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Gut Apr 2021Non-alcoholic fatty liver disease (NAFLD)-associated hepatocellular carcinoma (HCC) is an increasing healthcare burden worldwide. We examined the role of dietary...
OBJECTIVE
Non-alcoholic fatty liver disease (NAFLD)-associated hepatocellular carcinoma (HCC) is an increasing healthcare burden worldwide. We examined the role of dietary cholesterol in driving NAFLD-HCC through modulating gut microbiota and its metabolites.
DESIGN
High-fat/high-cholesterol (HFHC), high-fat/low-cholesterol or normal chow diet was fed to C57BL/6 male littermates for 14 months. Cholesterol-lowering drug atorvastatin was administered to HFHC-fed mice. Germ-free mice were transplanted with stools from mice fed different diets to determine the direct role of cholesterol modulated-microbiota in NAFLD-HCC. Gut microbiota was analysed by 16S rRNA sequencing and serum metabolites by liquid chromatography-mass spectrometry (LC-MS) metabolomic analysis. Faecal microbial compositions were examined in 59 hypercholesterolemia patients and 39 healthy controls.
RESULTS
High dietary cholesterol led to the sequential progression of steatosis, steatohepatitis, fibrosis and eventually HCC in mice, concomitant with insulin resistance. Cholesterol-induced NAFLD-HCC formation was associated with gut microbiota dysbiosis. The microbiota composition clustered distinctly along stages of steatosis, steatohepatitis and HCC. and increased sequentially; while and were depleted in HFHC-fed mice, which was corroborated in human hypercholesteremia patients. Dietary cholesterol induced gut bacterial metabolites alteration including increased taurocholic acid and decreased 3-indolepropionic acid. Germ-free mice gavaged with stools from mice fed HFHC manifested hepatic lipid accumulation, inflammation and cell proliferation. Moreover, atorvastatin restored cholesterol-induced gut microbiota dysbiosis and completely prevented NAFLD-HCC development.
CONCLUSIONS
Dietary cholesterol drives NAFLD-HCC formation by inducing alteration of gut microbiota and metabolites in mice. Cholesterol inhibitory therapy and gut microbiota manipulation may be effective strategies for NAFLD-HCC prevention.
Topics: Animals; Atorvastatin; Carcinoma, Hepatocellular; Case-Control Studies; Cholesterol, Dietary; Disease Progression; Fecal Microbiota Transplantation; Gastrointestinal Microbiome; Liver Neoplasms; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease
PubMed: 32694178
DOI: 10.1136/gutjnl-2019-319664 -
JAMA Apr 2023In patients with coronary artery disease, some guidelines recommend initial statin treatment with high-intensity statins to achieve at least a 50% reduction in... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
In patients with coronary artery disease, some guidelines recommend initial statin treatment with high-intensity statins to achieve at least a 50% reduction in low-density lipoprotein cholesterol (LDL-C). An alternative approach is to begin with moderate-intensity statins and titrate to a specific LDL-C goal. These alternatives have not been compared head-to-head in a clinical trial involving patients with known coronary artery disease.
OBJECTIVE
To assess whether a treat-to-target strategy is noninferior to a strategy of high-intensity statins for long-term clinical outcomes in patients with coronary artery disease.
DESIGN, SETTING, AND PARTICIPANTS
A randomized, multicenter, noninferiority trial in patients with a coronary disease diagnosis treated at 12 centers in South Korea (enrollment: September 9, 2016, through November 27, 2019; final follow-up: October 26, 2022).
INTERVENTIONS
Patients were randomly assigned to receive either the LDL-C target strategy, with an LDL-C level between 50 and 70 mg/dL as the target, or high-intensity statin treatment, which consisted of rosuvastatin, 20 mg, or atorvastatin, 40 mg.
MAIN OUTCOMES AND MEASURES
Primary end point was a 3-year composite of death, myocardial infarction, stroke, or coronary revascularization with a noninferiority margin of 3.0 percentage points.
RESULTS
Among 4400 patients, 4341 patients (98.7%) completed the trial (mean [SD] age, 65.1 [9.9] years; 1228 females [27.9%]). In the treat-to-target group (n = 2200), which had 6449 person-years of follow-up, moderate-intensity and high-intensity dosing were used in 43% and 54%, respectively. The mean (SD) LDL-C level for 3 years was 69.1 (17.8) mg/dL in the treat-to-target group and 68.4 (20.1) mg/dL in the high-intensity statin group (n = 2200) (P = .21, compared with the treat-to-target group). The primary end point occurred in 177 patients (8.1%) in the treat-to-target group and 190 patients (8.7%) in the high-intensity statin group (absolute difference, -0.6 percentage points [upper boundary of the 1-sided 97.5% CI, 1.1 percentage points]; P < .001 for noninferiority).
