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Expert Review of Clinical Pharmacology Mar 2024Concerns regarding statin-related neurocognitive disorders have emerged in recent years. However, previous studies have reported inconsistent results. We evaluated the...
BACKGROUND
Concerns regarding statin-related neurocognitive disorders have emerged in recent years. However, previous studies have reported inconsistent results. We evaluated the association between statins and neurocognitive disorders using the FDA Adverse Event Reporting System (FAERS).
RESEARCH DESIGN AND METHODS
Data from 2004 to 2022 were obtained from the FAERS database. After deduplication and standardization of drug names, we extracted neurocognitive disorder event (NCDE) cases reported with statins as the suspected drugs. The significant association between statins and NCDE was evaluated using the reporting odds ratio (ROR) and information component.
RESULTS
In total, 6,959 NCDE cases with statins as the primary suspected drugs were identified. Signals were detected in pravastatin (ROR, 1.49; 95% CI: 1.32-1.67), atorvastatin (ROR, 1.39; 95% CI: 1.34-1.44), and simvastatin (ROR, 1.31; 95% CI: 1.25-1.38). Age-stratified analysis showed that (1) in the population aged 65 years and older, signals were detected for atorvastatin, simvastatin, rosuvastatin, pravastatin, lovastatin, fluvastatin, and pitavastatin; and (2) in populations under 65 years of age, signals were detected for atorvastatin, simvastatin, rosuvastatin, pravastatin, and lovastatin.
CONCLUSIONS
This study suggests a significant association between the NCDE and statins, including atorvastatin, simvastatin, and pravastatin. The intensity of the association increased with age.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Rosuvastatin Calcium; Atorvastatin; Pravastatin; Pharmacovigilance; Adverse Drug Reaction Reporting Systems; Simvastatin; Lovastatin; Neurocognitive Disorders
PubMed: 38275183
DOI: 10.1080/17512433.2024.2311875 -
Cell Death & Disease Jul 2023Cell-to-cell propagation of protein aggregates has been implicated in the progression of neurodegenerative diseases. However, the underlying mechanism and modulators of...
Cell-to-cell propagation of protein aggregates has been implicated in the progression of neurodegenerative diseases. However, the underlying mechanism and modulators of this process are not fully understood. Here, we screened a small-molecule library in a search for agents that suppress the propagation of α-synuclein and mutant huntingtin (mHtt). These screens yielded several molecules, some of which were effective against both α-synuclein and mHtt. Among these molecules, we focused on simvastatin and pravastatin. Simvastatin administration in a transgenic model of synucleinopathy effectively ameliorated behavioral deficits and α-synuclein accumulation, whereas pravastatin had no effect. Because only simvastatin enters the brain effectively, these results suggest that inhibition of brain cholesterol synthesis is important in simvastatin effects. In cultured cells, accumulation of intracellular cholesterol, induced by genetic ablation of the NPC1 gene or by pharmacological treatment with U18666A, increased α-synuclein aggregation and secretion. In contrast, lowering cholesterol using methyl-β-cyclodextrin or statins reversed α-synuclein aggregation and secretion in NPC1-knockout cells. Consistent with these observations, feeding a high-fat diet aggravated α-synuclein pathology and behavioral deficits in the preformed fibril-injected mouse model, an effect that was also reversed by simvastatin administration. These results suggest that statins suppress propagation of protein aggregates by lowering cholesterol in the brain.
Topics: Animals; Mice; alpha-Synuclein; Cholesterol; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Pravastatin; Protein Aggregates; Simvastatin
PubMed: 37500624
DOI: 10.1038/s41419-023-05977-9 -
Hypertension (Dallas, Tex. : 1979) Apr 2024Chemerin, an inflammatory adipokine, is upregulated in preeclampsia, and its placental overexpression results in preeclampsia-like symptoms in mice. Statins may lower...
BACKGROUND
Chemerin, an inflammatory adipokine, is upregulated in preeclampsia, and its placental overexpression results in preeclampsia-like symptoms in mice. Statins may lower chemerin.
