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Improvement of endothelial dysfunction is mediated through reduction of remnant lipoprotein after statin therapy in patients with coronary artery disease.
Nakamura, T, Uematsu, M, Yoshizaki, T, Kobayashi, T, Watanabe, Y, Kugiyama, K
Journal of cardiology. 2020;(3):270-274
Abstract
BACKGROUND Remnant lipoproteinemia with high levels of low-density lipoprotein cholesterol (LDL-C) is a high risk for endothelial dysfunction. Statins are the first-line lipid-lowering drugs for this combined hyperlipidemia. However, it remains undetermined whether reduction of remnant lipoprotein mediates the relationship between improvement in endothelial dysfunction and reduction of LDL-C level after statin treatment. METHODS A total of 122 coronary artery disease (CAD) patients with impaired flow-mediated dilation (FMD; <5.5%), high levels of LDL-C (≥100 mg/dL), and remnant-like lipoprotein particle cholesterol (RLP-C) (≥5 mg/dL) were examined in this study. The lipid profiles and FMD were measured before and after 6-9 months of statin treatment. The association between changes in LDL-C levels and its relationship with changes in FMD was investigated. Furthermore, mediation analysis was performed to assess the changes in RLP-C level as a mediator of the relationship between the reduction in LDL-C level and improvement of FMD. RESULTS Treatment with statins improved FMD in 69 (56.5%) patients. Patients with improved FMD showed lower percent changes of LDL-C, triglyceride (TG), RLP-C, RLP-C/TG, and C-reactive protein (CRP) levels, and higher percent change of HDL-C level, compared to patients who did not show improved FMD. The percent changes in FMD levels had a significant inverse correlation with the percent changes in LDL-C, (r = -0.18, p = 0.03), RLP-C (r = -0.39, p < 0.001), RLP-C/TG (r = -0.34, p < 0.001), and CRP (r = -0.27, p < 0.01). Mediation analysis showed that the relationship between reduction in LDL-C and improvement of FMD was mediated by reduction of RLP-C (34.5%), RLP-C/TG (24.4%), and CRP (24.9%) levels. CONCLUSION Improvement of remnant lipoproteinemia may be an important mediator for the relationship between improvement of endothelial dysfunction and LDL-lowering after statin treatment in patients with CAD.
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Expression of MMP-2, MMP-9, and NGAL in Tissue and Serum of Patients with Vascular Aneurysms and Their Modulation by Statin Treatment: A Pilot Study.
Cione, E, Piegari, E, Gallelli, G, Caroleo, MC, Lamirata, E, Curcio, F, Colosimo, F, Cannataro, R, Ielapi, N, Colosimo, M, et al
Biomolecules. 2020;(3)
Abstract
BACKGROUND Matrix metalloproteinases (MMPs) are involved in vascular wall degradation, and drugs able to modulate MMP activity can be used to prevent or treat aneurysmal disease. In this study, we evaluated the effects of statins on MMP-2, MMP-9, and neutrophil gelatinase-associated lipocalin (NGAL) in both plasma and tissue in patients with aneurysmal disease. METHODS We performed a prospective, single-blind, multicenter, control group clinical drug trial on 184 patients of both sexes >18 years old with a diagnosis of arterial aneurysmal disease. Enrolled patients were divided into two groups: Group I under statin treatment and Group II not taking statins. In addition, 122 patients without aneurysmal disease and under statin treatment were enrolled as a control group (Group III). The expression of MMPs and NGAL in plasma was evaluated using ELISA, while their expression in endothelial tissues was evaluated using Western blot. RESULTS The ELISA test revealed greater plasma levels (p < 0.01) of MMPs and NGAL in Groups I and II vs. Group III. Western blot analysis showed higher expression (p < 0.01) of MMPs and NGAL in Group II vs. Group I, and this increase was significantly higher (p < 0.01) in patients treated with low potency statins compared to high potency ones. CONCLUSIONS MMPs and NGAL seem to play a major role in the development of aneurysms, and their modulation by statins suggests that these drugs could be used to prevent arterial aneurysmal disease.
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Vascular Quality of Care Assessment: Clinicians' Adherence to Lipid-Lowering Therapy for Patients with Atherosclerotic Cardiovascular Disease.
