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Asian Biomedicine : Research, Reviews... Jun 2023Statins are the most widely used lipid-lowering agents for patients with hyperlipidemia. However, interindividual variations in efficacy and risk of adverse drug... (Review)
Review
BACKGROUND
Statins are the most widely used lipid-lowering agents for patients with hyperlipidemia. However, interindividual variations in efficacy and risk of adverse drug reactions to statin treatment have been widely reported. Ethnicity is well known to be one of the contributing factors to this variation, particularly among Asians.
OBJECTIVES
To identify genetic variants associated with statin treatment responses among Asian populations with a focus on four commonly prescribed statins: atorvastatin, rosuvastatin, simvastatin, and pravastatin.
METHODS
A literature search was conducted in Medline and Embase databases. Studies published from 2008 to 2021 were included. The title and abstract of each article were screened by two reviewers and verified by another two reviewers. Data charted include information on authors, year of study, study population, statin studied, gene studied, study findings, and data of significant statistical value.
RESULTS
A total of 35 articles were included from the 1,939 original studies related to treatment efficacy and 5 articles out of the 284 original studies related to adverse effects. Genetic variants in transmembrane transporters, cytochrome P450 isoenzymes, and apolipoproteins are the most extensively studied among Asian populations, with a main focus on ethnic Chinese. However, Asia consists of genetically different populations, and the results of this review indicated that there is a paucity of studies on other ethnic groups within Asia.
CONCLUSIONS
Considering the ethnicity of patients could provide a potential value to personalized medicine in statin therapy.
PubMed: 37818163
DOI: 10.2478/abm-2023-0050 -
BioRxiv : the Preprint Server For... Sep 2023The incidental use of statins during radiation therapy has been associated with a reduced long-term risk of developing atherosclerotic cardiovascular disease.
BACKGROUND
The incidental use of statins during radiation therapy has been associated with a reduced long-term risk of developing atherosclerotic cardiovascular disease.
OBJECTIVES
Determine if irradiation causes chronic vascular injury and whether short-term administration of statins during and after irradiation is sufficient to prevent chronic injury compared to long-term administration.
METHODS
C57Bl/6 mice were pretreated with pravastatin for 72 hours and then exposed to 12 Gy x-ray head-and-neck irradiation. Subsequently, they received pravastatin either for one additional day or for one year. Carotid arteries were tested for vascular reactivity and altered gene expression one year after irradiation.
RESULTS
Treatment with pravastatin for 24 hours reduced the loss of endothelium-dependent vasorelaxation and protected against enhanced vasoconstriction after IR. It reduced the expression of some markers associated with inflammation and oxidative stress and modulated that of subunits of the voltage and Ca activated K (BK) channel in the carotid artery one year after irradiation. Treatment with pravastatin for one year completely reversed the changes caused by irradiation.
CONCLUSIONS
In mice, short-term administration of pravastatin is sufficient to reduce chronic vascular injury after irradiation. Long-term administration eliminates the effects of irradiation. These findings suggest that a prospective treatment strategy involving statins could be effective in patients undergoing radiation therapy. The optimal duration of treatment in humans has yet to be determined.
PubMed: 37790532
DOI: 10.1101/2023.09.20.558723 -
American Journal of Obstetrics and... Aug 2023Preeclampsia, especially before term, increases the risk of child neurodevelopmental adverse outcomes. Biological plausibility, preclinical studies, and pilot clinical...
BACKGROUND
Preeclampsia, especially before term, increases the risk of child neurodevelopmental adverse outcomes. Biological plausibility, preclinical studies, and pilot clinical trials conducted by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the Obstetric-Fetal Pharmacology Research Centers Network support the safety and use of pravastatin to prevent preeclampsia.
OBJECTIVE
This study aimed to determine the effect of antenatal pravastatin treatment in high-risk pregnant individuals on their child's health, growth, and neurodevelopment.
