Pharmacokinetic Interactions Between the Fixed-Dose Combination of Ezetimibe/Rosuvastatin 10/20 Mg and the Fixed-Dose Combination of Telmisartan/Amlodipine 80/5 Mg in Healthy Subjects.

Background: Management of hypertension and hyperlipidemia, which are common comorbid risk factors for cardiovascular diseases, require multiple medications. The development of a fixed-dose combination (FDC) containing ezetimibe, rosuvastatin, telmisartan, and amlodipine aims to enhance patient adherence and persistence, but the potential interactions among the four medications have not been studied. This study aimed to evaluate the pharmacokinetic (PK) interactions between the FDC of ezetimibe/rosuvastatin 10/20 mg (ER) and the FDC of telmisartan/amlodipine 80/5 mg (TA). Methods: An open-label, single-sequence, three-period, three-treatment crossover study was conducted in healthy male subjects. All subjects received ER for 7 days, TA for 9 days and ER combined with TA for 7 days during each treatment period. For PK analysis of total/free ezetimibe, rosuvastatin, telmisartan, and amlodipine, serial blood samples were collected for 24 hours at steady state. Safety profiles were assessed throughout the study. Results: Thirty-eight subjects were enrolled, and 34 subjects completed the study. The systemic exposure to each active ingredient after coadministration of the two FDCs was similar to that after each FDC alone. The geometric mean ratios and 90% confidence intervals for the maximum plasma concentration (µg/L) and the area under the plasma concentration-time curve (h·µg/L) of the combination therapy to monotherapy, assessed at steady state, were as follows: total ezetimibe, 1.0264 (0.8765-1.2017) and 0.9359 (0.7847-1.1163); free ezetimibe, 1.5713 (1.2821-1.9257) and 0.9941 (0.8384-1.1788); rosuvastatin, 2.1673 (1.7807-2.6379) and 1.1714 (0.9992-1.3733); telmisartan, 1.0745 (0.8139-1.4186) and 1.1057 (0.8379-1.4591); and amlodipine, 0.9421 (0.8764-1.0126) and 0.9603 (0.8862-1.0405). Both combination therapy and monotherapy were well tolerated by the subjects. Conclusion: The coadministration of ezetimibe/rosuvastatin 10/20 mg and ezetimibe/rosuvastatin 10/20 mg was well tolerated in healthy subjects, and the PK interaction between those two FDCs was not clinically significant.

Association of Use and Dose of Lipid-Lowering Therapy Post Acute Myocardial Infarction With 5-Year Survival in Older Adults.

BACKGROUND: Older people are underrepresented in randomized trials. The association between lipid-lowering therapy (LLT) and its intensity after acute myocardial infarction and long-term mortality in this population deserves to be assessed. METHODS: The FAST-MI (French Registry of Acute ST-Elevation or Non-ST-Elevation Myocardial Infarction) program consists of nationwide French surveys including all patients admitted for acute myocardial infarction ≤48 hours from onset over a 1- to 2-month period in 2005, 2010, and 2015, with long-term follow-up. Numerous data were collected and a centralized 10-year follow-up was organized. The present analysis focused on the association between prescription of LLT (atorvastatin ≥40 mg or equivalent, or any combination of statin and ezetimibe) and 5-year mortality in patients aged ≥80 years discharged alive. Cox multivariable analysis and propensity score matching were used to adjust for baseline differences. RESULTS: Among the 2258 patients aged ≥80 years (mean age, 85±4 years; 51% women; 39% ST-segment elevation myocardial infarction; 58% with percutaneous coronary intervention), 415 were discharged without LLT (18%), 866 with conventional doses (38%), and 977 with high-dose LLT (43%). Five-year survival was 36%, 47.5%, and 58%, respectively. Compared with patients without LLT, high-dose LLT was significantly associated with lower 5-year mortality (adjusted hazard ratio, 0.78 [95% CI, 0.66-0.92]), whereas conventional-intensity LLT was not (adjusted hazard ratio, 0.93 [95% CI, 0.80-1.09]). In propensity score-matched cohorts (n=278 receiving high-intensity LLT and n=278 receiving no statins), 5-year survival was 52% with high-intensity LLT at discharge and 42% without statins (hazard ratio, 0.78 [95% CI, 0.62-0.98]). CONCLUSIONS: In these observational cohorts, high-intensity LLT at discharge after acute myocardial infarction was associated with reduced all-cause mortality at 5 years in an older adult population. These results suggest that high-intensity LLT should not be denied to patients on the basis of old age. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT00673036, NCT01237418, and NCT02566200.