METHODS
Chemerin was determined in a prospective cohort study in women suspected of preeclampsia and evaluated as a predictor versus the sFlt-1 (soluble fms-like tyrosine kinase-1)/PlGF (placental growth factor) ratio. Chemerin release was studied in perfused placentas and placental explants with or without the statins pravastatin and fluvastatin. We also addressed statin placental passage and the effects of chemerin in chorionic plate arteries.
RESULTS
Serum chemerin was elevated in women with preeclampsia, and its addition to a predictive model yielded significant effects on top of the sFlt-1/PlGF ratio to predict preeclampsia and its fetal complications. Perfused placentas and explants of preeclamptic women released more chemerin and sFlt-1 and less PlGF than those of healthy pregnant women. Statins reversed this. Both statins entered the fetal compartment, and the fetal/maternal concentration ratio of pravastatin was twice that of fluvastatin. Chemerin constricted plate arteries, and this was blocked by a chemerin receptor antagonist and pravastatin. Chemerin did not potentiate endothelin-1 in chorionic plate arteries. In explants, statins upregulated low-density lipoprotein receptor expression, which relies on the same transcription factor as chemerin, and NO release.
CONCLUSIONS
Chemerin is a biomarker for preeclampsia, and statins both prevent its placental upregulation and effects, in an NO and low-density lipoprotein receptor-dependent manner. Combined with their capacity to improve the sFlt-1/PlGF ratio, this offers an attractive mechanism by which statins may prevent or treat preeclampsia.
Topics: Humans; Pregnancy; Female; Animals; Mice; Placenta; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Placenta Growth Factor; Pravastatin; Up-Regulation; Prospective Studies; Pre-Eclampsia; Fluvastatin; Vascular Endothelial Growth Factor Receptor-1; Lipoproteins, LDL; Biomarkers; Chemokines; Intercellular Signaling Peptides and Proteins
PubMed: 38361240
DOI: 10.1161/HYPERTENSIONAHA.123.22457 -
Current Medicinal Chemistry 2024Previous studies have found a potential role for statins in liver cancer prevention. (Meta-Analysis)
Meta-Analysis
BACKGROUND
Previous studies have found a potential role for statins in liver cancer prevention.
OBJECTIVE
This study aimed to explore the effect of different types of statins on the incidence of liver cancer.
METHODS
Relevant articles were systematically retrieved from PubMed, EBSCO, Web of Science, and Cochrane Library databases from inception until July 2022 to explore the relationship between lipophilic statins or hydrophilic statins exposure and the incidence of liver cancer. The main outcome was the incidence of liver cancer.
RESULTS
Eleven articles were included in this meta-analysis. The pooled results showed a reduced incidence of liver cancer in patients exposed to lipophilic statins (OR=0.54, p < 0.001) and hydrophilic statins (OR=0.56, p < 0.001) compared with the non-exposed cohort. Subgroup analysis showed that both exposures to lipophilic (Eastern countries: OR=0.51, p < 0.001; Western countries: OR=0.59, p < 0.001) and hydrophilic (Eastern countries: OR=0.51, p < 0.001; Western countries: OR=0.66, p=0.019) statins reduced the incidence of liver cancer in Eastern and Western countries, and the reduction was most significant in Eastern countries. Moreover, atorvastatin (OR=0.55, p < 0.001), simvastatin (OR=0.59, p < 0.001), lovastatin (OR=0.51, p < 0.001), pitavastatin (OR=0.36, p=0.008) and rosuvastatin (OR=0.60, p=0.027) could effectively reduce the incidence of liver cancer, unlike fluvastatin, cerivastatin and pravastatin.
CONCLUSION
Both lipophilic and hydrophilic statins contribute to the prevention of liver cancer. Moreover, the efficacy was influenced by the region and the specific type of statins used.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Incidence; Simvastatin; Lovastatin; Liver Neoplasms
PubMed: 37393552
DOI: 10.2174/0929867330666230701000400 -
Frontiers in Pharmacology 2023Preterm birth rates and maternal and neonatal mortality remain concerning global health issues, necessitating improved strategies for testing therapeutic compounds...
