Influence of Statins and Fibrates Drugs on Bone Health and Regeneration

In the medical and dental field, the importance and need for the study of materials and drugs for use as bone grafts or regeneration in injured areas due to the presence of fractures, infections or tumors that cause extensive loss of bone tissue is observed. Bone is a specialized, vascularized and dynamic connective tissue that changes throughout the life of the organism. When injured, it has a unique ability to regenerate and repair without the presence of scars, but in some situations, due to the size of the defect, the bone tissue does not regenerate completely. Thus, due to its importance, there is a great development in therapeutic approaches for the treatment of bone defects through studies that include autografts, allografts and artificial materials used alone or in association with bone grafts. Pharmaceuticals composed of biomaterials and osteogenic active substances have been extensively studied because they provide potential for tissue regeneration and new strategies for the treatment of bone defects. Statins work as specific inhibitors of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMG-CoAreductase). They represent efficient drugs in lowering cholesterol, as they reduce platelet aggregation and thrombus deposition;in addition, they promote angiogenesis, reduce the β-amyloid peptide related to Alzheimer’s disease and suppress the activation of T lymphocytes. Furthermore, these substances have been used in the treatment of hypercholesterolemia and coronary artery disease. By inhibiting HMG-CoAreductase, statins not only inhibit cholesterol synthesis, but also exhibit several other beneficial pleiotropic effects. Therefore, there has been increasing interest in researching the effects of statins, including Simvastatin, on bone and osteometabolic diseases. However, statins in high doses cause inflammation in bone defects and inhibit osteoblastic differentiation, negatively contributing to bone repair. Thus, different types of studies with different concentrations of statins have been studied to positively or negatively correlate this drug with bone regeneration. In this review we will address the positive, negative or neutral effects of statins in relation to bone defects providing a comprehensive understanding of their application. Finally, we will discuss a variety of statin-based drugs and the ideal dose through a theoretical basis with preclinical, clinical and laboratory work in order to promote the repair of bone defects.

Mendelian randomization analysis:the causal relationship between statins and eye diseases

Background:The specific role of statins in the field of ophthalmology is not clear.Statins have the advantages of pleiotropic,relatively safety and low cost,and are a promising choice for the prevention and management of eye diseases.Nevertheless,there is a divergence of findings regarding the correlation between statin treatment and ocular conditions.Hence,our intention is to investigate the impact of statins on eye conditions through the utilization of Mendelian randomization(MR).Methods:The UK Biobank provided data on five statins,while the FinnGen database provided data on six eye diseases,including age-related macular degeneration,glaucoma,diabetic retinopathy,senile cataract,drug-induced cataract,and other cataracts.Causality exploration involved the utilization of various methods including inverse variance weighted(IVW),weighted median,weighted multivariate(weighted mode),and MR-Egger regression.To assess the reliability of the findings,funnel analysis,MR-Egger regression,leave-one-out method,and Cochran’s Q test were employed.Additionally,reverse MR analysis was performed to evaluate the potential for reverse causality between statin use and eye diseases.Results:Based on IVW analysis,there were three pairs of positive results with significant(P<0.05)causal relationship,including atorvastatin and drug-induced cataract(odds ratio(OR)=1.65E-05,95%confidence interval(CI):2.24E-09–0.12;P_(IVW)=0.02),rosuvastatin and drug-induced cataract(OR=2.77E-18,95%CI:7.53E-35–0.1;P_(IVW)=0.04)and fluvastatin with senile cataract(OR=0.5,95%CI:0.25–0.99;P_(IVW)=0.05).No significant causal relationship was observed between other types of statins and eye diseases.Sensitivity analysis found that the results were robust.Reverse MR analysis indicated no evidence of reverse causality between statin use and the examined eye diseases.Conclusion:Our study finally verified the strong causal relationship between three drugs and two diseases(atorvastatin and rosuvastatin and drug cataract,fluvastatin and senile cataract).This study confirms that statins may reduce the risk of certain eye diseases and provides new insights into the prevention and treatment of eye diseases.Furthermore,the lack of reverse causality reinforces the reliability of these associations.

Statins and the risk of colorectal cancer: An updated systematic review and meta-analysis of 40 studies

AIM: To investigate the association between statin use and colorectal cancer risk, we conducted an updated meta-analysis of published studies.

