ABSTRACT
Documented cases of ipsilateral ptosis caused by midbrain infarction remain rare. Herein, we present a patient with isolated ipsilateral ptosis that was initially considered to be a consequence of myasthenia gravis but was subsequently attributed to ventral midbrain infarction. We also discuss the possible underlying mechanisms; ipsilateral ptosis in our patient was attributed to selective damage of the levator palpebral muscle branch of the oculomotor nerve. The patient was started on aspirin (200 mg once daily) and atorvastatin (40 mg once daily). Improvement in ptosis occurred from day 5 of admission, and the patient was subsequently discharged. Ptosis disappeared 1 month after onset. This report describes an extremely rare case of ventral midbrain infarction presenting with isolated ipsilateral ptosis. Careful examination, including magnetic resonance imaging, is essential in such patients, especially in those with multiple cerebrovascular risk factors.
Subject(s)
Blepharoptosis , Magnetic Resonance Imaging , Mesencephalon , Humans , Blepharoptosis/etiology , Mesencephalon/diagnostic imaging , Mesencephalon/pathology , Male , Aspirin/therapeutic use , Atorvastatin/therapeutic use , Female , Aged , Cerebral Infarction/diagnostic imaging , Cerebral Infarction/complications , Middle AgedABSTRACT
BACKGROUND: The impact of rosuvastatin versus atorvastatin on new-onset diabetes mellitus (NODM) among patients treated with high-intensity statin therapy for coronary artery disease (CAD) remains to be clarified. This study aimed to evaluate the risk of NODM in patients with CAD treated with rosuvastatin compared to atorvastatin in the randomized LODESTAR trial. METHODS: In the LODESTAR trial, patients with CAD were randomly assigned to receive either rosuvastatin or atorvastatin using a 2-by-2 factorial randomization. In this post-hoc analysis, the 3-year incidence of NODM was compared between rosuvastatin and atorvastatin treatment in the as-treated population with high-intensity statin therapy as the principal population of interest. RESULTS: Among 2932 patients without diabetes mellitus at baseline, 2377 were included in the as-treated population analysis. In the as-treated population with high-intensity statin therapy, the incidence of NODM was not significantly different between the rosuvastatin and atorvastatin groups (11.4% [106/948] versus 8.8% [73/856], hazard ratio [HR] = 1.32, 95% confidence interval [CI] = 0.98 to 1.77, P = 0.071). When the risk of NODM with rosuvastatin versus atorvastatin was assessed according to the achieved low-density lipoprotein cholesterol (LDL-C) level, the risk of NODM began to increase at a LDL-C level below 70 mg/dL. The incidence of NODM was significantly greater in the rosuvastatin group than it was in the atorvastatin group when the achieved LDL-C level was < 70 mg/dL (13.9% versus 8.0%; HR = 1.79, 95% CI 1.18 to 2.73, P = 0.007). CONCLUSIONS: Among CAD patients receiving high-intensity statin therapy, the incidence of NODM was not significantly different between rosuvastatin and atorvastatin. However, a drug effect of the statin type on NODM was observed when the achieved LDL-C level was < 70 mg/dL. TRIAL REGISTRATION: ClinicalTrials.gov, Identifier: NCT02579499.
Subject(s)
Atorvastatin , Coronary Artery Disease , Diabetes Mellitus , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Rosuvastatin Calcium , Humans , Rosuvastatin Calcium/adverse effects , Rosuvastatin Calcium/therapeutic use , Atorvastatin/adverse effects , Atorvastatin/therapeutic use , Coronary Artery Disease/epidemiology , Coronary Artery Disease/blood , Coronary Artery Disease/diagnosis , Coronary Artery Disease/drug therapy , Male , Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Female , Middle Aged , Aged , Diabetes Mellitus/diagnosis , Diabetes Mellitus/epidemiology , Diabetes Mellitus/blood , Diabetes Mellitus/drug therapy , Incidence , Treatment Outcome , Risk Factors , Time Factors , Biomarkers/blood , Risk AssessmentABSTRACT
Breast cancer remains a significant health challenge with complex molecular mechanisms. While many studies have explored genetic markers in breast carcinogenesis, few have studied the potential impact of pharmacological interventions such as Atorvastatin on its genetic landscape. This study aimed to elucidate the molecular distinctions between normal and tumor-adjacent tissues in breast cancer and to investigate the potential protective role of atorvastatin, primarily known for its lipid-lowering effects, against breast cancer. Searching the Gene Expression Omnibus database identified two datasets, GSE9574 and GSE20437, comparing normal breast tissues with tumor-adjacent samples, which were merged, and one dataset, GSE63427, comparing paired pre- and post-treated patients with atorvastatin. Post-ComBat application showed merged datasets' consistency, revealing 116 DEGs between normal and tumor-adjacent tissues. Although initial GSE63427 data analysis suggested a minimal impact of atorvastatin, 105 DEGs post-treatment were discovered. Thirteen genes emerged as key players, both affected by Atorvastatin and dysregulated in tumor-adjacent tissues. Pathway analysis spotlighted the significance of these genes in processes like inflammation, oxidative stress, apoptosis, and cell cycle control. Moreover, there was a noticeable interaction between these genes and the immunological microenvironment in tumor-adjacent tissues, with Atorvastatin potentially altering the suppressive immune landscape to favor anti-tumor immunity. Survival analysis further highlighted the prognostic potential of the 13-gene panel, with 12 genes associated with improved survival outcomes. The 13-gene signature offers promising insights into breast cancer's molecular mechanisms and atorvastatin's potential therapeutic role. The preliminary findings advocate for an in-depth exploration of atorvastatin's impact on.
