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.

Statins decrease the risk of hepatocellular carcinoma in metabolic dysfunction-associated steatotic liver disease:A systematic review and meta-analysis

BACKGROUND Metabolic dysfunction-associated steatotic liver disease(MASLD)is a leading cause of chronic liver disease with a significant risk of developing hepatocellular carcinoma(HCC).Recent clinical evidence indicates the potential benefits of statins in cancer chemoprevention and therapeutics.However,it is still unclear if these drugs can lower the specific risk of HCC among patients with MASLD.AIM To investigate the impact of statin use on the risk of HCC development in patients with MASLD.METHODS A systematic review and meta-analysis of all the studies was performed that measured the effect of statin use on HCC occurrence in patients with MASLD.The difference in HCC risk between statin users and non-users was calculated among MASLD patients.We also evaluated the risk difference between lipophilic versus hydrophilic statins and the effect of cumulative dose on HCC risk reduction.RESULTS A total of four studies consisting of 291684 patients were included.MASLD patients on statin therapy had a 60%lower pooled risk of developing HCC compared to the non-statin group[relative risk(RR)=0.40,95%CI:0.31-0.53,I2=16.5%].Patients taking lipophilic statins had a reduced risk of HCC(RR=0.42,95%CI:0.28-0.64),whereas those on hydrophilic statins had not shown the risk reduction(RR=0.57,95%CI:0.27-1.20).The higher(>600)cumulative defined daily doses(cDDD)had a 70%reduced risk of HCC(RR=0.30,95%CI:0.21-0.43).There was a 29%(RR=0.71,95%CI:0.55-0.91)and 43%(RR=0.57,95%CI:0.40-0.82)decreased risk in patients receiving 300-599 cDDD and 30-299 cDDD,respectively.CONCLUSION Statin use lowers the risk of HCC in patients with MASLD.The higher cDDD and lipophilicity of statins correlate with the HCC risk reduction.

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.

Atorvastatin ameliorated myocardial fibrosis by inhibiting oxidative stress and modulating macrophage polarization in diabetic cardiomyopathy

In this editorial,we commented on the article published in the recent issue of the World Journal of Diabetes.Diabetic cardiomyopathy(DCM)is characterized by myocardial fibrosis,ventricular hypertrophy and diastolic dysfunction in diabetic patients,which can cause heart failure and threaten the life of patients.The pathogenesis of DCM has not been fully clarified,and it may involve oxidative stress,inflammatory stimulation,apoptosis,and autophagy.There is lack of effective therapies for DCM in the clinical practice.Statins have been widely used in the clinical practice for years mainly to reduce cholesterol and stabilize arterial plaques,and exhibit definite cardiovascular protective effects.Studies have shown that statins also have anti-inflammatory and antioxidant effects.We were particularly concerned about the recent findings that atorvastatin alleviated myocardial fibrosis in db/db mice by regulating the antioxidant stress and antiinflammatory effects of macrophage polarization on diabetic myocardium,and thereby improving DCM.

Statin, aspirin and metformin use and risk of hepatocellular carcinoma related outcomes following liver transplantation: A retrospective study

