Efficacy and safety of various doses of hybutimibe monotherapy or in combination with atorvastatin for primary hypercholesterolemia: a multicenter, randomized, double-blind, double-dummy, parallel-controlled phase Ⅲ clinical trial / 中华心血管病杂志

Objective: To evaluate the efficacy and safety of hybutimibe monotherapy or in combination with atorvastatin in the treatment of primary hypercholesterolemia. Methods: This was a multicenter, randomized, double-blind, double-dummy, parallel-controlled phase Ⅲ clinical trial of patients with untreated primary hypercholesterolemia from 41 centers in China between August 2015 and April 2019. Patients were randomly assigned, at a ratio of 1∶1∶1∶1∶1∶1, to the atorvastatin 10 mg group (group A), hybutimibe 20 mg group (group B), hybutimibe 20 mg plus atorvastatin 10 mg group (group C), hybutimibe 10 mg group (group D), hybutimibe 10 mg plus atorvastatin 10 mg group (group E), and placebo group (group F). After a dietary run-in period for at least 4 weeks, all patients were administered orally once a day according to their groups. The treatment period was 12 weeks after the first dose of the study drug, and efficacy and safety were evaluated at weeks 2, 4, 8, and 12. After the treatment period, patients voluntarily entered the long-term safety evaluation period and continued the assigned treatment (those in group F were randomly assigned to group B or D), with 40 weeks' observation. The primary endpoint was the percent change in low density lipoprotein cholesterol (LDL-C) from baseline at week 12. Secondary endpoints included the percent changes in high density lipoprotein cholesterol (HDL-C), triglyceride (TG), apolipoprotein B (Apo B) at week 12 and changes of the four above-mentioned lipid indicators at weeks 18, 24, 38, and 52. Safety was evaluated during the whole treatment period. Results: Totally, 727 patients were included in the treatment period with a mean age of (55.0±9.3) years old, including 253 males. No statistical differences were observed among the groups in demographics, comorbidities, and baseline blood lipid levels. At week 12, the percent changes in LDL-C were significantly different among groups A to F (all P<0.01). Compared to atorvastatin alone, hybutimibe combined with atorvastatin could further improve LDL-C, TG, and Apo B (all P<0.05). Furthermore, there was no significant difference in percent changes in LDL-C at week 12 between group C and group E (P=0.991 7). During the long-term evaluation period, there were intergroup statistical differences in changes of LDL-C, TG and Apo B at 18, 24, 38, and 52 weeks from baseline among the statins group (group A), hybutimibe group (groups B, D, and F), and combination group (groups C and E) (all P<0.01), with the best effect observed in the combination group. The incidence of adverse events was 64.2% in the statins group, 61.7% in the hybutimibe group, and 71.0% in the combination group during the long-term evaluation period. No treatment-related serious adverse events or adverse events leading to death occurred during the 52-week study period. Conclusions: Hybutimibe combined with atorvastatin showed confirmatory efficacy in patients with untreated primary hypercholesterolemia, which could further enhance the efficacy on the basis of atorvastatin monotherapy, with a good overall safety profile.

Eficacia de la atorvastatina en el infarto cerebral aterotrombótico agudo / Effectiveness of atorvastatin in acute atherothrombotic cerebral infartation

Introducción: Las enfermedades Cerebrovasculares constituyen un importante problema de salud a escala global y en Cuba ocupan la tercera causa de muerte y la primera causa de discapacidad. Objetivo: Evaluar el uso de atorvastatina en el infarto cerebral aterotrombótico agudo. Métodos: Se realizó un estudio prospectivo longitudinal en los pacientes que acudieron al cuerpo de guardia del Hospital Clínico Quirúrgico Julio Trigo López diagnosticados como infarto cerebral aterotrombótico agudo. De forma aleatoria y con previo consentimiento informado se les suministró una dosis de 0, 20 mg o 40 mg de atorvastatina. Se les realizó tomografía axial computarizada de cráneo, la cual fue repetida al tercer día y a los 30 días. Se determinó el valor de proteína C reactiva en el cuerpo de guardia, y a los 30 días fueron evaluados clínicamente de acuerdo a la escala de National Institute of Health Stroke Scale en cuerpo de guardia, diariamente durante su ingreso y 30 días después. Resultados: El tamaño del área infartada disminuyó un 19,4 por ciento con 40 mg de atorvastatina al igual que el valor de proteína C reactiva que se redujo en 16 mg/L. La evaluación clínica según la escala de National Institute of Health Stroke Scale mostró una reducción en más de 8 puntos de acuerdo a la dosis de atorvastatina empleada. Conclusiones: Se demostró la eficacia de la atorvastatina por la disminución del área infartada, la reducción de los valores de proteína C reactiva y la evolución clínica favorable. Todos estos factores fueron directamente proporcional a la dosis de atorvastatina empleada(AU)

