Impacto de la optimización del tratamiento hipolipemiante en el riesgo cardiovascular residual / Impact of Optimizing Lipid-Lowering Therapy on Residual Cardiovascular Risk

RESUMEN Introducción: el modelo SMART-REACH predice el riesgo de eventos cardiovasculares recurrentes. Objetivos: los objetivos de este estudio fueron: a) evaluar el riesgo residual en una población en prevención secundaria y niveles de colesterol asociado a lipoproteínas de baja densidad (C-LDL) fuera de meta; b) mediante un modelo de simulación, determinar el impacto de optimizar las terapias hipolipemiantes en términos de reducción del riesgo residual. Material y métodos: estudio transversal, descriptivo y multicéntrico. Se incluyeron consecutivamente pacientes con antecedentes cardiovasculares y un C-LDL mayor o igual que 55 mg/dL. El riesgo de eventos recurrentes (infarto agudo de miocardio, accidente cerebrovascular o muerte vascular) a 10 años y a lo largo de la vida se estimó utilizando el modelo SMART-REACH. Mediante una simulación, se optimizó el tratamiento hipolipemiante de cada paciente (utilizando estatinas, ezetimibe o inhibidores de proproteína convertasa subtilisina kexina tipo 9 [iPCSK9]), se estimó el descenso del C-LDL, se verificó el alcance del objetivo lipídico y se calculó la reducción del riesgo cardiovascular y el número necesario a tratar (NNT) correspondiente. Resultados: se incluyeron 187 pacientes (edad media 67,9 ± 9,3 años, 72,7% hombres). Los riesgos residuales calculados a 10 años y a lo largo de la vida fueron 37,1 ± 14,7% y 60,3 ± 10,7%, respectivamente. Globalmente, se pudo optimizar una sola estrategia farmacológica con estatinas, ezetimibe o un iPCSK9 en el 38,5%, el 11,5% y el 5,5% de la población, respectivamente. La optimización basada en dos tratamientos se realizó en el 27,5% (estatinas + ezetimibe), el 7,7% (estatinas + iPCSK9) y el 1,1% (ezetimibe + iPCSK9) de los casos. En 15 pacientes se optimizó el tratamiento considerando los tres fármacos. El 53,9% y el 62,9% de las acciones para optimizar el tratamiento mostraron un NNT menor que 30 para evitar un evento a 10 años o a lo largo de la vida, respectivamente. Conclusión: en este estudio, los pacientes con antecedentes cardiovasculares que no alcanzan la meta de C-LDL mostraron un riesgo residual considerable. La simulación mostró un importante margen para optimizar el tratamiento, con un impacto notable en el riesgo residual.

ABSTRACT Background: The SMART-REACH model predicts the risk or recurrent cardiovascular events. Objectives: The objectives of this study were: a) to evaluate the residual cardiovascular risk in a secondary prevention population with LDL-C levels above the recommended goal, using a simulation model; and b) to determine the impact of optimizing lipid-lowering therapies in terms of residual cardiovascular risk reduction. Methods: We conducted a cross-sectional, descriptive and multicenter study. Patient with a history of cardiovascular disease and a LDL-C ≥55 mg/dL were consecutively included. The 10-year and lifetime risk of recurrent events (myocardial infarction, stroke, or vascular death) were estimated using the SMART-REACH model. By means of a simulation, lipid-lowering treatment was optimized for each patient [using statins, ezetimibe and/or PCSK9 (PCSK9) inhibitors], with estimation of LDL-C reduction, checking if lipid-lowering goal was achieved and calculating the reduction in cardiovascular risk and the corresponding number needed to treat (NNT). Results: The cohort was made up of 187 patients; mean age was 67.9 ± 9.3 years and 72.7% were men. The calculated 10-year and lifetime residual risks were 37.1 ± 14.7% and 60.3 ± 10.7%, respectively. Overall, treatment was optimized with a single pharmacological strategy with statins, ezetimibe or PCSK9 inhibitor in 38.5%, 11.5% and 5.5% of the population, respectively. Optimization based on two treatments was performed in 27.5% (statins + ezetimibe), 7.7% (statins + PCSK9 inhibitor) and 1.1% (ezetimibe + PCSK9 inhibitor) of the cases. In 15 patients, treatment was optimized when the three drugs (statins + ezetimibe + PCSK9 inhibitor) were considered. Overall, 53.9% and 62.9% of the actions implemented to optimize treatment showed a 10-year or lifetime NNT < 30 to prevent an event, respectively. Conclusion: In this study, patients with a history of cardiovascular disease who do not reach LDL-C goal showed significant residual cardiovascular risk. The simulation model showed a significant margin for optimizing treatment, with a marked reduction in residual cardiovascular risk.

