Pitavastatin for lowering lipids.
Ontology highlight
ABSTRACT:
SUBMITTER: Adams SP
PROVIDER: S-EPMC7387421 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Hepatic steatosis develops when lipid influx and production exceed the liver's ability to utilize/export triglycerides. Obesity promotes steatosis and is characterized by leptin resistance. A role of leptin in hepatic lipid handling is highlighted by the observation that recombinant leptin reverses steatosis of hypoleptinemic patients with lipodystrophy by an unknown mechanism. Since leptin mainly functions via CNS signaling, we here examine in rats whether leptin regulates hepatic lipid flux via the brain in a series of stereotaxic infusion experiments. We demonstrate that brain leptin protects from steatosis by promoting hepatic triglyceride export and decreasing de novo lipogenesis independently of caloric intake. Leptin's anti-steatotic effects are generated in the dorsal vagal complex, require hepatic vagal innervation, and are preserved in high-fat-diet-fed rats when the blood brain barrier is bypassed. Thus, CNS leptin protects from ectopic lipid accumulation via a brain-vagus-liver axis and may be a therapeutic strategy to ameliorate obesity-related steatosis.
| S-EPMC6586634 | biostudies-literature
Project description:This study was designed to evaluate the dose-effect relationship of statins in patients with ischemic congestive heart failure (CHF), since the role of statins in CHF remains unclear.The South koreAn Pitavastatin Heart FaIluRE (SAPHIRE) study was designed to randomize patients with ischemic CHF into daily treatments of 10 mg pravastatin or 4 mg pitavastatin.The low density lipoprotein cholesterol level decreased by 30% in the pitavastatin group compared with 12% in the pravastatin (p < 0.05) group. Left ventricular systolic dimensions decreased significantly by 9% in the pitavastatin group and by 5% in the pravastatin group. Left ventricular ejection fraction (EF) improved significantly from 37% to 42% in the pitavastatin group and from 35% to 39% in the pravastatin group. Although the extent of the EF change was greater in the pitavastatin group (16% vs. 11%) than that in the pravastatin group, no significant difference was observed between the groups (p = 0.386). Exercise capacity, evaluated by the 6-min walking test, improved significantly in the pravastatin group (p < 0.001), but no change was observed in the pitavastatin group (p = 0.371).Very low dose/low potency pravastatin and high dose/high potency pitavastatin had a beneficial effect on cardiac reverse remodeling and improved systolic function in patients with ischemic CHF. However, only pravastatin significantly improved exercise capacity. These findings suggest that lowering cholesterol too much may not be beneficial for patients with CHF.
| S-EPMC4219965 | biostudies-literature
Project description:BackgroundStroke is a leading cause of death worldwide, but it is unclear whether circulating lipids and lipid-lowering drugs are causally associated with stroke and its subtypes.MethodsWe used two-sample Mendelian randomization (MR) to examine the effects of blood lipids and lipid-lowering drugs on stroke and its subtypes.ResultsThe inverse variance weighted Mendelian randomization (IVW-MR) revealed the low-density lipoprotein cholesterol (LDL-C) (OR, 1.46; 95% CI, 1.17-1.83; p = 0.0008) and apolipoprotein B (apoB) (OR, 1.46; 95% CI, 1.21-1.77; p = 0.0001) was positively correlated with large artery stroke (LAS). However, no causal effect was found in LDL-C and apoB on LAS risk when we conducted mvMR. The IVW-MR also found a suggestive evidence that decreased LDL-C levels mediated by the PCSK9 (proprotein convertase subtilisin-kexin type 9) gene were associated with a reduced risk of any stroke (AS) (OR, 1.31; 95% CI, 1.13-1.52; p = 0.0003), any ischemic stroke (AIS) (OR, 1.29; 95% CI, 1.10-1.51; p = 0.001), and LAS (OR, 1.73; 95% CI, 1.15-2.59; p = 0.008), while NPC1L1 (Niemann-Pick C1-like protein)-mediated LDL-C levels were associated with a higher risk of small vessel stroke (SVS) (OR, 6.10; 95% CI, 2.13-17.43; p = 0.0008). The SMR revealed that expression of PCSK9 was associated with risk of AS (OR, 1.15; 95% CI, 1.03-1.28; p = 0.01), AIS (OR, 1.02; 95% CI, 1.14-1.29; p = 0.03), cardioembolic stroke (CES) (OR, 1.28; 95% CI, 1.01-1.61; p = 0.04). And, a significant association was found between the expression of NPC1L1 and the risk of SVS (OR, 1.15; 95% CI, 1.00-1.32; p = 0.04).ConclusionWe cautiously find that LDL-C and apoB was positively correlated with LAS. These findings suggest that the reducing LDL-C levels could be an effective prevention strategy for reducing the risk of stroke.