Do statins reduce the mortality rate in stroke patients treated with systemic thrombolysis in a 5-year single-center study?

The present study investigated the association between pre-treatment with a cholesterol-lowering drug(statin) or new setting hereon and the effect on the mortality rate in patients with acute ischemic stroke who received intravenous systemic thrombolysis. During a 5-year period(starting in October 2008), 542 consecutive stroke patients who received intravenous systemic thrombolysis with recombinant tissue plasminogen activator(rt-PA) at the Department of Neurology, University Hospital Schleswig-Holstein, Campus Lübeck, Germany, were included. Patients were characterized according to statins. The primary endpoint was mortality;it was assessed twice: in hospital and 3 months after discharge. The secondary outcome was the rate of symptomatic intracerebral hemorrhage. Of the 542 stroke patients examined(mean age 72 ± 13 years;51% women, mean National Institutes of Health Stroke Scale(NIHSS) score 11), 138 patients(25.5%) had been pretreated with statin, while in 190 patients(35.1%) statin therapy was initiated during their stay in hospital, whereas 193(35.6%) never received statins. Patients pre-treated with statin were older and more frequently had previous illnesses(arterial hypertension, diabetes mellitus and previous cerebral infarctions), but were comparably similarly affected by the stroke(NIHSS 11 vs. 11;P = 0.76) compared to patients who were not on statin treatment at the time of cerebral infarction. Patients pretreated with statin did not differ in 3-month mortality from those newly treated to a statin(7.6% vs. 8%;P = 0.9). Interestingly, the group of patients pretreated with statin showed a lower rate of in hospital mortality(6.6% vs. 17.0;P = 0.005) and 3-month mortality(10.7% vs. 23.7%;P = 0.005) than the group of patients who had no statin treatment at all. The same effect was seen for patients newly adjusted to a statin during the hospital stay compared to patients who did not receive statins(3-month mortality: 7.1% vs. 23.7%;P < 0.001). With a good functional outcome(mRS ≤ 2), 60% of patients were discharged, the majority(69.6%;P < 0.001) of whom received a statin at discharge. The rate of symptomatic intracerebral hemorrhages in the course of cranial computed tomography was independent of whether the patients were pretreated with a statin or not(8.8% vs. 8.7%, P = 0.96). Pre-treatment with statin as well as new adjustment could reveal positive effect on prognosis of intravenous thrombolyzed stroke patients. Further investigations are required. The study was approved by the Ethic Committee of the University of Lübeck(approval No. 4-147).

Addition of statins to the standard treatment in patients with cirrhosis:Safety and efficacy

This review summarizes the safety and efficacy of statins in patients with cirrhosis.Due to concerns about the safety of statins in patients with impaired liver function,they have recently been investigated as a potential treatment option in cirrhosis.The most clinically significant adverse event is statin-related myopathy,and this may be related to the high serum statin concentrations in the setting of severely impaired liver function.Rhabdomyolysis is the most serious and potentially life-threatening manifestation.It has recently been demonstrated that the recommended dose of simvastatin in patients with decompensated cirrhosis would be 20 mg/d because higher values,such as 40 mg/d,are associated with many adverse events,especially muscle injury.Likewise,simvastatin should not be administered to patients with Model for End-stage Liver Disease score>12 and/or Child-Pugh class C because of the high risk of severe muscle injury.Due to the pleiotropic effects,the focus on statins has shifted from being considered harmful to something useful.Through these effects,statins could prevent liver-related morbidity and mortality in cirrhotic patients.Observational studies in large populations of patients with cirrhosis have shown that treatment with statins to decrease high cholesterol levels was associated with a reduced risk of hepatic decompensation,hepatocellular carcinoma development and death.The few randomized controlled trials in patients with cirrhosis and portal hypertension showed that statins lower portal pressure,quite likely through a reduction in hepatic resistance.Another large randomized controlled trial in patients with variceal bleeding showed that simvastatin in addition to standard of care did not prevent rebleeding but improved survival rate.Despite these encouraging outcomes,the quality of the evidence regarding the use of statins is low or very low due to the observational characteristics of most of the studies involved.Therefore,it is advisable to perform further randomized controlled trials on a large series of patients with hard clinical endpoints,using different statin types and varying doses.The objectives would be to prevent liver-related morbidity and mortality rather than treating cirrhosis complications to take additional information that makes it possible to add statins to the standard of care of these patients.