Subject(s)
Atorvastatin , Breast Neoplasms , Gene Expression Regulation, Neoplastic , Atorvastatin/therapeutic use , Atorvastatin/pharmacology , Humans , Breast Neoplasms/genetics , Breast Neoplasms/drug therapy , Female , Gene Expression Regulation, Neoplastic/drug effects , Gene Expression Profiling , Carcinogenesis/genetics , Carcinogenesis/drug effects , Tumor Microenvironment/drug effectsABSTRACT
Triple negative breast cancer (TNBC) as the most aggressive molecular subtype of breast cancer is characterized by high cancer cell proliferation and poor patient prognosis. Abnormal lipid metabolism contributes to the malignant process of cancers. Study observed significantly enhanced cholesterol biosynthesis in TNBC. However, the mechanisms underlying the abnormal increase of cholesterol biosynthesis in TNBC are still unclear. Hence, we identified a member of the serine/threonine protein kinase family PKMYT1 as a key driver of cholesterol synthesis in TNBC cells. Aberrantly high-expressed PKMYT1 in TNBC was indicative of unfavorable prognostic outcomes. In addition, PKMYT1 promoted sterol regulatory element-binding protein 2 (SREBP2)-mediated expression of enzymes related to cholesterol biosynthesis through activating the TNF/ TNF receptor-associated factor 1 (TRAF1)/AKT pathway. Notably, downregulation of PKMYT1 significantly inhibited the feedback upregulation of statin-mediated cholesterol biosynthesis, whereas knockdown of PKMYT1 promoted the drug sensitivity of atorvastatin in TNBC cells. Overall, our study revealed a novel function of PKMYT1 in TNBC cholesterol biosynthesis, providing a new target for targeting tumor metabolic reprogramming in the cancer.
Subject(s)
Atorvastatin , Cholesterol , Triple Negative Breast Neoplasms , Humans , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/genetics , Triple Negative Breast Neoplasms/pathology , Triple Negative Breast Neoplasms/metabolism , Atorvastatin/pharmacology , Atorvastatin/therapeutic use , Cholesterol/biosynthesis , Cholesterol/metabolism , Female , Cell Line, Tumor , Gene Knockdown Techniques , Gene Expression Regulation, Neoplastic/drug effects , Drug Resistance, Neoplasm/genetics , Drug Resistance, Neoplasm/drug effects , Sterol Regulatory Element Binding Protein 2/metabolism , Sterol Regulatory Element Binding Protein 2/genetics , Cell Proliferation/drug effects , Membrane Proteins , Protein-Tyrosine Kinases , Protein Serine-Threonine KinasesABSTRACT
BACKGROUND AND OBJECTIVE: Atorvastatin is a drug widely used to prevent cardiovascular and cerebrovascular diseases. Current observational studies suggest that atorvastatin may be associated with cognitive dysfunction (especially memory loss). However, some studies have suggested that dyslipidemia may be an important factor in cognitive dysfunction. The purpose of this study was to perform a pharmacovigilance analysis using real-world data from the US Food and Drug Administration's Adverse Event Reporting System (FAERS) to assess whether memory loss is an adverse effect of atorvastatin and to further clarify its causality through Mendelian randomization (MR). METHODS: We extracted real-world data from the FAERS database (Quarter 1 2004 to Quarter 1 2023). Disproportionality analysis methods and measures of association such as the reporting odds ratio (OR), proportional reporting ratio, Bayesian confidence interval progressive neural network, and polynomial Gamma Poisson distribution reduction were used to assess whether memory loss was an adverse effect of atorvastatin. In addition, we used MR to evaluate causality in depth. RESULTS: In the pharmacovigilance analysis of atorvastatin, we extracted four datasets of clinical symptoms associated with memory loss from the FAERS database [Amnesia (n = 1196), Memory impairment (n = 840), Transient global amnesia (n = 38), and Retrograde amnesia (n = 9)]. The reporting OR, proportional reporting ratio, Bayesian confidence interval progressive neural network, and Gamma Poisson distribution reduction all showed positive results for amnesia, transient global amnesia, and retrograde amnesia, while the reporting OR and Bayesian confidence interval progressive neural network also showed positive results for memory disorders. Thus, memory loss was a frequent side effect of atorvastatin. The MR analyses were used to further evaluate the association between statins and memory loss. The results of the MR analysis (statins and memory loss) are as follows: Ivw (mre) (ß = 0.11 [OR = 1.11], P = 0.01 < 0.05) and the OR and ß directions of MR-Egger and weighted mode were the same. The results of the MR analysis (statins and mitochondrial DNA copy number) are as follows: Ivw(mre) (ß = -0.03 [OR = 0.96], P < 0.01) and the OR and ß direction of MR-Egger and weighted mode are the same. The results of the MR analysis (DNA copy number and memory loss) are as follows: Ivw(ß = - 0.06 [OR = 0.94], P = 0.04 < 0.05) and the OR and ß direction of MR-Egger and weighted mode were the same. The pleiotropy test did not find horizontal diversity in our results. CONCLUSIONS: This study suggests that memory loss is a notable adverse event associated with atorvastatin and provides evidence indicating a potential causal relationship between atorvastatin and memory loss. We also found that statins may further affect memory by affecting mitochondrial function. Therefore, in the clinical use of atorvastatin, it is important to carefully monitor the changes in cognitive function of patients. Second, a pharmacovigilance analysis combined with MR was used in this study to provide a new approach for the study of adverse drug reactions. This comprehensive analysis method helps to evaluate the safety of drugs and the risk of adverse reactions more comprehensively and provides doctors with a more accurate clinical decision-making basis.