| S-EPMC10390065 | biostudies-literature
Project description:BackgroundWe aimed to investigate the effects of blood lipids and lipid-lowering agents on osteoarthritis (OA) risk.Materials and methodsWe performed Mendelian randomization (MR) analyses to estimate the causal effect of blood low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG) levels on knee and hip OA. Single nucleotide polymorphisms (SNPs) were selected from large genome-wide association studies (GWASs) of individuals of European ancestry as genetic instruments for blood lipid levels. The associations of selected genetic instruments with knee and hip OA were estimated in a recent GWAS of the UK Biobank and arcOGEN datasets. Univariate and multivariate MR analyses were performed to detect and adjust for potential pleiotropy. Furthermore, genetic instruments in HMGCR, NPC1L1, and PCSK9 regions were used to mimic LDL-C-lowering effects of statin, ezetimibe, and evolocumab, respectively.ResultsGenetically determined LDL-C increments led to reduced risks of both knee OA (OR = 0.91 per 1-SD increment, 95% CI: 0.86-0.95, P = 6.3 × 10-5) and hip OA (OR = 0.92, 95% CI: 0.85-0.99, P = 0.027). Multivariate MR analysis proved that the effect was independent of HDL-C, TG, and body mass index. TG increment was associated with reduced risks of hip OA in the univariate MR analysis; however, this was not supported by the multivariate MR analysis. Genetically proxied LDL-C-lowering effects of statins are related to increased risks of knee OA but not hip OA.ConclusionsThe findings suggested that LDL-C increments have independent protective effects on both knee and hip OA. LDL-C-lowering effects of statins may increase the risk of knee OA.
| S-EPMC9691771 | biostudies-literature
Project description:AIM: To examine the effects of ?3-adrenoceptor (?3-AR) activation on atherosclerotic plaque development in ApoE(-/-) mice. METHODS: Thirty six week-old male ApoE(-/-) mice on a high-fat diet were treated with atorvastatin (10 mg·kg(-1)·d(-1), po), BRL37344 (?3-AR agonist, 1.65 or 3.30 ?g/kg, ip, twice a week) or SR52390A (?3-AR antagonist, 50 ?g/kg, ip, twice a week) for 12 weeks. Wild-type C57BL/6J mice receiving a normal diet were taken as healthy controls. At the end of the treatments, serum levels of triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), non-high density lipoprotein cholesterol (nHDL-C), glucose and insulin were measured. The thoracic aortas were dissected out, the area of atherosclerotic plaques and extent of fibrosis in the plaques were examined using HE and Masson's trichome staining, respectively. RESULTS: Compared to wild-type mice, ApoE(-/-) mice fed on a high-fat diet exhibited prominent hyperlipidemia and insulin resistance, associated with large area of atherosclerotic plaques and great extent of fibrosis in aortas. Atorvastatin significantly decreased the serum levels of TC and nHDL-C, and reduced the plaque area and collagen content in aortas. BRL37344 significantly decreased the serum levels of TG, TC, nHDL-C, glucose and insulin, and increased HDL-C and the insulin sensitivity, and dose-dependently reduced the plaque area and collagen content in aortas. SR52390A treatment did not affect any parameters studied. CONCLUSION: The ?3-AR agonist impedes the progression of atherosclerosis in ApoE(-/-) mice, through improvement of the lipid and glucose profiles.