Comparative Safety and Efficacy of Low/Moderate-Intensity Statin plus Ezetimibe Combination Therapy vs. High-Intensity Statin Monotherapy in Patients with Atherosclerotic Cardiovascular Disease: An Updated Meta-Analysis.

AIM: Statin therapy is considered the gold standard for treating hypercholesterolemia. This updated meta-analysis aims to compare the efficacy and safety of a low/moderate-intensity statin in combination with ezetimibe compared with high-intensity statin monotherapy in patients with atherosclerotic cardiovascular disease (ASCVD). METHODS: A systematic search of two databases (PubMed and Cochrane CENTRAL) was conducted from inception to January 2023 and a total of 21 randomized clinical trials (RCTs) were identified and included in the analysis. Data were pooled using Hedges's g and a Mantel-Haenszel random-effects model to derive standard mean differences (SMDs) and 95% confidence intervals (Cis). The primary outcome studied was the effect of these treatments on lipid parameters and safety events. RESULTS: The results revealed that combination therapy was more effective in reducing low-density lipoprotein cholesterol (LDL-C) levels (SMD= - 0.41; CI - 0.63 to - 0.19; P = 0.0002). There was no significant change in the levels of high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), triglyceride (TG), high-sensitivity C-reactive protein (hs-CRP), Apo A1, or Apo B. The safety of these treatments was assessed by the following markers alanine aminotransferase (ALT), aspartate aminotransferase (AST), and creatine phosphokinase (CK), and a significant difference was only observed in CK (SMD: - 0.81; CI - 1.52 to - 0.10; P = 0.02). CONCLUSION: This meta-analysis demonstrated that the use of low/moderate-intensity statin combination therapy significantly reduced LDL-C levels compared with high-intensity statin monotherapy, making it preferable for patients with related risks. However, further trials are encouraged to evaluate potential adverse effects associated with combined therapy.

Risk of Hemorrhagic Stroke among Patients Treated with High-Intensity Statins versus Pitavastatin-Ezetimibe: A Population Based Study.

High-intensity statin (HIS) is recommended for high-risk patients in current guidelines. However, the risk of hemorrhagic stroke (HS) with HIS is a concern for Asians. Pitavastatin carries pharmacological differences compared with other statins. We compared the risk of HS in patients treated with pitavastatin-ezetimibe vs. HIS. We conducted a population-based, propensity score-matched cohort study using data from the Taiwan National Health Insurance Research Database. From January 2013 to December 2018, adults (≥ 18 years) who received pitavastatin 2-4 mg/day plus ezetimibe 10 mg/day (combination group, N = 3,767) and those who received atorvastatin 40 mg/day or rosuvastatin 20 mg/day (HIS group, N = 37,670) were enrolled. The primary endpoint was HS. We also assessed the difference of a composite safety endpoint of hepatitis or myopathy requiring hospitalization and new-onset diabetes mellitus. Multivariable Cox proportional hazards model was used to evaluate the relationship between study endpoints and different treatment. After a mean follow-up of 3.05 ± 1.66 years, less HS occurred in combination group (0.74%) than in HIS group (1.35%) [adjusted hazard ratio (aHR) 0.65, 95% confidence interval (CI) 0.44-0.95]. In subgroup analysis, the lower risk of HS in combination group was consistent among all pre-specified subgroups. There was no significant difference of the composite safety endpoint between the 2 groups (aHR 0.91, 95% CI 0.81-1.02). In conclusion, pitavastatin-ezetimibe combination treatment had less HS compared with high-intensity atorvastatin and rosuvastatin. Pitavastatin-ezetimibe may be a favorable choice for Asians who need strict lipid control but with concern of HS.

Comparison of the Efficacy of Ezetimibe Combination Therapy and High-Intensity Statin Monotherapy in Type 2 Diabetes.