Comparative study on efficacy and safety of atorvastatin in combination with ezetimibe and atorvastatin monotherapy among patients with dyslipidemia – A randomized and double-blind study

Background: Dyslipidemia is defined as the high-density lipoprotein and apolipoprotein A (apo A) levels <10th percentile and/or total cholesterol, triglycerides, low-density lipoprotein (LDL), apolipoprotein B, or Lipoprotein (a) levels more than the 90th percentile. Aim and Objectives: This study aimed to compare the efficacy and safety of the fixed-dose combination of Atorvastatin and Ezetimibe with Atorvastatin monotherapy among patients with dyslipidemia. Materials and Methods: The present study was a randomized, double-blinded, prospective, and parallel-group study. Ninety-two outpatients of age in between 18 and 70 years from the Department of General Medicine who attended the hospital for the treatment of dyslipidemia were selected as study participants. Among 92 patients, 12 patients did not meet the study criteria. The remaining 80 patients were divided into two treatment groups at random and under double-blind conditions (39 in Group A and 41 in Group B). Each patient in both groups was followed for a period of 4 weeks after initiation of therapy. Total cholesterol and LDL-cholesterol levels were recorded at day 1, 2 weeks, and 4 weeks of therapy. Results: In this study, by the end of the study period (4 weeks), tablet Atorvastatin + tablet Ezetimibe combination therapy showed statistical significance difference in reducing mean total cholesterol and mean serum LDL levels in dyslipidemia cases than the group receiving Atorvastatin monotherapy. Conclusion: Atorvastatin in combination with Ezetimibe was more efficacious than Atorvastatin monotherapy in reducing total blood cholesterol and serum LDL levels. Atorvastatin plus Ezetimibe is equally safer as Atorvastatin monotherapy and well tolerated with fewer adverse effects.

Ezetimibe increases resistance to oxidative stress and extends lifespan mimicking dietary restriction in Caenorhabditis elegans

Ezetimibe is an approved drug for lowering plasma LDL (low-density lipoprotein) level via inhibition of cholesterol absorption. Derivatives of ezetimibe reduce inflammatory response and oxidative stress. In the present study, we investigated the effect of dietary supplementation with ezetimibe in response to environmental stressors and found that ezetimibe increases resistance to oxidative stress and ultraviolet irradiation. Ezetimibe also significantly extended lifespan accompanying reduced fertility, which is a common trade-off for longevity in C. elegans. Cellular level of reactive oxygen species was increased and the expression of stress-responsive genes, hsp-16.2 and sod-3, was induced by dietary supplementation with ezetimibe, suggesting a hormetic effect on oxidative stress response and lifespan. Ezetimibe also significantly prevented amyloid beta-induced toxicity and completely reversed increased mortality by high-glucose diet. Nuclear localization of DAF-16 required for the prevention of amyloid beta-induced toxicity was enhanced by ezetimibe supplementation. Lifespan assay using known long-lived mutants, age-1, clk-1, and eat-2, revealed that lifespan extension by ezetimibe specifically overlapped with that of eat-2 mutants, which are genetic models of dietary restriction. Effect of ezetimibe on lifespan of worms fed with diluted bacteria suggested that ezetimibe mimics the effect of dietary restriction on lifespan. These findings suggest that ezetimibe exhibits anti-oxidative and anti-aging effects through hormesis and works as a dietary-restriction mimetic on lifespan extension.

Alopecia Universal após Tratamento com Sinvastatina e Ezetimiba: Impactos na Família / Alopecia Universalis after Treatment with Simvastatin and Ezetimibe: Affects on Family

Resumo A alopecia areata (AA) é uma doença autoimune que se desenvolve no couro cabeludo ou em outras partes do corpo. A alopecia universal, que é uma forma rara de alopecia areata, é caracterizada pela perda de pelos que afeta todo o corpo. Nos dois pacientes apresentados, o tratamento com atorvastatina foi iniciado com o diagnóstico de hipercolesterolemia, mas, quando as metas de valores não foram alcançadas, foi iniciado o tratamento com uma combinação de sinvastatina e ezetimiba. Depois de um período de tratamento com sinvastatina e ezetimiba, o distúrbio de AA, o qual começou com a perda de cabelo no couro cabeludo, espalhou pelo corpo todo e se transformou em alopecia universal. Embora as estatinas possam causar alopecia com reações autoimunes, elas geralmente são utilizadas no tratamento da alopecia, por seus efeitos imunomoduladores.

Abstract Alopecia areata (AA) is an autoimmune disease that grows in the scalp or in other parts of the body. Alopecia universalis, which is a rare form of alopecia areata, is characterized by a loss of hair that affects the entire body. In the two patients presented in this study, atorvastatin treatment was implemented, with the diagnosis of hypercholesterolemia; however, when the target values were not reached, a combination of simvastatin and ezetimibe was implemented. After a period of simvastatin/ezetimibe treatment, the AA disorder, which began with hair loss on the scalp, spread to the entire body and turned into Alopecia Universalis. Although statins can cause alopecia with autoimmune reactions, they are generally used in the treatment of alopecia due to their immunomodulatory effects.