STUDY DESIGN
This was an ancillary follow-up cohort study of children born to mothers who participated in the Obstetric-Fetal Pharmacology Research Centers Network pilot trials of pravastatin vs placebo in individuals at high risk of preeclampsia (ClinicalTrials.gov; identifier NCT01717586). After obtaining written informed consent (and assent as appropriate), the parent was instructed to complete the Child Behavior Checklist. To assess the child's motor, cognitive, and developmental outcomes, a certified and blinded study psychologist completed child motor, cognitive, emotional, and behavioral assessments using validated tools. Given the small number of individuals in the studies, the 10- and 20-mg pravastatin groups were combined into 1 group, and the results of the pravastatin group were compared with that of the placebo group.
RESULTS
Of 40 children born to mothers in the original trial, 30 (15 exposed in utero to pravastatin and 15 to placebo) were enrolled in this follow-up study. The time of follow-up, which was 4.7 years (interquartile range, 2.5-6.9), was not different between children in the pravastatin group and children in the placebo group. There was no difference in the child's body mass index percentiles per sex and corrected age, the rates of extremes of body mass index percentiles, or the report of any other medical or developmental complications between the 2 groups. No child born in the pravastatin group had any limitation in motor assessment compared with 2 children (13.3%) who walked with difficulty and 4 children (26.7%) who had reduced manual abilities in the placebo group. Moreover, children born to mothers who received pravastatin had a higher general mean conceptual ability score (98.2±16.7 vs 89.7±11.0; P=.13) and a lower frequency (15.4% vs 35.7%; P=.38) of having a score of <85 (ie, 1 standard deviation lower than the mean) compared with those in the placebo group. Finally, there was no difference in the parents' report on the Child Behavior Checklist between the 2 groups.
CONCLUSION
This study reported on the long-term neuromotor, cognitive, and behavioral outcomes among children exposed to pravastatin in utero during the second and third trimesters of pregnancy. Although the data were limited by the original trial's sample size, no identifiable long-term neurodevelopmental safety signal was evident with the use of pravastatin during pregnancy. This favorable neonatal risk-benefit analysis justifies continued research using pravastatin in clinical trials.
Topics: Child; Child, Preschool; Female; Humans; Pregnancy; Clinical Trials as Topic; Follow-Up Studies; Mothers; Parturition; Pravastatin; Pre-Eclampsia; Male
PubMed: 36842489
DOI: 10.1016/j.ajog.2023.02.016 -
Balkan Medical Journal Sep 2023Anticoagulants are the mainstay of treatment for venous thromboembolism (VTE). Studies have shown conflicting results regarding statins ability to reduce the incidence... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Anticoagulants are the mainstay of treatment for venous thromboembolism (VTE). Studies have shown conflicting results regarding statins ability to reduce the incidence of VTE.
AIMS
To perform a network meta-analysis to determine which lipid-lowering agent was more efficacious in and had more evidence regarding reducing the VTE risk.
STUDY DESIGN
Network meta-analysis of the randomized controlled trials (RCTs).
METHODS
RCTs that assessed the effectiveness and safety of statins or fibrates and compared them to a placebo or another statin were eligible for the study. The outcomes examined in the study were deep vein thrombosis, pulmonary embolism, and/or VTE. We conducted a comprehensive search of the Medline database from 1966 to February 2017, using specific search terms related to VTE and statins. Additionally, we screened, and cross-checked relevant systematic reviews and meta-analyses. We performed a network meta-analysis to compare the different lipid-lowering agents to each other and the placebo and their effectiveness.
RESULTS
Twenty-seven RCTs were included in the network meta-analysis (n = 137,940). Pairwise meta-analysis revealed a statistically significant lower incidence of VTE with statins than with placebos (0.79% vs 0.99%, respectively; risk ratios: 0.87, 0.77-0.98; = 0.022). Rosuvastatin had the most favorable effect in reducing VTE risk than the other statins, fenofibrate, and placebo. Fenofibrate was ranked the worst drug choice, because it increased risk of VTE when compared with the other statins. Rosuvastatin was the best choice for reducing the VTE risk when compared with the placebo (OR: 0.56, 0.42-0.75), atorvastatin (OR: 0.64, 0.44-0.95), pravastatin (OR: 0.50, 0.34-0.74), simvastatin (OR: 0.60, 0.42-0.86) and fenofibrate (OR: 0.37, 0.25-0.56). Compared with a placebo, rosuvastatin reduced the VTE risk by around 45% and fenofibrate increased the risk by 65%.
