Pleiotropic Effects Of Statins Research Articles

Effect of high-dose statin therapy on coagulation factors: Lowering of factor XI as a modifier of fibrin clot properties in coronary artery disease

BackgroundMultiple pleiotropic effects of statins include antithrombotic properties with formation of looser fibrin networks more susceptible to lysis. Recently, rosuvastatin 20 mg/d has been reported to decrease coagulation factors (F) VII, FVIII and FXI in venous thrombosis patients. ObjectivesWe investigated how high-dose statin therapy recommended in coronary artery disease (CAD) alters plasma levels of coagulation factors and if such changes might affect fibrin clot properties. MethodsWe studied 130 advanced CAD patients, who initially did not achieve the target low-density lipoprotein cholesterol (LDL-C). Before high-dose statin therapy (rosuvastatin 40 mg/d or atorvastatin 80 mg/d) and 6–12 months after its initiation, FII, FV, FVII, FVIII, FIX, FX, FXI and fibrinogen were assessed. We evaluated the impact of statin-induced alterations to the factors on plasma fibrin clot permeability (Ks) reflecting a fibrin pore size, and clot lysis time (CLT) reflecting fibrinolytic potential. ResultsAt baseline LDL-C (median 3.2, interquartile range 2.7–3.7 mmol/L) was independently associated solely with FXI (β = 0.58, P < 0.001). Median LDL-C reduction by 25% (P < 0.001) on high-dose statin treatment was accompanied by lowering of FVII, FVIII, and FXI (for all P < 0.001). On high-dose statin treatment, Ks (R = 0.65, P < 0.001) inversely associated with CRP (β = −0.41, P < 0.001), LDL-C (β = −0.26, P = 0.001), and FXI (β = −0.18, P = 0.016). In turn, CLT (R = 0.45, P < 0.001) was positively associated with LDL-C (β = 0.19, P = 0.043) and FXI (β = 0.17, P = 0.049). ConclusionsHigh-dose statin therapy in CAD patients decreases FVII, FVIII, and FXI. The statin-induced reduction in FXI may contribute to less prothrombotic fibrin clot phenotype, indicating additional antithrombotic effect of high-dose statins.

Pleiotropic Effects of Statins-What is their Clinical Significance?

Pleiotropic effects are effects not related to the primary effect of drugs. Statins, beside their primary effect, which is LDL-lowering, have several pleiotropic effects, such as anti-inflammation, anti-thrombotic effects, inhibition of smooth muscle cell proliferation and apoptosis, inhibition of migration and activation of macrophages. They increase blood glucose with the exception of pitavastatin. The clinical importance of these pleiotropic effects of statins however remains unclear. No matter of whether LDL-lowering was done by statins or by other means, the lowering of the cardiovascular risk is the same. The reduction in LDL-C per se is responsible for the beneficial effect. However, pleiotropic effects of statins might play a role with respect to micro vascular events. The difference in pleiotropic effects between the different statins might be a basis for a patient-oriented statin therapy.

A proteomic approach for investigating the pleiotropic effects of statins in the atherosclerosis risk in communities (ARIC) study

BackgroundStatins are prescribed to reduce LDL-c and risk of CVD. Statins have pleiotropic effects, affecting pathophysiological functions beyond LDL-c reduction. We compared the proteome of statin users and nonusers (controls). We hypothesized that statin use is associated with proteins unrelated to lipid metabolism. MethodsAmong 10,902 participants attending ARIC visit 3 (1993–95), plasma concentrations of 4955 proteins were determined using SOMAlogic's DNA aptamer-based capture array. 379 participants initiated statins within the 2 years prior. Propensity scores (PS) were calculated based on visit 2 (1990–92) LDL-c levels and visit 3 demographic/clinical characteristics. 360 statin users were PS matched to controls. Log2-transformed and standardized protein levels were compared using t-tests, with false discovery rate (FDR) adjustment for multiple comparisons. Analyses were replicated in visit 2. ResultsCovariates were balanced after PS matching, except for higher visit 3 LDL-c levels among controls (125.70 vs 147.65 mg/dL; p < 0.0001). Statin users had 11 enriched and 11 depleted protein levels after FDR adjustment (q < 0.05). Proteins related and unrelated to lipid metabolism differed between groups. Results were largely replicated in visit 2. ConclusionProteins unrelated to lipid metabolism differed by statin use. Pending external validation, exploring their biological functions could elucidate pleiotropic effects of statins. SignificanceStatins are the primary pharmacotherapy for lowering low-density lipoprotein (LDL) cholesterol and preventing cardiovascular disease. Their primary mechanism of action is through inhibiting the protein 3hydroxy-3-methylglutaryl CoA reductase (HMGCR) in the mevalonate pathway of LDL cholesterol synthesis. However, statins have pleiotropic effects and may affect other biological processes directly or indirectly, with hypothesized negative and positive effects. The present study contributes to identifying these pathways by comparing the proteome of stain users and nonusers with propensity score matching. Our findings highlight potential biological mechanisms underlying statin pleiotropy, informing future efforts to identify statin users at risk of rare nonatherosclerotic outcomes and identify health benefits of statin use independent of LDL-C reduction.