Subject(s)
Atorvastatin , Memory Disorders , Mendelian Randomization Analysis , Pharmacovigilance , Atorvastatin/adverse effects , Atorvastatin/therapeutic use , Humans , Memory Disorders/chemically induced , Adverse Drug Reaction Reporting Systems/statistics & numerical data , Male , Female , Bayes Theorem , Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects , United States/epidemiology , Middle Aged , Databases, Factual , United States Food and Drug Administration , Aged , AdultABSTRACT
PURPOSE: It was aimed to compare corneal endothelial changes during the initial 12-month period in which patients started using atorvastatin after a diagnosis of acute coronary syndrome (ACS). METHODS: Forty-six participants (group 1) who underwent cardiac angioplasty and stenting for ACS and started using 80 mg atorvastatin in the early period were included in the study. In the study, a control group comprising 71 healthy adults (group 2) was included. These individuals did not use medication for any known systemic disease, had never taken statins, had no history of ocular surgery, and did not have any cornea-related eye diseases. Baseline and 12th month endothelial evaluations of group 1 and 2 participants were compared using specular microscopy. RESULTS: There were 28 female and 18 male participants in group 1 and 48 female and 23 male participants in group 2 (P = 0.455). The mean baseline corneal endothelial cell density (CECD) was not significantly higher in group 1 compared to group 2 (2471.4 ± 200 cells/mm2 vs 2428.2 ± 539.8 cells/mm2, P = 0.230). When the change between baseline and 12th month CECD was examined, the decrease in group 2 was significantly different from that in group 1 (-15,2 ± 31,9 and -44,8 ± 49,6, P = 0,002). Although the percentage of hexagonal cells decreased significantly in group 2 participants, no significant change was observed in group 1 (respectively; P < 0.001, P = 0.073). The endothelial cell coefficient of variation did not differ significantly in group 1 participants over a 1-year period (P = 0.192), and a significant increase was observed in group 2 (P < 0.001). CONCLUSION: This study revealed that atorvastatin may have a positive effect on corneal endothelium cell density and morphology.
Subject(s)
Acute Coronary Syndrome , Atorvastatin , Endothelium, Corneal , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Humans , Atorvastatin/therapeutic use , Male , Female , Endothelium, Corneal/pathology , Endothelium, Corneal/drug effects , Middle Aged , Acute Coronary Syndrome/diagnosis , Acute Coronary Syndrome/drug therapy , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Follow-Up Studies , Cell Count , Time Factors , Aged , Corneal Endothelial Cell Loss/diagnosis , Prospective Studies , AdultABSTRACT
Contemporary treatment of vitiligo remains a great challenge to practitioners. The vast majority of currently conducted clinical trials of modern therapeutic methods are focused on systemic medications, while there is only a very limited number of reports on new topical treatment in vitiligo. With their pleiotropic activities statins turned out to be efficient in the treatment of various autoimmune/autoinflammatory disorders. The randomized, double-blind placebo-controlled study of topical administration of the active forms of simvastatin and atorvastatin has been designed to evaluate their efficacy in patients with vitiligo. The study was registered in clinicaltrials.gov (registration number NCT03247400, date of registration: 11th August 2017). A total of 24 patients with the active form of non-segmental vitiligo were enrolled in the study. The change of absolute area of skin lesions, body surface area and vitiligo area scoring index were evaluated throughout the 12 week application of ointments containing simvastatin and atorvastatin. Measurements were performed with planimetry and processed using digital software. Use of active forms of simvastatin and atorvastatin did not result in a significant repigmentation of the skin lesions throughout the study period. Within the limbs treated with topical simvastatin, inhibition of disease progression was significantly more frequent than in the case of placebo (p = 0.004), while the difference was not statistically significant for atorvastatin (p = 0.082). Further studies of topical simvastatin in vitiligo patients should be considered.
Subject(s)
Administration, Topical , Atorvastatin , Simvastatin , Vitiligo , Humans , Vitiligo/drug therapy , Atorvastatin/administration & dosage , Atorvastatin/therapeutic use , Simvastatin/administration & dosage , Simvastatin/therapeutic use , Simvastatin/analogs & derivatives , Male , Female , Double-Blind Method , Adult , Pilot Projects , Middle Aged , Young Adult , Treatment Outcome , AdolescentABSTRACT
Clinically, statins have long been used for the prevention and treatment of chronic renal diseases, however, the underlying mechanisms are not fully elucidated. The present study investigated the effects of atorvastatin on diabetes renal injury and ferroptosis signaling. A mouse model of diabetes was established by the intraperitoneal injection of streptozotocin (50 mg/kg/day) plus a high fat diet with or without atorvastatin treatment. Diabetes mice manifested increased plasma glucose and lipid profile, proteinuria, renal injury and fibrosis, atorvastatin significantly lowered plasma lipid profile, proteinuria, renal injury in diabetes mice. Atorvastatin reduced renal reactive oxygen species (ROS), iron accumulation and renal expression of malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), transferrin receptor 1 (TFR1), and increased renal expression of glutathione peroxidase 4 (GPX4), nuclear factor erythroid 2-related factor (NRF2) and ferritin heavy chain (FTH) in diabetes mice. Consistent with the findings in vivo, atorvastatin prevented high glucose-induced ROS formation and Fe2+ accumulation, an increase in the expression of 4-HNE, MDA and TFR1, and a decrease in cell viability and the expression of NRF2, GPX4 and FTH in HK2 cells. Atorvastatin also reversed ferroptosis inducer erastin-induced ROS production, intracellular Fe2+ accumulation and the changes in the expression of above-mentioned ferroptosis signaling molecules in HK2 cells. In addition, atorvastatin alleviated high glucose- or erastin-induced mitochondria injury. Ferroptosis inhibitor ferrostatin-1 and antioxidant N-acetylcysteine (NAC) equally reversed the expression of high glucose-induced ferroptosis signaling molecules. Our data support the notion that statins can inhibit diabetes-induced renal oxidative stress and ferroptosis, which may contribute to statins protection of diabetic nephropathy.