CONCLUSION
Rosuvastatin is significantly reduces the risk of VTE when compared with a placebo, other statin subtypes, and fibrate. Furthermore, fenofibrate increased the VTE risk when compared with a placebo and statins.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Venous Thromboembolism; Rosuvastatin Calcium; Fenofibrate; Network Meta-Analysis; Atorvastatin
PubMed: 37519020
DOI: 10.4274/balkanmedj.galenos.2023.2023-5-26 -
The British Journal of General Practice... Feb 2024UK cardiovascular disease (CVD) incidence and mortality have declined in recent decades but socioeconomic inequalities persist.
BACKGROUND
UK cardiovascular disease (CVD) incidence and mortality have declined in recent decades but socioeconomic inequalities persist.
AIM
To present a new CVD model, and project health outcomes and the impact of guideline-recommended statin treatment across quintiles of socioeconomic deprivation in the UK.
DESIGN AND SETTING
A lifetime microsimulation model was developed using 117 896 participants in 16 statin trials, 501 854 UK Biobank (UKB) participants, and quality-of-life data from national health surveys.
METHOD
A CVD microsimulation model was developed using risk equations for myocardial infarction, stroke, coronary revascularisation, cancer, and vascular and non-vascular death, estimated using trial data. The authors calibrated and further developed this model in the UKB cohort, including further characteristics and a diabetes risk equation, and validated the model in UKB and Whitehall II cohorts. The model was used to predict CVD incidence, life expectancy, quality-adjusted life years (QALYs), and the impact of UK guideline-recommended statin treatment across socioeconomic deprivation quintiles.
RESULTS
Age, sex, socioeconomic deprivation, smoking, hypertension, diabetes, and cardiovascular events were key CVD risk determinants. Model-predicted event rates corresponded well to observed rates across participant categories. The model projected strong gradients in remaining life expectancy, with 4-5-year (5-8 QALYs) gaps between the least and most socioeconomically deprived quintiles. Guideline-recommended statin treatment was projected to increase QALYs, with larger gains in quintiles of higher deprivation.
CONCLUSION
The study demonstrated the potential of guideline-recommended statin treatment to reduce socioeconomic inequalities. This CVD model is a novel resource for individualised long-term projections of health outcomes of CVD treatments.
PubMed: 38373851
DOI: 10.3399/BJGP.2023.0198 -
Biomedicines Sep 2023Fetal growth restriction (FGR) remains without an effective prenatal treatment. Evidence from murine FGR models suggests a beneficial effect of prenatal pravastatin....
Fetal growth restriction (FGR) remains without an effective prenatal treatment. Evidence from murine FGR models suggests a beneficial effect of prenatal pravastatin. Since the rabbit hemodichorial placenta more closely resembles the human condition, we investigated the effects of prenatal maternal pravastatin administration in the rabbit FGR model. At a gestational age of 25 days (term 31d), pregnant dams underwent partial uteroplacental vessel ligation (UPVL) in one uterine horn to induce FGR, leaving the other horn as a control. Dams were randomized to either receive 5 mg/kg/d pravastatin dissolved in their drinking water or normal drinking water until delivery. At GA 30d, the rabbits were delivered and were divided into four groups: control without pravastatin (C/NoPrav), FGR without pravastatin (FGR/NoPrav), FGR with pravastatin (FGR/Prav), and controls with pravastatin (C/Prav). The newborn rabbits underwent pulmonary functional assessment and neurobehavioral assessment, and they were harvested for alveolar morphometry or neuropathology. The placentas underwent histology examination and RNA expression. Birth weight was lower in the FGR groups (FGR/Prav, FGR/NoPrav), but there was no difference between FGR/Prav and C/NoPrav. No differences were noted in placental zone proportions, but eNOS in FGR/Prav placentas and VEGFR-2 in FGR/Prav and C/Prav were upregulated. There were no differences in pulmonary function assessment and alveolar morphometry. FGR/Prav kittens had increased neurosensory scores, but there were no differences in neuromotor tests, neuron density, apoptosis, and astrogliosis. In conclusion, in the rabbit FGR model, pravastatin upregulated the expression of VEGFR-2 and eNOS in FGR placentas and was associated with higher neurosensory scores, without measurable effects on birthweight, pulmonary function and morphology, and neuron density.
