were similar between participants with prevalent CHD vs diabetes in an older adult population in whom both glucose disorders and preexisting atherosclerosis are common.

Methods

The Cardiovascular Health Study is a longitudinal study of men and women (n = 5784) aged ≥65 years at baseline who were followed from baseline (1989/1992-1993) through 2005 for mortality. Diabetes was defined by fasting plasma glucose ≥7.0 mmol/L or use of diabetes control medications. Prevalent CHD was determined by confirmed history of myocardial infarction, angina, or coronary revascularization.

Results

Following multivariable adjustment for other cardiovascular disease risk factors and subclinical atherosclerosis, CHD mortality risk was similar between participants with CHD alone vs diabetes alone (hazard ratio [HR] 1.04, 95% confidence interval [CI], 0.83-1.30). The proportion of mortality attributable to prevalent diabetes (population-attributable risk percent = 8.4%) and prevalent CHD (6.7%) was similar in women, but the proportion of mortality attributable to CHD (16.5%) as compared with diabetes (6.4%) was markedly higher in men. Patterns were similar for cardiovascular disease mortality. By contrast, the adjusted relative hazard of total mortality was lower among participants with CHD alone (HR 0.85, 95% CI, 0.75-0.96) as compared with those who had diabetes alone.

Conclusions

Among older adults, diabetes alone confers a risk for cardiovascular mortality similar to that from established clinical CHD. The public health burden of both diabetes and CHD is substantial, particularly among women.     

Monotherapy with the PCSK9 inhibitor alirocumab versus ezetimibe in patients with hypercholesterolemia: Results of a 24 week,double-blind,randomized Phase 3 trial

Background

Efficacy and safety of alirocumab were compared with ezetimibe in hypercholesterolemic patients at moderate cardiovascular risk not receiving statins or other lipid-lowering therapy.

Methods

In a Phase 3, randomized, double-blind, double-dummy study (NCT01644474), patients (low-density lipoprotein cholesterol [LDL-C] 100–190 mg/dL, 10-year risk of fatal cardiovascular events ≥ 1%–<5% [systemic coronary risk estimation]) were randomized to ezetimibe 10 mg/day (n = 51) or alirocumab 75 mg subcutaneously (via 1­mL autoinjector) every 2 weeks (Q2W) (n = 52), with dose up-titrated to 150 mg Q2W (also 1 mL) at week 12 if week 8 LDL-C was ≥ 70 mg/dL. Primary endpoint was mean LDL-C % change from baseline to 24 weeks, analyzed using all available data (intent-to-treat approach, ITT). Analyses using on-treatment LDL-C values were also conducted.

Results

Mean (SD) baseline LDL-C levels were 141.1 (27.1) mg/dL (alirocumab) and 138.3 (24.5) mg/dL (ezetimibe). The 24-week treatment period was completed by 85% of alirocumab and 86% of ezetimibe patients. Least squares mean (SE) LDL-C reductions were 47 (3)% with alirocumab versus 16 (3)% with ezetimibe (ITT; p < 0.0001) and 54 (2)% versus 17 (2)% (on-treatment; p < 0.0001). At week 12, before up-titration, alirocumab 75 mg Q2W reduced LDL-C by 53 (2)% (on-treatment). Injection site reactions were infrequent (< 2% and < 4% of alirocumab and ezetimibe patients, respectively).

Conclusions

Alirocumab demonstrated significantly greater LDL-C lowering versus ezetimibe after 24 weeks with the lower 75 mg Q2W dose sufficient to provide ≥ 50% LDL-C reduction in the majority of the patients. Adverse events were comparable between groups.     

Effect of ezetimibe/simvastatin compared with atorvastatin on lipoprotein subclasses in patients with type 2 diabetes and hypercholesterolaemia