Review of Recent Laboratory and Experimental Data on Cardiotoxicity of Statins.

Due to the fact that statins are among the most high-demand therapeutic agents used for the treatment and prevention of the most common cardiovascular diseases, a significant amount of research is focused on these drugs. As a result, the study and discovery of new effects in statin drugs continues. Research methods are constantly being improved in terms of their sensitivity and specificity, which leads to a change in ideas. In addition to the main lipid-lowering effect, statins have a number of additional effects, which can be conditionally divided into positive (pleiotropic) and negative (side effects). Moreover, information about many of the pleiotropic effects of statins is controversial and may subsequently change as new data become available. To a large extent, this is due to the introduction of new and the improvement of old methods of study: clinical, laboratory and morphological ones. Recent studies report the possibility of statins having potential cardiotoxic properties, which is expressed by an increase in the concentration of highly sensitive cardiac troponins, as well as various adverse changes in cardiac myocytes at the ultrastructural and molecular levels. This paper discusses possible mechanisms of statin cardiotoxicity. This narrative review is based on an analysis of publications in the Medline, PubMed, PubMed Central and Embase databases. The terms "statins", "troponin", "troponin I", "troponin T" in combination with "cardiotoxicity", "false positive", "mechanisms of increase", "pathophysiological mechanisms", "oxidative stress" and "cardiomyocyte apoptosis" were used to search publications.

Cabergoline-Induced Hypoprolactinemia May Attenuate Cardiometabolic Effects of Atorvastatin: A Pilot Study

Introduction: Hypoprolactinemia, which is usually a consequence of treatment with inadequate high doses of dopaminergic agents, is a poorly understood clinical condition. The aim of the current study was to investigate whether the cardiometabolic effects of statin therapy differ between patients with low prolactin production and patients with normal levels of this hormone. Methods: We studied two groups of cabergoline-treated premenopausal women with hypercholesterolemia matched for age, plasma lipids, cabergoline dose, and treatment duration: 11 women with hypoprolactinemia (group A) and 15 women with plasma levels of this hormone within the reference range (group B). The control group (C) included 25 dopaminergic-naïve normoprolactinemic women, matched for age and lipid levels. Plasma lipids, insulin sensitivity, and levels of uric acid, high-sensitivity C-reactive protein (hsCRP), fibrinogen, homocysteine, and 25-hydroxyvitamin D were measured before and after 14-week treatment with atorvastatin (20 mg daily). Results: Patients with hypoprolactinemia were more insulin-resistant, had lower values of total testosterone and free androgen index, and had higher levels of hsCRP and fibrinogen than individuals with normal prolactin levels. Although atorvastatin reduced total and LDL cholesterol and hsCRP in all study groups, this effect was stronger in groups B and C than in group A. Only in groups B and C, the drug decreased uric acid, fibrinogen, and homocysteine and increased 25-hydroxyvitamin D. In turn, only in group A, atorvastatin worsened insulin sensitivity and reduced free androgen index. Conclusion: Coexisting hypoprolactinemia may have an unfavorable impact on the pleiotropic effects of statins.

