High-dose simvastatin exhibits enhanced lipid-lowering effects relative to simvastatin/ezetimibe combination therapy.

Statins are the frontline in cholesterol reduction therapies; however, their use in combination with agents that possess complimentary mechanisms of action may achieve further reductions in low-density lipoprotein cholesterol. Thirty-nine patients were treated with either 80 mg simvastatin (n=20) or 10 mg simvastatin plus 10 mg ezetimibe (n=19) for 6 weeks. Dosing was designed to produce comparable low-density lipoprotein cholesterol reductions, while enabling assessment of potential simvastatin-associated pleiotropic effects. Baseline and post-treatment plasma were analyzed for lipid mediators (eg, eicosanoids and endocannabinoids) and structural lipids by liquid chromatography tandem mass spectrometry. After statistical analysis and orthogonal projections to latent structures multivariate modeling, no changes were observed in lipid mediator levels, whereas global structural lipids were reduced in response to both monotherapy (R(2)Y=0.74; Q(2)=0.66; cross-validated ANOVA P=7.0×10(-8)) and combination therapy (R(2)Y=0.67; Q(2)=0.54; cross-validated ANOVA P=2.6×10(-5)). Orthogonal projections to latent structures modeling identified a subset of 12 lipids that classified the 2 treatment groups after 6 weeks (R(2)Y=0.65; Q(2)=0.61; cross-validated ANOVA P=5.4×10(-8)). Decreases in the lipid species phosphatidylcholine (15:0/18:2) and hexosyl-ceramide (d18:1/24:0) were the strongest discriminators of low-density lipoprotein cholesterol reductions for both treatment groups (q<0.00005), whereas phosphatidylethanolamine (36:3e) contributed most to distinguishing treatment groups (q=0.017). Shifts in lipid composition were similar for high-dose simvastatin and simvastatin/ezetimibe combination therapy, but the magnitude of the reduction was linked to simvastatin dosage. Simvastatin therapy did not affect circulating levels of lipid mediators, suggesting that pleiotropic effects are not associated with eicosanoid production. Only high-dose simvastatin reduced the relative proportion of sphingomyelin and ceramide to phosphatidylcholine (q=0.008), suggesting a pleiotropic effect previously associated with a reduced risk of cardiovascular disease.

[Effects of different statins, ezetimibe/simvastatin combination on hsCRP levels in unstable angina pectoris and non-ST elevation myocardial infarction patients: a randomized trial]. / Kararsiz anjina pektoris ve ST-elevasyonsuz miyokart enfarktüslü hastalarda degisik statinlerin, ezetimib/simvastatin kombinasyonunun hsCRP düzeyleri üzerine etkileri: randomize bir çalisma.

OBJECTIVE: The aim of our study was to evaluate the effects of two different statins and a statin/ezetimibe combination on high sensitive C-reactive protein (hsCRP) values, which were given at high doses in the early period of acute coronary syndromes. METHODS: A total of 150 patients with non-ST elevation myocardial infarction and unstable angina pectoris were enrolled to our prospective, randomized, single-blind study. Patients were divided into three groups by block randomization method. One group received 20 mg/day atorvastatin, one group received 10 mg/day rosuvastatin and the other group received 10 mg/day ezetimibe/simvastatin combination therapy, which was initiated within the first 24 hours of admission. Follow-up duration was 2 months . Biochemical investigations and hsCRP levels (by nephelometric method) were performed with 138 patients evaluated at baseline, 10th and 60th days of therapy. Decreases of hsCRP levels were analyzed with one-way MANOVA and repeated measures of ANOVA methods. Post-hoc Tukey HSD test was performed for finding the different group, when the difference was detected between the groups. RESULTS: Tenth day hsCRP levels in ezetimibe/simvastatin group was significantly lower than the other groups (p<0.001). Further, after 60 days of follow-up a significant reduction was seen in hsCRP levels in ezetimib/simvastatin group (in ezetimibe/simvastatin group the mean hsCRP was reduced from 38.4±15.0 mg/L to 2.4±1.3 mg/L, in atorvastatin group the mean hsCRP was reduced from 27.3±11.7 mg/L to 4.1±2.4 mg/L and in rosuvastatin group the mean hsCRP was reduced from 22.0±6.9 mg/L to 3.6±1.7 mg/L (F (1.1, 148.2) = 746.9, p<0.01 and the difference between drugs; F (2.2, 148.2) = 32.1, p<0.01). No side effects related to drugs were seen during follow-up in all three treatment groups. CONCLUSION: This study showed that ezetimibe/simvastatin 10 mg/day combination treatment was superior to atorvastatin 20 mg/day and rosuvastatin 10 mg/day treatment in reducing the inflammatory markers when high dose statins was started in the early period of unstable angina and non ST elevation myocardial infarction.