Subject(s)
Atorvastatin , Diabetic Nephropathies , Ferroptosis , Oxidative Stress , Reactive Oxygen Species , Signal Transduction , Ferroptosis/drug effects , Animals , Diabetic Nephropathies/drug therapy , Diabetic Nephropathies/metabolism , Diabetic Nephropathies/pathology , Diabetic Nephropathies/prevention & control , Oxidative Stress/drug effects , Atorvastatin/pharmacology , Atorvastatin/therapeutic use , Male , Signal Transduction/drug effects , Mice , Reactive Oxygen Species/metabolism , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/complications , Mice, Inbred C57BL , Humans , Kidney/drug effects , Kidney/metabolism , Kidney/pathology , Cell Line , Phenylenediamines/pharmacology , Phenylenediamines/therapeutic useABSTRACT
BACKGROUND: Statins are lipid-lowering drugs with favorable anti-inflammatory effects. This study aimed to explore different statin-based lipid-lowering strategies to reduce high-sensitivity C-reactive protein (hs-CRP). HYPOTHESIS: The hypothesis is that different statin-based lipid-lowering strategies might reduce hs-CRP. METHODS: This retrospective study included 3653 patients who underwent percutaneous coronary intervention (PCI). Three statin-based lipid-lowering strategies were investigated, including different types of statins (atorvastatin vs. rosuvastatin), statin combined with ezetimibe therapy (vs. without), and intensive statin therapy (vs. regular). The hs-CRP levels and blood lipid indicators were measured at baseline and after 1-month lipid-lowering therapy. Multivariable linear regression analysis and structural equation mode analysis were conducted to verify the association between different lipid-lowering strategies, Δhs-CRP (%) and ΔLDL-C (%). RESULTS: Totally, 3653 patients were enrolled with an average age of 63.81 years. Multivariable linear regression demonstrated that statin combined with ezetimibe therapy was significantly associated with decreased Δhs-CRP (%) (ß = -0.253, 95% CI: [-0.501 to -0.005], p = 0.045). The increased ΔLDL-C (%) was an independent predictor of elevated levels of Δhs-CRP (%) (ß = 0.487, 95% CI: [0.15-0.824], p = 0.005). Furthermore, structural equation model analysis proved that statin combined with ezetimibe therapy (ß = -0.300, p < 0.001) and intensive statin therapy (ß = -0.032, p = 0.043) had an indirect negative effect on Δhs-CRP via ΔLDL-C. CONCLUSIONS: Compared with routine statin use, statin combined with ezetimibe therapy and intensive statin therapy could further reduce hs-CRP levels.
Subject(s)
Biomarkers , C-Reactive Protein , Coronary Artery Disease , Ezetimibe , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Percutaneous Coronary Intervention , Humans , Male , Retrospective Studies , Female , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , C-Reactive Protein/analysis , C-Reactive Protein/metabolism , Coronary Artery Disease/blood , Coronary Artery Disease/drug therapy , Middle Aged , Biomarkers/blood , Treatment Outcome , Percutaneous Coronary Intervention/methods , Ezetimibe/therapeutic use , Drug Therapy, Combination , Aged , Rosuvastatin Calcium/therapeutic use , Atorvastatin/therapeutic use , Cholesterol, LDL/blood , Anticholesteremic Agents/therapeutic use , Dyslipidemias/blood , Dyslipidemias/drug therapy , Dyslipidemias/diagnosisABSTRACT
Bosentan, an endothelin receptor antagonist (ERA), has potential anti-atherosclerotic properties. We investigated the complementary effects of bosentan and atorvastatin on the progression and composition of the atherosclerotic lesions in diabetic mice. Forty-eight male ApoE-/- mice were fed high-fat diet (HFD) for 14 weeks. At week 8, diabetes was induced with streptozotocin, and mice were randomized into four groups: (1) control/COG: no intervention; (2) ΒOG: bosentan 100 mg/kg/day per os; (3) ATG: atorvastatin 20 mg/kg/day per os; and (4) BO + ATG: combined administration of bosentan and atorvastatin. The intra-plaque contents of collagen, elastin, monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-a (TNF-a), matrix metalloproteinases (MMP-2, -3, -9), and TIMP-1 were determined. The percentage of lumen stenosis was significantly lower across all treated groups: BOG: 19.5 ± 2.2%, ATG: 12.8 ± 4.8%, and BO + ATG: 9.1 ± 2.7% compared to controls (24.6 ± 4.8%, p < 0.001). The administration of both atorvastatin and bosentan resulted in significantly higher collagen content and thicker fibrous cap versus COG (p < 0.01). All intervention groups showed lower relative intra-plaque concentrations of MCP-1, MMP-3, and MMP-9 and a higher TIMP-1concentration compared to COG (p < 0.001). Importantly, latter parameters presented lower levels when bosentan was combined with atorvastatin compared to COG (p < 0.05). Bosentan treatment in diabetic, atherosclerotic ApoE-/- mice delayed the atherosclerosis progression and enhanced plaques' stability, showing modest but additive effects with atorvastatin, which are promising in atherosclerotic cardiovascular diseases.