Paradoxical association between lipid levels and incident atrial fibrillation according to statin usage

Abstract Background In epidemiology studies, a higher level of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) is associated with a lower risk of atrial fibrillation (AF). Statin use might exert possible confounding effects in the paradoxical relationship; however, the inverse link between AF and cholesterol level that distinguishes statin users from non-users has not been evaluated. Objective We investigated the epidemiological relationships of TC–AF and LDL-C–AF in statin users and non-users, respectively. Methods From the Korean National Health Insurance Service database, we included 9,778,014 adults who underwent a health examination in 2009 and had no prior AF history. The levels of TC and LCL-C at the health exam were categorized in quartile (Q) and decile (D) values of the total study population. The study population was grouped into statin users and non-users, and TC–AF and LDL-C–AF relationships were evaluated. Results 867,336 (8.9%) were on statin use among the total population. Statin users showed higher TC level (208.4±55.6 vs. 194.1±39.5 mg/dL, p&amp;lt;0.001) and LDL-C level (123.0±102.2 vs. 121.3±226.3, p&amp;lt;0.001) compared to non-users. Inverse associations of TC–AF and LCL-C–AF were observed; higher levels of TC and LDL-C were associated with a lower risk of AF. The hazard ratios (HR) and 95% confidence intervals (CI) were 0.797 (0.786–0.809) for the highest quartile of TC (Q4, TC ≥218) and 0.832 (0.82–0.843) for the highest quartile of LDL-C (Q4, LDL-C ≥135) when adjusted by age, sex, lifestyle behaviors, comorbidities, and low-income status. Statin users exhibited higher AF incidence rate than non-statin users, but the association in statin users generally tracked that seen among non-statin users demonstrating similar HR in Q4 of TC [0.812 (0.790–0.835) for statin users and 0.812 (0.798–0.826) for non-statin users] and LDL-C [0.842 (0.819–0.865) for statin users and 0.849 (0.835–0.863) for non-statin users]. Conclusion The paradoxical relationship between lipid levels (TC and LDL-C) and incident AF remained consistent both in statin users and non-users. Further research is required to investigate an underlying mechanism for the cholesterol paradox of AF which still seems evident despite the pleiotropic effects of statin. Funding Acknowledgement Type of funding sources: None.

Statins benefit in androgen levels and target organ damage in hypertensive males with erectile dysfunction

Abstract Background Statins may benefit cardiovascular physiology by cholesterol independent or pleiotropic actions. Target organ damage (TOD) amplifies cardiovascular risk in essential hypertension and endogenous testosterone (TT) exhibit vasoprotective effects. Erectile dysfunction (ED) is frequent in hypertensive middle aged men when androgen levels typically fall, impairing thus quality of life. Purpose To investigate the effect of statins in TT and TOD in hypertensive middle aged men with ED, independently of cholesterol levels. Methods 248 hypertensive ED males (mean age: 57 yo) with no history of diabetes mellitus or overt cardiovascular disease enrolled the study. Of those 95 (38%) were on statin therapy for treatment of dyslipidemia. There were all screened for the presence of microalbuminuria, defined as urinary albumin loss 30–300 mg in a 24 h urine volume collection. TT, total cholesterol (Tchol) and low density lipoprotein (LDL) levels were measured on blood samples taken before 09:00 am. All individuals underwent a non invasive evaluation of the carotid-femoral pulse wave velocity (PWV), estimation of central pressures and augmentation index (AIx) a parameter of wave reflection amplification (Sphygmocor device). ED severity was assessed by the SHIM-5 score (range: 0–25) and higher values indicate a better erectile ability. Results In bivariate analysis statin use was positively related to TT (p&amp;lt;0.05 – Figure 1) and negatively to microalbuminuria, Tchol and LDL (p&amp;lt;0.005). Moreover TT was negatively related to PWV, AIx, microalbuminuria (all p&amp;lt;0.005) and positively to the SHIM-5 score (p: 0.003). By linear regression analysis association of TT to statins remained significant after correction for age, BMI, PWV, AIx, Tchol and LDL levels. Conclusions Statin therapy benefits endogenous testosterone in hypertensive middle aged men with ED and so lessens TOD and enhances erectile ability independently of cholesterol levels. In such population group pleiotropic effects of statins may help restoring androgen levels, decrease cardiovascular risk and ameliorate quality of life. Funding Acknowledgement Type of funding sources: None.

Effect of Statins on All-Cause Mortality in Adults: A Systematic Review and Meta-Analysis of Propensity Score-Matched Studies.

