Avaliação de desfecho de pacientes com dislipidemia em uso de terapia tripla combinada: sinvastatina, ezetimiba e ômega 3 / Outcome evaluation of patients with dyslipidemia using combined triple therapy: simvastatin, ezetimibe and omega 3

Introdução: As doenças crônicas configuram importante problema de saúde coletiva no Brasil, principalmente hipertensão arterial, doenças cardiovasculares, acidentes vasculares cerebrais e diabetes, sendo um dos principais fatores de risco, as dislipidemias. Numerosos estudos clínicos mundiais estabeleceram a associação entre dislipidemia e aumento da mortalidade. O Brasil acompanha este fenômeno internacional. Observa-se uma pobre cultura sanitária sobre o problema, bem como hábitos de vida da população e pouca informação sobre o tema. Considerando este cenário, o presente estudo avaliou a melhoria do perfil lipídico dos pacientes atendidos no Ambulatório de Clínica Médica do Hospital do Servidor Público Municipal em uso de terapia tripla combinada (sinvastatina, ezetimiba e ômega 3). Resultados: apresentou-se uma grande redução do perfil lipídico dos pacientes analisados. A síndrome metabólica foi a comorbidade a qual apresentou a queda mais expressiva do perfil lipídico, chegando ao valor de redução do LDL em 43,99%, colesterol total 33,06% e triglicerídeos 38,77%. Discussão: foi visto uma redução no perfil lipídico de forma significativa, levantando a possibilidade que a terapia tripla pode ter efeitos sinérgicos na redução do colesterol e triglicerídeos. Conclusão: administração da terapia tripla combinada com sinvastatina 40mg, ezetimiba 10mg e ômega 3 (EPA e DHA 900mg ­ 1000mg), não induziu algum efeito tóxico ou evento cardiovascular, assim como efeito adverso novo. Além disso, demonstrou uma redução significante do perfil lipídico. Palavras-chave: Dislipidemia. Estatinas. Doenças crônicas. Promoção da saúde.

Fixed-dose combination of rosuvastatin and ezetimibe: treating hypercholesteremia according to cardiovascular risk.

Introduction: Reducing low-density lipoprotein cholesterol (LDL-C) with lipid-lowering therapies has been associated with a decrease in the frequency of cardiovascular events.Areas covered: A systematic search was conducted on PubMed (MEDLINE), using the MeSH terms [Rosuvastatin] + [Ezetimibe] + [Dyslipidemia] + [treatment]. Original data from clinical trials, prospective and retrospective studies and more useful reviews were selected.Expert opinion: While statins continue to be the cornerstone of dyslipidemia management, many patients do not attain LDL-C targets with high-intensity statins alone. Rosuvastatin is a high-intensity statin with a low risk of adverse effects and drug-drug interactions and proven benefits in the prevention of cardiovascular disease. Rosuvastatin and ezetimibe have complementary mechanisms of action that enhance their ability to reduce LDL-C levels. Various studies have shown that the combination of rosuvastatin 10-40 mg and ezetimibe 10 mg enables considerable reductions in LDL-C (up to 60-75%) with a good safety profile in a broad spectrum of patients with hypercholesterolemia, including those at high risk and those with atherosclerotic cardiovascular disease. In addition, a fixed-dose combination of rosuvastatin and ezetimibe may improve adherence to medication. In this review, the available evidence on the combination of rosuvastatin and ezetimibe is updated.

The comparative impact among different intensive statins and combination therapies with niacin/ezetimibe on carotid intima-media thickness: a systematic review, traditional meta-analysis, and network meta-analysis of randomized controlled trials.