PubMed: 37893059
DOI: 10.3390/biomedicines11102685 -
Journal of Diabetes Jun 2024Pravastatin is an oral lipid-lowering drug, commonly used by patients with diabetes that is positively correlated with the occurrence of vascular calcification (VC), but...
BACKGROUND
Pravastatin is an oral lipid-lowering drug, commonly used by patients with diabetes that is positively correlated with the occurrence of vascular calcification (VC), but the mechanism is unclear.
METHODS
In this study, 16S rRNA sequencing and qRT-PCR wereused to detect the differential gut bacteria. Metabolomics and ELISA were used to analyze the differential metabolites. qRT-PCR and western blotting (WB) were used to detect genes expression. Flow cytometry was used to analyze macrophage phenotype. Immunohistochemistry was used to analyze aortic calcification.
RESULTS
We found that gut Bacteroides fragilis (BF) increased significantly in patients who took pravastatin or type 2 diabetes (T2D) mice treated with pravastatin. In vitro experiments showed that pravastatin had little effect on BF but significantly promoted BF proliferation in vivo. Further analysis showed that ArsR was an important gene for pravastatin to regulate the activation of BF, and overexpression of ArsR significantly promoted the secretion of 3,4,5-trimethoxycinnamic acid (TMCA). Importantly, pravastatin significantly promoted BF secretion of TMCA and significantly increased TMCA secretion in T2D patients or T2D mice. TMCA had little effect on vascular smooth muscle cell calcification but significantly promoted macrophage M1 polarization, which we had demonstrated that M1 macrophages promoted T2D VC. In vivo studies found that pravastatin significantly upregulated TMCA levels in the feces and serum of T2D mice transplanted with BF and promoted the macrophage M1 polarization in bone marrow and the osteoblastic differentiation of aortic cells. Similar results were obtained in T2D mice after intravenous infusion of TMCA.
CONCLUSIONS
Promoting intestinal BF to secrete TMCA, which leads to macrophage M1 polarization, is an important mechanism by which pravastatin promotes calcification, and the result will be used for the optimization of clinical medication strategies of pravastatin supplying a theoretical basis and experimental basis.
Topics: Pravastatin; Animals; Vascular Calcification; Mice; Macrophages; Humans; Diabetes Mellitus, Type 2; Bacteroides fragilis; Male; Gastrointestinal Microbiome; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Mice, Inbred C57BL; Female
PubMed: 38112268
DOI: 10.1111/1753-0407.13514 -
Journal of Thoracic Oncology : Official... Aug 2023To determine the effect of statin use during concurrent chemoradiotherapy (CCRT) on overall survival and esophageal squamous cell carcinoma (ESCC)-specific survival in...
INTRODUCTION
To determine the effect of statin use during concurrent chemoradiotherapy (CCRT) on overall survival and esophageal squamous cell carcinoma (ESCC)-specific survival in patients with ESCC receiving standard CCRT.
METHODS
In this propensity score-matching cohort study, we used data from the Taiwan Cancer Registry Database and National Health Insurance Research Database to investigate the effects of statin use during the period of CCRT on overall survival and ESCC-specific survival.
RESULTS
Statin use during the period of CCRT was found to be a considerable and independent prognostic factor for overall survival and ESCC-specific survival. The adjusted hazard ratio (aHR) for all-cause mortality in the statin group compared with that of the non-statin group was 0.65 (95% confidence interval: 0.51-0.84, p = 0.0009). The aHR for ESCC-specific mortality in the statin group compared with that of the non-statin group was 0.63 (95% confidence interval: 0.47-0.84, p = 0.0016). The use of hydrophilic statins such as rosuvastatin and pravastatin was associated with the greatest survival benefits. A dose-response relationship was also found, with higher cumulative defined daily doses and higher daily intensity of statin use associated with lower mortality.