| S-EPMC4003164 | biostudies-literature
Project description:BackgroundThe impact of lipid-lowering medications on sepsis is still not well defined. A Mendelian randomization (MR) study was carried out to probe the causal connections between genetically determined lipids, lipid-reducing drugs, and the risk of sepsis.Materials and methodsData on total serum cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A-I (ApoA-I), apolipoprotein B (ApoB), and triglycerides (TG) were retrieved from the MR-Base platform and the Global Lipids Genetics Consortium in 2021 (GLGC2021). Our study categorized sepsis into two groups: total sepsis and 28-day mortality of sepsis patients (sepsis28). The inverse-variance weighted (IVW) method was the primary method used in MR analysis. Cochran's Q test and the MR-Egger intercept method were used to assess the heterogeneity and pleiotropy.ResultsIn the MR analysis, we found that ApoA-I played a suggestively positive role in protecting against both total sepsis (OR, 0.863 per SD increase in ApoA-I; 95% CI, 0.780-0.955; P = 0.004) and sepsis28 (OR, 0.759; 95% CI, 0.598-0.963; P = 0.023). HDL-C levels were also found to suggestively reduce the incidence of total sepsis (OR, 0.891 per SD increase in HDL-C; 95% CI, 0.802-0.990; P = 0.031). Reverse-MR showed that sepsis28 led to a decrease in HDL-C level and an increase in TG level. In drug-target MR, we found that HMGCR inhibitors positively protected against total sepsis (1OR, 0.719 per SD reduction in LDL-C; 95% CI, 0.540-0.958; P = 0.024). LDL-C and HDL-C proxied CETP inhibitors were found to have a protective effect on total sepsis, with only LDL-C proxied CETP inhibitors showing a suggestively protective effect on sepsis28. In Mediated-MR, BMI exhibited a negative indirect effect in HMGCR inhibitors curing sepsis. The indirect impact of ApoA-I explained over 50% of the curative effects of CETP inhibitors in sepsis.ConclusionsOur MR study suggested that ApoA-I and HDL-C protected against sepsis, while HMGCR and CETP inhibitors showed therapeutic potential beyond lipid-lowering effects. ApoA-I explained the effects of CETP inhibitors. Our study illuminates how lipids affect sepsis patients and the effectiveness of new drugs, opening new avenues for sepsis treatment.
| S-EPMC10446761 | biostudies-literature
Project description:Accumulating observational studies suggested that hypercholesterolemia is associated with vascular dementia (VaD); however, the causality between them remains unclear. Hence, the aim of this study is to infer causal associations of circulating lipid-related traits [including high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), apolipoprotein A-I (apoA-I), and apolipoprotein B (apoB)] with VaD jointly using univariable MR (uvMR), multivariable MR (mvMR) and bidirectional two-sample MR methods. Then, the summary-data-based MR (SMR) and two-sample MR analysis were conducted to investigate the association of lipid-lowering drugs target genes expression (including HMGCR, PCSK9, NPC1L1, and APOB) and LDL-C level mediated by these target genes with VaD. The results of forward MR analyses found that genetically predicted HDL-C, LDL-C, TG, apoA-I, and apoB concentrations were not significantly associated with the risk of VaD (all p > 0.05). Notably, there was suggestive evidence for a causal effect of genetically predicted VaD on HDL-C via reverse MR analysis [odds ratio (OR), 0.997; 95% confidence interval (CI), 0.994−0.999; p = 0.022]. On the contrary, the MR results showed no significant relationship between VaD with LDL-C, TG, apoA-I, and apoB. The results for the SMR method found that there was no evidence of association for expression of HMGCR, PCSK9, NPC1L1, and APOB gene with risk of VaD. Furthermore, the result of MR analysis provided evidence for the decreased LDL-C level mediated by gene HMGCR reduced the risk of VaD (OR, 18.381; 95% CI, 2.092−161.474; p = 0.009). Oppositely, none of the IVW methods indicated any causal effects for the other three genes. Using genetic data, this study provides evidence that the VaD risk may cause a reduction of HDL-C level. Additionally, the finding supports the hypothesis that lowering LDL-C levels using statins may be an effective prevention strategy for VaD risk, which requires clinical trials to confirm this result in the future.
| S-EPMC9824558 | biostudies-literature
Project description:Studies on the relationship of cholesterol concentrations and lipid-lowering medications with dementia risk have yielded inconsistent findings. Therefore, we investigated the association of lipid concentrations and lipid-lowering medications with cognitive function in the Multi-Ethnic Study of Atherosclerosis across 3 different cognitive domains assessed by means of the Cognitive Abilities Screening Instrument (CASI; version 2), the Digit Symbol Coding (DSC) Test, and the Digit Span (DS) Test in 2010-2012. After adjustment for sociodemographic and confounding factors, including concentrations of other lipids and use of lipid-lowering medication, higher total cholesterol, low-density lipoprotein cholesterol, and non-high-density-lipoprotein cholesterol concentrations were modestly associated with higher DS Test scores. None of the lipid parameters were associated with CASI or DSC Test scores. Similarly, changes in lipid concentrations were not associated with any cognitive function test score. Using treatment effects model analysis and after adjusting for confounding factors, including lipid concentrations, the use of any lipid-lowering medication, especially statins, was associated with higher scores on the CASI and backward DS tests but not on the DSC and forward DS tests. Our study does not support a robust association between lipid concentrations and cognitive function or between the use of lipid-lowering medication, especially statins, and worse cognitive function.