PURPOSE: To compare the impact of different statins therapies on the reduction of carotid intima-media thickness (CIMT) may reflect their cardiovascular benefits which is useful in clinical decision. METHODS: PubMed, EMBASE, Cochrane Library, and Web of Science were searched, and 3539 articles published from 1992 to 2020 were retrieved. CIMT in randomized controlled trials for statins therapies were included for traditional and network meta-analyses analyzed by Stata 16. The quality of included studies was assessed by the Cochrane Collaboration's tool. RESULTS: Thirty-three randomized controlled trials (n=8762) were eligible for network meta-analysis, of which 18 randomized controlled trials (n=5252) were included for comparison between statins and no statins and 11 randomized controlled trials (n=1338) were included for comparison between high-intensity statins or combination with niacin/ezetimibe and moderate/low-intensity statins in 2 traditional meta-analyses. In the traditional meta-analyses, the statins groups significantly reduce CIMT compared to no statins (standard mean difference=-0.207, 95% confidence interval: -0.291 to -0.123, p<0.001), while high-intensity statins or combination with niacin/ezetimibe performed significant CIMT reduction compared to moderate/low-intensity statins (standard mean difference=-0.287, 95% confidence interval: -0.460 to -0.114, p=0.001). In the network meta-analysis, a relative rank for the ability to reduce CIMT was given as follows: combination therapy with niacin (mean rank: 1.7), high-intensity statins, combination therapy with ezetimibe, and moderate/low-intensity statins. CONCLUSION: Statins combined with niacin performed a greater CIMT reduction compared to high-intensity statins alone and combination therapies with ezetimibe. The advantage of niacin-combined statins therapies to improve cardiovascular endpoint needs further validation through randomized controlled trials. CLINICAL TRIAL REGISTRATION: PROSPERO, CRD42020175972.

Comparison of High-Dose Rosuvastatin Versus Low-Dose Rosuvastatin Plus Ezetimibe on Carotid Atherosclerotic Plaque Inflammation in Patients with Acute Coronary Syndrome.

We compared the effects of ezetimibe/rosuvastatin 10/5 mg versus rosuvastatin 20 mg on carotid atherosclerotic plaque inflammation measured by 18FDG PET/CT. Fifty patients with acute coronary syndrome (ACS) were randomly assigned to the ezetimibe/rosuvastatin 10/5 mg and rosuvastatin 20 mg groups. The primary outcome was the percent change in the target-to-background ratio (TBR) of the index vessel in the most diseased segment (MDS), as assessed by 18FDG PET/CT at baseline and at 6 months. Forty-eight patients completed follow-up PET/CT. MDS TBR was - 6.2 ± 13.9% for patients in the ezetimibe/rosuvastatin group and - 10.8 ± 17.7% for those in the rosuvastatin group (difference, 4.6 percentage points; upper limitation of one-sided confidence interval = 13.8; p = 0.60 for noninferiority). In conclusion, combination therapy with ezetimibe 10 mg and rosuvastatin 5 mg compared with rosuvastatin 20 mg did not meet the criterion for non-inferiority for primary outcome, and the present study was not conclusive on whether the former was non-inferior to the latter. Graphical Abstract.

An overview of rosuvastatin/ezetimibe association for the treatment of hypercholesterolemia and mixed dyslipidemia.

Introduction: Although statin therapy is a powerful lipid-lowering strategy, only one-fifth of statin users currently reach their lipid goals. In addition, statin treatment alone has relatively low efficacy in reducing other lipid fractions than low-density lipoprotein-cholesterol (LDL-C). In such cases, most guidelines recommend adding the cholesterol absorption inhibitor ezetimibe.Areas covered: This paper summarizes the main pharmacological characteristics of rosuvastatin and ezetimibe (mechanism of action, metabolism), their lipid-lowering and pleiotropic effects, with particular attention to the clinical effects of the combined drugs in hypercholesterolemia and mixed dyslipidemia patients (such as the ones affected by diabetes mellitus and Acquired Immune Deficiency Syndrome (AIDS)).Expert opinion: The additive effect of rosuvastatin and ezetimibe helps to reach lipid goals in a large number of high-risk patients, while avoiding some safety issues related to high dosages of intensive statin therapy. Patients with diabetes receive additional benefits from ezetimibe as they seem to absorb cholesterol more effectively than non-diabetic ones, because of increased NPC1L1 gene expression. Ezetimibe augments rosuvastatin triglyceride-lowering and anti-inflammatory effects, as well. Taking into account its excellent safety profile and lack of clinically relevant drug-drug interactions, the rosuvastatin/ezetimibe association is a valuable alternative to statin dose uptitration.