Statins are lipid-lowering medications used for the prevention of cardiovascular disease (CVD), but the pleiotropic effects of statins might be beneficial in other chronic diseases. This meta-analysis investigated the association between statin use and mortality in different chronic conditions. Eligible studies were real-world studies that compared all-cause mortality over at least 12 months between propensity score-matched statin users and non-users. Overall, 54 studies were included: 21 in CVD, 6 in chronic kidney disease, 6 in chronic inflammatory diseases, 3 in cancer, and 18 in other diseases. The risk of all-cause mortality was significantly reduced in statin users (hazard ratio: 0.72, 95% confidence interval: 0.66–0.76). The reduction in mortality risk was similar in CVD studies (0.73, 0.66–0.76) and non-CVD studies (0.70, 0.67–0.79). There were no significant differences in the risk reduction between cohorts with different diseases (p = 0.179). The greatest mortality reduction was seen in studies from Asia (0.61, 0.61–0.73) and the lowest in studies from North America (0.78, 0.73–0.83) and Australia (0.78, 0.62–0.97). There was a significant heterogeneity (I2 = 95%, tau2 = 0.029, p < 0.01). In conclusion, statin use was associated with a significantly reduced risk of all-cause mortality in real-world cohorts with CVD and non-CVD.

The Effects of Statin Treatment on Serum Ferritin Levels: A Systematic Review and Meta-Analysis.

Background: Statins are the most widely used drugs for decreasing elevated serum LDL-cholesterol (LDL-C) and thus for the prevention of atherosclerotic cardiovascular disease (ASCVD), but they have also some pleiotropic effects, including anti-inflammatory properties. Atherosclerosis is a low-grade inflammatory disease, and elevated ferritin is considered to be one of the markers of inflammation. Since the results of studies on the effects of statins on serum ferritin levels are conflicting, this meta-analysis was performed. Methods: A literature search was performed using major electronic databases (MEDLINE/PubMed, Scopus, Embase, and ISI Web of Science) from inception up to 5 March 2022 to find studies evaluating the effect of different statins on serum ferritin levels. The effect size was determined using weighted mean differences (WMDs) and the corresponding 95% confidence intervals (CIs). Results: The meta-analysis of nine studies (1611 patients) analyzing the effects of statins on serum ferritin levels that were included showed a significant decrease in circulating ferritin levels caused by statins. The results did not suggest any significant association between the changes in concentrations of serum ferritin and the duration of treatment with statins. Conclusions: Statin therapy decreases the circulating concentrations of ferritin, which might be beneficial for the prevention and/or progression of ASCVD. This effect might be explained by the anti-inflammatory effects and maybe some other pleiotropic effects of statins and not by their lipid-lowering effects.

Simvastatin Nanoparticles Loaded Polymeric Film as a Potential Strategy for Diabetic Wound Healing: In Vitro and In Vivo Evaluation.

The pleiotropic effects of statins are recently explored for wound healing through angiogenesis and lymph-angiogenesis that could be of great importance in diabetic wounds. The aim of the present study is to fabricate nanofilm embedded with simvastatin-loaded chitosan nanoparticles (CS-SIM-NPs) and to explore the efficacy of SIM in diabetic wound healing. The NPs, prepared via ionic gelation, were 173 nm ± 2.645 in size with a zeta potential of -0.299 ± 0.009 and PDI 0.051 ± 0.088 with excellent encapsulation efficiency (99.97%). The optimized formulation (CS: TPP, 1:1) that exhibited the highest drug release (91.64%) was incorporated into the polymeric nanofilm (HPMC, Sodium alginate, PVA), followed by in vitro characterization. The optimized nanofilm was applied to the wound created on the back of diabetes-induced (with alloxan injection 120 mg/kg) albino rats. The results showed a significant (p < 0.05) improvement in the wound healing process compared to the diabetes-induced non-treated group. The results highlighted the importance of nanofilms loaded with SIM-NPs in diabetic wound healing through angiogenesis promotion at the wound site. Thus, CS-SIM-NPs loaded polymeric nanofilms could be an emerging diabetic wound healing agent in the industry of nanomedicines.