Subject(s)
Atherosclerosis , Atorvastatin , Bosentan , Endothelin Receptor Antagonists , Animals , Bosentan/pharmacology , Bosentan/therapeutic use , Atorvastatin/pharmacology , Atorvastatin/therapeutic use , Mice , Male , Atherosclerosis/drug therapy , Atherosclerosis/metabolism , Atherosclerosis/pathology , Endothelin Receptor Antagonists/pharmacology , Endothelin Receptor Antagonists/therapeutic use , Diabetes Mellitus, Experimental/drug therapy , Drug Therapy, Combination , Collagen/metabolism , Diet, High-Fat/adverse effects , Chemokine CCL2/metabolism , Chemokine CCL2/genetics , Tumor Necrosis Factor-alpha/metabolism , Plaque, Atherosclerotic/drug therapy , Plaque, Atherosclerotic/pathology , Plaque, Atherosclerotic/metabolism , Mice, Knockout , Tissue Inhibitor of Metalloproteinase-1/metabolismABSTRACT
ABSTRACT: In vitro investigations have established metformin's capacity to downregulate proprotein convertase subtilisin/kexin type 9 (PCSK9) expression, suggesting a potential beneficial effect on atherogenic lipoprotein particles when combined with metformin therapy. Our objective was to assess whether metformin could mitigate statin-induced adverse effects on PCSK9, thereby improving lipid profiles in patients with coronary artery disease (CAD) but without diabetes. Employing an open-label, placebo-controlled, randomized trial, we randomized patients with CAD but without diabetes into CLA (cholesterol-lowering agents alone: atorvastatin ± ezetimibe, n = 38) and Met + CLA groups (metformin plus CLA, n = 33) in a 1:1 ratio. The primary end point was the therapeutic impact of 1-month metformin combination treatment on low-density lipoprotein cholesterol (LDL-C) and PCSK9 levels. Baseline LDL-C and PCSK9 levels were 76.18 mg·dL -1 and 80.54 ng·mL -1 , respectively. After 1 month, metformin significantly reduced LDL-C (-20.81%, P < 0.001), enabling 72% of patients to attain guideline-recommended LDL-C goals. Noteworthy reductions in PCSK9 levels (-15.03%, P < 0.001) were observed. Moreover, Met + CLA markedly reduced LDL particle number more than CLA alone (-10.65% vs. 1.45%, P = 0.009), primarily due to diminished small-dense LDL particle count. Mechanistically, our study demonstrated metformin's inhibition of statin-induced PCSK9 expression in human hepatocellular cells. In summary, a 1-month metformin combination regimen reduced LDL-C levels in patients with CAD but without diabetes by inhibiting PCSK9 expression. TRIAL REGISTRATION: Chinese Clinical Trial Registry identifier: ChiCTR1900026925 (26/10/2019).
Subject(s)
Biomarkers , Cholesterol, LDL , Coronary Artery Disease , Drug Therapy, Combination , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Metformin , PCSK9 Inhibitors , Proprotein Convertase 9 , Humans , Metformin/pharmacology , Male , Coronary Artery Disease/drug therapy , Coronary Artery Disease/blood , Middle Aged , Female , Cholesterol, LDL/blood , Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Proprotein Convertase 9/metabolism , Aged , Treatment Outcome , Biomarkers/blood , Time Factors , Atorvastatin/adverse effects , Atorvastatin/therapeutic use , Ezetimibe/therapeutic use , Ezetimibe/adverse effects , Dyslipidemias/drug therapy , Dyslipidemias/blood , Dyslipidemias/diagnosis , Dyslipidemias/enzymology , Serine Proteinase Inhibitors/adverse effects , Serine Proteinase Inhibitors/therapeutic use , Hypoglycemic Agents/therapeutic use , Hypoglycemic Agents/adverse effects , Anticholesteremic Agents/adverse effects , Anticholesteremic Agents/therapeutic useABSTRACT
OBJECTIVES: Atherosclerotic cardiovascular disease (ASCVD) events have been shown to occur at higher frequency in patients with peripheral arterial disease (PAD). In this study, our aim is to evaluate whether statin is being used appropriately in patients with PAD and also evaluate its usage with the number of vascular beds involved. MATERIALS AND METHODS: This retrospective cross-sectional study reviewed data of patients with a confirmed diagnosis of PAD based on invasive or noninvasive imaging. Demographic, clinical, laboratory, and treatment data collected were described using descriptive statistics. Multiple logistic regression analysis was conducted to determine the predictors for the prescription of statins (HIS). High-intensity statin therapy was defined as atorvastatin ≥40 mg per day, rosuvastatin ≥20 mg per day, or simvastatin ≥80 mg per day, according to American College of Cardiology (ACC)/American Heart Association (AHA) guidelines. RESULTS: We analyzed data from 166 patients who met the inclusion criteria. The mean age was 63.34 years. The most common comorbidity was diabetes mellitus (DM) (68.86%). Statins were used in 82% of patients, among whom only 39% were on high-intensity statins. Multiple logistic regression analysis revealed that patients with cerebrovascular disease (CVD) [odds ratio (OR) = 0.19, 95% confidence interval (CI) = 0.06-0.61, p = 0.005], on oral anticoagulants (OAC) (OR = 0.16, 95% CI = 0.04-0.62, p = 0.008) and on dual antiplatelet therapy (DAPT) (OR = 0.20, 95% CI = 0.08-0.47, p < 0.000) had lower odds of receiving lower extremity revascularization (LIS) therapy. CONCLUSION: Despite having a high risk of future adverse cardiac events, patients with PAD are less likely to receive appropriate statin therapy. Involvement of more vascular beds was associated with higher chances of initiating high-intensity statin.
Subject(s)
Hydroxymethylglutaryl-CoA Reductase Inhibitors , Peripheral Arterial Disease , Humans , Peripheral Arterial Disease/drug therapy , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Middle Aged , Male , Female , Cross-Sectional Studies , Retrospective Studies , Aged , Rosuvastatin Calcium/therapeutic use , Atorvastatin/therapeutic useABSTRACT
BACKGROUND: Obesity is associated with airway hyperresponsiveness and lung fibrosis, which may reduce the effectiveness of standard asthma treatment in individuals suffering from both conditions. Statins and proprotein convertase subtilisin/kexin-9 inhibitors not only reduce serum cholesterol, free fatty acids but also diminish renin-angiotensin system activity and exhibit anti-inflammatory effects. These mechanisms may play a role in mitigating lung pathologies associated with obesity. METHODS: Male C57BL/6 mice were induced to develop obesity through high-fat diet for 16 weeks. Conditional TGF-ß1 transgenic mice were fed a normal diet. These mice were given either atorvastatin or proprotein convertase subtilisin/kexin-9 inhibitor (alirocumab), and the impact on airway hyperresponsiveness and lung pathologies was assessed. RESULTS: High-fat diet-induced obesity enhanced airway hyperresponsiveness, lung fibrosis, macrophages in bronchoalveolar lavage fluid, and pro-inflammatory mediators in the lung. These lipid-lowering agents attenuated airway hyperresponsiveness, macrophages in BALF, lung fibrosis, serum leptin, free fatty acids, TGF-ß1, IL-1ß, IL-6, and IL-17a in the lung. Furthermore, the increased RAS, NLRP3 inflammasome, and cholecystokinin in lung tissue of obese mice were reduced with statin or alirocumab. These agents also suppressed the pro-inflammatory immune responses and lung fibrosis in TGF-ß1 over-expressed transgenic mice with normal diet. CONCLUSIONS: Lipid-lowering treatment has the potential to alleviate obesity-induced airway hyperresponsiveness and lung fibrosis by inhibiting the NLRP3 inflammasome, RAS and cholecystokinin activity.