CONTEXT: Low-density lipoprotein cholesterol (LDL-C)-lowering therapy is considerably important in preventing cardiovascular disease (CVD) among patients with diabetes. Studies comparing CVD, stroke, and mortality outcomes of low- or moderate-intensity statins with ezetimibe combination therapy and high-intensity statin monotherapy in patients with diabetes remain lacking. OBJECTIVE: This study compared the primary prevention effect of myocardial infarction (MI), stroke, and all-cause death between combination therapy of low- or moderate-intensity statins and ezetimibe and high-intensity statin monotherapy in patients with diabetes using the Korean National Health Insurance claims database. METHODS: Patients aged ≥20 years with type 2 diabetes and dyslipidemia were enrolled. The combination therapy of low- or moderate-intensity statin and ezetimibe was compared with high-intensity statin monotherapy after a propensity score-matched analysis. The incidence of composite outcomes consisting of MI, stroke, and all-cause death and each component were analyzed. RESULTS: In moderate-intensity statin therapy with ezetimibe combination therapy, LDL-C (74 ± 37.9 mg/dL vs 80.8 ± 38.8 mg/dL, P < .001) and the incidence of composite outcomes were lower (hazard ratio 0.85, 95% CI 0.74-0.98) than those in high-intensity statin monotherapy. Meanwhile, no significant difference was observed in the LDL-C levels and composite outcomes between low-intensity statins with ezetimibe combination therapy and high-intensity statin monotherapy. CONCLUSION: Adding ezetimibe to a moderate-intensity statin in patients with type 2 diabetes has a greater LDL-C-lowering effect and greater primary prevention of composite outcomes than that of high-intensity statin monotherapy.

Efficacy and Safety of Single-Pill Combination of Rosuvastatin and Ezetimibe in Chinese Patients with Primary Hypercholesterolemia Inadequately Controlled by Statin Treatment (ROZEL): A Randomized, Double-Blind, Double Dummy, Active-Controlled Phase 3 Clinical Trial.

INTRODUCTION: Many patients with primary hypercholesterolemia do not achieve their plasma low-density lipoprotein cholesterol (LDL-C) goals with statin alone under a recommended dose of statin (e.g., 10 mg rosuvastatin) in China. The objective of this phase III study was to evaluate the efficacy and safety of a new single-pill combination (SPC) of rosuvastatin 10 mg/ezetimibe 10 mg (R10/E10) in this population. METHODS: This was a randomized, double-blind, double-dummy, active-controlled study in patients with primary hypercholesterolemia inadequately controlled with statin alone. The participants were randomized 1:1 to receive SPC R10/E10 or R10. The primary objective was to demonstrate the superiority of SPC R10/E10 vs. R10 in reducing the LDL-C levels after 8 weeks. RESULTS: This trial randomized 305 participants to SPC R10/E10 (n = 153) and R10 (n = 152). The superiority of SPC R10/E10 over R10 was demonstrated with the least square (LS) mean difference of percent change in LDL-C from baseline to week 8: - 13.85% (95% confidence interval [CI] - 20.15% to - 7.56%, P < 0.0001). The proportion of participants who achieved the LDL-C target (< 2.6 mmol/l) at week 8 was larger with SPC R10/E10 (n = 80, 54.1%) than with R10 (n = 42, 29.2%) (Odds ratio = 2.80, 95% CI 1.70 to 4.61, P < 0.0001). No unexpected safety findings were reported. CONCLUSION: The results suggest that SPC R10/E10 improve LDL-C reduction and goal achievement in Chinese patients with primary hypercholesterolemia not adequately controlled on statin therapy, without new safety findings. TRIAL REGISTRATION: ClinicalTrials.gov (NCT04669041).

Bioequivalence Study of Ezetimibe Tablets After a Single Oral Dose of 10 mg in Healthy Japanese Subjects Under Fasting Conditions.