Preterm birth rates and maternal and neonatal mortality remain concerning global health issues, necessitating improved strategies for testing therapeutic compounds during pregnancy. Current 2D or 3D cell models and animal models often fail to provide data that can effectively translate into clinical trials, leading to pregnant women being excluded from drug development considerations and clinical studies. To address this limitation, we explored the utility of in silico simulation modeling and microfluidic-based organ-on-a-chip platforms to assess potential interventional agents. We developed a multi-organ feto-maternal interface on-chip (FMi-PLA-OOC) utilizing microfluidic channels to maintain intercellular interactions among seven different cell types (fetal membrane-decidua-placenta). This platform enabled the investigation of drug pharmacokinetics in vitro. Pravastatin, a model drug known for its efficacy in reducing oxidative stress and inflammation during pregnancy and currently in clinical trials, was used to test its transfer rate across both feto-maternal interfaces. The data obtained from FMi-PLA-OOC were compared with existing data from in vivo animal models and ex vivo placenta perfusion models. Additionally, we employed mechanistically based simulation software (Gastroplus®) to predict pravastatin pharmacokinetics in pregnant subjects based on validated nonpregnant drug data. Pravastatin transfer across the FMi-PLA-OOC and predicted pharmacokinetics in the in silico models were found to be similar, approximately 18%. In contrast, animal models showed supraphysiologic drug accumulation in the amniotic fluid, reaching approximately 33%. The results from this study suggest that the FMi-PLA-OOC and in silico models can serve as alternative methods for studying drug pharmacokinetics during pregnancy, providing valuable insights into drug transport and metabolism across the placenta and fetal membranes. These advanced platforms offer promising opportunities for safe, reliable, and faster testing of therapeutic compounds, potentially reducing the number of pregnant women referred to as "therapeutic orphans" due to the lack of consideration in drug development and clinical trials. By bridging the gap between preclinical studies and clinical trials, these approaches hold great promise in improving maternal and neonatal health outcomes.
PubMed: 37663251
DOI: 10.3389/fphar.2023.1241815 -
Pharmacogenetics and Genomics Sep 2023The association of SLCO1B1 c.521T>C with simvastatin-induced muscle toxicity is well characterized. However, different statins are subject to metabolism and transport...
OBJECTIVE
The association of SLCO1B1 c.521T>C with simvastatin-induced muscle toxicity is well characterized. However, different statins are subject to metabolism and transport also by other proteins exhibiting clinically meaningful genetic variation. Our aim was to investigate associations of SLCO1B1 c.521T>C with intolerance to atorvastatin, fluvastatin, pravastatin, rosuvastatin, or simvastatin, those of ABCG2 c.421C>A with intolerance to atorvastatin, fluvastatin, or rosuvastatin, and that of CYP2C9*2 and *3 alleles with intolerance to fluvastatin.
METHODS
We studied the associations of these variants with statin intolerance in 2042 patients initiating statin therapy by combining genetic data from samples from the Helsinki Biobank to clinical chemistry and statin purchase data.
RESULTS
We confirmed the association of SLCO1B1 c.521C/C genotype with simvastatin intolerance both by using phenotype of switching initial statin to another as a marker of statin intolerance [hazard ratio (HR) 1.88, 95% confidence interval (CI) 1.08-3.25, P = 0.025] and statin switching along with creatine kinase measurement (HR 5.44, 95% CI 1.49-19.9, P = 0.011). No significant association was observed with atorvastatin and rosuvastatin. The sample sizes for fluvastatin and pravastatin were relatively small, but SLCO1B1 c.521T>C carriers had an increased risk of pravastatin intolerance defined by statin switching when compared to homozygous reference T/T genotype (HR 2.11, 95% CI 1.01-4.39, P = 0.047).
CONCLUSION
The current results can inform pharmacogenetic statin prescribing guidelines and show feasibility for the methodology to be used in larger future studies.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Atorvastatin; Rosuvastatin Calcium; Pravastatin; Cytochrome P-450 CYP2C9; Fluvastatin; Pharmacogenetics; Simvastatin; Liver-Specific Organic Anion Transporter 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; Neoplasm Proteins
PubMed: 37490620
DOI: 10.1097/FPC.0000000000000504 -
Journal of Affective Disorders Mar 2024Depression is a common mental disorder. Some studies have demonstrated that people with diabetes are more likely to suffer from depression. Statins are an everyday use...
BACKGROUND
Depression is a common mental disorder. Some studies have demonstrated that people with diabetes are more likely to suffer from depression. Statins are an everyday use for diabetes. Trials of statin therapy have had conflicting findings on the potential risk of depression.