Efficacy of Ezetimibe tablets in the treatment of sitosterolemia with thrombocytopenia / 中华实用儿科临床杂志

The clinical features and genetic variants of the patient with sitosterolemia who was referred to Shanghai Children′s Medical Center, Shanghai Jiaotong University School of Medicine from June 2019 to January 2020 were retrospectively analyzed.The patient was treated with Ezetimibe tablets combined with diet control, and the follow-up was performed regularly.Besides, a relevant literature review was conducted.A 7-year and 5-month-old boy was referred to the hospital for " repeated thrombocytopenia for 7 months" with normal serum cholesterol.The whole exome sequencing showed that compound heterozygous mutations (p.Arg446*, p.Gln251*) in ABCG5 gene were inherited from their parents respectively.Hence, he was diagnosed with sitosterolemia.After 29 days of treatment with Ezetimibe tablets combined with diet control, the patient′s platelets returned to normal values without obvious adverse reactions related to drugs.Children with sitosterolemia may present with rare thrombocytopenia, and the therapeutic effects of Ezetimibe tablets combined with diet control are favorable.

An Update on Pharmacotherapy of Dyslipidemia for Adults

Dyslipidemia is an important cause of atherosclerotic cardiovascular disease (ASCVD) worldwide that leads to increased risk of morbidity and mortality; treating dyslipidemia to goal reduces the risks. This article reviews the pharmacological therapy of dyslipidemiawhich is often required in addition to life style intervention to achieve target lipid levels.Currently, there are seven types of approvedlipid modifying drugs which are effective in treating dyslipidemiawhen used singly or in combination. Statins are considered as first line drug and havebeen used extensively in the primary and secondary prevention of ASCVD. Ezetimibe is used as a first line add-on drug for patients already on a statin who have not reached their low density lipoprotein (LDL-C) goals;however,ezetimibe can be used as initial drug in statin intolerant patients. Bile acid sequestrants are a useful alternative to statins or ezetimibe in pregnant women or patients with liver disease. They also lower blood glucose and are useful in diabetes mellitus (DM). The PCSK9 inhibitors are powerful lipid modifying drugs, are expensive, needinjection for delivery, and are used when statin in maximum doses with other drugs cannot lower the LDL-C level to targets in patients with very high CV risk. Fibrates have recently shown to slow the progression of microvascular diseases and are found beneficial for DM with hypertriglyceridemia and microvascular complications. Currently, niacin use is markedly decreased due to development of more effective alternative drugs for managing dyslipidemia andbecause of the adverse effects related to niacin use.Recent trials reveal that, ω-3 fatty acids, when added in pharmacological doses to statin therapy (after controlling LDL-C), are effective in reducing CV events in patientshaving moderate hypertriglyceridemia with high or very high CV risks

Preparation and in vitro-in vivo evaluation of ezetimibe tablets / 国际药学研究杂志

Objective: To prepare ezetimibe tablets by direct compression technology. Methods: By comparison with the reference standard, the formulation of self-made ezetimibe tablets was optimized using the disintegration time and the release profile similarity factor f2 as the main indexes by the single factor experiments. The pharmacokinetic parameters of ezetimibe tablets in Beagle dog were determined by LC-MS/MS. The pharmacodynamic effects of ezetimibe tablets were evaluated by measuring serum total cholesterol (TC), triglycerides(TG), high-density lipoprotein cholesterol(HDL-C)and low-density lipoprotein cholesterol(LDL-C)levels. Results: Three batches of self-made ezetimibe tablets with the optimal formulation had similar in vitro dissolution behaviors as the reference preparations(f2>70). There was no significant difference in pharmacokinetic parameters in Beagle between the self-made ezetimibe tablets and the reference standard tablets, and the effect on the high serum cholesterol level was similar. Conclusion: The preparation process of the ezetimibe tablet developed in this study is simple, and the self-made tablet has bioequivalence with the reference standard, which provides a reference for the development of the ezetimibe generic drug.