Endothelial progenitor cells:Exploring the pleiotropic effects of statins

Statins have become a cornerstone of risk modification for ischaemic heart disease patients. A number of studies have shown that they are effective and safe. However studies have observed an early benefit in terms of a reduction in recurrent infarct and or death after a myocardial infarction,prior to any significant change in lipid profile. Therefore,pleiotropic mechanisms,other than lowering lipid profile alone,must account for this effect. One such proposed pleiotropic mechanism is the ability of statins to augment both number and function of endothelial progenitor cells. The ability to augment repair and maintenance of a functioning endothelium may have profound beneficial effect on vascular repair and potentially a positive impact on clinical outcomes in patients with cardiovascular disease. The following literature review will discuss issues surrounding endothelial progenitor cell(EPC) identification,role in vascular repair,factors affecting EPC numbers,the role of statins in current medical practice and their effects on EPC number.

Pleiotropic effects of statins in the diseases of the liver

Statins are a class of molecules that inhibit HMG Co A reductase. They are usually prescribed as a lipid lowering medication. However, there is accumulating evidence that statins have multiple secondary effects both related and unrelated to their lipid-lowering effect. This narrative review of the literature aims to provide the reader with information from clinical studies related to the effect of statin and statins' potential use in patients with liver diseases. In patients with advanced liver disease due to any etiology, statins exhibit an antifibrotic effect possibly through the prevention of hepatic sinusoidal microthrombosis. Two randomized controlled trials confirmed that statins decrease hepatic vein pressure gradient in patients with portal hypertension and improve the survival of patients after variceal bleeding. Lower rates of infections were observed in patients with cirrhosis who received statin treatment. Statins decrease the risk of hepatocellular carcinoma(HCC) in patients with advanced liver disease in general but particularly in patients with chronic hepatitis B and C. Statins in patients with chronic hepatitis C likely increase the virological response to the treatment with pegylated interferon and ribavirin and have the potential to decrease the rate of fibrosis. Finally, data from randomized controlled trials also confirmed that the addition of statin prolongs the survival of patients with advanced HCC even more than sorafenib. Statins are a very promising group of drugs especially in patients with liver disease, where therapeutic options can often be limited. Some indications, such as the prevention of re-bleeding from esophageal varices and the palliative treatment of HCC have been proven through randomized controlled trials, while additional indications still need to be confirmed through prospective studies.

Neuroprotective effects of statins against amyloid β-induced neurotoxicity

A growing body of evidence suggests that disruption of the homeostasis of lipid metabolism affects the pathogenesis of Alzheimer＇s disease （AD）. In particular, dysregulation of cholesterol homeostasis in the brain has been reported to considerably increase the risk of developing AD. Thus, dysregulation of lipid homeostasis may increase the amyloid β （Aβ） levels by affecting amyloid precursor protein （APP） cleavage, which is the most important risk factor involved in the pathogenesis of AD. Previous research demonstrated that Aβ can trigger neuronal insulin resistance, which plays an important role in response to Aβ-induced neurotoxicity in AD. Epidemiological studies also suggested that statin use is associated with a decreased incidence of AD. Therefore, statins are believed to be a good candidate for conferring neuropro- tective effects against AD. Statins may play a beneficial role in reducing A^-induced neurotoxicity. Their effect involves a putative mechanism beyond its cholesterol-lowering effects in preventing A[3-induced neurotoxicity. However, the underlying molecular mechanisms of the protective effect of statins have not been clearly determined in Aβ-induced neurotoxicity. Given that statins may provide benefits beyond the inhibition of 3-hydroxy-3-methylglutaryl coenzyme A （HMG-CoA） reductase, these drugs may also improve the brain. Thus, statins may have beneficial effects on impaired insulin signaling by activating AMP-activated protein kinase （AMPK） in neuronal cells. They play a potential therapeutic role in targeting Aβ-mediated neurotoxicity.