CONCLUSIONS AND RELEVANCE
Among patients with coronary artery disease, a treat-to-target LDL-C strategy of 50 to 70 mg/dL as the goal was noninferior to a high-intensity statin therapy for the 3-year composite of death, myocardial infarction, stroke, or coronary revascularization. These findings provide additional evidence supporting the suitability of a treat-to-target strategy that may allow a tailored approach with consideration for individual variability in drug response to statin therapy.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02579499.
Topics: Aged; Female; Humans; Cholesterol, LDL; Coronary Artery Disease; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Myocardial Infarction; Stroke; Treatment Outcome; Hyperlipoproteinemias; Male; Middle Aged; Rosuvastatin Calcium; Atorvastatin
PubMed: 36877807
DOI: 10.1001/jama.2023.2487 -
BMJ (Clinical Research Ed.) Oct 2023To compare the long term efficacy and safety of rosuvastatin with atorvastatin treatment in adults with coronary artery disease. (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To compare the long term efficacy and safety of rosuvastatin with atorvastatin treatment in adults with coronary artery disease.
DESIGN
Randomised, open label, multicentre trial.
SETTING
12 hospitals in South Korea, September 2016 to November 2019.
PARTICIPANTS
4400 adults (age ≥19 years) with coronary artery disease.
INTERVENTIONS
Participants were assigned to receive either rosuvastatin (n=2204) or atorvastatin (n=2196) using 2×2 factorial randomisation.
MAIN OUTCOME MEASURES
The primary outcome was a three year composite of all cause death, myocardial infarction, stroke, or any coronary revascularisation. Secondary outcomes were safety endpoints: new onset diabetes mellitus; hospital admissions due to heart failure; deep vein thrombosis or pulmonary thromboembolism; endovascular revascularisation for peripheral artery disease; aortic intervention or surgery; end stage kidney disease; discontinuation of study drugs owing to intolerance; cataract surgery; and a composite of laboratory detected abnormalities.
RESULTS
4341 of the 4400 participants (98.7%) completed the trial. Mean daily dose of study drugs was 17.1 mg (standard deviation (SD) 5.2 mg) in the rosuvastatin group and 36.0 (12.8) mg in the atorvastatin group at three years (P<0.001). The primary outcome occurred in 189 participants (8.7%) in the rosuvastatin group and 178 (8.2%) in the atorvastatin group (hazard ratio 1.06, 95% confidence interval 0.86 to 1.30; P=0.58). The mean low density lipoprotein (LDL) cholesterol level during treatment was 1.8 mmol/L (SD 0.5 mmol/L) in the rosuvastatin group and 1.9 (0.5) mmol/L in the atorvastatin group (P<0.001). The rosuvastatin group had a higher incidence of new onset diabetes mellitus requiring initiation of antidiabetics (7.2% 5.3%; hazard ratio 1.39, 95% confidence interval 1.03 to 1.87; P=0.03) and cataract surgery (2.5% 1.5%; 1.66, 1.07 to 2.58; P=0.02). Other safety endpoints did not differ between the two groups.
CONCLUSIONS
In adults with coronary artery disease, rosuvastatin and atorvastatin showed comparable efficacy for the composite outcome of all cause death, myocardial infarction, stroke, or any coronary revascularisation at three years. Rosuvastatin was associated with lower LDL cholesterol levels but a higher risk of new onset diabetes mellitus requiring antidiabetics and cataract surgery compared with atorvastatin.
TRIAL REGISTRATION
ClinicalTrials.gov NCT02579499.
Topics: Adult; Humans; Young Adult; Atorvastatin; Cataract; Cholesterol, LDL; Coronary Artery Disease; Diabetes Mellitus; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Myocardial Infarction; Rosuvastatin Calcium; Stroke; Treatment Outcome
PubMed: 37852649
DOI: 10.1136/bmj-2023-075837 -
Journal of the American Society of... Sep 2022Despite reports of hematuria and proteinuria with rosuvastatin use at the time of its approval by the US Food and Drug Association (FDA), little postmarketing...