BACKGROUND Liver transplantation(LT)is a potentially curative therapy for patients with hepatocellular carcinoma(HCC).HCC-recurrence following LT is associated with reduced survival.There is increasing interest in chemoprophylaxis to improve HCC-related outcomes post-LT.AIM To investigate whether there is any benefit for the use of drugs with proposed chemoprophylactic properties against HCC,and patient outcomes following LT.METHODS This was a retrospective study of adult patients who received Deceased Donor LT for HCC from 2005-2022,from a single Australian centre.Drug use was defined as statin,aspirin or metformin therapy for≥29 days,within 24 months post-LT.A cox proportional-hazards model with time-dependent covariates was used for survival analysis.Outcome measures were the composite-endpoint of HCC-recurrence and all-cause mortality,HCC-recurrence and HCC-related mortality.Sensitivity analysis was performed to account for immortality time bias and statin dosing.RESULTS Three hundred and five patients were included in this study,with 253(82.95%)males with a median age of 58.90 years.Aetiologies of liver disease were 150(49.18%)hepatitis C,73(23.93%)hepatitis B(HBV)and 33(10.82%)non-alcoholic fatty liver disease(NAFLD).56(18.36%)took statins,51(16.72%)aspirin and 50(16.39%)metformin.During a median follow-up time of 59.90 months,34(11.15%)developed HCC-recurrence,48(15.74%)died,17(5.57%)from HCC-related mortality.Statin,aspirin or metformin use was not associated with statistically significant differences in the composite endpoint of HCC-recurrence or all-cause mortality[hazard ratio(HR):1.16,95%CI:0.58-2.30;HR:1.21,95%CI:0.28-5.27;HR:0.61,95%CI:0.27-1.36],HCC-recurrence(HR:0.52,95%CI:0.20-1.35;HR:0.51,95%CI:0.14-1.93;HR 1.00,95%CI:0.37-2.72),or HCC-related mortality(HR:0.32,95%CI:0.033-3.09;HR:0.71,95%CI:0.14-3.73;HR:1.57,95%CI:0.61-4.04)respectively.Statin dosing was not associated with statist-ically significant differences in HCC-related outcomes.CONCLUSION Statin,metformin or aspirin use was not associated with improved HCC-related outcomes post-LT,in a largely historical cohort of Australian patients with a low proportion of NAFLD.Further prospective,multicentre studies are required to clarify any potential benefit of these drugs to improve HCC-related outcomes.

Prevention of hepatocellular carcinoma by correction of metabolic abnormalities: Role of statins and metformin

Hepatocellular carcinoma is the third leading cause of cancer-related deaths in the world. It is associated with an important mortality rate and the incidence is increasing. Patients showing metabolic syndrome seem to have higher incidence and mortality rates from hepatocellular carcinoma than healthy subjects, especially those with type 2 diabetes mellitus and obesity. Thus, metformin and statins, both to treat features of metabolic syndrome, have been proposed to decrease the risk of hepatocellular carcinoma. Otherwise, liver cancer is the result of a complex process which impairs several signaling cascades, such as RAS/RAF/mitogen-activated protein kinase kinase(MEK)/extracellularsignal-regulated kinase(ERK), phosphatidylinositol-4,5-bisphosphate 3-kinase(PI3K)/AKT/mammalian target of rapamycin(m TOR) and Wnt/β-catenin signaling. Metformin(through 5′-adenosine monophosphateactivated protein kinase pathway activation) and statins(through 3-hydroxy-3-methylglutaryl coenzyme A inhibition) show anti-tumoral properties modifying several steps of RAS/RAF/MEK/ERK, PI3K/AKT/m TOR and Wnt/β-catenin signaling cascades. On the other hand, metformin and statins have been found to reduce the risk of hepatocellular carcinoma up to 50% and 60%, respectively. Furthermore, both drugs have shown a dose-dependent protective effect. However, information about chemopreventive role of metformin and statins is mainly obtained of observational studies,which could not take into account some bias. In conclusion, given the rising of incidence of hepatocellular carcinoma and the important morbidity and mortality rates associated with this cancer, looking for chemopreventive strategies is an essential task. Randomized controlled trials are needed to determine the definite role of metformin and statins on the prevention of hepatocellular carcinoma.

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.

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.

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.

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.

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.

Non-steroidal anti-inflammatory drugs and statins in relation to colorectal cancer risk