Subject(s)
Diet, High-Fat , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Mice, Inbred C57BL , Mice, Transgenic , Obesity , Pulmonary Fibrosis , Animals , Male , Diet, High-Fat/adverse effects , Obesity/drug therapy , Obesity/metabolism , Mice , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Pulmonary Fibrosis/prevention & control , Pulmonary Fibrosis/pathology , Pulmonary Fibrosis/metabolism , Pulmonary Fibrosis/drug therapy , PCSK9 Inhibitors , Atorvastatin/pharmacology , Atorvastatin/therapeutic use , Mice, Obese , Proprotein Convertase 9/metabolism , Proprotein Convertase 9/genetics , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal/therapeutic use , Bronchial Hyperreactivity/prevention & control , Bronchial Hyperreactivity/drug therapy , Bronchial Hyperreactivity/metabolism , Bronchial Hyperreactivity/physiopathology , Antibodies, Monoclonal, HumanizedABSTRACT
BACKGROUND: The 2013 ACC/AHA Guideline was a paradigm shift in lipid management and identified the four statin-benefit groups. Many have studied the guideline's potential impact, but few have investigated its potential long-term impact on MACE. Furthermore, most studies also ignored the confounding effect from the earlier release of generic atorvastatin in Dec 2011. METHODS: To evaluate the potential (long-term) impact of the 2013 ACC/AHA Guideline release in Nov 2013 in the U.S., we investigated the association of the 2013 ACC/AHA Guideline with the trend changes in 5-Year MACE survival and three other statin-related outcomes (statin use, optimal statin use, and statin adherence) while controlling for generic atorvastatin availability using interrupted time series analysis, called the Chow's test. Specifically, we conducted a retrospective study using U.S. nationwide de-identified claims and electronic health records from Optum Labs Database Warehouse (OLDW) to follow the trends of 5-Year MACE survival and statin-related outcomes among four statin-benefit groups that were identified in the 2013 ACC/AHA Guideline. Then, Chow's test was used to discern trend changes between generic atorvastatin availability and guideline potential impact. RESULTS: 197,021 patients were included (ASCVD: 19,060; High-LDL: 33,907; Diabetes: 138,159; High-ASCVD-Risk: 5,895). After the guideline release, the long-term trend (slope) of 5-Year MACE Survival for the Diabetes group improved significantly (P = 0.002). Optimal statin use for the ASCVD group also showed immediate improvement (intercept) and long-term positive changes (slope) after the release (P < 0.001). Statin uses did not have significant trend changes and statin adherence remained unchanged in all statin-benefit groups. Although no other statistically significant trend changes were found, overall positive trend change or no changes were observed after the 2013 ACC/AHA Guideline release. CONCLUSIONS: The 2013 ACA/AHA Guideline release is associated with trend improvements in the long-term MACE Survival for Diabetes group and optimal statin use for ASCVD group. These significant associations might indicate a potential positive long-term impact of the 2013 ACA/AHA Guideline on better health outcomes for primary prevention groups and an immediate potential impact on statin prescribing behaviors in higher-at-risk groups. However, further investigation is required to confirm the causal effect of the 2013 ACA/AHA Guideline.
Subject(s)
Guideline Adherence , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Interrupted Time Series Analysis , Practice Guidelines as Topic , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects , United States , Time Factors , Retrospective Studies , Male , Female , Aged , Middle Aged , Treatment Outcome , Guideline Adherence/standards , Biomarkers/blood , Dyslipidemias/drug therapy , Dyslipidemias/blood , Dyslipidemias/diagnosis , Dyslipidemias/mortality , Dyslipidemias/epidemiology , Atorvastatin/therapeutic use , Atorvastatin/adverse effects , Cardiovascular Diseases/mortality , Cardiovascular Diseases/prevention & control , Cardiovascular Diseases/blood , Databases, Factual , Practice Patterns, Physicians'/standards , Cholesterol/blood , Medication Adherence , Drugs, Generic/therapeutic use , Drugs, Generic/adverse effects , Risk AssessmentABSTRACT
BACKGROUND: Statins are the first-line treatment for dyslipidemia, which is a major modifiable risk factor for atherosclerotic cardiovascular disease. Studies have shown that in addition to the beneficial lipid-lowering effect, statins also exhibit a number of pleiotropic effects that may find application in other diseases, including osteoporosis. This study aimed to assess the effect of statins on bone turnover, as measured by the concentration of bone turnover markers, and to compare the effect of atorvastatin as a lipophilic statin and rosuvastatin as a hydrophilic statin. METHODS: This study included 34 postmenopausal women agedâ <â 65 years with newly diagnosed dyslipidemia requiring statin therapy. Patients were randomly assigned to receive a statin drug. Statins were initiated at standard doses of 5 to 10 mg of rosuvastatin and 20 mg of atorvastatin. The levels of C-terminal telopeptide of type I collagen as a bone resorption marker and N-terminal propeptide of procollagen type I as a marker of bone formation, lipid concentrations and other biochemical parameters were assessed at baseline and after 6 and twelve months of treatment. RESULTS: There were no statistically significant differences between the levels of bone turnover markers before and 6 months after statin implementation (Pâ >â .05) - for all patients or subgroups according to statin use. Analysis of the results showed that after 12 months, there was a statistically significant decrease in N-terminal propeptide of procollagen type I concentration in all subjects (Pâ =â .004). By statin subgroup, a statistically significant decrease in N-terminal propeptide of procollagen type I was observed only in patients receiving rosuvastatin (Pâ =â .012) and not in those receiving atorvastatin (Pâ =â .25). Moreover, changes in bone turnover markers did not correlate with changes in lipid concentrations. CONCLUSIONS: These results may indicate the superiority of atorvastatin over rosuvastatin in inhibiting adverse changes in bone turnover in postmenopausal women. Confirmed by studies involving a larger population, the observed differences might find particular applications in clinical practice, and the choice of atorvastatin over rosuvastatin for women could be considered in the early postmenopausal period to reduce the risk of osteoporosis and subsequent osteoporotic fractures.