This study compared the pharmacokinetic and safety profiles between a new generic and a branded reference product of 10-mg ezetimibe (EZE) tablets in 24 healthy Japanese male volunteers under fasting conditions, obtaining sufficient evidence for the marketing approval of the new generic product. The bioequivalence study was conducted with an open-label, 2 × 2, single-dose, crossover design in which the test and reference products were administered to volunteers after fasting for ≥10 hours. Blood samples were collected 24 times before to 72 hours after the administration of the investigational drug. We evaluated the peak drug concentration and the area under the plasma concentration-time curve up to the last measured concentration of EZE, EZEG, and total EZE (EZE + ezetimibe glucuronide [EZEG]). The 90% confidence intervals of the geometric mean ratios for peak drug concentration and area under the plasma concentration-time curve up to the last measured concentration of the test and reference products fell within the bioequivalence limits of 0.80 to 1.25 for EZE, EZEG, and total EZE. The test and reference products were well tolerated, and no adverse events occurred during the study. The test product was bioequivalent to the reference product.

Detecção de microalbuminúria em pacientes diabéticos tipo 2 como preditor de lesão endotelial / Detection of microalbuminuria in type 2 diabetic patients as a predictor of endothelial injury

Introdução: A detecção da microalbuminúria tem sido amplamente estudada como um indicador precoce de lesão endotelial em pacientes com diabetes tipo 2. A microalbuminúria é caracterizada pela presença de níveis aumentados de albumina na urina, refletindo disfunção endotelial e comprometimento da barreira glomerular. A lesão endotelial é um importante fator de risco para o desenvolvimento de complicações vasculares, como doença arterial coronariana, acidente vascular cerebral e insuficiência renal. Objetivos: Investigar a detecção da microalbuminúria através do teste rápido de urina de fita, como um preditor de lesão endotelial em pacientes diabéticos tipo 2. Métodos: Estudo observacional, analítico e transversal, realizado no Ambulatório de Geriatria do Hospital do Servidor Público Municipal de São Paulo. A amostra foi composta por 36 pacientes diabéticos tipo 2, avaliados entre dezembro de 2022 e abril de 2023. Todos os pacientes consentiram e assinaram o Termo de Consentimento Livre e Esclarecido. Resultados: Perfil composto principalmente por mulheres, com idade média de 76,9 anos e tempo médio de diagnóstico de 12,5 anos. A maioria dos pacientes não apresentava complicações macro ou microvasculares. Entre aqueles com complicações macrovasculares(19,4%), a doença arterial coronariana foi a mais comum. Apenas 8,3% dos pacientes possuíam clearence de creatinina abaixo de 30ml/min e os níveis de albuminuria avaliados pelo teste rápido estavam alterados em 52,8% dos participantes. Conclusão: Embora a microalbuminúria possa ser um indicador importante de lesão endotelial em pacientes diabéticos tipo 2 em trabalhos prévios, nossa pesquisa não conseguiu demonstrar associação com relevância estatística entre presença de complicação macro e microvascular e microalbuminúria, provavelmente devido ao número reduzido de pacientes analisados. Ainda assim, a detecção da microalbuminúria deve ser considerada na avaliação e monitoramento desses pacientes, visando uma intervenção precoce e o controle adequado das complicações vasculares. Palavras-chave: Diabetes Mellitus. Microalbuminúria. Angiopatias Diabéticas. Controle glicêmico. Testes de Função Renal.

Non-statin lipid-lowering therapy over time in very-high-risk patients: effectiveness of fixed-dose statin/ezetimibe compared to separate pill combination on LDL-C.

BACKGROUND: Many patients at very-high atherosclerotic cardiovascular disease risk do not reach guideline-recommended targets for LDL-C. There is a lack of data on real-world use of non-statin lipid-lowering therapies (LLT) and little is known on the effectiveness of fixed-dose combinations (FDC). We therefore studied prescription trends in oral non-statin LLT and their effects on LDL-C. METHODS: A retrospective analysis was conducted of electronic medical records of outpatients at very-high cardiovascular risk treated by general practitioners (GPs) and cardiologists, and prescribed LLT in Germany between 2013 and 2018. RESULTS: Data from 311,242 patients were analysed. Prescriptions for high-potency statins (atorvastatin and rosuvastatin) increased from 10.4% and 25.8% of patients treated by GPs and cardiologists, respectively, in 2013, to 34.7% and 58.3% in 2018. Prescription for non-statin LLT remained stable throughout the period and low especially for GPs. Ezetimibe was the most prescribed non-statin LLT in 2018 (GPs, 76.1%; cardiologists, 92.8%). Addition of ezetimibe in patients already prescribed a statin reduced LDL-C by an additional 23.8% (32.3 ± 38.4 mg/dL), with a greater reduction with FDC [reduction 28.4% (40.0 ± 39.1 mg/dL)] as compared to separate pills [19.4% (27.5 ± 33.8 mg/dL)]; p < 0.0001. However, only a small proportion of patients reached the recommended LDL-C level of < 70 mg/dL (31.5% with FDC and 21.0% with separate pills). CONCLUSIONS: Prescription for high-potency statins increased over time. Non-statin LLT were infrequently prescribed by GPs. The reduction in LDL-C when statin and ezetimibe were prescribed in combination was considerably larger for FDC; however, a large proportion of patients still remained with uncontrolled LDL-C levels.