Cost-Effectiveness Analysis of Ezetimibe as the Add-on Treatment to Moderate-Dose Rosuvastatin versus High-Dose Rosuvastatin in the Secondary Prevention of Cardiovascular Diseases in China: A Markov Model Analysis.

BACKGROUND: For patients with inadequate control of cholesterol using moderate-dose statins in the secondary prevention of cardiovascular diseases (CVD), either doubling the dose of statins or adding ezetimibe should be considered. The cost-effectiveness of them is unknown in the Chinese context. The aim of this study is to compare the cost and effectiveness of the two regimens, and estimate the incremental cost-effectiveness ratio (ICER). METHODS: A Markov model of five health statuses were used to estimate long-term costs and quality-adjusted life-years (QALYs) of the two treatment regimens from the healthcare perspective. The effectiveness data used to calculate the transition probability was based on a previously published randomized trial. The utility data was gathered from literature and the costs were gathered from the electronic medical record system of West China Hospital in Chinese Yuan (CNY) in 2017 price. One-way sensitivity analysis and probabilistic sensitivity analysis were conducted. RESULTS: The ICER for ezetimibe plus moderate-dose rosuvastatin was 47,102.99 CNY per QALY for 20 years simulation, which did not reach the threshold of per capita gross domestic product (GDP) of 59,660 CNY per QALY in 2017 in China. Non-CVD-related mortality and CVD-related mortality contributed most to the ICER. CONCLUSION: Adding ezetimibe to the moderate-dose statin in secondary prevention for CVD is cost-effective, compared with the high-dose statin in the Chinese context whose low-density lipoprotein cholesterol (LDL-c) was not inadequately controlled by moderate-dose statin alone.

Cost-Effectiveness of Simvastatin Plus Ezetimibe for Cardiovascular Prevention in Patients With a History of Acute Coronary Syndrome: Analysis of Results of the IMPROVE-IT Trial.

BACKGROUND: Simvastatin plus ezetimibe reduced the risk of cardiovascular events in the IMProved Reduction of Outcomes: Vytorin Efficacy International (IMPROVE-IT) study. The aim of this study is to investigate the cost-effectiveness of adding ezetimibe to simvastatin treatment for patients with ACS based on the recently completed IMPROVE-IT trial. METHODS: We constructed a Markov state-transition model to evaluate the costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness (ICER) associated with co-therapy compared with simvastatin alone from a health care perspective. We ran separate base-case analyses assuming a trial-length and longer term follow-up. One-way sensitivity analyses were used to explore uncertainty in model parameters. RESULTS: In the trial-length model, the ICERs compared with simvastatin alone were $114,400 per QALY for the combination therapy. In 5- and 10-year time horizons, the ICERs remained above the cost-effectiveness threshold of $50,000 per QALY. In the lifetime horizon model, The ICER was $45,046 per QALY for combination treatment compared with simvastatin alone. The combination therapy is cost-effective at an 80% decrease in the current branded simvastatin and ezetimibe cost. Probabilistic sensitivity analysis suggested simvastatin and ezetimibe co-therapy would be a cost-effective alternative to simvastatin monotherapy 60.7% of the time. CONCLUSIONS: In our trial-length, 5-year, and 10-year models, the co-therapy was not a cost-effective alternative; however, as follow-up was extended to lifetime, the co-therapy became a cost-effective treatment compared with the simvastatin monotherapy in patients with histories of ACS.

The acute impact of high-dose lipid-lowering treatment on endothelial progenitor cells in patients with coronary artery disease-The REMEDY-EPC early substudy.