Lipid-lowering drug prescriptions in a group of Colombian patients / Patrones de prescripción de hipolipemiantes en pacientes de Colombia

Introduction. Lipid-lowering drugs, especially statins, have shown great relevance in preventing and treating cardiovascular diseases. Objective. To determine the prescription patterns of lipid-lowering drugs and the variables associated with their use in a Colombian population. Materials and methods. This is a cross-sectional descriptive study. From a drugdispensing database of approximately 4.5 million Colombian health system affiliates, patients of all ages and both sexes treated with lipid-lowering agents (statins, fibrates, ezetimibe) were identified between January and March, 2017. Demographic, pharmacological and co-medication variables were included. Results. In total, 103,624 patients were identified as being treated with lipid-lowering agents. The average age was 67.5 years, and 49.8% were 65 years or older. Women comprised 58.0% of the patients. Statins were the most used (n=96,910; 93.5%), and atorvastatin (n=80,812; 78.0%) and lovastatin (n=12,621; 12.2%) were the most frequent. The mean atorvastatin dose was 30.3 mg/day, and 49.9% of its users received presentations of 40 mg or more. A total of 9,258 (8.9%) patients received fibrates, and only 780 (0.8%) were taking ezetimibe. Of this population, 94.9% were treated with lipid-lowering monotherapy, and 97.3% (n=100,813) had co-medication for their comorbidities, with the most frequent being antihypertensive (89.1%), antiplatelet (57.8%), antidiabetic (31.5%) and antiulcerative agents (34.2%). Conclusions. Atorvastatin is currently the most frequently used lipid-lowering drug in this group of Colombian patients, especially in monotherapy and at doses close to the defined daily dose. Only half received high-intensity doses. New studies are required to verify the efficacy of these therapies.

Introducción. Los fármacos hipolipemiantes, especialmente las estatinas, han demostrado gran relevancia para la prevención y el tratamiento de las enfermedades cardiovasculares. Objetivo. Determinar los patrones de prescripción de los fármacos hipolipemiantes y las variables asociadas con su uso en una población de Colombia. Materiales y métodos. Se trata de un estudio descriptivo y transversal. A partir de una base de datos de dispensación de medicamentos de 4,5 millones de afiliados al sistema de salud de Colombia, se identificaron los pacientes de cualquier edad y sexo en tratamiento con hipolipemiantes (estatinas, fibratos, ezetimibe), entre enero y marzo de 2017. Se incluyeron variables demográficas, farmacológicas y de comedicaciones. Resultados. Se identificaron 103.624 pacientes en tratamiento con hipolipemiantes. La edad promedio fue de 67,5 años y el 49,8 % tenía 65 o más años. El 58,0 % eran mujeres. Las estatinas fueron los más utilizados (n=96.910; 93,5 %), siendo la atorvastatina (n=80.812; 78,0 %) y la lovastatina (n=12.621; 12,2 %) las más frecuentes. La dosis promedio de atorvastatina fue de 30,3 mg/día y el 49,9 % de sus usuarios recibía presentaciones de 40 mg o más. Un total de 9.258 (8,9 %) pacientes recibían fibratos y solo 780 (0,8 %) tomaban ezetimibe. El 94,9 % de casos recibió tratamiento en monoterapia hipolipemiante y el 97,3 % (n=100.813) tenía comedicaciones para comorbilidades, siendo las más frecuentes antihipertensivos (89,1 %), antiagregantes plaquetarios (57,8 %), antidiabéticos (31,5 %) y antiulcerosos (34,2 %). Conclusiones. La atorvastatina es actualmente el medicamento hipolipemiante más utilizado en este grupo de pacientes de Colombia, especialmente en monoterapia y a dosis cercanas a las definidas, aunque solo la mitad recibían dosis recibían dosis de alta intensidad. Se requieren nuevos estudios que verifiquen la efectividad de estos tratamientos.

Isolation, Identification And Characterization Of Degradation Impurity Of Atorvastatin In Fixed Dose Combination Of Atorvastatin And Ezetimibe

The objective of this study is to isolation and characterization of unknown degradation product of Atorvastatin calcium in combination formulation product with Ezetimibe by using modern techniques of separation and characterization. An unknown impurity is generating during a forced degradation study of Atorvastatin and Ezetimibe fixed-dose combination tablets. By using the gradient reversed-phase high-pressure liquid chromatographic method, unknown degradation impurity was detected and quantified in the range of 0.05% to 0.2% of Atorvastatin. The impurity was enriched by extreme oxidation degradation of Atorvastatin and isolated through preparative HPLC. The structure of the impurity was characterized by mass and NMR spectrum.