BACKGROUND
Despite reports of hematuria and proteinuria with rosuvastatin use at the time of its approval by the US Food and Drug Association (FDA), little postmarketing surveillance exists to assess real-world risk. Current labeling suggests dose reduction (maximum daily dose of 10 mg) for patients with severe CKD.
METHODS
Using deidentified electronic health record data, we analyzed 152,101 and 795,799 new users of rosuvastatin and atorvastatin, respectively, from 2011 to 2019. We estimated inverse probability of treatment-weighted hazard ratios (HRs) of hematuria, proteinuria, and kidney failure with replacement therapy (KFRT) associated with rosuvastatin. We reported the initial rosuvastatin dose across eGFR categories and evaluated for a dose effect on hematuria and proteinuria.
RESULTS
Overall, we identified 2.9% of patients with hematuria and 1.0% with proteinuria during a median follow-up of 3.1 years. Compared with atorvastatin, rosuvastatin was associated with increased risk of hematuria (HR, 1.08; 95% confidence interval [95% CI], 1.04 to 1.11), proteinuria (HR, 1.17; 95% CI, 1.10 to 1.25), and KFRT (HR, 1.15; 95% CI, 1.02 to 1.30). A substantial share (44%) of patients with eGFR <30 ml/min per 1.73 m was prescribed high-dose rosuvastatin (20 or 40 mg daily). Risk was higher with higher rosuvastatin dose.
CONCLUSIONS
Compared with atorvastatin, rosuvastatin was associated with increased risk of hematuria, proteinuria, and KFRT. Among patients with eGFR <30 ml/min per 1.73 m, 44% were prescribed a rosuvastatin daily dose exceeding the FDA's recommended 10 mg daily dose. Our findings suggest the need for greater care in prescribing and monitoring rosuvastatin, particularly in patients who receive high doses or who have severe CKD.
Topics: Humans; Rosuvastatin Calcium; Atorvastatin; Hematuria; Proteinuria; Renal Insufficiency, Chronic; Hydroxymethylglutaryl-CoA Reductase Inhibitors
PubMed: 35853713
DOI: 10.1681/ASN.2022020135 -
United European Gastroenterology Journal Sep 2021Drug-induced liver injury (DILI) should be considered in all patients with recent elevation of liver tests without obvious etiology and normal hepatobiliary imaging.... (Review)
Review
Drug-induced liver injury (DILI) should be considered in all patients with recent elevation of liver tests without obvious etiology and normal hepatobiliary imaging. There is currently no biomarker that is helpful in diagnosis which relies on clinical and laboratory findings. Diagnosis is dependent on temporal relationship with a recently started drug or herbal and dietary supplement and elevated liver tests with exclusion of competing etiologies. The implicated agent should be discontinued and the patient should be observed closely. This is particularly important in patients with jaundice who have approximately 10% risk of liver related mortality and/or need for liver transplantation. There is no specific therapy for DILI which is only symptomatic such as for itching. Patients with jaundice and coagulopathy usually require hospitalization.
Topics: Acetylcysteine; Aged; Anti-Bacterial Agents; Anticholesteremic Agents; Atorvastatin; Azithromycin; Checklist; Chemical and Drug Induced Liver Injury; Female; Humans; Jaundice; Middle Aged; Pruritus; Symptom Assessment
PubMed: 35084797
DOI: 10.1002/ueg2.12113 -
Journal of Comparative Effectiveness... Mar 2023To summarize the evidence in terms of efficacy and safety of head-to-head studies of high-intensity statins regardless of the underlying population. A systematic... (Meta-Analysis)
Meta-Analysis Review
To summarize the evidence in terms of efficacy and safety of head-to-head studies of high-intensity statins regardless of the underlying population. A systematic review and meta-analysis was conducted to summarize the effect sizes in randomized controlled trials and cohort studies that compared high-intensity statins. Based on 44 articles, similar effectiveness was observed across the statins in reducing LDL levels from baseline. All statins were observed to have similar adverse drug reactions (ADRs), although higher dosages were associated with more ADRs. Based on a pooled quantitative analysis of atorvastatin 80 mg versus rosuvastatin 40 mg, rosuvastatin was statistically more effective in reducing LDL. This review further confirms that high-intensity statins reduce LDL by ≥50%, favoring rosuvastatin over atorvastatin. Additional data are needed to confirm the clinical significance on cardiovascular outcomes using real-world studies.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Rosuvastatin Calcium; Atorvastatin; Cohort Studies