Subject(s)
Atorvastatin , Bone Remodeling , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Postmenopause , Rosuvastatin Calcium , Humans , Rosuvastatin Calcium/therapeutic use , Rosuvastatin Calcium/administration & dosage , Female , Atorvastatin/therapeutic use , Atorvastatin/pharmacology , Middle Aged , Bone Remodeling/drug effects , Postmenopause/drug effects , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Biomarkers/blood , Collagen Type I/blood , Osteoporosis, Postmenopausal/drug therapy , Dyslipidemias/drug therapy , Dyslipidemias/bloodABSTRACT
Statin-induced immune-mediated necrotising myopathy (IMNM) is an inflammatory myopathy that can present as proximal muscle weakness and, in some cases, as dysphagia and respiratory distress. In this report, we present a case of statin-induced IMNM in a 78-year-old male. The patient had significantly high levels of creatinine kinase and myoglobinuria and experienced gradual weakness in the proximal muscles for 1 month after initiating a 20 mg dose of Atorvastatin 10 months before admission. Rapid clinical improvement was observed with the use of high-dose glucocorticoids in conjunction with methotrexate.
Subject(s)
Atorvastatin , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Myositis , Humans , Male , Aged , Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Myositis/chemically induced , Myositis/drug therapy , Atorvastatin/therapeutic use , Atorvastatin/adverse effects , Methotrexate/therapeutic use , Methotrexate/adverse effects , Pyrroles/adverse effects , Pyrroles/therapeutic use , Immunosuppressive Agents/therapeutic use , Immunosuppressive Agents/adverse effects , Heptanoic Acids/adverse effects , Heptanoic Acids/therapeutic use , Necrosis/chemically induced , Glucocorticoids/therapeutic use , Muscular Diseases/chemically induced , Muscular Diseases/drug therapyABSTRACT
BACKGROUND: The response of low-density lipoprotein cholesterol (LDL-C) to statin therapy is variable, and may be affected by the presence of co-morbid conditions or the use of concomitant medications. Systematic variation in the response to statins based on these factors could affect the selection of the statin treatment regimen in population subgroups. We investigated whether common comorbidities and co-medications had clinically important effects on statin responses in individual patients. METHODS: This register-based cohort study included 89,006 simvastatin or atorvastatin initiators with measurements of pre-statin and on-statin LDL-C levels, in Denmark, 2008-2018. We defined statin response as the percentage reduction in LDL-C, and used linear regression to estimate percentage reduction differences (PRD) according to 175 chronic comorbidities and 99 co-medications. We evaluated both the statistical significance (P-values corrected for multiple testing) and the clinical importance (PRD of 5 percentage points or more) of the observed associations. RESULTS: Concomitant use of oral blood-glucose lowering drugs, which included metformin in 96% of treated individuals, was associated with a greater response to statin therapy that was both statistically significant and clinically important, with a PRD of 5.18 (95% confidence interval: 4.79 to 5.57). No other comorbidity or co-medication reached the prespecified thresholds for a significant, clinically important effect on statin response. Overall, comorbidities and co-medications had little effect on statin response, and altogether explained only 1.7% of the total observed population variance. CONCLUSION: Most of the studied comorbidities and co-medications did not have a clinically important effect on statin response, suggesting no need to modify treatment regimens. However, use of metformin was associated with a significantly enhanced LDL-C response to statins, suggesting that lower statin doses may be effective in patients taking metformin.
Subject(s)
Cholesterol, LDL , Comorbidity , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Female , Male , Cholesterol, LDL/blood , Denmark/epidemiology , Middle Aged , Aged , Atorvastatin/therapeutic use , Registries , Simvastatin/therapeutic use , Hypoglycemic Agents/therapeutic use , Metformin/therapeutic use , Cohort StudiesABSTRACT
BACKGROUND: Hyperlipidemia is a common feature of chronic diseases. The aim of this work was designed to assess the role of probiotics (Lactobacillus casei Zhang, Bifidobactetium animalis subsp. lactis V9, and Lactobacillus plantarum P-8) in the treatment of hyperlipidemia. METHODS: Thirty three patients with hyperlipidemia were randomly divided into a probiotic group (nâ =â 18) and a control group (nâ =â 15). The probiotic group was administered probiotics (2 g once daily) and atorvastatin 20 mg (once daily), and the control group was administered a placebo (2 g once daily) and atorvastatin 20 mg (once daily). Serum and fecal samples were gathered for subsequent analyses. RESULTS: Time had a significant effect on the total cholesterol (TC), triglycerides (TG), and low-density lipoprotein-cholesterol (LDL-C) levels in the probiotic and control groups (Pâ <â .05). The gut microbial abundance in the probiotic group was markedly higher than that in the control group following 3-month probiotic treatment (Pâ <â .05). At the phylum level, probiotics exerted no notable effects on the relative abundance of Firmicutes, Bacteroidetes, and Actinobacteria but elevated that of Tenericutes and reduced Proteobacteria. At the genus level, probiotics increased the relative abundance of Bifidobacterium, Lactobacillus, and Akkermansia, and decreased that of Escherichia, Eggerthella, and Sutterella relative to the control group in months 1, 2, and 3 (Pâ <â .05). CONCLUSIONS: Probiotics optimize the gut microbiota structure and decrease the amount of harmful bacteria in patients with hyperlipidemia. Probiotics can influence the composition of gut microorganisms and increase their diversity and abundance in vivo. It is recommended to use probiotics combined with atorvastatin to treat patients with hyperlipidemia.