| S-EPMC5888993 | biostudies-literature
Project description:BackgroundSome observational studies found that dyslipidaemia is a risk factor for non-alcoholic fatty liver disease (NAFLD), and lipid-lowering drugs may lower NAFLD risk. However, it remains unclear whether dyslipidaemia is causative for NAFLD. This Mendelian randomisation (MR) study aimed to explore the causal role of lipid traits in NAFLD and evaluate the potential effect of lipid-lowering drug targets on NAFLD.MethodsGenetic variants associated with lipid traits and variants of genes encoding lipid-lowering drug targets were extracted from the Global Lipids Genetics Consortium genome-wide association study (GWAS). Summary statistics for NAFLD were obtained from two independent GWAS datasets. Lipid-lowering drug targets that reached significance were further tested using expression quantitative trait loci data in relevant tissues. Colocalisation and mediation analyses were performed to validate the robustness of the results and explore potential mediators.FindingsNo significant effect of lipid traits and eight lipid-lowering drug targets on NAFLD risk was found. Genetic mimicry of lipoprotein lipase (LPL) enhancement was associated with lower NAFLD risks in two independent datasets (OR1 = 0.60 [95% CI 0.50-0.72], p1 = 2.07 × 10-8; OR2 = 0.57 [95% CI 0.39-0.82], p2 = 3.00 × 10-3). A significant MR association (OR = 0.71 [95% CI, 0.58-0.87], p = 1.20 × 10-3) and strong colocalisation association (PP.H4 = 0.85) with NAFLD were observed for LPL expression in subcutaneous adipose tissue. Fasting insulin and type 2 diabetes mediated 7.40% and 9.15%, respectively, of the total effect of LPL on NAFLD risk.InterpretationOur findings do not support dyslipidaemia as a causal factor for NAFLD. Among nine lipid-lowering drug targets, LPL is a promising candidate drug target in NAFLD. The mechanism of action of LPL in NAFLD may be independent of its lipid-lowering effects.FundingCapital's Funds for Health Improvement and Research (2022-4-4037). CAMS Innovation Fund for Medical Sciences (CIFMS, grant number: 2021-I2M-C&T-A-010).
| S-EPMC10070091 | biostudies-literature
Project description:Dyslipidaemia is a major risk factor for cardiovascular (CV) disease. Despite the widespread availability of effective lipid-lowering agents, an unacceptably large proportion of patients fail to attain their target low-density lipoprotein cholesterol (LDL-C) level in clinical practice. Reasons for this include undertreatment, poor adherence/persistence with therapy and failure to address non-LDL-C residual risk factors such as high levels of triglycerides, low high-density lipoprotein cholesterol (HDL-C) concentrations and raised apolipoprotein B: apolipoprotein A1 ratios. Pitavastatin is a novel, well-tolerated statin with a noninferior or superior lipid-lowering efficacy to comparable doses of atorvastatin, simvastatin, and prava-statin in a wide range of patients with hypercholesterolemia or combined dyslipidaemia. Compared with other statins, pitavastatin produces consistently greater increases in HDL-C levels that are sustained over the long term. In addition to pravastatin's potent effects on lipid profiles, a number of pleiotropic benefits have been identified that may contribute to a reduction in residual cardiovascular risk in people with dyslipidaemia and could partly account for pitavastatin's ability to regress coronary plaques in patients with acute coronary syndrome. Pitavastatin's unique metabolic profile results in a high efficacy at low (1-4 mg) doses and minimal drug interactions with cytochrome CYP3A4 substrates, making it an excellent choice for people requiring multiple medications. Although future trials are required to assess the impact of pitavastatin treatment on CV morbidity and mortality, studies to date suggest that pitavastatin will play an important role in the future management of dyslipidaemia and in the overall reduction of CV risk.
| S-EPMC3513875 | biostudies-literature