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.
Male ; Humans ; Middle Aged ; Atorvastatin/therapeutic use* ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use* ; Hypercholesterolemia/drug therapy* ; Cholesterol, LDL/therapeutic use* ; Anticholesteremic Agents/therapeutic use* ; Treatment Outcome ; Triglycerides ; Apolipoproteins B/therapeutic use* ; Double-Blind Method ; Pyrroles/therapeutic use*

OBJECTIVE: To investigate the influence and mechanism of atorvastatin on glycolysis of adriamycin resistant acute promyelocytic leukemia (APL) cell line HL-60/ADM. METHODS: HL-60/ADM cells in logarithmic growth phase were treated with different concentrations of atorvastatin, then the cell proliferation activity was measured by CCK-8 assay, the apoptosis was detected by flow cytometry, the glycolytic activity was checked by glucose consumption test, and the protein expressions of PTEN, p-mTOR, PKM2, HK2, P-gp and MRP1 were detected by Western blot. After transfection of PTEN-siRNA into HL-60/ADM cells, the effects of low expression of PTEN on atorvastatin regulating the behaviors of apoptosis and glycolytic metabolism in HL-60/ADM cells were further detected. RESULTS: CCK-8 results showed that atorvastatin could inhibit the proliferation of HL-60/ADM cells in a concentration-dependent and time-dependent manner (r=0.872, r=0.936), and the proliferation activity was inhibited most significantly when treated with 10 μmol/L atorvastatin for 24 h, which was decreased to (32.3±2.18)%. Flow cytometry results showed that atorvastatin induced the apoptosis of HL-60/ADM cells in a concentration-dependent manner (r=0.796), and the apoptosis was induced most notably when treated with 10 μmol/L atorvastatin for 24 h, which reached to (48.78±2.95)%. The results of glucose consumption test showed that atorvastatin significantly inhibited the glycolytic activity of HL-60/ADM cells in a concentration-dependent and time-dependent manner (r=0.915, r=0.748), and this inhibition was most strikingly when treated with 10 μmol/L atorvastatin for 24 h, reducing the relative glucose consumption to (46.53±1.71)%. Western blot indicated that the expressions of p-mTOR, PKM2, HK2, P-gp and MRP1 protein were decreased in a concentration-dependent manner (r=0.737, r=0.695, r=0.829, r=0.781, r=0.632), while the expression of PTEN protein was increased in a concentration-dependent manner (r=0.531), when treated with different concentrations of atorvastatin for 24 h. After PTEN-siRNA transfected into HL-60/ADM cells, it showed that low expression of PTEN had weakened the promoting effect of atorvastatin on apoptosis and inhibitory effect on glycolysis and multidrug resistance. CONCLUSION Atorvastatin can inhibit the proliferation, glycolysis, and induce apoptosis of HL-60/ADM cells. It may be related to the mechanism of increasing the expression of PTEN, inhibiting mTOR activation, and decreasing the expressions of PKM2 and HK2, thus reverse drug resistance.
Humans ; Atorvastatin/pharmacology* ; PTEN Phosphohydrolase/pharmacology* ; Sincalide/metabolism* ; Drug Resistance, Neoplasm/genetics* ; TOR Serine-Threonine Kinases/metabolism* ; Leukemia, Promyelocytic, Acute/drug therapy* ; Doxorubicin/pharmacology* ; Apoptosis ; RNA, Small Interfering/pharmacology* ; Glycolysis ; Glucose/therapeutic use* ; Cell Proliferation