CONCLUSIONS
This study is the first to reveal that statin use during the period of CCRT for ESCC is associated with improvement in overall survival and ESCC-specific survival. In addition, we found that use of rosuvastatin, pravastatin, and simvastatin was associated with better survival outcomes for patients with ESCC receiving CCRT. Furthermore, we found a dose-response relationship of statin use associated with lower ESCC-specific mortality.
Topics: Humans; Esophageal Squamous Cell Carcinoma; Carcinoma, Squamous Cell; Esophageal Neoplasms; Cohort Studies; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Propensity Score; Rosuvastatin Calcium; Pravastatin; Lung Neoplasms; Chemoradiotherapy
PubMed: 37085031
DOI: 10.1016/j.jtho.2023.04.005 -
Current Atherosclerosis Reports Sep 2023The aim of this study is to investigate the protective effects of different statin classes, intensity, and cumulative dose-dependent against primary ischemic stroke in... (Review)
Review
PURPOSE OF REVIEW
The aim of this study is to investigate the protective effects of different statin classes, intensity, and cumulative dose-dependent against primary ischemic stroke in patients with T2DM.
RECENT FINDINGS
The Cox hazards model was used to evaluate statin use on primary ischemic stroke. Case group: T2DM patients who received statins; control group: T2DM patients who received no statins during the follow-up. Adjusted hazard ratio (aHR) for primary ischemic stroke was 0.45 (95% CI: 0.44 to 0.46). Cox regression analysis showed significant reductions in primary ischemic stroke incidence in users of different statin classes. Corresponding aHRs (95% CI) were 0.09 to 0.79 for pitavastatin, rosuvastatin, atorvastatin, pravastatin, simvastatin, fluvastatin, and lovastatin. Multivariate analyses indicated significant reductions in primary ischemic stroke incidence for patients who received different cumulative defined daily doses (cDDDs) per year (cDDD-year). Corresponding aHRs (95% CI) were 0.17 to 0.77 for quartiles 4 to 1 of cDDD-years, respectively (P for trend < .0001). Optimal intensity daily dose of statin use was 0.89 DDD with the lowest aHR of primary ischemic stroke compared with other DDDs. Persistent statin use reduces the risk of primary ischemic stroke in T2DM patients. Higher cDDD-year values are associated with higher reductions in primary ischemic stroke risk in T2DM patients.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Diabetes Mellitus, Type 2; Ischemic Stroke; Rosuvastatin Calcium; Simvastatin
PubMed: 37515725
DOI: 10.1007/s11883-023-01135-w -
Computers in Biology and Medicine Aug 2023Metabolic processes in the human body play an important role in maintaining normal life activities, and the abnormal concentration of metabolites is closely related to...
Metabolic processes in the human body play an important role in maintaining normal life activities, and the abnormal concentration of metabolites is closely related to the occurrence and development of diseases. The use of drugs is considered to have a major impact on metabolism, and drug metabolites can contribute to efficacy, drug toxicity and drug-drug interaction. However, our understanding of metabolite-drug associations is far from complete, and individual data source tends to be incomplete and noisy. Therefore, the integration of various types of data sources for inferring reliable metabolite-drug associations is urgently needed. In this study, we proposed a computational framework, MultiDS-MDA, for identifying metabolite-drug associations by integrating multiple data sources, including chemical structure information of metabolites and drugs, the relationships of metabolite-gene, metabolite-disease, drug-gene and drug-disease, the data of gene ontology (GO) and disease ontology (DO) and known metabolite-drug connections. The performance of MultiDS-MDA was evaluated by 5-fold cross-validation, which achieved an area under the ROC curve (AUROC) of 0.911 and an area under the precision-recall curve (AUPRC) of 0.907. Additionally, MultiDS-MDA showed outstanding performance compared with similar approaches. Case studies for three metabolites (cholesterol, thromboxane B2 and coenzyme Q10) and three drugs (simvastatin, pravastatin and morphine) also demonstrated the reliability and efficiency of MultiDS-MDA, and it is anticipated that MultiDS-MDA will serve as a powerful tool for future exploration of metabolite-drug interactions and contribute to drug development and drug combination.
Topics: Humans; Reproducibility of Results; Information Sources; Algorithms; Computational Biology
PubMed: 37276756
DOI: 10.1016/j.compbiomed.2023.107067