Aim: To evaluate the effects of the usual starting and next higher doses of ezetimibe/simvastatin and atorvastatin on the cholesterol content of lipoprotein subclasses in patients with type 2 diabetes and hypercholesterolaemia. Methods: This post hoc analysis compared the effects of treatment with ezetimibe/simvastatin 10/20 mg vs. atorvastatin 10 and 20 mg/day and ezetimibe/simvastatin 10/40 mg/day vs. atorvastatin 40 mg/day on the cholesterol content of lipoprotein subclasses in the modified intent‐to‐treat (mITT) population (n = 1013) and in subgroups of patients with triglyceride (TG) levels <200 mg/dl (n = 600) and ≥200 mg/dl (2.6 mmol/l) (n = 413). Results: Ezetimibe/simvastatin significantly reduced low‐density lipoprotein cholesterol (LDL‐C) subclasses LDL₁‐C, LDL₂‐C and LDL₃‐C; real LDL‐C (LDL‐C^r); intermediate‐density lipoprotein cholesterol (IDL‐C), IDL₁‐C, IDL₂‐C; very low‐density lipoprotein cholesterol (VLDL‐C), VLDL₃‐C; and remnant‐like lipoprotein cholesterol (RLP‐C) from baseline more than atorvastatin at all dose comparisons (p < 0.01) in the mITT population. Significant improvements were also observed in high‐density lipoprotein cholesterol (HDL‐C) subclass HDL₃‐C at the ezetimibe/simvastatin 10/20 mg vs. atorvastatin 20 mg and highest dose comparisons (p < 0.001) and in VLDL_{1 + 2}‐C at the lowest and highest dose comparisons (p < 0.001). Changes in LDL₄‐C and LDL‐C subclass patterns (A, B and I) were comparable for both treatments. Generally, similar results were observed for patients with TG levels <200 and ≥200 mg/dl (2.3 mmol). For both treatments, notable differences between TG subgroups were that patients with elevated TGs had smaller reductions in LDL₂‐C, slightly smaller decreases in all IDL subclasses and greater decreases in all VLDL‐C subclasses than those with lower TG levels. Frequency of pattern B was also reduced more in patients with higher TGs for both treatments. Conclusions: Ezetimibe/simvastatin reduced the cholesterol content of most lipoprotein subclasses from baseline with generally similar efficacy in patients with low and high TGs. Despite the different mechanism of action of ezetimibe, the response to ezetimibe/simvastatin and atorvastatin treatment related to these lipoprotein subclasses was generally consistent with the overall effects of these therapies on the major lipid/lipoprotein classes. The clinical significance of these results awaits further study.     

Ezetimibe: A First‐in‐Class,Novel Cholesterol Absorption Inhibitor

Significant numbers of patients at risk for coronary heart disease (CHD) fail to reach National Cholesterol Education Program (NCEP)‐designated low density lipoprotein cholesterol (LDL‐C) goals in spite of the wide range of currently available treatments, including combination therapies. Ezetimibe, the first in a class of novel cholesterol absorption inhibitors, demonstrated lipid‐lowering and antiatherosclerotic activity in experimental and clinical hypercholesterolemia. Studies in hypercholesterolemic dogs showed that ezetimibe coadministered with statins caused greater lipid‐lowering effects compared to either drug alone. These effects were confirmed in clinical studies of patients with primary hypercholesterolemia where initiation of treatment with ezetimibe plus a statin, or addition of ezetimibe to ongoing statin therapy, produced significant incremental reductions in LDL‐C, as well as incremental increases in high‐density lipoprotein cholesterol (HDL‐C) and reductions in triglyceride levels. Combination therapy also significantly increased the number of patients attaining LDL‐C goal at the end of treatment, compared to statin monotherapy. In studies using simvastatin, atorvastatin, pravastatin, and lovastatin, addition of ezetimibe to low dose statin was as effective as a 2‐ to 3‐fold upward titration of the corresponding statin dose. Ezetimibe‐statin combination therapy provided similar improvements in patients with primary hypercholesterolemia, as well as with heterozygous and homozygous familial hypercholesterolemia. Ezetimibe monotherapy effectively reduced plasma campesterol and sitosterol in patients with homozygous sitosterolemia. Clinical studies showed that ezetimibe was well tolerated, with a safety profile comparable to placebo when administered as monotherapy and comparable to statin alone when coadministered with a statin. These data provide strong evidence that, through their complementary lipid‐lowering mechanisms, ezetimibe coadministered with a statin offers an effective combination treatment option for patients with hypercholesterolemia, including those with genetically inherited disease.     

Effectiveness of ezetimibe alone or in combination with twice a week Atorvastatin (10 mg) for statin intolerant high-risk patients

This study was undertaken to investigate the effect of ezetimibe (10 mg/day) alone or in combination with atorvastatin (10 mg twice a week) on hypercholesterolemia in 56 high-risk patients intolerant to daily statin use. Ezetimibe monotherapy was well tolerated (2 withdrawals) and induced a mean reduction in low-density lipoprotein (LDL) cholesterol of 20% (p <0.05) at the third month. However, of the 54 patients still taking ezetimibe, only 5 (9%) were at their LDL cholesterol targets. Atorvastatin 10 mg twice a week was then added to ezetimibe and was well tolerated (3 withdrawals). This combination reduced LDL cholesterol (in a treatment-based analysis) by 37% compared with baseline (p <0.001), with 43 (84%) patients reaching their LDL cholesterol goals. When patients (n = 34, 25 men) with baseline serum creatinine values in the upper 2 tertiles were analyzed separately, there was a significant (p = 0.041) decrease in serum creatinine levels after 6 months of treatment. In conclusion, the combination of ezetimibe plus atorvastatin 10 mg twice a week might be a therapeutic option for high-risk patients intolerant to daily statin monotherapy.     