To investigate the effect of atorvastatin on reflow in patients with acute ST-segment elevation myocardial infarction (STEMI) after percutaneous coronary intervention (PCI) and its relation to serum uric acid levels.One hundred and fourteen STEMI patients undergoing primary PCI were enrolled and randomly divided into two groups:55 cases received oral atorvastatin 20 mg before PCI (routine dose group) and 59 cases received oral atorvastatin 80 mg before PCI (high dose group). According to the initial serum uric acid level, patients in two groups were further divided into normal uric acid subgroup and hyperuricemia subgroup. The changes of uric acid level and coronary artery blood flow after PCI were observed. Correlations between the decrease of uric acid, the dose of atorvastatin and the blood flow of coronary artery after PCI were analyzed.Serum uric acid levels were decreased after treatment in both groups (all<0.05), and patients with hyperuricemia showed more significant decrease in serum uric acid level (<0.05). Compared with the routine dose group, serum uric acid level in patients with hyperuricemia decreased more significantly in the high dose group (<0.05), but no significant difference was observed between patients with normal serum uric acid levels in two groups (>0.05). Among 114 patients, there were 19 cases without reflow after PCI (16.7%). In the routine dose group, there were 12 patients without reflow, in which 3 had normal uric acid and 9 had high uric acid levels (<0.01). In the high dose group, there were 7 patients without reflow, in which 2 had normal uric acid and 5 had high uric acid (<0.05). Logistic regression analysis showed that hyperuricemia was one of independent risk factors for no-reflow after PCI (=1.01, 95%:1.01-1.11,<0.01). The incidence of no-flow after PCI in the routine dose group was 21.8% (12/55), and that in the high dose group was 11.9% (7/59) (<0.01).High dose atorvastatin can decrease serum uric acid levels and improve reflow after PCI in patients with STEMI.
Acute Disease ; Atorvastatin Calcium ; therapeutic use ; Female ; Heptanoic Acids ; Humans ; Hyperuricemia ; complications ; drug therapy ; Male ; Myocardial Reperfusion ; methods ; Percutaneous Coronary Intervention ; adverse effects ; Pyrroles ; Risk Factors ; ST Elevation Myocardial Infarction ; surgery ; Uric Acid ; blood ; metabolism

OBJECTIVETo investigate whether intensive statin therapy during the perioperative period improves outcomes in patients undergoing middle cerebral artery (MCA) stent implantation for ischemic stroke.

METHODSForty patients with ischemic stroke undergoing delayed stent implantation in our department from January, 2010 to November, 2014 were randomized to intensive statin group (atorvastatin, 80 mg/day, 3 days before till 3 days after intervention; n=20) and standard therapy group (atorvastatin, 20 mg/day, n=20). All the patients received long-term atorvastatin treatment thereafter (20 mg/day). Serum levels of C-reactive protein (CRP), vascular cell adhesion molecule-1 (VCAM-1), and soluble extracellular matrix metalloproteinase inducer (EMMPRIN/CD147) were measured at 24 h before and 24 h after the intervention. The primary end point was procedure-related intra-stent thrombosis, 1-month incidence of major adverse cerebrovascular events (stroke, transient ischemic attack, in-stent restenosis, death or unplanned revascularization).

RESULTSThe basic clinical data were similar between the two groups before the intervention (P>0.05). In the intensive therapy group, the levels of CRP, VCAM-1, and sCD147 were significantly lower at 24 h after the intervention than the levels before intervention (P<0.05) and the postoperative levels in the standard therapy group (P<0.05). The levels of CRP, VCAM-1, and sCD147 were all increased after the intervention in the standard therapy group (P>0.05). The incidence of primary end point was lower in intensive therapy group than in standard therapy group (P<0.05).

CONCLUSIONIn patients undergoing MCA intravascular stent implantation for ischemic stroke, perioperative intensive statin therapy improves the patients' outcomes, reduces the levels of CRP, VCAM-1 and sCD147 molecules, and lowers the incidences of cerebrovascular events.

Angioplasty, Balloon, Coronary ; Atorvastatin Calcium ; therapeutic use ; Basigin ; blood ; C-Reactive Protein ; analysis ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; therapeutic use ; Middle Cerebral Artery ; surgery ; Stents ; Stroke ; drug therapy ; Vascular Cell Adhesion Molecule-1 ; blood

OBJECTIVETo observe the effects of different loading doses of atorvastatin calcium on the outcomes of percutaneous coronary intervention (PCI) in elderly patients with coronary heart disease (CHD).

METHODSA total of 120 CHD patients aged over 80 years were randomly assigned into 3 equal groups to receive intensive pretreatment with statin at the doses of 20, 40, or 60 mg prior to PCI performed within 48 to 72 h after admission. The changes of postoperative cardiac biochemical markers including creatine kinase isoenzyme (CKMB), troponin I (cTNI) and high-sensitivity c-reactive protein (hs-CRP) were observed and the incidence of major adverse cardiac events (MACE, including cardiac death, myocardial infarction, and target vessel revascularization) were recorded within 30 days after PCI.