Statins redux:A re-assessment of how statins lower plasma cholesterol

Obesity associated dyslipidemia and its negative effects on the heart and blood vessels have emerged as a major healthcare challenge around the globe. The use of statins, potent inhibitors of hydroxyl-methyl glutaryl (HMG) Co-A reductase, a rate-limiting enzyme in cholesterol biosynthesis, has significantly reduced the rates of cardiovascular and general mortality in patients with coronary artery disease. How statins lower plasma cholesterol levels presents a mechanistic conundrum since persistent exposure to these drugs in vitro or in vivo is known to induce overexpression of the HMG Co-A reductase gene and protein. In an attempt to solve this mechanistic puzzle, Schonewille et al, studied detailed metabolic parameters of cholesterol synthesis, inter-organ flux and excretion in mice treated with 3 common statins, rosuvastatin, atorvastatin or lovastatin, each with its unique pharmacokinetics. From the measurements of the rates of heavy water (D2O) and [13C]-acetate incorporation into lipids, the authors calculated the rates of whole body and organ-specific cholesterol synthesis in control and statin-treated mice. These analyses revealed dramatic enhancement in the rates of hepatic cholesterol biosynthesis in statin-treated mice that concomitantly elicited lower levels of cholesterol in their plasma. The authors have provided strong evidence to indicate that statin treatment in mice led to induction of compensatory metabolic pathways that apparently mitigated an excessive accumulation of cholesterol in the body. It was noted however that changes in cholesterol metabolism induced by 3 statins were not identical. While sustained delivery of all 3 statins led to enhanced rates of biliary excretion of cholesterol and its fecal elimination, only atorvastatin treated mice elicited enhanced trans-intestinal cholesterol excretion. Thus, blockade of HMGCR by statins in mice was associated with profound metabolic adaptations that reset their cholesterol homeostasis. The findings of Schonewille et al, deserve to be corroborated and extended in patients in order to more effectively utilize these important cholesterol-lowering drugs in the clinic.

Real world effectiveness of PCSK-9 inhibitors combined with statins versus statins-based therapy among patients with very high risk of atherosclerotic cardiovascular disease in China(RWE-PCSK study)

BACKGROUND The efficacy and safety of proprotein convertase subtilisin/kexin type 9(PCSK-9) inhibitors were confirmed by several clinical trials, but its effectiveness in routine clinical practice in China has not been evaluated. This study aims to describe the real world effectiveness of PCSK-9 inhibitors combined with statins compared with statins-based therapy among patients with very high risk of atherosclerotic cardiovascular disease(ASCVD).METHODS This is a multi-center observational study, enrolled patients from 32 hospitals who underwent percutaneous coronary intervention(PCI) from January to June in 2019. There are 453 patients treated with PCSK-9 inhibitors combined with statins in PCSK-9 inhibitor group and 2,610 patients treated with statins-based lipid lowering therapies in statins-based group. The lipid control rate and incidence of major adverse cardiovascular events(MACE) over six months were compared between two groups.A propensity score-matched(PSM) analysis was used to balance two groups on confounding factors. Survival analysis using Kaplan-Meier methods was applied for MACE.RESULTS In a total of 3,063 patients, 89.91% of patients had received moderate or high-intensity statins-based therapy before PCI, but only 9.47% of patients had low-density lipoprotein cholesterol(LDL-C) levels below 1.4 mmol/L at baseline. In the PSM selected patients, LDL-C level was reduced by 42.57% in PCSK-9 inhibitor group and 30.81%(P < 0.001) in statins-based group after six months. The proportion of LDL-C ≤ 1.0 mmol/L increased from 5.29% to 29.26% in PCSK-9 inhibitor group and 0.23% to 6.11% in statins-based group, and the proportion of LDL-C ≤ 1.4 mmol/L increased from 10.36% to 47.69% in PCSK-9 inhibitor group and 2.99% to 18.43% in statins-based group(P < 0.001 for both). There was no significant difference between PCSK-9 inhibitor and statins-based treatment in reducing the risk of MACE(hazard ratio = 2.52, 95% CI: 0.49-12.97, P = 0.250).CONCLUSIONS In the real world, PCSK-9 inhibitors combined with statins could significantly reduce LDL-C levels among patients with very high risk of ASCVD in China. The long-term clinical benefits for patients received PCSK-9 inhibitor to reduce the risk of MACE is still unclear and requires further study.