Cholesterol goal achievement and lipid-lowering therapy in patients with stable or acute coronary heart disease in Singapore: results from the Dyslipidemia International Study II

INTRODUCTION@#Dyslipidaemia is a major risk factor for coronary heart disease (CHD). There is a lack of data on the extent of lipid abnormalities and lipid-lowering therapy (LLT) in Singapore.@*METHODS@#The Dyslipidemia International Study (DYSIS) II was a multinational observational study of patients with stable CHD and hospitalised patients with an acute coronary syndrome (ACS). A full lipid profile and use of LLT were documented at baseline, and for the ACS cohort, at four months post-hospitalisation.@*RESULTS@#325 patients were recruited from four sites in Singapore; 199 had stable CHD and 126 were hospitalised with an ACS. At baseline, 96.5% of the CHD cohort and 66.4% of the ACS cohort were being treated with LLT. In both cohorts, low-density lipoprotein cholesterol (LDL-C) levels were lower for the treated than the non-treated patients; accordingly, a higher proportion of patients met the LDL-C goal of < 70 mg/dL (CHD: 28.1% vs. 0%, p = 0.10; ACS: 20.2% vs. 0%, p < 0.01). By the four-month follow-up, a higher proportion of the ACS patients that were originally not treated with LLT had met the LDL-C goal (from 0% to 54.5%), correlating with the increased use of medication. However, there was negligible improvement in the patients who were treated prior to the ACS.@*CONCLUSION@#Dyslipidaemia is a significant concern in Singapore, with few patients with stable or acute CHD meeting the recommended European Society of Cardiology/European Atherosclerosis Society goal. LLT was widely used but not optimised, indicating considerable scope for improved management of these very-high-risk patients.

Effects of ezetimibe and rosuvastatin on the expression of Caveolin-1 mRNA in smooth muscle derived foam cells / 中国医师杂志

Objective To investigate the influence of ezetimibe combined with rosuvastatin on expression of Caveolin-1 in smooth muscle derived foam cells induced by oxidized low density lipoprotein (oxLDL).Methods The rat thoracic aortic smooth muscle cells (VSMCs) were selected from generations 3-5 in logarithmic growth cycle.The rat vascular smooth cells were induced using oxidized low density lipoprotein(ox-LDL 50 μg/ml for 48 h) to establish foam cell model.The normal cultured rat thoracic aortic smooth muscle cells were used as blank control group.Foam cells were divided into foam cell group,different concentrations of ezetimibe group,different concentrations of rosuvastatin group,combination group.The foam cells were incubated with different doses of ezetimibe (3.0,10.0,30.0 μmol/L) or rosuvastatin (0.1,1.0,5.0 μmol/L) for 24 h,or cultured with rosuvastatin 5.0 μmol/L + ezetimibe 30.0 μmol/L in combination groups.Oil red O staining was used to identify foam cell models.The expression of Caveolin-1 mRNA was detected by real-time fluorescent quantitative polymerase chain reaction (qRT-PCR).Results Compared with blank control group,the mRNA expression of Caveolin-1 in foam cell group were decreased significantly [(0.248 7 ± 0.042 0) vs (1.004 1 ± 0.017 1),P ＜ 0.05].Compared with foam cell group,the mRNA expression of Caveolin-1 was increased in a dose-dependent manner in ezetimibe group and rosuvastatin group [(0.371 3 ±0.025 2),(0.489 8 ±0.027 9),(0.726 1 ±0.029 1) vs (0.248 7 ±0.042 0);(0.460 2±0.022 8),(0.623 7 ±0.028 8),(0.751 8 ±0.043 1) vs (0.248 7 ±0.042 0),P ＜0.05].Compared with the ezetimibe (30.0 μmol/L) and the rosuvastatin (5.0 μmol/L),the mRNA expression of Caveolin-1 in combined group were increased,the difference was statistically significant [(0.726 1 ±0.029 1),(0.751 8 ± 0.043 1) vs (0.937 6 ± 0.029 7),P ＜ 0.05].Conclusions Ezetimibe and rosuvastatin can promote the reverse transport of cholesterol (RCT) in smooth muscle derived foam cells by upregulating expression of Caveolin-1 mRNA.And the combination of ezetimibe (30.0 μmol/L) and rosuvastatin (5.0 μmol/L) has more significant effect.

Pharmacological Strategies beyond Statins: Ezetimibe and PCSK9 Inhibitors

Dyslipidemia, highly elevated, low-density lipoprotein (LDL) cholesterol, is a major cardiovascular risk factor. Statins have been proven to effectively reduce the risk of atherosclerotic cardiovascular disease (ASCVD) and are recommended as a first-line therapy for the primary and secondary prevention of ASCVD. However, statins may not be sufficient in decreasing LDL cholesterol levels and pose a significant on-treatment residual risk of major cardiovascular events (i.e., residual cholesterol risk) according to meta-analyses of statin trials. Current guidelines for cholesterol management to achieve additional LDL cholesterol reduction and reduce ASCVD risk recommend two hyperlipidemic agents besides statins. Use of ezetimibe, a cholesterol absorption inhibitor, leads to additional LCL cholesterol reduction and decreased ASCVD risk, when added to statin therapy, without raising significant safety concerns. Furthermore, in combination with a mild-to-moderate statin intensity, ezetimibe is used in situations of statin-associated adverse effects such as myalgia and the combination therapy is relatively safer. Monoclonal antibody of proprotein convertase subtilisin/kexin type 9 (PCSK9), alirocumab, and evolocumab, have been approved to lower LDL cholesterol level. While there are drawbacks to the use of PCSK9 inhibitors, including high cost and adverse events such as injection site reaction, they significantly decreased serum LDL cholesterol levels and thereby ASCVD risks when added to maximally tolerated statin therapy.