RESULTSThirty-four patients in 20 mg statin group, 40 in 40 mg statin group, and 38 in 60 mg statin group completed this study. In all the 3 groups, hs-CRP level significantly increased at 12 and 24 h after PCI compared with the preoperative levels (P<0.05). The patients in 60 mg statin group showed significantly lower levels of CKMB, cTNI, and hs-CRP at 24 h after PCI than those in 20 mg statin group (P<0.05), and had also a significantly lower incidence of total MACE within 30 days after PCI (2.6% vs 26.5%, P=0.003) resulting primarily from significantly reduced myocardial infarction associated with PCI (2.6% vs 20.6%, P=0.016). The adverse drug reactions were comparable among the 3 groups (P>0.05).

CONCLUSIONSIntensive pretreatment with 60 mg/day atorvastatin calcium can significantly reduce myocardial infarction related to PCI with good safety in elderly patients with CHD.

Aged, 80 and over ; Atorvastatin Calcium ; Biomarkers ; metabolism ; Coronary Disease ; drug therapy ; surgery ; Dose-Response Relationship, Drug ; Heptanoic Acids ; therapeutic use ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; therapeutic use ; Myocardial Infarction ; prevention & control ; Percutaneous Coronary Intervention ; Pyrroles ; therapeutic use

OBJECTIVETo explore the effect of atorvastatin on cardiac hypertrophy and to determine the potential mechanism involved.

METHODSAn in vitro cardiomyocyte hypertrophy from neonatal rats was induced with angiotensin II (Ang II) stimulation. Before Ang II stimulation, the cultured rat cardiac myocytes were pretreated with atorvastatin at different concentrations (0.1, 1, and 10 μmol/L). The following parameters were evaluated: the myocyte surface area, 3H-leucine incorporation into myocytes, mRNA expressions of atrial natriuretic peptide, brain natriuretic peptide, matrix metalloproteinase 9, matrix metalloproteinase 2, and interleukin-1β, mRNA and protein expressions of the δ/β peroxisome proliferator-activated receptor (PPAR) subtypes.

RESULTSIt was shown that atorvastatin could ameliorate Ang II-induced neonatal cardiomyocyte hypertrophy in the area of cardiomyocytes, 3H-leucine incorporation, and the expression of atrial natriuretic peptide and brain natriuretic peptide markedly. Meanwhile, atorvastatin also inhibited the augmented mRNA level of several cytokines in hypertrophic myocytes. Furthermore, the down-regulated expression of PPAR- δ/β at both the mRNA and protein levels in hypertrophic myocytes could be significantly reversed by atorvastatin treatment.

CONCLUSIONSAtorvastatin could improve Ang II-induced cardiac hypertrophy and inhibit the expression of cytokines. Such effect might be partly achieved through activation of the PPAR-δ/β pathway.

Angiotensin II ; pharmacology ; Animals ; Atorvastatin Calcium ; pharmacology ; therapeutic use ; Cardiomegaly ; metabolism ; pathology ; prevention & control ; Cells, Cultured ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; pharmacology ; PPAR delta ; genetics ; PPAR-beta ; genetics ; Rats ; Rats, Wistar

OBJECTIVEStatins are still underused for the prevention of cardiovascular disease (CVD) in China. Hence, we conducted a systemic review on the pharmacology, clinical efficacy, and adverse events of atorvastatin, as well as on patient adherence.

DATA SOURCESWe conducted a systemic search in PubMed with the following keywords: "atorvastatin" (Supplementary concept) or "atorvastatin" (All field) and ("China" [AD] or "China" [all field] or "Chinese" [All field]).

STUDY SELECTIONClinical or basic research articles on atorvastatin were included.

RESULTSAtorvastatin is a reversible and competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, decreasing the de novo cholesterol synthesis. The pharmacokinetics of atorvastatin among Chinese is similar to those in Caucasians, and several gene polymorphisms have proved to be associated with the metabolism of atorvastatin in the Chinese population. Several international multiple-center randomized control trials have demonstrated the benefit of atorvastatin for primary and secondary prevention of CVD. None of them, however, included the Chinese, and current evidence in the population is still inadequate, due to the small sample size, low study quality, short study duration, and the use of surrogate endpoints instead of clinical endpoints. The overall incidence of adverse events observed with atorvastatin did not increase in the 10-80 mg dose range, and was similar to that observed with placebo and in patients treated with other statins, which makes atorvastatin well-tolerated in the Chinese population. Moreover, high patient adherence was observed in clinical studies.