Treatment of dyslipidemia in chronic kidney disease: Effectiveness and safety of statins

Several cardiovascular(CV)risk factors may explain the high rate of CV death among patients with chronic kidney disease(CKD).Among them both traditional and uremia-related risk factors are implicated and,moreover,the presence of kidney disease represents"per se"a multiplier of CV risk.Plasma lipid and lipoprotein profiles are changed in quantitative,but above all in qualitative,structural,and functional ways,and lipoprotein metabolism is influenced by the progressive loss of renal function.Statin therapy significantly reduces cholesterol synthesis and both CV morbidity and mortality either directly,by reducing the lipid profile,or via pleiotropic effects;it is supposed to be able to reduce both the progression of CKD and also proteinuria.These observations derive from a post-hoc analysis of large trials conducted in the general population,but not in CKD patients.However,the recently published SHARP trial,including over 9200 patients,either on dialysis or pre-dialysis,showed that simvastatin plus ezetimibe,compared with placebo,was associated with a significant low-density lipoprotein cholesterol reduction and a 17%reduction in major atherosclerotic events.However,no benefit was observed in overall survival nor in preserving renal function in patients treated.These re-cent data reinforce the conviction among nephrologists to consider their patients at high CV risk and that lipid lowering drugs such as statins may represent an important tool in reducing atheromatous coronary disease which,however,represents only a third of CV deaths in patients with CKD.Therefore,statins have no protective effect among the remaining two-thirds of patients who suffer from sudden cardiac death due to arrhythmia or heart failure,prevalent among CKD patients.The safety of statins is demonstrated in CKD by several trials and recently confirmed by the largest SHARP trial,in terms of no increase in cancer incidence,muscle pain,creatine kinase levels,severe rhabdomyolysis,hepatitis,gallstones and pancreatitis;thus confirming the handiness of statins in CKD patients.Here we will review the latest data available concerning the effectiveness and safety of statin therapy in CKD patients.

The role of statins in erectile dysfunction： a systematic review and meta-analysis

To evaluate the effect of statins for erectile dysfunction （ED）, a systematic review of the literature was conducted in the Cochrane Library, Embase and PubMed from the inception of each database to June 2013. Only randomized controlled trials （RCTs） comparing treatment for ED with statins were identified. Placebo RCTs with the International Index of Erectile Function （IIEF） as the outcome measure were eligible for meta-analysis. A total of seven RCTs including two statins with a total of 586 patients strictly met our criteria for systematic review and five of them qualified for the meta-analysis. A meta-analysis using a random effects model showed that statins were associated with a significant increase in IIEF-5 scores （mean difference （MD）： 3.27; 95% confidential interval （CI）：1.51 to 5.02; P〈 0.01） and an overall improvement of lipid profiles including total cholesterol （MD： -1.08; 95% Ch -1.68 to -0.48; P 〈 0.01）, low-density lipoprotein （LDL） cholesterol （MD： -1.43; 95% Ch -2.07 to -0.79; P 〈 0.01）, high-density lipoprotein （HDL） cholesterol （MD： 0.24; 95% Ch 0.13 to 0.35; P〈 0.01） and triglycerides （TGs） （MD. -0.55; 95% Ch -0.61 to -0.48; P 〈 0.01）. In summary, our study revealed positive consequences of these lipid-lowering drugs on erectile function, especially for nonresponders to phosphodiesterase type 5 inhibitors （PDE51s）. However, it has been reported that statin therapy may reduce levels of testosterone and aggravate symptoms of ED. Therefore, larger, well-designed RCTs are needed to investigate the double-edged role of statins in the treatment of ED.

Do statins reduce hepatitis C RNA titers during routine clinical use?