Comparison of the Efficacy of Rosuvastatin Monotherapy 20 mg with Rosuvastatin 5 mg and Ezetimibe 10 mg Combination Therapy on Lipid Parameters in Patients with Type 2 Diabetes Mellitus

BACKGROUND: The apolipoprotein B/A1 (apoB/A1) ratio is a stronger predictor of future cardiovascular disease than is the level of conventional lipids. Statin and ezetimibe combination therapy have shown additional cardioprotective effects over statin monotherapy. METHODS: This was a single-center, randomized, open-label, active-controlled study in Korea. A total of 36 patients with type 2 diabetes mellitus were randomized to either rosuvastatin monotherapy (20 mg/day, n=20) or rosuvastatin/ezetimibe (5 mg/10 mg/day, n=16) combination therapy for 6 weeks. RESULTS: After the 6-week treatment, low density lipoprotein cholesterol (LDL-C) and apoB reduction were comparable between the two groups (−94.3±15.4 and −62.0±20.9 mg/dL in the rosuvastatin group, −89.9±22.7 and −66.8±21.6 mg/dL in the rosuvastatin/ezetimibe group, P=0.54 and P=0.86, respectively). In addition, change in apoB/A1 ratio (−0.44±0.16 in the rosuvastatin group and −0.47±0.25 in the rosuvastatin/ezetimibe group, P=0.58) did not differ between the two groups. On the other hand, triglyceride and free fatty acid (FFA) reductions were greater in the rosuvastatin/ezetimibe group than in the rosuvastatin group (−10.5 mg/dL [interquartile range (IQR), −37.5 to 29.5] and 0.0 µEq/L [IQR, −136.8 to 146.0] in the rosuvastatin group, −49.5 mg/dL [IQR, −108.5 to −27.5] and −170.5 µEq/L [IQR, −353.0 to 0.8] in the rosuvastatin/ezetimibe group, P=0.010 and P=0.049, respectively). Both treatments were generally well tolerated, and there were no differences in muscle or liver enzyme elevation. CONCLUSION: A 6-week combination therapy of low-dose rosuvastatin and ezetimibe showed LDL-C, apoB, and apoB/A1 ratio reduction comparable to that of high-dose rosuvastatin monotherapy in patients with type 2 diabetes mellitus. Triglyceride and FFA reductions were greater with the combination therapy than with rosuvastatin monotherapy.

Lipid-lowering therapy in the post-statin era / 中华全科医师杂志

Atherosclerotic cardiovascular disease is one of the leading causes of death and disability worldwide.Dyslipidemia mainly with elevated LDL-C is closely related to atherosclerotic cardiovascular disease.Statins are the most effective drugs for lowering LDL-C and play an important role in the prevention and treatment of atherosclerotic cardiovascular disease.However,a considerable number of patients receiving statin therapy can not tolerate its adverse reactions or their low-density lipoprotein can not meet the standard,and the cardiovascular risk remains high.The clinical application of new lipid-lowering drugs such as ezetimibe,PCSK9 inhibitors and cholesterol ester transfer protein(CETP) inhibitors has marked the post-statin era of lipid-lowering therapy.

Pharmacokinetics of fixed-dose combination of rosuvastatin 20 mg and ezetimibe 10 mg compared to concurrent administration of individual tablets in healthy Korean subjects

This study aimed to compare the pharmacokinetics of fixed-dose combination (FDC) tablet of rosuvastatin 20 mg/ezetimibe 10 mg with that of concurrent administration of individual rosuvastatin 20 mg tablet and ezetimibe 10 mg tablet in healthy subjects. A randomized, open label, single-dose, two-way crossover study was conducted. Subjects randomly received test formulation (FDC tablet of rosuvastatin 20 mg/ezetimibe 10 mg) or reference formulation (co-administration of rosuvastatin 20 mg tablet and ezetimibe 10 mg tablet). After 2 weeks of washout, subjects received the other treatment. Blood samples were collected up to 72 hours post-dose in each period. Plasma concentrations of rosuvastatin, ezetimibe and total ezetimibe (ezetimibe + ezetimibe glucuronide) were analyzed by liquid chromatography-tandem mass spectrometry (LC/MS/MS). The geometric mean ratio (GMR) of Cmax and AUClast (90% confidence interval, CI) for rosuvastatin was 1.036 (0.979–1.096) and 1.024 (0.981–1.070), respectively. The corresponding values for ezetimibe were 0.963 (0.888–1.043) and 1.021 (0.969–1.074), respectively. The corresponding values for total ezetimibe were 0.886 (0.835–0.940) and 0.983 (0.946–1.022), respectively. FDC tablet containing rosuvastatin 20 mg and ezetimibe 10 mg is bioequivalent to the co-administration of commercially available individual tablets of rosuvastatin and ezetimibe as GMR with 90% CI of Cmax and AUClast of rosuvastatin, ezetimibe and total ezetimibe were contained within conventionally accepted bioequivalence criteria.