Chan, J, Rajalingam, T, Fossella, J, Zhou, H, Eisenberg, N, Roche-Nagle, G
Annals of vascular surgery. 2020;:197-205
Abstract
BACKGROUND Lipid-lowering medication can considerably lessen the risk for cardiovascular events in patients with atherosclerotic cardiovascular disease (ASCVD). Despite well-publicized guidelines and the accessibility of effective therapies, many patients do not attain their lipid goals and remain at high cardiovascular risk. Guidelines recommend statins as first-line therapy to reduce cardiovascular morbidity and mortality in ASCVD. We aimed to analyze admission lipid levels in a broad contemporary population of patients with ASCVD attending a vascular clinic or admitted to an inpatient vascular unit. METHODS Patients with known ASCVD, current cholesterol levels, and lipid-lowering medications were documented and compared with published current Canadian Cardiovascular Society Guidelines recommendations for achieving <2.0 mmol/L or >50% reduction in low-density lipoprotein cholesterol (LDL-C). Cholesterol levels (current and previous), demographic characteristics, cardiovascular risk factors, and medical therapy were assessed from available patient records. RESULTS Two hundred eight adult patients were identified. The mean age of the patients was 72 (±10) years, and 76% were men. About half had peripheral arterial disease (n = 118, 56.7%), one-third had coronary artery disease (n = 78, 37.5%), and one-third had diabetes (n = 76, 36.5%). Most were hypertensive (n = 140, 67.3%) and half gave a history of dyslipidemia (n = 103, 49.5%). Most patients (n = 183, 88%) were taking a statin and the majority at a moderate-intensity dose (n = 79, 43.2%) or high-intensity dose (n = 101, 55.2%). However, 32.7% of patients (n = 68) did not reach target of LDL-C level of <2.0 mmol/L or had ≤50% reduction from the baseline level. Of the patients who did not reach goals, 7 (10.3%) did not fill their statin prescriptions in the last 3 months. Only 26 patients (12.5%) were also on ezetimibe, a guideline-recommended second-line therapy if targets are not reached with maximally tolerated statin therapy. One patient, who was able to reach target LDL-C, was on evolocumab monotherapy, a PCSK9 inhibitor, a contemporary nonstatin therapy that could be considered in ASCVD in those not at LDL-C goal. Of the 16 patients who were not prescribed any lipid-lowering therapy and did not reach target, 8 (50%) did not have any identified or documented reasons. Of the remaining 8 patients, 7 (87.5%) reported intolerance or side effects to statins only, and could benefit from nonstatin LDL-lowering therapy. CONCLUSIONS In this observational study, we established suboptimal adherence to guideline recommendations for statin therapy and hesitancy to use nonstatin LDL-lowering agents in high-risk patients with ASCVD. These treatment gaps have an enormous effect on achieving improved cardiovascular clinical outcomes and must be tackled.
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The challenge of multiple cardiovascular risk factor control outside Western Europe: Findings from the International ChoLesterol management Practice Study.
Blom, DJ, Santos, RD, Daclin, V, Mercier, F, Ruiz, AJ, Danchin, N, ,
European journal of preventive cardiology. 2020;(13):1403-1411
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Abstract
BACKGROUND Comprehensive control of multiple cardiovascular risk factors reduces cardiovascular risk but is difficult to achieve. DESIGN A multinational, cross-sectional, observational study. METHODS The International ChoLesterol management Practice Study (ICLPS) investigated achievement of European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guideline low-density lipoprotein cholesterol (LDL-C) targets in patients receiving lipid-modifying therapy in countries outside Western Europe. We examined the rate of, and association between, control of multiple risk factors in ICLPS participants with dyslipidaemia, diabetes and hypertension (N = 2377). RESULTS Mean (standard deviation) age of patients was 61.4 (10.4) years; 51.3% were male. Type 2 diabetes was the most common form of diabetes (prevalence, 96.9%). The prevalence of metabolic syndrome was 67.8%, obesity 40.4%, atherosclerotic disease 39.6% and coronary artery disease 33.5%. All patients were at high (38.2%) or very high (61.8%) cardiovascular risk according to ESC/EAS guidelines. Body mass index (BMI) was <25 kg/m2 in 20.3% of patients, 62.8% had never smoked and 25.2% were former smokers. Overall, 12.2% achieved simultaneous control of LDL-C, diabetes and blood pressure. Risk factor control was similar across all participating countries. The proportion of patients achieving individual guideline-specified treatment targets was 43.9% for LDL-C, 55.5% for blood pressure and 39.3% for diabetes. Multiple correspondence analysis indicated that control of LDL-C, control of blood pressure, control of diabetes, BMI and smoking were associated. CONCLUSION Comprehensive control of multiple cardiovascular risk factors in high-risk patients is suboptimal worldwide. Failure to control one risk factor is associated with poor control of other risk factors.
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Interplay Between Statins, Cav1 (Caveolin-1), and Aldosterone.