AIM: To compare hepatitis C virus (HCV) titers in patients with chronic hepatitis C with and without exposure to 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins).METHODS: Medical records were reviewed for 6463 patients with documented HCV infection at a single center between March 2004 and September 2006. Patients with confi rmed viremia and meeting inclusion criteria were assigned to one of three groups: Group A (n = 50), dyslipidemic patients with statin usage during HCV RNA polymerase chain reaction (PCR) determination; Group B (n = 49), dyslipidemic patients with prior or future statin usage but not at the time of HCV RNA PCR determination; and Group C (n = 102), patients without statin usage during the study period. The primary analysis explored the effect of statin therapy on HCV viremia. Secondary analyses assessed class effect, dose response, and effect of other lipid-lowering therapies on HCV viral titers.RESULTS: Median HCV RNA titers did not signif icantly differ among the three groups (Group A: 4 550 000 IU/mL, Group B: 2 850 000 IU/mL, Group C: 3 055 000 IU/mL).For those subjects with longitudinal assessment of HCV viremia prior to and while on statins, there were no signif icant differences between pre- and post-HCV viral titers. Additionally, no differences in HCV titers were observed at any dose level of the most prescribed statin, simvastatin. However, hypertriglyceridemia independently correlated with HCV titers, and niacin exposure was associated with signif icantly lower viral titers (P < 0.05).CONCLUSION: There was no apparent effect of statins on HCV viral replication in this analysis. Further investigation is warranted to explore the possible antiviral properties of triglyceride-lowering agents and their potential role as adjuncts to standard HCV therapy.

Can statins reduce risk of lung cancer,especially among elderly people? A meta-analysis

Objective： As the most common cause of cancer mortality throughout the world, lung cancer has drawn people＇s attention on how to reduce the risk with chemopreventive ways. Many epidemiological studies have shown inconsistent effects of statins on lung cancer, but some observational studies have showed that statins had protective effect on lung cancer among elderly people. So we preformed this meta-analysis to find whether statins were chemopreventive. Methods： We searched MEDLINE, EMBASE and Web of Science databases from inception to September, 2013. A total of 23 studies were selected, including 15 observational studies and 8 randomized controlled trials （RCTs）. Both fixed and random-effects models were used to calculate pooled estimates in primary and sensitivity analyses. We used Q and 12 statistics to assess statistical heterogeneity, and evaluated publication bias by Begg＇s test and Egger＇s test. Results： No association between statins and lung cancer risk was identified either in the meta-analysis among RCTs [relative risk （RR）： 0.95, 95% confidence interval （95% CI）： 0.85-1.06] or observational studies （RR： 0.89, 95% CI： 0.77-1.04）. We also selected 6 observational studies that all researched on elderly people. The result of meta-analysis showed that there was still no protective effect between statins and lung cancer among elderly people （RR： 1.03, 95% CI： 0.96-1.11）. Conclusions： Our results did not support a protective effect of statins on the overall lung cancer risk and the lung cancer risk among elderly people. More well-designed RCTs are needed to enhance our understanding of the chemopreventive effect of statins on lung cancer.

Role of chemoprophylaxis with either NSAIDs or statins in patients with Barrett's esophagus

The incidence of esophageal adenocarcinoma,a poor prognosis neoplasia,has risen dramatically in recent decades.Barrett’s esophagus represents the best-known risk factor for esophageal adenocarcinoma development.Non-steroidal anti-inflammatory drugs through cyclooxygenase-2 inhibition and prostaglandin metabolism regulation could control cell proliferation,increase cell apoptosis and regulate the expression of growth and angiogenic factors.Statins can achieve equivalent effects through prenylation and subsequently control of cellular signaling cascades.At present,epidemiological studies are small and underpowered.Their data could not justify either medication as a chemo-preventive agent.Population based studies have shown a 43%reduction of the odds of developing an esophageal adenocarcinoma,leaving out or stating a 25%reduction in patients consuming non-aspirin nonsteroidal antiinflammatory drugs and a 50%reduction in those patients consuming aspirin.They have also stated a 19%reduction of esophageal cancer incidence when statins have been used.Observational studies have shown that non-steroidal anti-inflammatory drugs could reduce theadenocarcinoma incidence in patients with Barrett’s esophagus by 41%,while statins could reduce the risk by 43%.The cancer preventive effect has been enhanced in those patients taking a combination of non-steroidal anti-inflammatory drugs and statins(a 74%decrease).Observational data are equivocal concerning the efficacy of non-steroidal anti-inflammatory drug subclasses.Non-steroidal anti-inflammatory drugs clearly have substantial potential for toxicity,while statins are rather safe drugs.In conclusion,both non-steroidal anti-inflammatory drugs and statins are promising chemopreventive agents and deserve further exploration with interventional studies.In the meanwhile,their use is justified only in patients with cardiovascular disease.