Efficacy and safety of rosuvastatin and atorvastatin in patients with hypercholesterolemia and a high risk of coronary heart disease: a randomized, controlled trial

Background

This double-blind, multicenter, randomized trial compared rosuvastatin and atorvastatin for reducing low-density lipoprotein cholesterol (LDL-C) in adults with hypercholesterolemia and a high risk of coronary heart disease.

Methods

After a 6-week dietary lead-in period, patients with LDL-C levels ≥160 and <250 mg/dL and triglyceride levels ≤400 mg/dL were randomly assigned to 24 weeks' treatment in 1 of 3 groups, each with forced dose titrations at 12 and 18 weeks. Starting and titrated doses for each group were rosuvastatin 5, 20, and 80 mg (n = 127); rosuvastatin 10, 40, and 80 mg (n = 128); and atorvastatin 10, 40, and 80 mg (n = 128).

Results

At 24 weeks, LDL-C was reduced significantly more with 80 mg rosuvastatin (combined rosuvastatin group) than with atorvastatin 80 mg (60% vs 52% [P < .001]). At 12 weeks, rosuvastatin 5 and 10 mg reduced LDL-C significantly more than atorvastatin 10 mg (40% [P < .01], 47% [P < .001] vs 35%). At 18 weeks, LDL-C reductions were also significantly greater in both rosuvastatin groups than in the atorvastatin group (52% [P < .01], 59% [P < .001] vs 47%). Consequently, more patients receiving rosuvastatin achieved LDL-C goals. Total cholesterol, high-density lipoprotein cholesterol (HDL-C), non-HDL-C, apolipoproteins B and A-I, and all lipid ratios were more favorably modified by rosuvastatin at 24 weeks (P < .01). Effects of the 2 agents on triglycerides were similar.

Conclusions

Rosuvastatin was more efficacious than atorvastatin in modifying lipids in patients with hypercholesterolemia and a high coronary heart disease risk.     

Treatment with ezetimibe plus low-dose atorvastatin compared with higher-dose atorvastatin alone: is sufficient cholesterol-lowering enough to inhibit platelets?

OBJECTIVES: We sought to test the platelet inhibitory and anti-inflammatory effects of a higher statin dosage compared with combined treatment with ezetimibe plus a low statin dose. BACKGROUND: Reducing the level of low-density lipoprotein cholesterol (LDL-C) with statins induces important pleiotropic effects such as platelet inhibition. An insufficient LDL-C reduction often is treated with ezetimibe, an intestinal cholesterol absorption inhibitor, in combination with a low statin dose. It is not known whether this combination therapy has the same pleiotropic effects as a statin monotherapy. METHODS: Fifty-six patients with coronary artery disease were assigned randomly to receive either 40 mg/day of atorvastatin or 10 mg/day of ezetimibe plus 10 mg/day of atorvastatin for 4 weeks. The levels of LDL-C, platelet activation markers after stimulation, platelet aggregation, and plasma chemokine levels (i.e., regulated on activation normally T-cell expressed and secreted [RANTES]) were measured before and after changing lipid-lowering medication. RESULTS: Platelet activation markers (P-selectin) after stimulation (adenosine diphosphate) were reduced by 40 mg/day of atorvastatin (-5.2 +/- 1.6 arbitrary units) but not by ezetimibe plus low-dose atorvastatin (2.1 +/- 1.8 arbitrary units; p < 0.005) despite a similar reduction of LDL-C (atorvastatin -1.01 +/- 0.18 mmol/l vs. ezetimibe plus atorvastatin -1.36 +/- 0.22 mmol/l, p = NS). Thrombin receptor-activating peptide-induced platelet aggregation as well as plasma RANTES levels were reduced by 40 mg/day of atorvastatin but not by ezetimibe plus low-dose atorvastatin. CONCLUSIONS: Platelet reactivity and a proinflammatory chemokine were reduced more by the higher atorvastatin dose than by ezetimibe plus low-dose atorvastatin. In patients with coronary artery disease, it might be important to combine ezetimibe with higher statin dosages to benefit from cholesterol-independent pleiotropic effects.