Statins are associated with reduced likelihood of sarcopenia in a sample of heart failure outpatients: a cross-sectional study

BackgroundSarcopenia is prevalent in heart failure (HF) patients, contributing to its poor prognosis. Statin use is postulated as a probable risk for developing sarcopenia, but little is known regarding this association in HF patients. This work aims at classifying and characterising sarcopenia and at describing the association of statin use with sarcopenia in a sample of Portuguese HF outpatients.MethodsIn this cross-sectional study, a sample of 136 HF patients (median age: 59 years, 33.8% women) was recruited from an HF outpatients’ clinic of a University Hospital in Portugal. Sarcopenia was defined according to the European Working Group on Sarcopenia in Older People 2. Clinical, nutritional, and dietary data were collected.ResultsA total of 25 (18.4%) individuals were categorised as sarcopenic, ranging from 12.2% in younger (< 65 years) participants vs. 30.4% in older ones and from 3.3% in men vs. 47.8% in women. Severe sarcopenia accounted for 7.4% of the sample and sarcopenic obesity was identified in 5.1% of the individuals. A total of 65.4% of the participants were statin users. In multivariable analysis (n = 132, 25 sarcopenic), the use of statins was inversely associated with sarcopenia (OR = 0.03; 95% CI = 0.01, 0.30). Each additional age year was associated with a 9% increase in the likelihood of being sarcopenic (OR = 1.09; 95% CI = 1.01, 1.17), and each Kg.m−2 increment in body mass index was associated with a 21% decrease in the likelihood of sarcopenia (OR = 0.79; 95% CI = 0.65, 0.96). The daily use of five or more medicines was also directly associated with sarcopenia (OR = 26.87; 95% CI = 2.01, 359.26). On the other hand, being a man and being physically active were inversely associated with sarcopenia (OR = 0.01; 95% CI = 0.00, 0.07 and OR = 0.09; 95% CI = 0.01, 0.65, respectively).ConclusionsContrary to what was expected, patients medicated with statins were less likely to be sarcopenic. Although this finding deserves further research, we hypothesise that this might be related to the pleiotropic effects of statins on endothelial function, contributing to better neuromuscular fitness.

Exploration of dual LET-7 MIMIC/statin therapy targeting vascular smooth muscle cell dysfunction in atherosclerosis

Background and Aims : Micro-RNA (miRNA) act as negative post-transcriptional regulators of gene expression and are involved in every stage of atherosclerotic plaque development. Statins remain the most common therapeutic agent for lipid lowering, and there is great interest in understanding the pleiotropic effects of statins as well as investigating drug combination therapies alongside statins. Here we investigated a dual statin/miRNA combination therapy approach to target human aortic SMC (HAoSMC) activation.

THE ROLE OF STATINS IN PERIODONTAL THERAPY – A REVIEW

Periodontitis is an inflammatory mechanism causing step by step destruction of the periodontal tissues and alveolar bone. Periodontal treatment is intended to restore the tissues damaged by the disease. Various periodontal procedures have been introduced to lower the destruction; statins are being one among them. They are cholesterol-reducing drugs which have shown to promote bone formation and proven to be effective in periodontal therapy. However, statins have numerous actions, with anti-inflammatory and immunomodulatory effects, as well as the capacity to accelerate new bone formation. The pleiotropic effects of statins have been assessed for their prospective advantage in the therapy of several inflammatory and immune-mediated diseases including periodontitis. Such features could be beneficial for periodontal therapies. This article goes through the history and effects of statins and explores its potential role in periodontal regenerative therapy.

Pleiotropic effects of statins in treatment of generalized periodontitis in patients with coronary artery disease: clinical and experimental study (literature review)

The high prevalence of generalized periodontitis in patients with coronary artery disease (CAD) requires improving the existing ways of periodontal treatment of this category of cardiac patients and finding new ones. Statins are a group of lipid-lowering medications that are widely used for primary and secondary prevention of cardiovascular diseases due to atherosclerotic vascular lesions. In addition to the cholesterol-lowering effect, statins have several pleiotropic effects, including anti-inflammatory, immune-stimulating, antibacterial, antioxidant, osteotropic etc. The analysis of scientific studies of native and foreign authors devoted to studying the influence of pleiotropic effects of statins on the condition of periodontal tissues revealed improvement of periodontal indicators, in particular, gum structure, reduction of the periodontal pockets depth, gum bleeding, and tooth mobility in patients on statin therapy. Experimental in vitro and in vivo studies show a decrease in proinflammatory cytokines (IL-6, IL-8, IL-1β, TNF-a, etc.), which play a key role in the development of generalized periodontitis, as well as the acceleration of reparative processes in alveolar bone tissue when administering topical statins. Despite the prospects of using statins as the main or additional agent in the treatment of periodontal diseases, the question of dosage and method of local delivery of the medication for avoiding the undesirable side effects remains controversial and requires further research.