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.

Main differences between two highly effective lipid-lowering therapies in subclasses of lipoproteins in patients with acute myocardial infarction.

BACKGROUND: Large observational studies have shown that small, dense LDL subfractions are related to atherosclerotic cardiovascular disease. This study assessed the effects of two highly effective lipid-lowering therapies in the atherogenic subclasses of lipoproteins in subjects with ST-segment elevation myocardial infarction (STEMI). METHODS: Patients of both sexes admitted with their first myocardial infarction and submitted to pharmacoinvasive strategy (N = 101) were included and randomized using a central computerized system to receive a daily dose of simvastatin 40 mg plus ezetimibe 10 mg or rosuvastatin 20 mg for 30 days. Intermediate-density lipoprotein (IDL) and low-density lipoprotein (LDL) subfractions were analysed by polyacrylamide gel electrophoresis (Lipoprint System) on the first (D1) and 30th days (D30) of lipid-lowering therapy. Changes in LDL and IDL subfractions between D1 and D30 were compared between the lipid-lowering therapies (Mann-Whitney U test). RESULTS: The classic lipid profile was similar in both therapy arms at D1 and D30. At D30, the achievement of lipid goals was comparable between lipid-lowering therapies. Cholesterol content in atherogenic subclasses of LDL (p = 0.043) and IDL (p = 0.047) decreased more efficiently with simvastatin plus ezetimibe than with rosuvastatin. CONCLUSIONS: Lipid-lowering therapy with simvastatin plus ezetimibe was associated with a better pattern of lipoprotein subfractions than rosuvastatin monotherapy. This finding was noted despite similar effects in the classic lipid profile and may contribute to residual cardiovascular risk. TRIAL REGISTRATION: ClinicalTrials.gov , NCT02428374, registered on 28/09/2014.

Race/ethnic and sex differences in the initiation of non-statin lipid-lowering medication following myocardial infarction.

BACKGROUND: Adults with atherosclerotic cardiovascular disease (ASCVD) at very high-risk for recurrent events who have low-density lipoprotein cholesterol ≥ 70 mg/dL despite maximally-tolerated statin therapy are recommended to initiate ezetimibe or a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor. OBJECTIVE: Compare the initiation of ezetimibe and a PCSK9 inhibitor after a myocardial infarction (MI) among very high-risk ASCVD patients by race/ethnicity and sex. METHODS: We analyzed data from 374,786 adults ≥ 66 years of age with Medicare fee-for-service coverage who had an MI between July 1, 2015 and December 31, 2018, were not taking ezetimibe or a PCSK9 inhibitor, and had very high-risk ASCVD defined by the 2018 American Heart Association/American College of Cardiology multi-society cholesterol guideline. Pharmacy claims through December 31, 2018 were used to determine ezetimibe and PCSK9 inhibitor initiation. RESULTS: Overall, 6980 (1.9%) beneficiaries initiated ezetimibe, and 1433 (0.4%) initiated a PCSK9 inhibitor. Adjusted hazard ratios (aHR) for ezetimibe initiation among non-Hispanic Black, Hispanic, and Asian versus non-Hispanic White beneficiaries were 0.77 (95% confidence interval [95%CI]: 0.70-0.86), 0.92 (95%CI: 0.76-1.11) and 0.73 (95%CI: 0.59-0.89), respectively. Compared to non-Hispanic White beneficiaries, the aHRs for PCSK9 inhibitor initiation were 0.63 (95%CI: 0.48-0.81) among non-Hispanic Black, 0.70 (95%CI: 0.43-1.13) among Hispanic, and 0.93 (95%CI: 0.62-1.39) among Asian beneficiaries. The aHRs for ezetimibe and PCSK9 inhibitor initiation comparing women to men were 1.11 (95%CI: 1.06-1.17) and 1.13 (95%CI: 1.01-1.25), respectively. CONCLUSION: There are race/ethnic and sex disparities in the initiation of ezetimibe and a PCSK9 inhibitor following MI among very high-risk ASCVD patients.

