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Atorvastatin 40 mg (ATOR 40) and ezetimibe 10 mg/simvastatin 20 mg (EZ-SIM 20) have similar reductions of low-density lipoprotein cholesterol (LDL-C) but cardiovascular (CV) outcomes between these two therapies are unclear. Our real-world cohort study is to test the hypothesis of pleiotropic effects of purely higher dose statin on CV outcomes beyond similar reductions of LDL-C, especially for extremely CV risk patients. Between January 1, 2007 and December 31, 2013, a total of 3,372 patients with type 2 diabetes mellitus (T2DM) admitted due to acute coronary syndrome (ACS) or acute ischemic stroke (AIS) were selected as the study cohort from the Taiwan National Health Insurance Research Database. Clinical outcomes were evaluated by ATOR 40 group (n = 1686) matched with EZ-SIM 20 group (n = 1686). Primary composite outcome includes CV death, non-fatal myocardial infarction, and non-fatal stroke. Secondary composite outcome includes hospitalization for unstable angina (HUA), percutaneous coronary intervention (PCI), and coronary artery bypass grafting (CABG). With a mean follow-up of 2.4 years, no significant difference of primary composite outcome was observed between ATOR 40 and EZ-SIM 20 groups (subdistribution hazard ratio [SHR], 1.09; 95% confidence interval [CI], 0.95-1.25). Nevertheless, ATOR 40 group had lower risks of HUA (SHR, 0.50; 95% CI, 0.35-0.72), PCI (SHR, 0.82; 95% CI, 0.69-0.97) and CABG (SHR, 0.62; 95% CI, 0.40-0.97) than EZ-SIM 20 group. For T2DM patients after ACS or AIS, ATOR 40 and EZ-SIM 20 had similar major CV outcomes, which still supported the main driver for CV risk reductions is LDL-C lowering.

Background and Objectives: Triglyceride-rich lipoproteins may contribute to the high cardiovascular risk of patients with CKD. This study evaluated associations of apo-B and markers of triglyceride-rich lipoproteins with cardiovascular events in people with CKD., Design, Setting, Participants, & Measurements: Analyses were conducted in 9270 participants with CKD in the Study of Heart and Renal Protection (SHARP): 6245 not on dialysis (mean eGFR 26.5 ml/min per 1.73 m 2 ), and 3025 on dialysis when recruited. Cox regression methods were used to evaluate associations of lipids with incident atherosclerotic and nonatherosclerotic vascular events, adjusting for demographics and clinical characteristics. Hazard ratios (HRs) were calculated per 1 SD higher level for apo-B, HDL cholesterol, LDL cholesterol, triglyceride-rich lipoprotein cholesterol ( i.e. , total cholesterol minus LDL cholesterol minus HDL cholesterol), non-HDL cholesterol, log triglyceride, and log ratio of triglyceride to HDL cholesterol., Results: During a median follow-up of 4.9 years (interquartile range, 4.0-5.5 years), 1406 participants experienced at least one atherosclerotic vascular event. In multivariable adjusted models, positive associations with atherosclerotic vascular events were observed for apo-B (HR per 1 SD, 1.19; 95% confidence interval, 1.12 to 1.27), triglycerides (1.06; 1.00 to 1.13), the ratio of triglyceride to HDL cholesterol (1.10; 1.03 to 1.18), and triglyceride-rich lipoprotein cholesterol (1.14; 1.05 to 1.25). By contrast, inverse associations with nonatherosclerotic vascular events were observed for each of these lipid markers: apo-B (HR per 1 SD, 0.92; 0.85 to 0.98), triglycerides (0.86; 0.81 to 0.92), the ratio of triglyceride to HDL cholesterol (0.88; 0.82 to 0.94), and triglyceride-rich lipoprotein cholesterol (0.85; 0.77 to 0.94)., Conclusions: Higher apo-B, triglycerides, ratio of triglyceride to HDL cholesterol, and triglyceride-rich lipoprotein cholesterol concentrations were associated with increased risk of atherosclerotic vascular events in CKD. Reducing triglyceride-rich lipoproteins using novel therapeutic agents could potentially lower the risk of atherosclerotic cardiovascular disease risk in the CKD population., (Copyright © 2020 by the American Society of Nephrology.)