CONCLUSIONSBased on the current available evidence, there is no significant difference between Chinese and non-Chinese population in term of pharmacology and clinical efficacy/safety. High-quality evidence is still needed to support the use of atorvastatin in high-risk Chinese population.

Atorvastatin Calcium ; Cardiovascular Diseases ; drug therapy ; China ; Heptanoic Acids ; therapeutic use ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; therapeutic use ; Pyrroles ; therapeutic use

OBJECTIVETo evaluate the efficacy and safety of using Jiangzhi Tongluo Soft Capsule (JTSC) combined with Atorvastatin Calcium Tablet (ACT) or ACT alone in treatment of combined hyperlipidemia.

METHODSA randomized, double blinded, parallel control, and multi-center clinical research design was adopted. Totally 138 combined hyperlipidemia patients were randomly assigned to the combined treatment group (A) and the atorvastatin treatment group (B) by random digit table, 69 in each group. All patients took ACT 20 mg per day. Patients in the A group took JTSC 100 mg each time, 3 times per day. Those in the B group took JTSC simulated agent, 100 mg each time, 3 times per day. The treatment period for all was 8 weeks. Serum levels of triglyceride (TG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), and high density lipoprotein cholesterol (HDL-C) were observed before treatment, at week 4 and 8 after treatment; and safety was assessed as well.

RESULTSAt week 4 and 8 after treatment serum TG decreased by 26.69% and 33.29% respectively in the A group (both P < 0.01), while it was decreased by 25.7% and 22.98% respectively in the B group (both P < 0.01). At week 8 decreased serum TG was obviously higher in the A group than in the B group (P < 0.05). Compared with before treatment, serum levels of LDL-C and TC levels decreased significantly in the two groups (all P < 0.01). There was no statistical difference in the drop-out value and the drop-out rate of serum LDL-C and TC levels (P > 0.05). At week 8 the serum HDL-C level showed an increasing tendency in the two groups. No obvious increase in peptase or creatase occurred in the two groups after treatment.

CONCLUSIONJTSC combined with ACT could lower the serum TG level of combined hyperlipidemia patients with safety.

Adult ; Atorvastatin Calcium ; Double-Blind Method ; Drug Therapy, Combination ; Drugs, Chinese Herbal ; therapeutic use ; Female ; Heptanoic Acids ; therapeutic use ; Humans ; Hyperlipidemias ; drug therapy ; Male ; Middle Aged ; Pyrroles ; therapeutic use ; Treatment Outcome ; Triglycerides ; blood

BACKGROUNDAtherosclerosis is a kind of disease with multiple risk factors, of which hyperlipidemia is a major classical risk factor resulting in its pathogenesis and development. The aim of this study was to determine the effects of short-term intensive atorvastatin (IA) therapy on vascular endothelial function and explore the possible mechanisms that may help to explain the clinical benefits from short-term intensive statin therapy.

METHODSAfter exposure to high-fat diet (HFD) for 8 weeks, the animals were, respectively, treated with IA or low-dose atorvastatin (LA) for 5 days. Blood lipids, C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), nitric oxide (NO), endothelin-1 (ET-1), and endothelium-dependent vasorelaxation function were, respectively, measured. mRNA and protein expression of CRP, TNF-α, IL-6, macrophage chemoattractant protein-1 (MCP-1), and 5-lipoxygenase (5-LO) were also evaluated in pericarotid adipose tissue (PCAT) and cultured adipocytes.