Effect of statins use on the prevention of venous thromboembolism: a meta-analysis

Objective: To estimate the effect of statins use on the prevention of venous thromboembolism (VTE). Methods: We systematically searched MEDLINE (1980-June 2012), EMBASE (1980-June 2012), Google Scholar, Cochrane Library, and ISI Web of Science, manually reviewed references, and contacted experts. Case-control studies and cohort studies that compared any dose of statin with no statin or placebo are included. Data extraction and study quality evaluation were independently conducted in duplicate. Results: 12 studies including four cohort studies and eight case-control studies were identified and eligible for meta-analysis. Upon meta-analysis, statin use was associated with a statistically significant reduction in the odds of developing VTE (OR 0.91, 95% CI 0.86-0.96). Conclusion: This meta-analysis of current and available literature suggests that statins can reduce patient's risk of developing VTE. Due to the limitations of observational study, this conclusion should be considered with caution, and additionally, specifical well-designed trials are needed.

Statins and Breast Cancer: An Overview of the Current Situation

Statins [(3-hydroxy-3-methylglutaryl-coenzyme A reductase, HMG-CoA reductase, abbreviated HMGCR) inhibitors] inhibit cholesterol synthesis and are commonly used in the treatment and prevention of cardiovascular diseases. Preclinical and clinical studies have shown that the drug can be effective in several cancers including breast cancer which is the second most frequent cancer in the world and the commonest one among women. In breast cancer cell lines statins reduce proliferation, increase apoptosis, decrease invasion and sensitize them to radiation. Clinical trials in breast cancer patients have shown positive outcome in terms of decreased recurrence rate, decreased mortality and positive role as neoadjuvant agent. They may have a particular role in treatment-resistant cases like triple-negative or inflammatory breast cancer which have a poorer prognosis. There is also evidence of their potential use in metastatic bone disease from breast cancer. When statins inhibit 3-hydroxy-3-methylgutaryl CoA reductase which is the rate-limiting enzyme of the mevalonate pathway, the levels of mevalonate as well as its downstream products are decreased. Hence cancer growth is inhibited by reduced prenylation of CAAX proteins, N-Glycosylation of growth factor receptors and synthesis of membrane and steroid among others. Also statins are relatively cheap and can contribute to decrease the high cost of cancer treatment. However studies till now have not shown any association with decreased breast cancer incidence. In addition there are doubts regarding safety of statins when used over a prolonged period of time. Although statins are relatively safe with myotoxicity and hepatotoxicity being their major side effects, evidence regarding issues like drug interactions with anti-cancer drugs is lacking.

Statins for primary cardiovascular prevention in the elderly

The elderly population is increasing worldwide, with subjects 〉 65 years of age constituting the fastest-growing age group. Furthermore, the elderly face the greatest risk and burden of cardiovascular disease mortality and morbidity. Although elderly patients, particularly those older 〉 75, have not been well represented in randomized clinical trials evaluating lipid-lowering therapy, the available evidence supporting the use of statin therapy in primary prevention in older individuals is derived mainly from subgroup analyses and post-hoc data. On the other hand, elderly patients often have multiple co-morbidities that require a high number of concurrent medications; this may increase the risk for drug-drug interactions, thereby reducing the potential benefits of statin therapy. The aim of this review was to present the relevant literature regarding statin use in the elderly for theft primary cardiovascular disease, with the associated risks and benefits of treatment.

Is there evidence for statins in the treatment of aortic valve stenosis?

Research revealed that the pathogenesis of aortic stenosis(AS) not merely comprises of a mechanical wear and tear process yet that active biological processes, similar to those of coronary artery disease are involved, a promising role for statins in disease-modifying therapy was suggested. However, recently, many prospective studies could not observe decreased progression nor regression of the disease. Here, we review the current knowledge on the pathomechanisms of AS and its similarities and differences with atherosclerosis. Moreover, we discuss whether there is still a place for statins in the treatment of particular AS patient subgroups.

Statins, diabetes, obesity, nonalcoholic fatty liver disease, and hepatocellular carcinoma

To the Editor:We read with great interest the recent article by Chang et al.[1].By analyzing the data of 1350 cirrhotic patients,the authors concluded that statin significantly decreases the risk of decompensation of cirrhosis,mortality and hepatocellular carcinoma(HCC)incidence,and these effects are dose dependent.