PubMed: 36847307
DOI: 10.57264/cer-2022-0163 -
JPMA. the Journal of the Pakistan... Nov 2022The study was designed to compare Rosuvastatin with Atorvastatin in terms of their efficacy to reduce low-density lipoproteins (LDL-C) in patients with type 2 diabetes... (Randomized Controlled Trial)
Randomized Controlled Trial
The study was designed to compare Rosuvastatin with Atorvastatin in terms of their efficacy to reduce low-density lipoproteins (LDL-C) in patients with type 2 diabetes mellitus. For this purpose, a cross-sectional analytical study was conducted in the OPD of Nishtar Medical Hospital, Multan, for six months. The study enrolled 66 patients who were consecutively allocated for double-blind therapy with 10mg Atorvastatin (n = 33) and 10mg Rosuvastatin (n = 33) for one month. The doses titration was carried up to four months in certain patients who failed to achieve 1998 European LDL-C level in the first month. A significant number of patients who were given 10mg Rosuvastatin matched the 1998 LDL-C goal in compared to the patients with 10mg dose of atorvastatin at one month (51% vs 46%, p< 0.0001) and at four months (94% vs 88%, p<0.05). Conclusively, Rosuvastatin was significantly more efficacious than Atorvastatin in its ability to reduce LDL-C.
Topics: Humans; Rosuvastatin Calcium; Atorvastatin; Cholesterol, LDL; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Diabetes Mellitus, Type 2; Cross-Sectional Studies; Hypercholesterolemia; Heptanoic Acids; Fluorobenzenes; Pyrimidines; Sulfonamides; Pyrroles; Treatment Outcome
PubMed: 37013304
DOI: 10.47391/JPMA.4823 -
European Heart Journal. Cardiovascular... Sep 2023Anthracyclines can cause cancer therapy-related cardiac dysfunction (CTRCD). We aimed to assess whether statins prevent decline in left ventricular ejection fraction... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND AIMS
Anthracyclines can cause cancer therapy-related cardiac dysfunction (CTRCD). We aimed to assess whether statins prevent decline in left ventricular ejection fraction (LVEF) in anthracycline-treated patients at increased risk for CTRCD.
METHODS
In this multicenter double-blinded, placebo-controlled trial, patients with cancer at increased risk of anthracycline-related CTRCD (per ASCO guidelines) were randomly assigned to atorvastatin 40 mg or placebo once-daily. Cardiovascular magnetic resonance (CMR) imaging was performed before and within 4 weeks after anthracyclines. Blood biomarkers were measured at every cycle. The primary outcome was post-anthracycline LVEF, adjusted for baseline. CTRCD was defined as a fall in LVEF by >10% to <53%. Secondary endpoints included left ventricular (LV) volumes, CTRCD, CMR tissue characterization, high sensitivity troponin I (hsTnI), and B-type natriuretic peptide (BNP).
RESULTS
We randomized 112 patients (56.9 ± 13.6 years, 87 female, and 73 with breast cancer): 54 to atorvastatin and 58 to placebo. Post-anthracycline CMR was performed 22 (13-27) days from last anthracycline dose. Post-anthracycline LVEF did not differ between the atorvastatin and placebo groups (57.3 ± 5.8% and 55.9 ± 7.4%, respectively) when adjusted for baseline LVEF (P = 0.34). There were no significant between-group differences in post-anthracycline LV end-diastolic (P = 0.20) or end-systolic volume (P = 0.12), CMR myocardial edema and/or fibrosis (P = 0.06-0.47), or peak hsTnI (P ≥ 0.99) and BNP (P = 0.23). CTRCD incidence was similar (4% versus 4%, P ≥ 0.99). There was no difference in adverse events.
CONCLUSIONS
In patients at increased risk of CTRCD, primary prevention with atorvastatin during anthracycline therapy did not ameliorate early LVEF decline, LV remodeling, CTRCD, change in serum cardiac biomarkers, or CMR myocardial tissue changes.
TRIAL REGISTRATION
NCT03186404.
Topics: Humans; Female; Anthracyclines; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Cardiotoxicity; Stroke Volume; Atorvastatin; Ventricular Function, Left; Heart Diseases; Breast Neoplasms; Antibiotics, Antineoplastic; Biomarkers
PubMed: 37120736
DOI: 10.1093/ehjcvp/pvad031 -
Stem Cell Research & Therapy Aug 2020Mesenchymal stem cell (MSC)-derived exosomes emerge as promising candidates for treating delayed wound healing in diabetes due to the promotion of angiogenesis....