RESULTSHFD increased serum inflammatory factor levels; induced significant hyperlipidemia and endothelial dysfunction, including imbalance between NO and ET-1; enhanced inflammatory factors and 5-LO expression; and promoted macrophage infiltration into adipose tissue. Five-day IA therapy could significantly decrease serum inflammatory factor levels and their expression in PCAT; restore the balance between NO and ET-1; and improve endothelial function and macrophage infiltration without significant changes in blood lipids. However, all of the above were not observed in LA therapy. In vitro experiment found that lipopolysaccharide (LPS) enhanced the expression of inflammatory factors and 5-LO in cultured adipocytes, which could be attenuated by short-time (6 hours) treatment of high-dose (5 µmol/L) but not low-dose (0.5 µmol/L) atorvastatin. In addition, inhibiting 5-LO by Cinnamyl-3,4-dihydroxy-α-cyanocinnamate (CDC, a potent and direct 5-LO inhibitor) could significantly downregulate the above-mentioned gene expression in LPS-treated adipocytes.

CONCLUSIONShort-term IA therapy could significantly ameliorate endothelial dysfunction induced by HFD, which may be partly due to attenuating inflammation of PCAT through inhibiting 5-LO pathway.

Adipose Tissue ; drug effects ; immunology ; Animals ; Arachidonate 5-Lipoxygenase ; metabolism ; Atorvastatin Calcium ; Heptanoic Acids ; therapeutic use ; Hyperlipidemias ; drug therapy ; immunology ; Inflammation ; drug therapy ; immunology ; Lipid Metabolism ; drug effects ; Male ; Pyrroles ; therapeutic use ; Rabbits

BACKGROUNDPercutaneous coronary intervention (PCI) could develop periprocedural myocardial infarction and inflammatory response and statins can modify inflammatory responses property. The aim of this study was to evaluate whether short-term high-dose atorvastatin therapy can reduce inflammatory response and myocardial ischemic injury elicited by PCI.

METHODSFrom March 2012 to May 2014, one hundred and sixty-five statin-naive patients with unstable angina referred for PCI at Department of Cardiology of the 306th Hospital, were enrolled and randomized to 7-day pretreatment with atorvastatin 80 mg/d as high dose group (HD group, n = 56) or 20 mg/d as normal dose group (ND group, n = 57) or an additional single high loading dose (80 mg) followed 6-day atorvastatin 20 mg/d as loading dose group (LD group, n = 52). Plasma C-reactive protein (CRP) and interleukin-6 (IL-6) levels were determined before intervention and at 5 minutes, 24 hours, 48 hours, 72 hours, and 7 days after intervention. Creatine kinase-myocardial isoenzyme (CK-MB) and cardiac troponin I (cTnI) were measured at baseline and then 24 hours following PCI.

RESULTSPlasma CRP and IL-6 levels increased from baseline after PCI in all groups. CRP reached a maximum at 48 hours and IL-6 level reached a maximum at 24 hours after PCI. Plasma CRP levels at 24 hours after PCI were significantly lower in the HD group ((9.14±3.02) mg/L) than in the LD group ((11.06±3.06) mg/L) and ND group ((12.36±3.08) mg/L, P < 0.01); this effect persisted for 72 hours. IL-6 levels at 24 hours and 48 hours showed a statistically significant decrease in the HD group ((16.19±5.39) ng/L and (14.26±4.12) ng/L, respectively)) than in the LD group ((19.26±6.34) ng/L and (16.03±4.08) ng/L, respectively, both P < 0.05) and ND group ((22.24±6.98) ng/L and (17.24±4.84) ng/L, respectively). IL-6 levels at 72 hours and 7 days showed no statistically significant difference among the study groups. Although PCI caused a significant increase in CK-MB and cTnI at 24 hours after the procedure in all groups, the elevated CK-MB and cTnI values were lower in the HD group ((4.71±4.34) ng/ml and (0.086±0.081) ng/ml, respectively) than in the ND group ((7.24±6.03) ng/ml and (0.138±0.103) ng/ml, respectively, both P < 0.01) and LD group ((6.80±5.53) ng/ml and (0.126±0.101) ng/ml, respectively, both P < 0.01).

CONCLUSIONShort-term high-dose atorvastatin treatment before PCI significantly reduced systemic inflammatory response and myocardial ischemic injury elicited by PCI.

Aged ; Angina, Unstable ; therapy ; Atorvastatin Calcium ; administration & dosage ; therapeutic use ; Female ; Humans ; Male ; Middle Aged ; Myocardial Reperfusion Injury ; drug therapy ; Myocardium ; pathology ; Percutaneous Coronary Intervention ; Systemic Inflammatory Response Syndrome ; drug therapy ; Treatment Outcome