RATIONALE AND OBJECTIVE: Endothelial progenitor cells (EPCs) play a role in vascular repair, while circulating endothelial cells (CECs) are biomarkers of vascular damage and regeneration. Statins may promote EPC/CEC mobilization in the peripheral blood. We evaluated whether pre-procedural exposure to different lipid-lowering drugs (statins±ezetimibe) can acutely increase levels/activity of EPCs/CECs in patients with stable coronary artery disease (CAD). METHODS: In a planned sub-analysis of the Rosuvastatin For REduction Of Myocardial DamagE During Coronary AngioplastY (REMEDY) trial, 38 patients with stable CAD on chronic low-dose statin therapy were randomized, in a double-blind, placebo-controlled design, into 4 groups before PCI: i. placebo (n = 11); ii. atorvastatin (80 mg+40 mg, n = 9); iii. rosuvastatin (40 mg twice, n = 9); and iv. rosuvastatin (5 mg) and ezetimibe (10 mg) twice, (n = 9). At baseline and 24 h after treatment-before PCI-, patients underwent blinded analyses of EPCs [colony forming units-endothelial cells (CFU-ECs), endothelial colony-forming cells (ECFCs) and tubulization activity] and CECs in peripheral blood. RESULTS: We found no significant treatment effects on parameters investigated such as number of CECs [Median (IQR): i. 0(0), ii. 4.5(27), iii. 1.9(2.3), iv. 1.9(2.3)], CFU-ECs [Median (IQR): i. 27(11), ii. 19(31), iii. 47(36), iv. 30(98)], and ECFCs [Median (IQR): i. 86(84), ii. 7(84), iii. 8/(42.5), iv. 5(2)], as well as tubulization activity [total tubuli (well), Median (IQR): i. 19(7), ii. 5(4), iii. 25(13), iv. 15(24)]. CONCLUSIONS: In this study, we found no evidence of acute changes in levels or activity of EPCs and CECs after high-dose lipid-lowering therapy in stable CAD patients.

Efficacy of alirocumab according to background statin type and dose: pooled analysis of 8 ODYSSEY Phase 3 clinical trials.

Low-density lipoprotein cholesterol (LDL-C) reductions with the PCSK9 monoclonal antibody alirocumab may be affected by background statin dose due to increased PCSK9 levels with higher statin doses. Data from 8 Phase 3 trials conducted with background statin (n = 4629) were pooled by alirocumab dose (75 or 150 mg every 2 weeks) and control (placebo/ezetimibe), and analyzed by background statin type/dose. Overall, 58.4% received high-dose statins (atorvastatin 40-80 mg, rosuvastatin 20-40 mg, simvastatin 80 mg), 28.6% moderate-dose statins (atorvastatin 20-<40 mg, rosuvastatin 10-<20 mg, simvastatin 40-<80 mg), and 12.9% low-dose statins (atorvastatin <20 mg, rosuvastatin <10 mg, simvastatin <40 mg). Mean baseline PCSK9 levels were higher with high versus moderate and low statin doses (318.5 vs 280.6 ng/mL). Baseline LDL-C levels were similar across pools, regardless of statin intensity. No associations were observed between statin type/dose and LDL-C % change from baseline or % of patients achieving LDL-C goals at Week 24 for alirocumab versus control (interaction P-values non-significant). Incidence of adverse events was similar for alirocumab versus control, except for a higher rate of injection-site reactions with alirocumab. In summary, alirocumab provided consistent LDL-C reductions and was generally well tolerated independent of background statin type/dose.

Aortic Calcification Progression in Heterozygote Familial Hypercholesterolemia.