Introduction: Cererovascular diseases represent an important health problem worldwide and in Cuba they rank the third cause of death and the first cause of disability. Objective: To evaluate the use of astorvastin in acute atherotrombotic cerebral infactation. Methods: A longitudinal prospective study was carried out in patients who attended the emergency room of Julio Trigo López Surgical Clinical Hospital diagnosed with acute atherothrombotic cerebral infarction. Randomly and with prior informed consent, they were given a dose of 0, 20 mg or 40 mg of atorvastatin. Computerized axial tomography of the skull was performed, which was repeated on day 3 and day 30. The value of C-reactive protein in the emergency room was determined, and at day 30, they were clinically evaluated daily during admission and 30 days later, according to the scale of the National Institute of Health Stroke Scale in emergency room. Results: The size of the infarcted area decreased by 19.4 percent with 40 mg of atorvastatin, as well as the value of C-reactive protein, which decreased by 16 mg/L. The clinical evaluation according to the National Institute of Health Stroke Scale showed reduction of more than 8 points according to the dose of atorvastatin used. Conclusions: The efficacy of atorvastatin was demonstrated by the reduction of the infarcted area, the reduction of C-reactive protein values and the favorable clinical evolution. All of these factors were directly proportional to the dose of atorvastatin used(AU)

O efeito da atorvastatina + aspirina na função endotelial difere com a idade em pacientes com HIV: Um estudo de caso-controle / The effect of atorvastatin + aspirin on the endothelial function differs with age in patients with HIV: A case-control study

Resumo Fundamento Pacientes com HIV têm maior probabilidade de apresentar doenças cardiovasculares quando comparados à população em geral. Objetivo Este foi um estudo de caso-controle que teve como objetivo avaliar quais fatores estavam associados a uma redução na espessura médio-intimal da carótida (IMT) da carótida e ao aumento na dilatação mediada por fluxo (DMF) da artéria braquial em pacientes com HIV que receberam atorvastatina + aspirina por um período de 6 meses. Métodos Foi realizada uma análise secundária de um ensaio clínico, que incluiu pessoas vivendo com HIV e baixo risco cardiovascular. Um total de 38 pacientes alocados para o braço de intervenção e tratados por 6 meses com uma combinação de atorvastatina + aspirina foram incluídos. Todos os participantes foram submetidos a ultrassonografia da carótida e da artéria braquial, tanto no início quanto no final do estudo. Os casos que responderam com aumento >10% da dilatação braquial (DMF) e redução da espessura médio-intimal da carótida (IMT) foram considerados casos, e aqueles que não responderam foram considerados controles. Avaliamos os fatores associados às respostas positivas obtidas através da IMT e DMF. Resultados A redução do IMT não se associou significativamente a nenhum dos fatores de risco avaliados: idade (p = 0,211), sexo (p = 0,260), tabagismo (p = 0,131) ou tempo de diagnóstico do HIV (p = 0,836). Um aumento na DMF foi significativamente associado com a idade entre aqueles na faixa etária de 40-59 anos, p = 0,015 (OR = 4,37; IC 95%: 1,07-17,79). Conclusões Os indivíduos mais velhos foram mais propensos a apresentar um aumento na DMF após 6 meses de tratamento com atorvastatina + aspirina.

Abstract Background Patients with HIV are more likely to present with cardiovascular disease when compared to the general population. Objective This was a case-control study that aimed to assess which factors were associated with a reduction in the carotid intima-media thickness (IMT) and an increase in the brachial artery flow-mediated dilation (FMD) in HIV patients who received atorvastatin + aspirin during a period of 6 months. Methods A secondary analysis of a clinical trial was conducted, which included people living with HIV infection and low cardiovascular risk. A total of 38 patients allocated to the intervention arm and treated for 6 months with a combination of atorvastatin + aspirin were included. All participants underwent a carotid and brachial artery ultrasound, both at the beginning and the end of the study. Cases that responded with an increase of >10% of the brachial dilatation (FMD) and reduction of the carotid intima-media thickness (IMT) were considered cases, and those who did not respond were considered controls. We assessed the factors associated with the positive responses obtained through IMT and FMD. Results A reduction in the IMT was not significantly associated with any of the evaluated risk factors: age (p=0.211), gender (p=0.260), smoking (p=0.131) or time since HIV diagnosis (p=0.836). An increase in the FMD was significantly associated with age amongst those in the 40-59 age group, p = 0.015 (OR = 4.37; 95% CI: 1.07-17.79). Conclusions Older individuals were more likely to present with an increased FMD after 6 months of treatment with atorvastatin + aspirin.