Background In randomized trials (SHARP [Study of Heart and Renal Protection], IMPROVE -IT [Improved Reduction of Outcomes: Vytorin Efficacy International Trial]), combination of statin and ezetimibe resulted in additional reduction of cardiovascular events. The reduction was greater in patients with type 2 diabetes mellitus (T2 DM ), where elevated remnant cholesterol and high cardiovascular disease risk is characteristic. To evaluate possible causes behind these results, 40 patients eligible for cholecystectomy, randomized to simvastatin, ezetimibe, combined treatment (simvastatin+ezetimibe), or placebo treatment during 4 weeks before surgery, were studied. Methods and Results Fasting blood samples were taken before treatment start and at the end (just before surgery). Bile samples and liver biopsies were collected during surgery. Hepatic gene expression levels were assessed with qPCR . Lipoprotein, apolipoprotein levels, and content of cholesterol, cholesteryl ester, and triglycerides were measured after lipoprotein fractionation. Lipoprotein subclasses were analyzed by nuclear magnetic resonance. Apolipoprotein affinity for human arterial proteoglycans ( PG ) was measured. Biomarkers of cholesterol biosynthesis and intestinal absorption and bile lipid composition were analyzed using mass spectrometry. Combined treatment caused a statistically significant decrease in plasma remnant particles and apolipoprotein B (ApoB)/lipoprotein content of cholesterol, cholesteryl esters, and triglycerides. All treatments reduced ApoB-lipoprotein PG binding. Simvastatin and combined treatment modified the composition of lipoproteins. Changes in biomarkers of cholesterol synthesis and absorption and bile acid synthesis were as expected. No adverse events were found. Conclusions Combined treatment caused atheroprotective changes on ApoB-lipoproteins, remnant particles, bile components, and in ApoB-lipoprotein affinity for arterial PG . These effects might explain the decrease of cardiovascular events seen in the SHARP and IMPROVE - IT trials. Clinical Trial Registration URL : www.clinicaltrialsregister.eu . Unique identifier: 2006-004839-30).

Clinical trials suggested that the benefits of ezetimibe-statin combination therapy on major adverse cardiovascular events (MACE) might be greater in patients with diabetes. We aimed to investigate the differential association of ezetimibe-statin combination with incident MACE by presence of diabetes. In this retrospective cohort study, subjects treated with simvastatin 20 mg plus ezetimibe 10 mg (S + E) or simvastatin 20 mg alone (S) between 2005 and 2015 were 1:1 matched using propensity score as stratified by diabetes. Primary outcome was newly-developed MACE composed of cardiovascular death, ACS, coronary revascularization, or non-hemorrhagic stroke. During 5,077 and 12,439 person-years, the incidence rates of MACE were 24.9, 20.1, 35.3, and 22.8/1000 person-years among no diabetes S, no diabetes S + E, diabetes S, and diabetes S + E, respectively. Relative to no diabetes S, adjusted HR (aHR) for MACE in diabetes S was 1.23 (p = 0.086), whereas S + E was associated with a lower risk of MACE in both non-diabetic patients (aHR 0.76, p = 0.047) and diabetic patients (aHR 0.60, p = 0.007) with significant difference (relative excess risk due to interaction = -0.39, p = 0.044). In conclusion, reduction of MACE risk associated with ezetimibe plus simvastatin therapy relative to simvastatin alone was greater in patients with diabetes than in patients without diabetes.

Background: Ezetimibe, when added to simvastatin, reduces cardiovascular events after acute coronary syndrome. We explored outcomes stratified by diabetes mellitus (DM)., Methods: In IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial), 18 144 patients after acute coronary syndrome with low-density lipoprotein cholesterol 50 to 125 mg/dL were randomized to 40 mg ezetimibe/simvastatin (E/S) or 40 mg placebo/simvastatin. The primary composite end point was cardiovascular death, major coronary events, and stroke. DM was a prespecified subgroup., Results: The 4933 (27%) patients with DM were more often older and female, had had a prior myocardial infarction and revascularization, and presented more frequently with non-ST segment elevation acute coronary syndrome compared with patients without DM (each P <0.001). The median admission low-density lipoprotein cholesterol was lower among patients with DM (89 versus 97 mg/dL, P <0.001). E/S achieved a significantly lower median time-weighted average low-density lipoprotein cholesterol compared with placebo/simvastatin, irrespective of DM (DM: 49 versus 67 mg/dL; no DM: 55 versus 71 mg/dL; both P <0.001). In patients with DM, E/S reduced the 7-year Kaplan-Meier primary end point event rate by 5.5% absolute (hazard ratio, 0.85; 95% confidence interval, 0.78-0.94); in patients without DM, the absolute difference was 0.7% (hazard ratio, 0.98; 95% confidence interval, 0.91-1.04; P int =0.02). The largest relative reductions in patients with DM were in myocardial infarction (24%) and ischemic stroke (39%). No differences in safety outcomes by treatment were present regardless of DM. When stratified further by age, patients ≥75 years of age had a 20% relative reduction in the primary end point regardless of DM ( P int =0.91), whereas patients <75 years of age with DM had greater benefit than those without ( P int =0.011). When stratified by the TIMI (Thrombolysis in Myocardial Infarction) Risk Score for Secondary Prevention, all patients with DM demonstrated benefit with E/S regardless of risk. In contrast, among patients without DM, those with a high risk score experienced a significant (18%) relative reduction in the composite of cardiovascular death, myocardial infarction, and ischemic stroke with E/S compared with placebo/simvastatin, whereas patients without DM at low or moderate risk demonstrated no benefit with the addition of ezetimibe to simvastatin ( P int =0.034)., Conclusions: In IMPROVE-IT, the benefit of adding ezetimibe to statin was enhanced in patients with DM and in high-risk patients without DM., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00202878., (© 2017 American Heart Association, Inc.)