BACKGROUND: Patients with homozygous and heterozygous familial hypercholesterolemia (HeFH) develop severe aortic calcifications in an age- and gene dosage-dependent manner. The purpose of this study was to determine the rate of progression of aortic calcification in patients with HeFH. METHODS: We performed thoracoabdominal computed tomography scans and quantified aortic calcium (AoCa) score in 16 HeFH patients, all with the null low-density lipoprotein (LDL) receptor DEL15Kb mutation. Patients (12 men, 4 women) were rescanned an average of 8.2 ± 0.8 years after the first scan. RESULTS: Mean LDL cholesterol (LDL-C) during treatment was 2.53 mmol/L; all patients were receiving high-dose statin/ezetimibe; 5 of 16 were receiving evolocumab. Baseline LDL-C was 7.6 ± 1.3 mmol/L. Aortic calcifications increased in all patients in an exponential fashion with respect to age. Age was the strongest correlate of AoCa score. Cholesterol, LDL-C, or age × cholesterol did not correlate with AoCa score or its progression. Control patients (n = 31; 8 male, 23 female; mean age 61 ± 11 years) who underwent virtual colonoscopy were rescanned over the same period and showed an abdominal AoCa score of 1472 ± 2489 compared with 7916 ± 7060 Agatston U (P < 0.001) in patients with HeFH during treatment (mean age, 60 ± 14 years). The rate of progression was 159 vs 312 Agatston U/y in control participants vs those with HeFH. CONCLUSIONS: HeFH patients exhibit accelerated aortic calcification that increases exponentially with age. LDL-C at baseline or during treatment seems to have little effect on the rate of progression of AoCa score. Strategies to prevent aortic calcifications with statins have not met with clinical success and novel approaches are required; statins might also contribute to the process of arterial calcification.

A randomized, controlled comparison of different intensive lipid-lowering therapies in Chinese patients with non-ST-elevation acute coronary syndrome (NSTE-ACS): Ezetimibe and rosuvastatin versus high-dose rosuvastatin.

BACKGROUND: Statin combined with ezetimibe demonstrates significant benefit in lowering low density lipid cholesterol (LDL-C) and cardiovascular events abroad, but whether intermediate intensity statins combined with ezetimibe is superior to high-intensity statin monotherapy in Chinese people is unknown. METHODS: A total of 125 patients were randomly assigned to a intermediate intensity rosuvastatin group (rosuvastatin 10mg/d, n=42), high-dose rosuvastatin group (rosuvastatin 20mg/d, n=41) or combination therapy group (ezetimibe 10mg/d and rosuvastatin 10mg/d, n=42) with a 12-week follow-up. The primary end point was the proportion of patients who achieved the 2011 ESC/EAS LDL-C goal <70mg/dL (1.8mmol/L) at week 12. Secondary end points included changes from baseline in lipids, the occurrence of all cardiovascular events, high-sensitivity C-reactive protein and safety markers. RESULTS: The combination therapy group in the primary end point was significantly higher than rosuvastatin (20mg) and rosuvastatin (10mg) at week 12 (81.0% vs 68.3% vs 33.3%, P<0.001). And the similar change was observed in reducing LDL-C levels at week 12 (67.28% vs 52.80% vs 43.89%, P<0.001). The incidence of drug-related adverse events was much higher in the rosuvastatin 20mg group than the rosuvastatin 10mg group and the combination therapy group (17.0% vs 2.4% vs 4.8%, P<0.05). CONCLUSIONS: The combination of rosuvastatin 10mg/ezetimibe 10mg was an effectively alternative therapy superior to rosuvastatin 20mg or 10mg with a greater effect on lowering LDL-C and a lower incidence of drug-related adverse events in Chinese patients.

Influence of ezetimibe in addition to high-dose atorvastatin therapy on plaque composition in patients with ST-segment elevation myocardial infarction assessed by serial: Intravascular ultrasound with iMap: the OCTIVUS trial.