Atorvastatina Reduz o Acúmulo de Células Musculares Lisas Vasculares para Inibir a Hiperplasia Intimal pela Inibição de Via p38 MAPK em um Modelo de Enxerto de Veia em Ratos / Atorvastatin Reduces Accumulation of Vascular Smooth Muscle Cells to Inhibit Intimal Hyperplasia via p38 MAPK Pathway Inhibition in a Rat Model of Vein Graft

Resumo Fundamento: A taxa de falha de enxerto de veia safena um ano após a cirurgia de revascularização do miocárdio varia de 10% a 25%. O objetivo deste estudo foi de investigar se a atorvastatina pode reduzir o acúmulo de células musculares lisas vasculares para inibir a hiperplasia intimal por meio da inibição da via p38 MAPK. Métodos: Quarenta e cinco ratos Sprague-Dawley foram randomizados em três grupos. Trinta ratos foram submetidos à cirurgia de enxerto de veia e randomizados para tratamento com veículo ou atorvastatina; quinze ratos foram submetidos à cirurgia sham. Detectamos a hiperplasia intimal por meio de coloração com hematoxilina-eosina e a expressão de proteínas relacionadas por meio de análise imuno-histoquímica e Western blot. Foram realizadas as comparações por análise de variância de fator único e pelo teste da diferença mínima significativa de Fisher, com p < 0,05 considerado significativo. Resultados: A íntima analisada pela coloração com hematoxilina-eosina era dramaticamente mais espessa no grupo controle que no grupo atorvastatina e no grupo sham (p < 0,01). Os resultados da coloração imuno-histoquímica de α-SMA demonstraram que a porcentagem de células positivas para α-SMA no grupo controle era mais alta que no grupo atorvastatina (p < 0,01). Nós também avaliamos α-SMA, PCNA, p38 MAPK e fosforilação de p38 MAPK após o tratamento com estatina por meio de análise de Western blot e os resultados indicaram que a atorvastatina não levou à redução de p38 MAPK (p < 0,05); no entanto, resultou na inibição da fosforilação de p38 MAPK (p < 0,01) e reduziu significativamente os níveis de α-SMA e PCNA, em comparação com o grupo controle (p < 0,01). Conclusão: Nós demonstramos que a atorvastatina pode inibir o acúmulo de células musculares lisas vasculares por meio da inibição da via p38 MAPK e é capaz de inibir a hiperplasia intimal em modelos de enxerto de veia em ratos.

Abstract Background: The rate of saphenous vein graft failure one year after coronary artery bypass grafting ranges from 10% to 25%. The aim of this study was to explore whether atorvastatin can reduce accumulation of vascular smooth muscle cells to inhibit intimal hyperplasia via p38 MAPK pathway inhibition. Methods: Forty-five Sprague-Dawley rats were randomized to three groups. Thirty rats received a vein graft operation, and they were randomized to be treated with vehicle or atorvastatin; fifteen rats received a sham operation. We detected intimal hyperplasia by hematoxylin-eosin staining and related protein expression by immunohistochemical and Western blot analysis. Comparisons were analyzed by single-factor analysis of variance and Fisher's least significant difference test, with p < 0.05 considered significant. Results: The intima analyzed by hematoxylin-eosin staining was dramatically thicker in the control group than in the atorvastatin group and sham group (p < 0.01). The outcomes of immunohistochemical staining of α-SMA demonstrated that the percentage of α-SMA-positive cells in the control group was higher than in the atorvastatin group (p < 0.01). We also evaluated α-SMA, PCNA, p38 MAPK, and phosphorylation of p38 MAPK after statin treatment by Western blot analysis, and the results indicated that atorvastatin did not lead to p38 MAPK reduction (p < 0.05); it did, however, result in inhibition of p38 MAPK phosphorylation (p < 0.01), and it significantly reduced α-SMA and PCNA levels, in comparison with the control group (p < 0.01). Conclusion: We have demonstrated that atorvastatin can inhibit accumulation of vascular smooth muscle cells by inhibiting the p38 MAPK pathway, and it is capable of inhibiting intimal hyperplasia in a rat vein graft model.