Comparison of effects of morning versus evening administration of ezetimibe/simvastatin on serum cholesterol in patients with primary hypercholesterolemia.

BACKGROUND: Ezetimibe, a first-in-its-class inhibitor of cholesterol absorption, is an effective agent for combined use with statins to achieve low-density lipoprotein cholesterol (LDL-C) goals. Ezetimibe in combination with simvastatin as a single-tablet formulation has proven to be highly effective in reducing serum LDL-C through the dual inhibition of cholesterol absorption and biosynthesis. The effect of time of administration on efficacy of this combination therapy has not been evaluated. OBJECTIVE: To compare the effects of morning versus evening administration of ezetimibe/simvastatin on serum cholesterol levels of patients with primary hypercholesterolemia. METHODS: In this multicenter, open-label, randomized, 2-sequence, 2-period crossover study, patients with primary hypercholesterolemia randomly received ezetimibe/simvastatin 10 mg/20 mg once daily, either in the morning (within 1 hour of breakfast) or in the evening (within 1 hour of dinner) for 6 weeks. RESULTS: Data on 171 patients (87 in the morning administration group and 84 in the evening administration group) were analyzed. A significant reduction (p ≤ 0.001) in the total cholesterol, triglyceride, high-density lipoprotein cholesterol, LDL-C, apo-lipoprotein B, and high-sensitivity C-reactive protein (hs-CRP) from baseline was achieved after each treatment. Noninferiority of morning administration versus evening administration was shown in the percentage reduction of the LDL-C level from baseline (difference, -1.62%; 90% CI -4.94 to 1.70). No significant difference was found between groups with respect to the percentage of changes in other lipid parameters from baseline. Furthermore, there was no significant difference in the percentage of change in hs-CRP as an antiinflammatory marker between the morning and evening administration groups. The frequency of adverse events was similar between groups. CONCLUSIONS: Morning administration of ezetimibe/simvastatin 10 mg/20 mg is noninferior to evening administration with respect to LDL-C-lowering ability.

Switching statin therapy using a pharmacist-managed therapeutic conversion program versus usual care conversion among indigent patients.

UNLABELLED: STUDY OBJECTIVE. To evaluate the effectiveness of switching statin therapy using a therapeutic conversion program versus usual care conversion among patients enrolled in the Colorado Indigent Care Program when atorvastatin was removed from the formulary. DESIGN: Prospective cohort study. SETTING: Family medicine center and other ambulatory care clinics of a university-based health care system. PATIENTS: One hundred seventeen ambulatory care patients with dyslipidemia who were treated with atorvastatin. INTERVENTION: Clinical pharmacists in the family medicine center implemented a therapeutic conversion program (30 patients), switching atorvastatin to a new formulary regimen of simvastatin, rosuvastatin, or ezetimibe-simvastatin, using an algorithm designed to achieve patient-specific goals for low-density lipoprotein cholesterol (LDL). Usual care occurred in the other ambulatory care clinics without clinical pharmacists (87 patients), where medical providers switched atorvastatin to a formulary regimen based on a suggested (but optional) equipotency conversion algorithm. MEASUREMENTS AND MAIN RESULTS: Primary end points were LDL concentration and LDL goal attainment before and after conversion. Before and after conversion, respectively, mean LDL concentrations were 86.7 and 82.3 mg/dl in the therapeutic conversion group (p=0.44) versus 78.3 and 85.2 mg/dl in the usual care group (p=0.01). Percentages of patients attaining LDL goal were 80% before and 97% after conversion in the therapeutic conversion group (p=0.04) compared with 90% before and 75% after conversion in the usual care group (p=0.01). CONCLUSION: Use of a prospective, therapeutic statin conversion program was associated with increased control of dyslipidemia, whereas usual care statin conversion was associated with decreased control. These data suggest that proactive involvement of clinical pharmacists in converting lipid-lowering drugs results in superior patient care outcomes compared with a less aggressive approach.

Ezetimibe/simvastatin single tablet versus rosuvastatin in patients with hypercholesterolemia.