BACKGROUND: The aim of this study was to examine the influence of ezetimibe in addition to atorvastatin on plaque composition in patients with first-time ST-segment Elevation Myocardial Infarction treated with primary percutaneous intervention. METHODS: Eighty-seven patients were randomized (1:1) to ezetimibe 10mg or placebo in addition to Atorvastatin 80mg. Intravascular ultrasound with iMap was performed at baseline and after 12months in a non-infarct-related artery. Primary endpoint was change in necrotic core (NC). Secondary endpoints were total atheroma volume (TAV) and percentage atheroma volume (PAV). RESULTS: NC did not change significantly: ezetimibe group 24.9 (11.9, 51.3) mm3 to 24.9 (15.3, 54.5) mm3, p=0.76, placebo group 29.4 (16.3, 78.5) mm3 to 32.0 (16.0, 88.7) mm3, p=0.30, (p=0.35 between groups). TAV was reduced in the ezetimibe group only: ezetimibe (200.0 (135.6, 311.9) mm3 to 189.3 (126.4, 269.1) mm3, p<0.001) compared to placebo group (218.4 (163.5, 307.9) mm3 to 212.2 (149.9, 394.8) mm3, p=0.07) (p=0.56 between groups). PAV was reduced in the ezetimibe group only (40.1±8.6% to 39.2±9.0%, p=0.036) compared to placebo group (43.3±9.4% to 42.2±10.7%, p=0.07), p=0.91 between groups. CONCLUSIONS: Ezetimibe in addition to atorvastatin therapy did not influence NC content, but was associated with regression of coronary atherosclerosis.

Inhibitory effect of ezetimibe can be prevented by an administration interval of 4 h between α-tocopherol and ezetimibe.

Tocopherol is used not only as an ethical drug but also as a supplement. In 2008, it was reported that α-tocopherol is partly transported via an intestinal cholesterol transporter, Niemann-Pick C1-Like 1 (NPC1L1). Ezetimibe, a selective inhibitor of NPC1L1, is administered for a long time to inhibit cholesterol absorption and there is a possibility that the absorption of α-tocopherol is also inhibited by ezetimibe. This study investigated the influence of ezetimibe on the absorption of α-tocopherol with single administration and long-term administration. An approach to avoid its undesirable consequence was also examined. α-Tocopherol (10 mg/kg) and ezetimibe (0.1 mg/kg) were administered to rats, and the plasma concentration profiles of α-tocopherol and tissue concentrations were investigated. The plasma concentration of α-tocopherol was decreased by the combination use of ezetimibe in the case of concurrent single administration. On the other hand, inhibition of the absorption of α-tocopherol was prevented by an administration interval of 4 h. In a group of rats administered for 2 months with a 4 h interval, not only the plasma concentration but also the liver concentration was increased compared with those in a group with concurrent combination intake of α-tocopherol and ezetimibe. The absorption of α-tocopherol was inhibited by ezetimibe. The inhibitory effect of ezetimibe can be prevented by an administration interval of 4 h, although ezetimibe is a medicine of enterohepatic circulation. Attention should be paid to the use of ezetimibe and components of NPC1L1 substrates such as α-tocopherol. Copyright © 2016 John Wiley & Sons, Ltd.

The Treatment of Disorders of Lipid Metabolism.