Effect of ischemic postconditioning and atorvastatin in the prevention of remote lung reperfusion injury

Abstract Objective: The aim of the present study was to evaluate the ability of ischemic postconditioning, atorvastatin and both associated to prevent or minimize reperfusion injury in the lung of rats subjected to ischemia and reperfusion by abdominal aortic clamping. Methods: We used 41 Wistar norvegic rats, which were distributed into 5 groups: ischemia and reperfusion (I/R), ischemic postcondictioning (IPC), postconditioning + atorvastatin (IPC+A), atorvastatin (A) and SHAM. It was performed a medium laparotomy, dissection and isolation of the infra-renal abdominal aorta; except for the SHAM group, all the others were submitted to the aortic clamping for 70 minutes (ischemia) and posterior clamp removal (reperfusion, 70 minutes). In the IPC and IPC+A groups, postconditioning was performed between the ischemia and reperfusion phases by four cycles of reperfusion and ischemia lasting 30 seconds each. In the IPC+A and A groups, preceding the surgical procedure, administration of 3.4 mg/day of atorvastatin was performed for seven days by gavage. After the surgical procedure, the right caudal lobe was removed from the lung for histological study, using tissue injury score ranging from grade 1 (normal tissue) to grade 4 (intense lesion). Results: The mean lung injury was 3.6 in the I/R group, 1.6 in the IPC group, 1.2 in the IPC+A group, 1.2 in the A group, and 1 in the SHAM group (P<0.01). Conclusion: Ischemic postconditioning and atorvastatin were able to minimize lung reperfusion injury, alone or in combination.

Evaluation of the effects of atorvastatin and ischemic postconditioning preventing on the ischemia and reperfusion injury: experimental study in rats

Abstract Introduction: Reperfusion injury leads to systemic morphological and functional pathological alterations. Some techniques are already estabilished to attenuate the damage induced by reperfusion. Ischemic preconditioning is one of the standard procedures. In the last 20 years, several experimental trials demonstrated that the ischemic postconditioning presents similar effectiveness. Recently experimental trials demonstrated that statins could be used as pharmacological preconditioning. Methods: 41 Wistar rats (Rattus norvegicus albinus) were distributed in 5 groups: Ischemia and Reperfusion (A), Ischemic Postconditioning (B), Statin (C), Ischemic Postconditioning + Statins (D) and SHAM (E). After euthanasia, lungs, liver, kidneys and ileum were resected and submitted to histopathological analysis. Results: The average of lung parenchymal injury was A=3.6, B=1.6, C=1.2, D=1.2, E=1 (P=0.0029). The average of liver parenchymal injury was A=3, B=1.5, C=1.2, D=1.2, E = 0 (P<0.0001). The average of renal parenchymal injury was A=4, B=2.44, C=1.22, D=1.11, E=1 (P<0.0001). The average of intestinal parenchymal injury was A=2, B=0.66, C=0, D=0, E=0 (P=0.0006). The results were submitted to statistics applying Kruskal-Wallis test, estabilishing level of significance P<0.05. Conclusion: Groups submitted to ischemic postconditioning, to pre-treatment with statins and both methods associated demonstrated less remote reperfusion injuries, compared to the group submitted to ischemia and reperfusion without protection.

Atorvastatin can prevent hepatic remote reperfusion injury / Atorvastatina é capaz de prevenir a lesão de reperfusão remota no fígado

ABSTRACT Background: Some studies have shown that statins have a promising effect on protection against reperfusion injury. Aim: To evaluate the ability of ischemic postconditioning, statins and both associated to prevent or minimize reperfusion injury in the liver of rats subjected to ischemia and reperfusion by abdominal aorta clamping. Method: Were used 41 Wistar rats, which were distributed into five groups: ischemia and reperfusion (I/R), ischemic postcondictioning (IPC), postconditioning + statin (IPC+S), statin (S) and Sham. It was performed a medium laparotomy, dissection and isolation of the infra-renal abdominal aorta; excepting Sham group, all the others were submitted to the aorta clamping for 70 min (ischemia) and posterior clamping removing (reperfusion, 70 min). In the IPC and IPC+S groups, postconditioning was performed between the ischemia and reperfusion phases by four cycles of reperfusion and ischemia lasting 30 s each. In IPC+S and S groups, preceding the surgical procedure, administration of 3.4 mg/day of atorvastatin was performed for seven days by gavage. The left hepatic lobe was removed for histological study and euthanasia was performed. Results: The mean hepatic injury was 3 in the I/R group, 1.5 in the IPC group, 1.2 in the IPC+S group, 1.2 in the S group, and 0 in the SHAM group. The I/R group had a higher degree of tissue injury compared to the others in the statistical analysis and there was no difference between the others (p<0.01). Conclusion: Ischemic postconditioning and atorvastatin were able to minimize hepatic reperfusion injury, either alone or in combination.