Dose-dependent impact of statin therapy intensity on circulating progenitor cells in patients undergoing percutaneous coronary intervention for the treatment of acute versus chronic coronary syndrome

BackgroundBy low-density lipoprotein (LDL) reduction, statins play an important role in cardiovascular risk modification. Incompletely understood pleiotropic statin effects include vasoprotection that might originate from mobilisation and differentiation of vascular progenitor cells. Data on the potentially differential impact of statin treatment intensity on circulating progenitor cells in patients undergoing percutaneous coronary intervention (PCI) are scarce. This study examines the potential association of different permanent statin treatment regimens on circulating progenitor cells in patients with coronary syndrome.Methods and resultsIn a monocentric prospective all-comers study, 105 consecutive cases scheduled for coronary angiography due to either (A) non-invasive proof of ischemia and chronic coronary syndrome (CCS) or (B) troponin-positive acute coronary syndrome (ACS) were included. According to the 2018 American College of Cardiology Guidelines on Blood Cholesterol, patients were clustered depending on their respective permanent statin treatment regimen in either a high- to moderate-intensity statin treatment (HIST) or a low-intensity statin treatment (LIST) group. Baseline characteristics including LDL levels were comparable. From blood drawn at the time of PCI, peripheral blood mononuclear cells were isolated, cultivated and counted and, by density gradient centrifugation, levels of circulating progenitor cells were determined using fluorescence-activated cell sorting (FACS) analysis. In ACS patients both absolute and relative numbers of circulating early-outgrowth endothelial progenitor cells (EPCs) concurrently were significantly lower in the HIST group as compared to the LIST group. This effect was more pronounced in ACS patients than in CCS patients. Both in ACS and CCS patients, HIST caused a significant reduction of the number of circulating SMPCs.ConclusionsIn patients undergoing PCI, a dose intensity-dependent and LDL level-independent pro-differentiating vasoprotective pleiotropic capacity of statins for EPC and SMPC is demonstrated.

Effects of statins on specialized pro-resolving mediators: An additional pathway leading to resolution of inflammation

Statins are a class of cholesterol-lowering drugs that inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Anti-inflammatory and antioxidant properties, as well as improvement of endothelial function and plaque stabilization have also been proposed as parts of the pleiotropic effects of statins. Specialized pro-resolving mediators (SPMs) are endogenous lipid-derived molecules originating from ω-6 and ω-3 polyunsaturated fatty acids, such as arachidonic, docosahexaenoic and eicosapentaenoic acid that trigger and modulate the resolution of inflammation. Impaired SPM biosynthesis can lead to excessive or chronic inflammation and is implicated in the pathogenesis of several diseases. Exogenous administration of SPMs, including lipoxin, maresin, protectin, have been shown to improve both bacterial and viral infections, mainly in preclinical models, thus minimizing inflammation. Statin-triggered-SPM production in several in vitro and in vivo models may represent another anti-inflammatory pathway involving these drugs. This commentary discusses scientific publications on the effects of statins on SPMs and the resolution of inflammation process.

Undertreatment or Overtreatment With Statins: Where Are We?

Statins, in addition to healthy lifestyle interventions, are the cornerstone of lipid-lowering therapy. Other low-density lipoprotein (LDL)-lowering drugs include ezetimibe, bile acid sequestrants, and PCSK9 inhibitors. As new evidence emerges from new clinical trials, therapeutic goals change, leading to renewed clinical guidelines. Nowadays, LDL goals are getting lower, leading to the “lower is better” paradigm in LDL-cholesterol (LDL-C) management. Several observational studies have shown that LDL-C control in real life is suboptimal in both primary and secondary preventions. It is critical to enhance the adherence to guideline recommendations through shared decision-making between clinicians and patients, with patient engagement in selecting interventions based on individual values, preferences, and associated conditions and comorbidities. This narrative review summarizes the evidence regarding the benefits of lipid-lowering drugs in reducing cardiovascular events, the pleiotropic effect of statins, real-world data on overtreatment and undertreatment of lipid-lowering therapies, and the changing LDL-C in targets in the clinical guidelines of dyslipidemias over the years.