METHODS
The National Health and Nutrition Examination Survey (NHANES) 2005-2018 was used to collect a representative sample. Weighted multivariate logistic regression models were used to evaluate odds ratios (ORs) and 95 % CIs for having depression symptoms. We performed stratified analyses to compare the effects of statins in subsamples with and without diabetes on depression symptoms.
RESULTS
Statin use showed a significant and strong decreasing effect on having depression symptoms in participants with diabetes (aOR (adjusted OR) 0.59, p = 0.014) compared with that in non-diabetics (aOR 0.78, p = 0.128). Diabetic individuals with statin use for >5 years had a lower risk of having depression symptoms (aOR 0.42, p = 0.002) than those with shorter-term statin use (1-5 years, aOR 0.69, p = 0.111; <1 year: aOR 0.83, p = 0.646). Atorvastatin was more effective in decreasing depression symptoms either in diabetes (aOR 0.49, p = 0.018) or in non-diabetes (aOR 0.58, p = 0.033).
LIMITATIONS
First, the dosage of statins cannot be obtained from NHANES datasets. Second, after being stratified, the number of participants for several statins was insufficient. Third, recall bias may exist in the survey.
CONCLUSIONS
Diabetics with depression symptoms may benefit from long-term statin therapy. Atorvastatin and pravastatin should be recommended for diabetic patients with depression.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Atorvastatin; Nutrition Surveys; Depression; Diabetes Mellitus
PubMed: 38199416
DOI: 10.1016/j.jad.2024.01.013 -
The Journal of Pharmacology and... Nov 2023Drug biliary clearance (CL) in vivo is among the most difficult pharmacokinetic parameters to predict accurately and quantitatively because biliary excretion is...
Drug biliary clearance (CL) in vivo is among the most difficult pharmacokinetic parameters to predict accurately and quantitatively because biliary excretion is influenced by metabolic enzymes, transporters, and passive diffusion across hepatocyte membranes. The purpose of this study is to demonstrate the use of Hu-FRG mice [ (FRG) mice transplanted with human-derived hepatocytes] to quantitatively predict human organic anion transporting polypeptide (OATP)-mediated drug disposition and CL To predict OATP-mediated disposition, six OATP substrates (atorvastatin, fexofenadine, glibenclamide, pitavastatin, pravastatin, and rosuvastatin) were administered intravenously to Hu-FRG and Mu-FRG mice (FRG mice transplanted with mouse hepatocytes) with or without rifampicin as an OATP inhibitor. We calculated the hepatic intrinsic clearance (CL) and the change of hepatic clearance (CL) caused by rifampicin (CL ratio). We compared the CL of humans with that of Hu-FRG mice and the CL ratio of humans with that of Hu-FRG and Mu-FRG mice. For predicting CL, 20 compounds (two cassette doses of 10 compounds) were administered intravenously to gallbladder-cannulated Hu-FRG and Mu-FRG mice. We evaluated the CL and investigated the correlation of human CL with that of Hu-FRG and Mu-FRG mice. We found good correlations between humans and Hu-FRG mice in CL (100% within threefold) and CL ratio (R = 0.94). Moreover, we observed a much better relationship between humans and Hu-FRG mice in CL (75% within threefold). Our results suggest that OATP-mediated disposition and CL can be predicted using Hu-FRG mice, making them a useful in vivo drug discovery tool for quantitatively predicting human liver disposition. SIGNIFICANCE STATEMENT: OATP-mediated disposition and biliary clearance of drugs are likely quantitatively predictable using Hu-FRG mice. The findings can enable the selection of better drug candidates and the development of more effective strategies for managing OATP-mediated DDIs in clinical studies.
Topics: Humans; Mice; Animals; Rifampin; Liver; Hepatocytes; Bile; Organic Anion Transporters
PubMed: 37142442
DOI: 10.1124/jpet.123.001595 -
Liver International : Official Journal... Oct 2023Non-alcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome and poses a significant threat to patients with type 2 diabetes mellitus...