RESUMO Racional: Alguns estudos têm demonstrado que as estatinas apresentam efeito promissor contra a lesão de reperfusão. Objetivo: Avaliar a capacidade do pós-condicionamento, estatina e ambos associados em prevenir ou minimizar a lesão de reperfusão à distância no fígado em ratos submetidos à isquemia e reperfusão por clampeamento aórtico. Método: Foram utilizados 41 ratos Wistar distribuídos em cinco grupos: isquemia e reperfusão (I/R), pós-condicionamento isquêmico (PCI), pós-condicionamento + estatina (PCI+E), estatina (E) e SHAM. Os animais foram anestesiados, submetidos à laparotomia, dissecção e isolamento da aorta abdominal infrarrenal; exceto o grupo SHAM, todos os outros foram submetidos ao clampeamento aórtico por 70 min (isquemia) e posterior retirada do clampe (reperfusão). Nos grupos PCI e PCI+E o pós-condicionamento foi realizado entre as fases de isquemia e reperfusão por quatro ciclos de reperfusão e isquemia durando 30 s cada. Nos grupos PCI+E e E, previamente ao procedimento cirúrgico foi realizada a administração de 3,4 mg/dia de atorvastatina durante sete dias por gavagem. Resultados: A média de lesão hepática foi 3 no grupo I/R, 1,5 no grupo PCI, 1,2 no grupo PCI+E, 1,2 no grupo E e 0 no grupo SHAM. O grupo I/R teve maior grau de lesão tecidual (p<0,01). Conclusão: O pós-condicionamento isquêmico e atorvastatina foram capazes de minimizar a lesão hepática de reperfusão remota, isoladamente e em associação.

Asociación de la atorvastatina sistémica en las características clínicas inflamatorias de la periodontitis crónica / Association of atorvastatin in systemic inflammatory characteristics of chronic periodontitis

Determinar el efecto de la atorvastatina sistémica en el índice gingival y el índice de carga inflamatoria periodontal (PIBI), en pacientes con periodontitis crónica en una población adulta del sector norte de la ciudad de Antofagasta. Este estudio se realizó en pacientes derivados a la clínica de periodoncia del Centro Asistencial Norte Antofagasta, departamento dependiente del Servicio de Salud Antofagasta. Se seleccionó un grupo de 60 pacientes, mayores 40 años de edad, diagnosticados con periodontitis crónica, con al menos 14 dientes en la cavidad oral y sin tratamiento antibiótico en los últimos 6 meses. Se dividieron estos pacientes en dos grupos; 30 de ellos en tratamiento con atorvastatina por al menos 1 año (Grupo I) y 30 que no estaban en tratamiento con este medicamento (Grupo II). Las variables analizadas fueron el índice de placa bacteriana simplificado, el índice gingival y el PIBI, de la abreviación del inglés Periodontal inflammatory burden index. La atorvastatina sistémica se asocia a una disminución en el índice gingival y el PIBI, en pacientes adultos con periodontitis crónica.

To determine the effect of systemic atorvastatin on gingival index and periodontal inflammatory burden index (PIBI) in patients with chronic periodontitis in an adult population of the northern sector of the city of Antofagasta. This study was conducted in patients referred from the clinic of periodontology of Centro Asistencial Norte under the Department of Health Service of Antofagasta. A group of 60 patients over 40 years old was selected, diagnosed with chronic periodontitis, with at least 14 teeth in the mouth without antibiotic treatment in the last 6 months. These patients were divided into two groups; 30 of them were treated with atorvastatin for at least 1 year (Group I) and 30 who were not treated with this drug (Group II). The variables analyzed were simplified plaque index, gingival index and PIBI. The atorvastatin systemic is associated with adecrease in gingival index and PIBI in adult patients with chronic periodontitis.