Subject(s)
Atorvastatin , Gastrointestinal Microbiome , Hyperlipidemias , Probiotics , Humans , Atorvastatin/administration & dosage , Atorvastatin/therapeutic use , Probiotics/administration & dosage , Probiotics/therapeutic use , Hyperlipidemias/drug therapy , Double-Blind Method , Male , Female , Middle Aged , Gastrointestinal Microbiome/drug effects , Adult , Treatment Outcome , Triglycerides/blood , Cholesterol, LDL/blood , Anticholesteremic Agents/administration & dosage , Anticholesteremic Agents/therapeutic use , Lactobacillus plantarum , Feces/microbiology , Aged , Combined Modality TherapyABSTRACT
BACKGROUND: Chronic subdural hematoma (CSDH) is a common neurological condition, especially in the elderly population. Atorvastatin has shown the potential to reduce the recurrence of CSDH and improve overall outcomes. New studies have emerged since the last meta-analysis, increasing the sample size and the variety of outcomes analyzed. METHODS: We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials for studies comparing the use of atorvastatin in CSDH patients with a control group or placebo. The primary outcome was the recurrence of CSDH. Secondary outcomes of interest were hematoma volume, composite adverse effects, mortality, and neurological function, measured by the Glasgow Outcome Scale and Barthel index for activities of daily living. RESULTS: Seven studies, of which 2 were randomized controlled trials, were included, containing 1192 patients. Overall recurrence significantly decreased compared to the control group (risk ratio [RR] 0.46; 95% confidence interval [CI] 0.25-0.83; P=0.009). The benefits of atorvastatin were sustained in the subgroup analysis of patients who underwent initial conservative therapy (RR 0.40; 95% CI 0.22-0.70; P=0.001). However, there was no significant difference when atorvastatin was combined with surgical intervention (RR 0.53; 95% CI 0.21-1.32; P=0.17). Adverse effects were not increased by atorvastatin (RR 0.82; 95% CI 0.51-1.34; P=0.44). CONCLUSIONS: Atorvastatin might be beneficial in reducing CSDH recurrence, especially in conservative treatment patients. Atorvastatin was not significantly associated with adverse effects. Larger, higher-quality randomized studies are needed to adequately evaluate the efficacy, safety, and optimal dose of atorvastatin in CSDH patients.
Subject(s)
Atorvastatin , Hematoma, Subdural, Chronic , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Humans , Atorvastatin/therapeutic use , Hematoma, Subdural, Chronic/drug therapy , Hematoma, Subdural, Chronic/surgery , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Randomized Controlled Trials as Topic , Recurrence , Treatment OutcomeABSTRACT
Importance: Comparisons are limited for immediate-intensive and delayed-intensive statin for secondary stroke prevention and neuroprotection in patients with acute mild ischemic stroke or transient ischemic attack (TIA) from atherosclerosis. Objective: To estimate whether immediate-intensive statin therapy is safe and can lower the risk of recurrent stroke compared with delayed-intensive statin in patients with acute mild ischemic stroke or high-risk TIA from atherosclerosis. Design, Setting, and Participants: The Intensive Statin and Antiplatelet Therapy for High-Risk Intracranial or Extracranial Atherosclerosis (INSPIRES) trial, a double-blind, placebo-controlled, 2 × 2 factorial, randomized clinical trial enrolled patients from September 2018 to October 2022. The trial was conducted at 222 hospitals in China. Patients aged 35 to 80 years with mild ischemic stroke or high-risk TIA of presumed atherosclerosis within 72 hours of symptom onset were assessed. Interventions: Patients were randomly assigned to receive immediate-intensive atorvastatin (80 mg daily on days 1-21; 40 mg daily on days 22-90) or 3-day delayed treatment (placebo for days 1-3, followed by placebo and atorvastatin, 40 mg daily on days 4-21, and then atorvastatin, 40 mg daily on days 22-90). Main Outcomes and Measures: The primary efficacy outcome was new stroke within 90 days, and a secondary efficacy outcome was poor functional outcome. Moderate to severe bleeding was the primary safety outcome. Results: A total of 11â¯431 patients were assessed for eligibility, and 6100 patients (median [IQR] age, 65 [57-71] years; 3915 men [64.2%]) were enrolled, with 3050 assigned to each treatment group. Within 90 days, new stroke occurred in 245 patients (8.1%) in the immediate-intensive statin group and 256 patients (8.4%) in the delayed group (hazard ratio, 0.95; 95% CI, 0.80-1.13). Poor functional outcome occurred in 299 patients (9.8%) and 348 patients (11.4%) in the immediate-intensive and delayed-intensive statin groups, respectively (odds ratio, 0.83; 95% CI, 0.71-0.98). Moderate to severe bleeding occurred in 23 of 3050 patients (0.8%) and 17 of 3050 patients (0.6%), in the immediate-intensive and delayed-intensive statin groups, respectively. Conclusions and Relevance: Immediate-intensive statin initiated within 72 hours did not reduce the risk of stroke within 90 days and may be associated with improved functional outcomes without significant difference in moderate to severe bleeding, compared with 3-day delayed-intensive statin in Chinese patients with acute mild ischemic stroke or TIA from atherosclerosis. Trial Registration: ClinicalTrials.gov Identifier: NCT03635749.