BACKGROUND: Disorders of lipid metabolism are very common. They play an important role in the pathogenesis of atherosclerosis and can be effectively treated by lifestyle changes and drugs. METHODS: This review is based on pertinent literature retrieved by a selective search. RESULTS: The main disorders of lipid metabolism are LDL-hypercholesterolemia, hypertriglyceridemia, mixed hyperlipoproteinemia, and low HDL cholesterol. The lipoprotein(a) level can also be elevated either in isolation or in combination with other disorders of lipid metabolism. According to the current European recommendations, an LDL-cholesterol target value should be defined on the basis of the overall cardiovascular risk. If this risk is very high, as in patients with documented atherosclerosis, the target value should be set at <70 mg/dL (<1.8 mmol/L). If the risk is lower, higher target values can be set: <100 mg/dL (<2.6 mmol/L) or <115 mg/dL (<3.0 mmol/L). Lifestyle changes are an effective treatment mainly for patients with hypertriglyceridemia and mixed disorders of lipid metabolism. Lowering the LDL-cholesterol concentration with statins is by far the most important type of pharmacotherapy. Patients who cannot tolerate statins or whose cholesterol level is not adequately lowered can be given ezetimibe instead. PCSK9 antibodies have been available since the autumn of 2015; they can apparently lower the LDL-cholesterol level by more than 50% , but no endpoint trials have yet been reported. At present, they should only be given to carefully selected patients. Fibrates and omega-3 fatty acids have been found to prevent cardiovascular events in monotherapy trials but yield no added benefit when given together with statins. The design of these trials was faulty, however, and the utility of such combinations in patients with mixed disorders of lipid metabolism or hypertriglyceridemia cannot yet be definitively assessed. CONCLUSION: There is a causal relationship between hypercholesterolemia and the risk of vascular and cardiovascular events. A reduction of LDL cholesterol lessens the risk of cardiovascular events.

[FIXED COMBINATION ATORVASTATIN-EZETIMIBE (ATOZET®)]. / Combinaison fixe atorvastatine-ézétimibe (Atozet®).

Cardiovascular prevention in subjects at high or very high risk requires a drastic reduction in LDL cholesterol according to the concept "the lower, the better". The combination of an inhibitor of cholesterol synthesis and a selective inhibitor of intestinal absorption results in a complementary and synergistic LDL-lowering activity. Besides a first fixed combination ezetimibe-simvastatin (Inegy®), a new fixed combination is presented, Atozet® that combines atorvastatin and ezetimibe. Because atorvastatin is more potent than simvastatin, this novel fixed combination should facilitate reaching therapeutic goals in terms of LDL cholesterol amongst patients with severe hypercholesterolaemia and/or at high or very high cardiovascular risk.

Additive effects of plant sterols supplementation in addition to different lipid-lowering regimens.

OBJECTIVE: Plant sterol (PS) supplementation has been widely used alone or combined with lipid-lowering therapies (LLTs) to reduce low-density lipoprotein (LDL) cholesterol. The effects of PS added to high-intensity LLT are less reported, especially regarding the effects on cholesterol synthesis and absorption. METHODS: A prospective, randomized, open-label study, with parallel arms and blinded end points was designed to evaluate the effects of addition of PS to LLT on LDL cholesterol, markers of cholesterol synthesis, and absorption. Eighty-six patients of both genders were submitted to a 4-wk run-in period with atorvastatin 10 mg (baseline). Following, subjects received atorvastatin 40 mg, ezetimibe 10 mg, or combination of both drugs for another 4-wk period (phase I). In phase II, capsules containing 2.0 g of PSs were added to previous assigned treatments for 4 wk. Lipids, apolipoproteins, plasma campesterol, ß-sitosterol, and desmosterol levels were assayed at all time points. Within and between-group analyses were performed. RESULTS: Compared with baseline, atorvastatin 40 mg reduced total and LDL cholesterol (3% and 22%, respectively, P < .05), increased ß-sitosterol, campesterol/cholesterol, and ß-sitosterol/cholesterol ratios (39%, 47%, and 32%, respectively, P < .05); ezetimibe 10 mg reduced campesterol and campesterol/cholesterol ratio (67% and 70%, respectively, P < .05), and the combined therapy decreased total and LDL cholesterol (22% and 38%, respectively, P < .05), campesterol, ß-sitosterol, and campesterol/cholesterol ratio (54%, 40%, and 27%, P < .05). Addition of PS further reduced total and LDL cholesterol by ∼ 7.7 and 6.5%, respectively, in the atorvastatin therapy group and 5.0 and 4.0% in the combined therapy group (P < .05, for all), with no further effects in absorption or synthesis markers. CONCLUSIONS: PS added to LLT can further improve lipid profile, without additional effects on intestinal sterol absorption or synthesis.

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)