BACKGROUND AND AIMS
Non-alcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome and poses a significant threat to patients with type 2 diabetes mellitus (T2DM) and metabolic dysregulation. Statins exert anti-inflammatory, antioxidative and antithrombotic effects that target mechanisms underlying NAFLD. However, the protective effects of the different doses, intensities and types of statins on the incidence of NAFLD-related decompensated liver cirrhosis (DLC) in patients with T2DM remain unclear.
METHODS
This study used the data of patients with T2DM who were non-HBV and non-HCV carriers from a national population database to examine the protective effects of statin use on DLC incidence through propensity score matching. The incidence rate (IR) and incidence rate ratios (IRRs) of DLC in patients with T2DM with or without statin use were calculated.
RESULTS
A higher cumulative dose and specific types of statins, namely rosuvastatin, pravastatin, atorvastatin, simvastatin and fluvastatin, reduced the risk of DLC in patients with T2DM. Statin use was associated with a significant reduction in the risk of DLC (HR: .65, 95% CI: .61-.70). The optimal daily intensity of statin use with the lowest risk of DLC was .88 defined daily dose (DDD).
CONCLUSIONS
The results revealed the protective effects of specific types of statins on DLC risk in patients with T2DM and indicated a dose-response relationship. Additional studies are warranted to understand the specific mechanisms of action of different types of statins and their effect on DLC risk in patients with T2DM.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Non-alcoholic Fatty Liver Disease; Diabetes Mellitus, Type 2; Incidence; Atorvastatin; Risk Factors
PubMed: 37381761
DOI: 10.1111/liv.15656 -
Expert Opinion on Drug Safety Mar 2024Statins, previously rated as pregnancy category X agents, were contraindicated during pregnancy due to the teratogenic effects observed in animal studies. However, it is...
BACKGROUND
Statins, previously rated as pregnancy category X agents, were contraindicated during pregnancy due to the teratogenic effects observed in animal studies. However, it is still controversial whether statins have detrimental impact on pregnant women or not, and some studies even suggest a potential benefit of statin use against pregnancy complications. The aim of this study was to explore whether maternal exposure to statins is associated with increased rates of pregnancy-related adverse events (AEs), including abortion, abortion spontaneous, preterm birth, low birth weight, stillbirth/fetal death, and fetal complications.
RESEARCH DESIGN AND METHODS
Data from 1 January 2004 to 30 June 2022 were extracted through the U.S. FDA Adverse Event Reporting System (FAERS) database, to conduct disproportionality analysis and Bayesian analysis by reporting odds ratio (ROR) and Bayesian confidence propagation neural network (BCPNN) algorithms. To identify the potential risks of pregnancy-related AEs, each statin was compared to all the other drugs, all the other statins, and the reference drugs (fenofibrate and evolocumab).
RESULTS
A total of 477 cases involving pregnancy-related AEs associated with stains were submitted to the FAERS database by healthcare professionals. No obvious disproportionate association of abortion, abortion spontaneous, or stillbirth/fetal death was identified for all statins during gestation. In comparison with all the other drugs, lovastatin showed an increased risk of fetal complications (ROR = 2.45, 95% CI, 1.22-4.95; IC = 0.63), and pravastatin demonstrated increased risks of preterm birth (ROR = 4.89, 95% CI, 3.65-6.54; IC = 1.69) and low birth weight (ROR = 9.60, 95% CI, 5.56-16.56; IC = 1.88). Similar results were found when compared lovastatin or pravastatin with fenofibrate. Furthermore, statins were associated with higher proportion of fetal complications and preterm birth when comparing with evolocumab.
CONCLUSIONS
Statins did not increase the risk of pregnancy-related AEs, including abortion, abortion spontaneous, or stillbirth/fetal death. However, we did find significant disproportionality signals for preterm birth and low birth weight associated with pravastatin, and lovastatin was related to a higher proportion of fetal complications. The results in this study may provide evidence on the safety of statins during pregnancy, which need to be verified in further investigations.
Topics: Humans; Infant, Newborn; Female; Pregnancy; United States; Pharmacovigilance; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Pravastatin; Premature Birth; Stillbirth; Bayes Theorem; Fenofibrate; Lovastatin; Adverse Drug Reaction Reporting Systems; United States Food and Drug Administration
PubMed: 37612600
DOI: 10.1080/14740338.2023.2251888