Haas, AV, Baudrand, R, Easly, RM, Murray, GR, Touyz, RM, Pojoga, LH, Jeunemaitre, X, Hopkins, PN, Rosner, B, Williams, JS, et al
Hypertension (Dallas, Tex. : 1979). 2020;(3):962-967
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Abstract
Statin use is associated with lower aldosterone levels. We hypothesized that caveolin-1 may be important for the uptake of statins into the adrenal gland and would affect statin's aldosterone-lowering effects. The aim of this study was to test whether the caveolin-1 risk allele (rs926198) would affect aldosterone levels associated with statin use. The Hypertensive Pathotype database includes healthy and hypertensive individuals who have undergone assessment of adrenal hormones. Individuals were studied off antihypertensive medications but were maintained on statins if prescribed by their personal physician. Adrenal hormones were measured at baseline and after 1 hour of angiotensin II stimulation on both high- and low-sodium diets. A mixed-model repeated-measures analysis was employed with a priori selected covariates of age, sex, body mass index, and protocol (low versus high sodium, baseline versus angiotensin II stimulated aldosterone). A total of 250 individuals were included in the study; 31 individuals were taking statins (12.4%) and 219 were not. Among statin users, carrying a caveolin-1 risk allele resulted in a 25% (95% CI, 1-43.2) lower aldosterone level (P=0.04). However, among nonstatin users, carrying a caveolin-1 risk allele resulted in no significant effect on aldosterone levels (P=0.38). Additionally, the interaction between caveolin-1 risk allele and statin use on aldosterone levels was significant (P=0.03). These findings suggest caveolin-1 risk allele carrying individuals are likely to receive the most benefit from statin's aldosterone-lowering properties; however, due to the observational nature of this study, these findings need further investigation.
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Administration of eicosapentaenoic acid may alter high-density lipoprotein heterogeneity in statin-treated patients with stable coronary artery disease: A 6-month randomized trial.
Tani, S, Matsuo, R, Yagi, T, Matsumoto, N
Journal of cardiology. 2020;(3):282-288
Abstract
BACKGROUND Combined statin plus eicosapentaenoic acid (EPA) therapy might be a potentially effective treatment option to prevent coronary artery disease (CAD). The serum EPA/arachidonic acid (AA) ratio has been identified as a potential new risk marker for CAD. Few data exist whether administration of EPA could affect high-density lipoprotein (HDL) particle size. We hypothesized that the addition of EPA to ongoing statin therapy may result in altered HDL heterogeneity. METHODS We conducted this 6-month, single-center, prospective, randomized open-label clinical trial to investigate the effect of the additional administration of EPA on the HDL heterogeneity (HDL2, HDL3, and HDL2/HDL3 ratio) in stable CAD patients receiving treatment with statins. We assigned stable CAD patients already receiving statin therapy to the EPA group (1800mg/day: n=50) or the control group (n=50). RESULTS A significant decrease in the serum HDL3 level (-4.7% vs. -0.5%, p=0.037), but not of the serum HDL2 level, and a significant increase in the HDL2/HDL3 ratio (5.5% vs. -5.1%, p=0.032) were observed in the EPA group as compared to the control group. Multiple regression analysis with adjustments for coronary risk factors identified the achieved EPA/ AA ratio as an independent and significant predictor of an increase of the HDL2/HDL3 ratio (β=0.295, p=0.001). Furthermore, the change in the serum cholesterol ester transfer protein mass was positively correlated with the change in the EPA/AA ratio in the EPA group (r=0.286, p=0.044), but not in the control group (r=0.121, p=0.401). CONCLUSION Administration of EPA might decrease the serum HDL3 level, resulting in an increase in the HDL2/HDL3 ratio. Furthermore, increased EPA/AA ratio by the addition of EPA to ongoing statin therapy might be an indicator of an increase in the HDL2/HDL3 ratio, thereby regulating HDL particle size. CLINICAL TRIAL REGISTRATION UMIN (http://www.umin.ac.jp/) Study ID: UMIN000010452.
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Association between statin use and incidence or progression of osteoarthritis: meta-analysis of observational studies.
Wang, J, Dong, J, Yang, J, Wang, Y, Liu, J
Osteoarthritis and cartilage. 2020;(9):1170-1179
Abstract
OBJECTIVE The objective of the study was to determine whether statin use could reduce the risk of the incidence or progression of osteoarthritis (OA). METHODS The PubMed, Embase, and Cochrane databases were systematically searched for observational studies on the association between statin use and OA. ORs and 95% CIs were directly retrieved or calculated. The Newcastle-Ottawa quality assessment scale was used for study quality assessment. Subgroup analysis, sensitivity analysis, and publication bias were conducted using Stata software. RESULTS A total of 11 studies (679807 participants) were identified from the systematic literature search. No significant association between statin use and incidence (OR = 1.010; 95% CI: 0.968 to 1.055; P = 0.638) or progression (OR = 1.076; 95% CI: 0.824 to 1.405; P = 0.589) of OA was found in our meta-analysis. The meta-analysis according to the symptomatic or radiological OA also found no significant association between statin use and OA. The subgroup analysis showed that atorvastatin (OR = 0.953; 95% CI: 0.911 to 0.998; P = 0.041) and rosuvastatin (OR = 1.180; 95% CI: 1.122 to 1.241; P < 0.0001) had opposite effects on OA. The results of the analysis according to the joint site, interval, and statin dose were all not significant. CONCLUSIONS Statin use may not be associated with a lower risk of incidence and progression of OA, regardless of joint site. The opposite effects of atorvastatin and rosuvastatin were detected in OA.