Comparison of the Effects of Ezetimibe-Statin Combination Therapy on Major Adverse Cardiovascular Events in Patients with and without Diabetes: A Meta-Analysis

BACKGROUND: Ezetimibe-statin combination therapy has been found to reduce low density lipoprotein cholesterol levels and the risk of major adverse cardiovascular events (MACEs) in large trials. We sought to examine the differential effect of ezetimibe on MACEs when added to statins according to the presence of diabetes. METHODS: Randomized clinical trials with a sample size of at least 50 participants and at least 24 weeks of follow-up that compared ezetimibe-statin combination therapy with a statin- or placebo-controlled arm and reported at least one MACE, stratified by diabetes status, were included in the meta-analysis and meta-regression. RESULTS: A total of seven trials with 28,191 enrolled patients (mean age, 63.6 years; 75.1% men; 7,298 with diabetes [25.9%]; mean follow-up, 5 years) were analysed. MACEs stratified by diabetes were obtained from the published data (two trials) or through direct contact (five trials). No significant heterogeneity was observed among studies (I 2=14.7%, P=0.293). Ezetimibe was associated with a greater reduction of MACE risk in subjects with diabetes than in those without diabetes (pooled relative risk, 0.84 vs. 0.93; P heterogeneity=0.012). In the meta-regression analysis, the presence of diabetes was associated with a greater reduction of MACE risk when ezetimibe was added to statins (β=0.87, P=0.038). CONCLUSION: Ezetimibe-statin combination therapy was associated with greater cardiovascular benefits in patients with diabetes than in those without diabetes. Our findings suggest that ezetimibe-statin combination therapy might be a useful strategy in patients with diabetes at a residual risk of MACEs.

What Do We Get from Recent Statin and CETP Inhibitors Trials?

Recent clinical trials and meta-analyses have indicated that high-intensive statin treatment lowers low-density lipoprotein cholesterol (LDL-C) levels and reduces the risk of nonfatal cardiovascular (CV) events compared with moderate-intensity statin treatment. However, there are residual risks of CV events and safety concerns associated with high-intensity statin treatment. The Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) study showed that ezetimibe plus moderate-intensity statin therapy after acute coronary syndromes incrementally lowers LDL-C levels and improved CV outcomes compared with moderate-intensity statin therapy. However, despite the LDL-C-lowering effects, a substantial residual CV risk still remains, which includes other lipid abnormalities such as low high-density lipoprotein cholesterol (HDL-C). The most representative agents that primarily increase HDL-C are cholesteryl ester transfer protein (CETP) inhibitors. Until now, 4 CETP inhibitors, including torcetrapib, dalcetrapib, evacetrapib, and anacetrapib, have been introduced and all have significantly raised the HDL-C from 30% to 133%. However, the results for CV outcomes in clinical trials differed, based on the 4 agents. Torcetrapib increased the risk of CV events and total mortality in patients at high CV risk (ILLUMINATE trial). Dalcetrapib and evacetrapib did not result in lower rate of CV events in patients with recent acute coronary syndrome and high risk vascular disease, respectively (dal-OUTCOMES and ACCELERATE trials). However, anacetrapib significantly decreased the incidence of major coronary events in patients with atherosclerotic vascular disease (REVEAL trial). This topic summarizes the major results of recent statin and CETP inhibitor trials and provides framework to interpret and implement the trial results in real clinical practice.

Therapeutic Efficacy of Ezetimibe Combined with Tirofiban in the Treatment of Acute Coronary Syndrome Patients and Its Influence on the Content of Ischemia Modified Albumin / 中国药房