Formulation and Evaluation of Linum usitatissimum Mucilage-Based Nanoparticles for Effective Delivery of Ezetimibe.

INTRODUCTION: The aim of current study was to prepare Linum usitatissimum mucilage (LUM) based nanoparticles, capable of encapsulating hydrophobic drug ezetimibe as nanocarriers. METHODS: Solvent evaporation and nanoprecipitation techniques were used to develop nanoparticles by encapsulating ezetimibe in the articulated matrix of polysaccharide fractions. Developed nanoparticles were characterized to determine the particle size, zeta potential, polydispersibility index (PDI), and entrapment efficiency (EE). Morphology and physicochemical characterization were carried out through SEM, FTIR, PXRD and thermal analysis. Saturation solubility and in vitro release studies were also performed. Safety assessment of ezetimibe loaded nanoparticles was evaluated via oral acute toxicity study. RESULTS: The mean particle size, zeta potential, PDI and EE for emulsion solvent evaporation were 683.6 nm, -28.3 mV, 0.39, 63.7% and for nanoprecipitation were 637.7 nm, 0.07, -27.1 mV and 80%, respectively. Thermal analysis confirmed enhanced thermal stability, whereas PXRD confirmed amorphous nature of drug. Saturation solubility (p-value <0.05) demonstrated improved solubility of drug when enclosed in linseed nanoparticles. Nanoprecipitation surpasses emulsion solvent evaporation in dissolution test by possessing smaller size. Acute oral toxicity study indicated no significant changes in behavioral, clinical or histopathological parameters of control and experimental groups. CONCLUSION: The in vitro release of ezetimibe was augmented by enhancing aqueous solubility through devised nanoparticles. Thus, linseed mucilage could act as biopolymer in the fabrication of nanoparticle formulation. The acute oral toxicological investigations provided evidence that LUMNs were safe after oral administration.

Identification of drugs associated with reduced severity of COVID-19 - a case-control study in a large population.

Background: Until coronavirus disease 2019 (COVID-19) drugs specifically developed to treat COVID-19 become more widely accessible, it is crucial to identify whether existing medications have a protective effect against severe disease. Toward this objective, we conducted a large population study in Clalit Health Services (CHS), the largest healthcare provider in Israel, insuring over 4.7 million members. Methods: Two case-control matched cohorts were assembled to assess which medications, acquired in the last month, decreased the risk of COVID-19 hospitalization. Case patients were adults aged 18 to 95 hospitalized for COVID-19. In the first cohort, five control patients, from the general population, were matched to each case (n=6202); in the second cohort, two non-hospitalized SARS-CoV-2 positive control patients were matched to each case (n=6919). The outcome measures for a medication were: odds ratio (OR) for hospitalization, 95% confidence interval (CI), and the p-value, using Fisher's exact test. False discovery rate was used to adjust for multiple testing. Results: Medications associated with most significantly reduced odds for COVID-19 hospitalization include: ubiquinone (OR=0.185, 95% CI [0.058 to 0.458], p<0.001), ezetimibe (OR=0.488, 95% CI [0.377 to 0.622], p<0.001), rosuvastatin (OR=0.673, 95% CI [0.596 to 0.758], p<0.001), flecainide (OR=0.301, 95% CI [0.118 to 0.641], p<0.001), and vitamin D (OR=0.869, 95% CI [0.792 to 0.954], p<0.003). Remarkably, acquisition of artificial tears, eye care wipes, and several ophthalmological products were also associated with decreased risk for hospitalization. Conclusions: Ubiquinone, ezetimibe, and rosuvastatin, all related to the cholesterol synthesis pathway were associated with reduced hospitalization risk. These findings point to a promising protective effect which should be further investigated in controlled, prospective studies. Funding: This research was supported in part by the Intramural Research Program of the National Institutes of Health, NCI.