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Statins as Anticancer Agents in the Era of Precision Medicine.
Longo, J, van Leeuwen, JE, Elbaz, M, Branchard, E, Penn, LZ
Clinical cancer research : an official journal of the American Association for Cancer Research. 2020;(22):5791-5800
Abstract
Statins are widely prescribed cholesterol-lowering drugs that inhibit HMG-CoA reductase (HMGCR), the rate-limiting enzyme of the mevalonate metabolic pathway. Multiple lines of evidence indicate that certain cancers depend on the mevalonate pathway for growth and survival, and, therefore, are vulnerable to statin therapy. However, these immediately available, well-tolerated, and inexpensive drugs have yet to be successfully repurposed and integrated into cancer patient care. In this review, we highlight recent advances and outline important considerations for advancing statins to clinical trials in oncology.
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Clinical Pharmacology of Statins: an Update.
Ferri, N, Corsini, A
Current atherosclerosis reports. 2020;(7):26
Abstract
PURPOSE OF REVIEW Statins represent the cornerstone for the treatment of hypercholesterolemia, although muscle-related side effects and dysregulation of glucose metabolism have strongly limited their adherence and compliance especially in primary prevention therapy. The purpose of the present review is to provide the most recent evidence of the efficacy and safety of statins in monotherapy or combination with new lipid-lowering drugs. RECENT FINDINGS Recent "life-long" analysis conducted on young familial hypercholesterolemia patients, elderly hypocholesterolemic subjects, and from a 20-year follow-up of randomized controlled trial (RCT) have been published confirming that the cardiovascular benefits of statin therapy, in patients for whom it is recommended by current guidelines, greatly outweigh the risks of side effects. In addition, recent therapies to be used in combination with statins have shown to increase the percentage of patients at goal for low-density lipoprotein - cholesterol (LDL-C) with a good safety profile. The cardiovascular (CV) benefits of monoclonal antibodies anti-proprotein convertase subtilisin/kexin type 9 (PCSK9) and ezetimibe, in patients under statin therapy, have been proven by specific RCT, while we are still waiting for the results of bempedoic acid and the small-interfering RNA (si-RNA) anti-PCSK9 inclisiran. Taken together, the approval of new pharmacological agents to be used in combination with statins represents the future for a tailored therapy of cardiovascular disease patients.
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Comparison of Percutaneous Coronary Intervention, Coronary Artery Bypass Grafting and Medical Therapy in Non-ST Elevation Acute Coronary Syndrome Patients With 3-Vessel Disease.
Jia, S, Zhang, C, Jiang, L, Xu, L, Tian, J, Zhao, X, Feng, X, Wang, D, Zhang, Y, Sun, K, et al
Circulation journal : official journal of the Japanese Circulation Society. 2020;(10):1718-1727
Abstract
BACKGROUND The aim of this study is to compare the long-term prognosis of non-ST elevation acute coronary syndrome (NSTE-ACS) patients with 3-vessel disease (3VD) who underwent percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG) or medical therapy (MT).Methods and Results:Overall, 3,928 NSTE-ACS patients with 3VD were consecutively enrolled from April 2004 to February 2011 at Fu Wai Hospital. Patients were followed up for a median of 7.5 years, and were divided into PCI, CABG or MT groups according to their treatment. Compared with patients undergoing PCI, CABG patients had lower rates of myocardial infarction (MI), unplanned revascularization, major adverse cardiovascular and cerebrovascular events (MACCE) and a higher rate of stroke (all P<0.05). Compared with MT, PCI and CABG had lower incidences of all adverse outcomes (all P<0.05), except for a similar rate of stroke between PCI and MT. Kaplan-Meier analysis showed similar results. After adjusting for confounders, CABG was independently associated with a lower risk of cardiac death, revascularization and MACCE compared with PCI (all P<0.05). Compared with MT, PCI reduced long-term risk of death, whereas CABG reduced long-term risk of death, revascularization and MACCE events (all P<0.05). CONCLUSIONS In NSTE-ACS patients with 3VD, CABG is independently associated with a lower risk of long-term cardiac death, revascularization and MACCE compared with PCI. Patients who received MT alone had the highest risk of long-term MACCE.