OBJECTIVE:To investigate therapeutic efficacy of ezetimibe combined with tirofiban in the treatment of acute coronary syndrome patients and its influence on the content of ischemia modified albumin (IMA) in peripheral blood.METHODS:A total of 82 patients with acute coronary syndrome in our hospital from Jan.2016 to Jan.2017 were divided into observe group and control group according to random number table,with 41 cases in each groups.All patients were given general treatment containing statins,glyceryl trinitrate and so on.Control group was additionally given Ezetimibe tablet 10 mg orally once a day.Observation group was additionally given Tirofiban hydrochloride sodium chloride injection 5 mg intravenously once a day,on the basis of control group,for consecutive 15 d.Clinical efficacies of 2 groups were evaluated.The dose of glyceryl trinitrate,duration and frequency of angina pectoris attack,left ventricular function indexes (SV,LVDD,CO,LVEF) were compared before treatment and after last medication.The contents of IMA in peripheral blood were detected before treatment and 3,6,9,12,15 h after the first day medication.ADR of the 2 groups were observed closely during the treatment.RESULTS:The total response rate of observation group was 92.7％,which was significantly higher than 72.3％ of control group (P＜0.05).Compared with before treatment,dose of glyceryl trinitrate and the content of IMA in 2 groups were decreased significantly after last medication,duration and frequency of angina pectoris attack were shortened significantly;the levels of SV,CO and LVEF were increased significantly while the level of LVDD was decrease significantly;the effect of observation group was significantly better than that of control group,with statistical significance (P＜0.05).No severe ADR was found in all patients during the treatment.CONCLUSIONS:Based on general treatment of glyceryl trinitrate therapeutic efficacy of ezetimibe combined with tirofiban is better than that of ezetimibe alone in the treatment acute coronary syndrome patients,and can decrease the content of IMA in peripheral blood more quickly.

Clinical efficacy of statin combined with ezetimibe in the treatment of patients with acute coronary syn-drome after percutaneous coronary intervention / 实用医学杂志

Objective To compare the clinical efficacy and safety with statin and ezetimibe in the treat-ment of ACS after PCI. Methods 126 patients with acute coronary syndrome(ACS)who underwent percutaneous coronary intervention(PCI )were divided into three groups according to the lipid-lowering strategy. group A:mod-erate-intensity statin group(n = 47),group B:Ezetimibe combined with moderate-intensity statin(n = 38), group C:Fortified statin(n = 41). The levels of serum lipids,liver enzymes,creatinine,creatine kinase(CK), and the compliance ratio of lipids were compared between the three groups at 1 month and 6 months after PCI re-spectively. All patients were followed up for 12 months,then reviewing coronary angiography and comparing MACE incidents within 12 months. Results The levels of cholesterol in group A,group B and group C decreased signifi-cantly(P < 0.05)at one month after PCI,the percentage of decrease of TC in three groups was 18.95%,35.61%and 19.84% and 24.89%,and LDL-C was 39.56%,23.99%,respectively. The percentage of TC and LDL-C in group B were significantly lower than those in other two groups(all P < 0.05). One months after PCI,the compli-ance rate of LDL-C in group B(65.8%)was higher than that in A group(34.0%)and C group(31.7%),P <0.05. Six months after PCI,the compliance rate of LDL-C in group B( 91.3% )was still significantly higher than that in group A(79.4%)and group C(84.2%),but P > 0.05. The incidence of MACE in group B was significant-ly lower than that in group A and C(P < 0.05)at 12 months after PCI,while the incidence of side effects in group C was significantly higher than that in group B and group A(P < 0.05). The incidence of neovascular steno-sis in group B was lower than that in group A and C(all P < 0.05). There was no significant difference in the intra-ventricular restenosis among the three groups(all P > 0.05). Conclusions Ezetimibe-statin combination therapy reduced TC and LDL-C levels more significantly than statin alone(including moderate-intensity statin therapy and strengthen statin therapy),and the compliance rate of LDL-C at 1 month after PCI was significantly higher than that of statin alone. The incidence of MACE was lower in combination group than in statin group at 12 months after operation,and the side effects were less. Above all,the combination of statin and ezetimibe may be the secondary prevention for CHD in patients with acute coronary syndrome after PCI.

Updates in the management of Dyslipidaemia in the high and very high risk individual for CV risk reduction

mortality and an important cause of morbidity in Malaysiafor several years. To reduce global cardiovascular (CV) riskin the population, primary preventive strategies need to beimplemented. Hypercholesterolaemia is one of the majorrisk factors for CVD. This paper is an expert review on themanagement of hypercholesterolemia focusing on high andvery high risk individuals. In low and Intermediate riskindividuals, therapeutic lifestyle changes (TLC) and ahealthy lifestyle alone may suffice. In high and very high riskindividuals, drug therapy in conjunction with TLC arenecessary to achieve the target LDL-C levels which havebeen shown to slow down progression and sometimes evenresult in regression of atherosclerotic plaques. Statins arefirst-line drugs because they have been shown in numerousrandomized controlled trials to be effective in reducing CVevents and to be safe. In some high risk individuals, despitemaximally tolerated statin therapy, target Low DensityLipoprotein Cholesterol (LDL-C) levels are not achieved.These include those with familial hypercholesterolaemia andstatin intolerance. This paper discusses non-statintherapies, such as ezetimibe and the newer Proproteinconvertase subtilisin/kexin type 9 Inhibitors (PCSK9-i).