Markers of inflammation, including plasma C-reactive protein (CRP), are associated with an increased risk of cardiovascular disease, and it has been suggested that this association is causal. However, the relationship between inflammation and cardiovascular disease has not been extensively studied in patients with chronic kidney disease. To evaluate this, we used data from the Study of Heart and Renal Protection (SHARP) to assess associations between circulating CRP and LDL cholesterol levels and the risk of vascular and non-vascular outcomes. Major vascular events were defined as nonfatal myocardial infarction, cardiac death, stroke or arterial revascularization, with an expanded outcome of vascular events of any type. Higher baseline CRP was associated with an increased risk of major vascular events (hazard ratio per 3x increase 1.28; 95% confidence interval 1.19-1.38). Higher baseline LDL cholesterol was also associated with an increased risk of major vascular events (hazard ratio per 0.6 mmol/L higher LDL cholesterol; 1.14, 1.06-1.22). Higher baseline CRP was associated with an increased risk of a range of non-vascular events (1.16, 1.12-1.21), but there was a weak inverse association between baseline LDL cholesterol and non-vascular events (0.96, 0.92-0.99). The efficacy of lowering LDL cholesterol with simvastatin/ezetimibe on major vascular events, in the randomized comparison, was similar irrespective of CRP concentration at baseline. Thus, decisions to offer statin-based therapy to patients with chronic kidney disease should continue to be guided by their absolute risk of atherosclerotic events. Estimation of such risk may include plasma biomarkers of inflammation, but there is no evidence that the relative beneficial effects of reducing LDL cholesterol depends on plasma CRP concentration., (Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Alopecia areata (AA) is an autoimmune disorder characterized by T lymphocytic infiltrates around the bulbar region of hair follicles. Statins have surfaced as potential therapeutic agents for AA, partly because of their modulation of the JAK/STAT pathway. Some data indicate that statins are a possible option for acute, but not chronic, longstanding AA. Animal studies suggest that treatment with statins increases CD4 + /CD25 + /Foxp3 + populations in AA-affected mice., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: The association of transaortic flow rate (FR) with outcomes was tested in 1,661 patients with aortic valve stenosis (AS) in the SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) study., Background: Low transaortic flow may complicate grading of AS. However, the association of lower transaortic FR with adverse outcomes has not been reported., Methods: Transaortic FR was calculated from Doppler-derived stroke volume in milliliters divided by systolic ejection time in seconds and considered low if <200 ml/s. The association of transaortic FR with cardiovascular and all-cause mortality during 4.3-year follow-up was tested in time-varying Cox regression models run with aortic valve replacement as competing risk and reported as hazard ratio (HR) and 95% confidence interval (CI)., Results: Low transaortic FR was found in 21% of patients at baseline. Patients with low transaortic FR were older, had lower systemic arterial compliance and left ventricular mass, and included more women and patients with inconsistently graded severe AS and low stroke volume index (<35 ml/m 2 ) (p < 0.01 for all). Low in-study transaortic FR was associated with higher rates of cardiovascular and all-cause mortality both in unadjusted analyses (HR: 2.56 [95% CI: 1.62 to 4.04]; and HR: 1.93 [95% CI: 1.35 to 2.75], respectively; p < 0.001 for both) and after adjustment for age, sex, randomized study treatment, hypertension, stroke volume index <35 ml/m 2 , LV mass, and mean aortic gradient (HR: 2.79 [95% CI: 1.65 to 4.73]; and HR: 1.90 [95% CI: 1.27 to 2.84], respectively; p < 0.01 for both)., Conclusions: In patients with AS without known cardiovascular disease or diabetes, low transaortic FR was independently associated with higher rates of cardiovascular and all-cause mortality. (An Investigational Drug on Clinical Outcomes in Patients With Aortic Stenosis (Narrowing of the Major Blood Vessel of the Heart) (MK-0653A-043 AM4); NCT00092677)., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)