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.

Clinical development of bempedoic acid: phase 2 and phase 3 clinical trials. / Desarrollo clínico de ácido bempedoico: estudios fase 2 y fase 3.

We review all the phase II and III studies carried out with bempedoic acid at the dose of 180mg, alone or in combination with different lipid-lowering drugs and in different subgroups of patients that unequivocally show the efficacy and safety of the drug. We point out some of the potential advantages of its use in clinical practice in patients with statin intolerance and the efficacy in reducing LDL-c when combined with statins, and with statins and ezetimibe, as well as in reducing inflammation markers pending the results of the CV Clear Outcomes trial that will end in 2022.

Ezetimibe-Loaded Nanostructured Lipid Carrier Based Formulation Ameliorates Hyperlipidaemia in an Experimental Model of High Fat Diet.

Ezetimibe (EZE) possesses low aqueous solubility and poor bioavailability and in addition, its extensive hepatic metabolism supports the notion of developing a novel carrier system for EZE. Ezetimibe was encapsulated into nanostructured lipid carriers (EZE-NLCs) via a high pressure homogenization technique (HPH). A three factor, two level (23) full factorial design was employed to study the effect of amount of poloxamer 188 (X1), pressure of HPH (X2) and number of HPH cycle (X3) on dependent variables. Particle size, polydispersity index (PDI), % entrapment efficiency (%EE), zeta potential, drug content and in-vitro drug release were evaluated. The optimized formulation displays pragmatic inferences associated with particle size of 134.5 nm; polydispersity index (PDI) of 0.244 ± 0.03; zeta potential of -28.1 ± 0.3 mV; % EE of 91.32 ± 1.8% and % CDR at 24-h of 97.11%. No interaction was observed after X-ray diffraction (XRD) and differential scanning calorimetry (DSC) studies. EZE-NLCs (6 mg/kg/day p.o.) were evaluated in the high fat diet fed rats induced hyperlipidemia in comparison with EZE (10 mg/kg/day p.o.). Triglyceride, HDL-c, LDL-c and cholesterol were significantly normalized and histopathological evaluation showed normal structure and architecture of the hepatocytes. The results demonstrated the superiority of EZE-NLCs in regard to bioavailability enhancement, dose reduction and dose-dependent side effects.

Effect of PCSK9 inhibitors on pulse wave velocity and monocyte-to-HDL-cholesterol ratio in familial hypercholesterolemia subjects: results from a single-lipid-unit real-life setting.

AIMS: Subjects with familial hypercholesterolemia (FH) are characterized by an increased amount of low-density lipoprotein cholesterol (LDL-C) that promotes a continuous inflammatory stimulus. Our aim was to evaluate the effect of PCSK9-i on inflammatory biomarkers, neutrophil-to-lymphocyte ratio, monocyte-to-high-density lipoprotein ratio (MHR), and on early atherosclerosis damage analyzed by pulse wave velocity (PWV) in a cohort of FH subjects. METHODS: In this prospective observational study, we evaluated 56 FH subjects on high-intensity statins plus ezetimibe and with an off-target LDL-C. All subjects were placed on PCSK9-i therapy and obtained biochemical analysis as well as PWV evaluation at baseline and after six months of PCSK9-i therapy. RESULTS: After six months of add-on PCSK9-i therapy, only 42.9% of FH subjects attained LDL-C targets. As expected, a significant reduction of LDL-C (- 49.61%, p < 0.001) was observed after PCSK9-i therapy. Neutrophil count (NC) and MHR were reduced by PCSK9-i (-13.82% and -10.47%, respectively, p value for both < 0.05) and PWV significantly decreased after PCSK9-i therapy (- 20.4%, p < 0.05). Finally, simple regression analyses showed that ∆ PWV was significantly associated with ∆ LDL-C (p < 0.01), ∆ NC and ∆ MHR (p value for both < 0.05). CONCLUSIONS: In conclusion, PCSK9-i therapy significantly improved lipid and inflammatory profiles and PWV values in FH subjects; our results support the positive effect of PCSK9-i in clinical practice.

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.