BACKGROUND
Mesenchymal stem cell (MSC)-derived exosomes emerge as promising candidates for treating delayed wound healing in diabetes due to the promotion of angiogenesis. Preconditioned MSC with chemical or biological factors could possibly enhance the biological activities of MSC-derived exosomes. The purpose of this research focused on whether exosomes derived from the bone marrow MSC (BMSC) pretreated with atorvastatin (ATV), could exhibit better pro-angiogenic ability in diabetic wound healing or not and its underlying molecular mechanism.
METHODS
We isolated exosomes from non-pretreated BMSC (Exos) and ATV pretreated BMSC (ATV-Exos) and evaluated their characterization by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA) and Western blotting. In vivo, we made full-thickness skin defects in streptozotocin (STZ)-induced diabetic rats and the defects received multiple-point injection with PBS, Exos, or ATV-Exos. Two weeks later, histological analysis was conducted to evaluate the impact of different treatments on wound healing and the neovascularization was measured by micro-CT. In vitro, cell proliferation, migration, tube formation, and vascular endothelial growth factor (VEGF) secretion were measured in human umbilical vein endothelial cells (HUVEC). The role of miRNAs and AKT/eNOS signaling pathway in the promoted angiogenesis of ATV-Exos were assessed with their inhibitors.
RESULTS
No significant difference in morphology, structure, and concentration was observed between ATV-Exos and Exos. In STZ-induced diabetic rats, ATV-Exos exhibited excellent abilities in facilitating the wound regeneration by promoting the formation of blood vessels compared with Exos without influencing liver and kidney function. Meanwhile, ATV-Exos promoted the proliferation, migration, tube formation, and VEGF level of endothelial cells in vitro. And AKT/eNOS pathway was activated by ATV-Exos and the pro-angiogenic effects of ATV-Exo were attenuated after the pathway being blocked. MiR-221-3p was upregulated by ATV-Exos stimulation, and miR-221-3p inhibitor suppressed the pro-angiogenesis effect of ATV-Exos.
CONCLUSIONS
Exosomes originated from ATV-pretreated MSCs might serve as a potential strategy for the treatment of diabetic skin defects through enhancing the biological function of endothelial cells via AKT/eNOS pathway by upregulating the miR-221-3p.
Topics: Animals; Atorvastatin; Cell Proliferation; Diabetes Mellitus, Experimental; Exosomes; Mesenchymal Stem Cells; MicroRNAs; Neovascularization, Physiologic; Proto-Oncogene Proteins c-akt; Rats; Vascular Endothelial Growth Factor A; Wound Healing
PubMed: 32787917
DOI: 10.1186/s13287-020-01824-2 -
Nature Communications May 2020Vascular disease remains the leading cause of death and disability, the etiology of which often involves atherosclerosis. The current treatment of atherosclerosis by...
Vascular disease remains the leading cause of death and disability, the etiology of which often involves atherosclerosis. The current treatment of atherosclerosis by pharmacotherapy has limited therapeutic efficacy. Here we report a biomimetic drug delivery system derived from macrophage membrane coated ROS-responsive nanoparticles (NPs). The macrophage membrane not only avoids the clearance of NPs from the reticuloendothelial system, but also leads NPs to the inflammatory tissues, where the ROS-responsiveness of NPs enables specific payload release. Moreover, the macrophage membrane sequesters proinflammatory cytokines to suppress local inflammation. The synergistic effects of pharmacotherapy and inflammatory cytokines sequestration from such a biomimetic drug delivery system lead to improved therapeutic efficacy in atherosclerosis. Comparison to macrophage internalized with ROS-responsive NPs, as a live-cell based drug delivery system for treatment of atherosclerosis, suggests that cell membrane coated drug delivery approach is likely more suitable for dealing with an inflammatory disease than the live-cell approach.
Topics: Animals; Aorta; Atherosclerosis; Atorvastatin; Biomimetic Materials; Cell Membrane; Cytokines; Drug Delivery Systems; Drug Liberation; Female; Macrophages; Mice; Nanoparticles; RAW 264.7 Cells; Reactive Oxygen Species; Treatment Outcome
PubMed: 32457361
DOI: 10.1038/s41467-020-16439-7