Recent guidelines recommend strict goals for low density lipoprotein cholesterol (LDL-C) (70-100 mg/dL; 1.8-2.6 mmol/L). These goals were set following the publication of several trials. In the current issue of the journal, a study compares different doses of the combination tablet (ezetimibe/simvastatin) with statin monotherapy (rosuvastatin). In keeping with previous literature, the combination therapy was more effective in achieving LDL-C goals. This editorial comments on the potential disadvantages of using monotherapy with high-dose statins and considers the issue of statin-induced proteinuria. Combination therapy may need to be increasingly used to achieve the LDL-C targets set by recent guidelines.

Complementary therapy to target LDL cholesterol: the role of the ezetimibe/simvastatin combination.

Cardiovascular (CV) disease remains the number 1 cause of death in the USA. Nonetheless, there has been a decline in the age-adjusted death rate for coronary heart disease (CHD) which may be due to more aggressive treatment guidelines for treating CV risk factors, such as hypertension, diabetes, and dyslipidemia. The recent update to the National Cholesterol Education Program (NCEP) guidelines have recommended lower low-density lipoprotein cholesterol (LDL-C) goals in high-risk patients. Based on the new targets for LDL-C, clinicians will need more efficacious lipid-lowering therapies. One of these newer therapies is the combination of ezetimibe and simvastatin. This article reviews the implications of the updated guidelines and discusses the efficacy and safety of ezetimibe/simvastatin for lowering LDL-C.

Doble inhibición del colesterol: papel de la regulación intestinal y hepática / Dual cholesterol inhibition: roles of intestinal and hepatic regulation

En pacientes con alto riesgo cardiovascular, la inhibición aislada de la síntesis de colesterol con estatinas no siempre consigue los objetivos terapéuticos, por lo que es deseable un método complementario para reducir el colesterol. Éste es la inhibición de la absorción intestinal, la segunda vía en la homeostasis del colesterol en el organismo. La regulación de la absorción intestinal del colesterol es una importante diana terapéutica, porque la eficiencia de este proceso determina tanto la excreción fecal como la cantidad que llega al hígado con los remanentes de quilomicrones. Tras su llegada al hígado, el colesterol de origen intestinal ejerce efectos reguladores importantes: inhibición variable de la síntesis de colesterol y expresión de receptores para las lipoproteínas de baja densidad (LDL). Esto se traduce generalmente en aumentos discretos de la colesterolemia en respuesta a una sobrecarga de colesterol en el intestino. La ezetimiba, un inhibidor selectivo de la absorción del colesterol, inactiva de forma reversible la acción de la proteína transportadora intestinal NPC1L1. Además de inhibir la absorción del colesterol, la ezetimiba reduce también la absorción de fitosteroles. Puesto que no se metaboliza por la vía del citocromo P450, la enzetimiba no presenta interacciones farmacocinéticas. La administración de 10 mg/día en monoterapia reduce un 50% la absorción de colesterol, lo cual se asocia con un descenso medio del cLDL de un 18%. El efecto hipocolesterolemiante de la ezetimiba es sinérgico con el de las estatinas, lo cual hace que esta combinación terapéutica sea actualmente de elección para lograr los objetivos de cLDL en la mayoría de pacientes con alto riesgo (AU)

Many patients at a high cardiovascular disease risk do not reach current treatment goals when given statins as monotherapy. A therapeutic approach that complements cholesterol synthesis inhibition is desirable in these patients; it is currently available: inhibition of intestinal cholesterol absorption, the second pathway for cholesterol homeostasis in the body. Regulation of intestinal cholesterol absorption is a critical therapeutic target because the efficiency of this process determines both fecal cholesterol loss and the amount of cholesterol delivered to the liver via chylomicron remnants. The mass of intestinal cholesterol reaching the liver exerts important regulatory effects: it suppresses, to a variable extent, both cholesterol synthesis and LDL receptor expression. Generally, this means that there are only small increases in blood cholesterol level in response to increased intestinal cholesterol load. Ezetimibe, a selective cholesterol absorption inhibitor, reversibly suppresses the activity of the intestinal transport protein NPC1L1. In addition to inhibiting cholesterol absorption, ezetimibe also inhibits net phytosterol absorption. Because it is not metabolized via the cytochrome P450 pathway, ezetimibe has little potential for pharmacokinetic interactions. The administration of 10 mg/day as monotherapy reduces cholesterol absorption by close to 50%, and this is associated with an average 18% decrease in LDL-cholesterol level. The hypocholesterolemic effects of ezetimibe are additive to those of statins, which is a reason why this drug combination is currently the treatment of choice for attaining LDL-cholesterol goals in most high-risk patients (AU)