AIM： To investigate the association between individual or combined use of non-steroidal anti-inflammatory drugs （NSAIDs） or statins and colorectal cancer risk.METHODS： In a population-based case-control study in women, we examined the association between NSAIDs and statin use and the risk of colorectal cancers. We further investigated whether the use of statins modifies the protective effect of NSAIDs. Female cases （n = 669）of colorectal cancer aged 50-74 years were identified from a storewide registry in Wisconsin during 1999-2001. Community control women （n = 1375） were randomly selected from lists of licensed drivers and Medicare beneficiaries. Medication use and risk factor information were gathered during a structured telephone interview. A multivariable logistic regression model was used to calculate odds ratio （OR） and 95% confidence interval （CI）.RESULTS： Overall, NSAIDs users had a 30% reduction in risk of colorectal cancer （95% CI： 0.56-0.88）. Statin use was not associated with colorectal cancer risk （OR = 1.17, 95% CI： 0.74-1.85）, regardless of structural type （lipophilic or hydrophilic）, duration of use, or recency. There was no evidence of an interaction between NSAIDs and statins and colorectal cancer risk （P-interaction = 0.28）.CONCLUSION： Although our results confirm the inverse association between NSAIDs use and colorectal cancer risk, they do not support a risk reduction in statin users, or an interaction effect of combined NSAIDs and statin use.

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).

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.

Statins and their role in acute pancreatitis: Case report and literature review

Statin induced pancreatitis has historically been considered a diagnosis of exclusion,with literature references typically in the form of case reports and observational studies. Recently,larger studies have challenged the correlations made by earlier case reports,and instead demonstrate a mild protective effect in statin users. We present a case report of likely statin induced pancreatitis in a 58-year-old male(which we have attributed to drug-drug interaction with resulting inhibition of hepatic cytochrome P450 enzymes) and have reviewed the apparent dichotomy in the available literature.

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.

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.

Pharmacological Effects of Statins Related to Gap Junction Modulation

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or “statins”, are widely using cholesterol-lowering drugs with pleiotropic pharmacological effects. In this review, we summarized the pharmacological effects of statins related to gap junction modulation. The main function of cellular gap junctions, which are composed of trans-membrane proteins named connexins (Cxs), is to mediate direct cell-to-cell communication through material exchange. Statins could rectify the disturbed expression, distribution, or phosphorylation of Cxs and thus modify the functions of gap junctions in a variety of tissues like the aorta, cardiomyocytes, or tumors. The effects of statins on Cxs and gap junctions were associated with their pharmacological activities against atherosclerosis, arrhythmias, and tumors. Despite some evidences suggested that the anti-inflammatory or HMG-CoA reductase inhibiting effects of statins may contribute in part to the modulation of Cxs and gap junctions, the detailed underlying mechanisms are largely unrevealed and merit further investigation. In addition, it is likely that the modulating effects of statins on gap junctions may also contribute to their pharmacological activities against some diabetic complications. Future studies of these issues will help to provide scientific evidences for the appropriate clinical application of statins.

The Ugly Side of Statins. Systemic Appraisal of the Contemporary Un-Known Unknowns

Cardio-vascular specialists have witnessed and actively participated in the revolutionary developments that have occurred in their field of specialization over the last few years. Cutting-edge technologies have led to dramatic improvements in life-expectancy and quality of life. An open-mind and pioneering attitude are necessary when exploring new frontiers to improve our patients’ health. However, naive indiscriminate acceptance of novel mainstream therapies is not always advisable and prudence is required in unearthing harmful, covert side effects. An objective review of contemporary vascular research was performed and industrial bias was sifted out for a fresh prospective on how to promote primary cardiovascular prevention with attainable lifestyle adjustments [1]. A comprehensive review of Pubmed, EM-BASE and Cochrane review databases was undertaken for articles relating to cardiovascular primary prevention and statin side effects with the aim of harmonising their roles within contemporary clinic practice. Particular attention was paid to large-scale randomised controlled trials on contemporary cardiovascular pharmacotherapies and their specific adverse effects on metabolic pathways which feature prominently in cardiovascular primary prevention and regenerative programmes. There is a categorical lack of clinical evidence to support the use of statin therapy in primary prevention. Not only is there a dearth of evidence for primary cardiovascular protection, there is ample evidence to show that statins actually augment cardiovascular risk in women, patients with Diabetes Mellitus and in the young. Furthermore statins are associated with triple the risk of coronary artery and aortic artery calcification. Cardiovascular primary prevention and regeneration programmes, through life style changes and abstaining from tobacco use have enhanced clinical efficacy and quality of life over any pharmaceutical or other conventional intervention.