Statins and Colorectal Cancer Risk: A Population-Based Case-Control Study and Synthesis of the Epidemiological Evidence.

(1) Background: The pleiotropic effects of statins may explain a chemoprotective action against colorectal cancer (CRC). Many studies have tested this hypothesis, but results have been inconsistent so far. Moreover, few have examined statins individually which is important for determining whether there is a class effect and if lipophilicity and intensity may play a role. (2) Methods: From 2001–2014, we carried out a study comprised of 15,491 incident CRC cases and 60,000 matched controls extracted from the primary healthcare database BIFAP. We fit a logistic regression model to compute the adjusted-odds ratios (AOR) with their 95% confidence intervals (CIs). Additionally, we carried out a systematic review and meta-analysis. (3) Results: Current use of statins showed a reduced risk of CRC (AOR = 0.87; 95% CI: 0.83–0.91) not sustained after discontinuation. The association was time-dependent, starting early (AOR6months–1year = 0.85; 95% CI: 0.76–0.96) but weakened beyond 3-years. A class effect was suggested, although only significant for simvastatin and rosuvastatin. The risk reduction was more marked among individuals aged 70 or younger, and among moderate-high intensity users. Forty-eight studies were included in the meta-analysis (pooled-effect-size = 0.90; 95% CI: 0.86–0.93). (4) Conclusions: Results from the case-control study and the pooled evidence support a moderate chemoprotective effect of statins on CRC risk, modified by duration, intensity, and age.

Pitavastatin activates mitophagy to protect EPC proliferation through a calcium-dependent CAMK1-PINK1 pathway in atherosclerotic mice

Statins play a major role in reducing circulating cholesterol levels and are widely used to prevent coronary artery disease. Although they are recently confirmed to up-regulate mitophagy, little is known about the molecular mechanisms and its effect on endothelial progenitor cell (EPC). Here, we explore the role and mechanism underlying statin (pitavastatin, PTV)-activated mitophagy in EPC proliferation. ApoE−/− mice are fed a high-fat diet for 8 weeks to induce atherosclerosis. In these mice, EPC proliferation decreases and is accompanied by mitochondrial dysfunction and mitophagy impairment via the PINK1-PARK2 pathway. PTV reverses mitophagy and reduction in proliferation. Pink1 knockout or silencing Atg7 blocks PTV-induced proliferation improvement, suggesting that mitophagy contributes to the EPC proliferation increase. PTV elicits mitochondrial calcium release into the cytoplasm and further phosphorylates CAMK1. Phosphorylated CAMK1 contributes to PINK1 phosphorylation as well as mitophagy and mitochondrial function recover in EPCs. Together, our findings describe a molecular mechanism of mitophagy activation, where mitochondrial calcium release promotes CAMK1 phosphorylation of threonine177 before phosphorylation of PINK1 at serine228, which recruits PARK2 and phosphorylates its serine65 to activate mitophagy. Our results further account for the pleiotropic effects of statins on the cardiovascular system and provide a promising and potential therapeutic target for atherosclerosis.

Pleiotrope Effekte von Statinen – Was ist ihre klinische Bedeutung?

Pleiotropic Effects of Statins - What Is Their Clinical Significance? Abstract. Pleiotropic Effects of Statins - What Is Their Clinical Significance? Statins have several pleiotropic effects, such as anti-inflammation, anti-thrombotic effects, inhibition of smooth muscle cell proliferation and apoptosis, inhibition of migration and activation of macrophages. They increase blood glucose with the exception of pitavastatin. The clnical importance of the pleiotropic effects of statins however remains unclear. The lowering of Low Density Lipoprotein cholesterol (LDL-C) has similar effects on the reduction of cardiovascular effects no matter whether this reduction was obtained by statin or by non-statin therapy, indicating that the reduction in LDL-C per se is responsible for the beneficial effect. However, pleiotropic effects of statins might play a role with respect to microvascular events. The difference in pleiotropic effects between the different statins might be a basis for a patient-oriented statin therapy.