Alder Hey Hospital, Liverpool and Harefield Hospital, Middlesex, United Kingdom

Clinical studies have clearly demonstrated that reduction of plasma cholesterol, particularly cholesterol transported in low-density lipoproteins (LDL), lowers the risk of cardiovascular events for both primary and secondary prevention. Significant cholesterol reductions may be produced by the 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors, commonly named as statins. It is implicit that the beneficial effect of statins on coronary events is related to their hypocholesterolemic properties. However, the immediate product of HMG-CoA reductase, mevalonic acid, is not only the substrate for cholesterol synthesis but also the precursor of isoprenoids and other metabolites involved in different cellular pathways of atherogenesis and thrombosis.¹ As a consequence, statins have the potential to result in pleiotropic effects, which are independent of cholesterol reduction and may explain many of the direct antiatherosclerotic and antithrombotic properties of these compounds.^1-6 

Better understanding of the various pleiotropic effects of statins has prompted a new surge of interest in their use to treat and/or prevent a wide range of chronic and lifethreatening disorders. Among the disorders targeted for statin therapy are ventricular arrhythmias, peripheral arterial disease (PDA), idiopathic dilated cardiomyopathy, cancer, osteoporosis, and even depression. Their effectiveness in treating these and other disorders suggest that the benefits of statins may not be limited to cholesterol lowering and that indications for the drugs’ use may extend to patient populations not considered traditional candidates for this therapy.

Recently, it has been proposed that statins reduce the incidence of arrhythmias in patients with atherosclerotic Loop-the-loop.pdf disease.^7-9 According to a substudy of the Antiarrhythmic Versus Implantable Defibrillators (AVID) trial, in patients with atherosclerotic Loop-the-loop.pdf disease treated for ventricular tachycardia/ventricular fibrillation (VT/VF) with implantable cardioverter defibrillators (ICDs), the use of statins and other lipid-lowering agents (e.g. fibric acid derivatives and bile acid resins) significantly reduced the probability of VT/VF recurrence.⁷ In addition, lipid lowering therapy was associated with significant reduction in both cardiac mortality and all-cause death in a larger cohort of patients treated with either ICDs or antiarrhythmic drug therapy. 

A recent study⁸ suggests that the antiinflammatory effects of statins can reduce the recurrence of atrial fibrillation (AF) in patients who undergo successful cardioversion. This study was based on the hypothesis that inflammation, evidenced by high levels of C-reactive protein, can induce AF and promote its persistence. Siu et al.⁸ found that after 2 years of follow-up, patients treated with statin therapy for high cholesterol had a significantly lower AF recurrence rate than the patients not on lipid lowering therapy (40% v. 84%, respectively; p=0.007). The benefits observed in patients on statin were observed early, and persisted throughout the follow-up period. 

The results of the above studies do not necessarily confirm a direct antiarrhythmic effect associated with statin therapy. However, both groups of authors attribute their findings to the slowing of atherosclerotic plaques, which lowers the risk of plaque rupture, “thereby preventing the ischemia-induced electrophysiologic effects that predispose to VT/VF.” Further, as AF in patients with coronary artery disease (CAD) is proposed to be caused by atrial ischemia,¹⁰ it is possible that in these patients, the beneficial effect of statin therapy in preventing AF may be mediated through its effects on the progression of CAD.¹¹ Also, in addition to this indirect antiarrhythmic effect, statins may exhibit direct antiarrhythmic effects by modulating the fatty acid composition and physiochemical properties of cell membranes, with resultant alterations in transmembrane ion channel properties.^12,13 Moreover, statins have multiple pleiotropic effects (independent of lipid lowering).¹¹ They decrease the messenger ribonucleic acid (mRNA) levels for interleukin-8, monocyte chemoattractant protein-1, plasminogen activator inhibitor-1, endothelin-1 and increase the levels of thrombomodulin and endothelial nitric oxide synthase (eNOS).¹⁴ Statins also on G-proteins (small GTPases, Rho, Rac, Cdc 42). This leads to reduced eNOS mRNA degradation and higher eNOS protein levels and activity.¹⁴ In addition, by scavenging free radicals and reactive oxygen species statins prevent nitric oxide degradation and preserve endothelial function.¹⁴All these mechanisms result in improved endothelial function leading to coronary vasodilation, increased coronary blood flow and less myocardial ischemia with reduced likelihood of AF.

According to a recent randomized, double-blind, paralleldesign by Mohler et al.¹⁵,atorvastatin achieved greater improvement in pain-free walking time and participation in physical activity in patients with intermittent claudication than did inactive placebo.¹⁵ The authors assessed the effects of low- and high-dose atorvastatin on maximal walking time (MWT). They randomised 354 patients with intermittent claudication caused by PAD to 1 of 3 regimens: atorvastatin 10 mg/day, atorvastatin 80 mg/day, or placebo for 1 year. 

After 1 year of atorvastatin therapy, MWT did not change significantly. However, the time in which patients could walk without pain improved by 63% (81±15 sec) in patients receiving atorvastatin 80 mg/day, whereas the placebo group exhibited only 38% improvement (39±8 sec), which was similar to the group receiving atorvastatin 10 mg/day. In post hoc analyses performed to determine whether smoking status or LDL-cholesterol (LDL-c) influenced the results, investigators found that neither variable had a response in overall MWT or pain-free walking time. They noted, however, that there was a slight trend toward greater improvement in patients with LDL-c levels >123 mg/dl. According to investigators, such improvements in pain-free walking time are consistent with those achieved with other approved pharmacotherapies. 

Physical activity questionnaires reported significant improvement in physical activity with both doses of atorvastatin compared with placebo, but no significant differences were seen between the groups on the qualityof- life questionnaires. Although not adequately powered to assess the effect of atorvastatin on vascular events in patients with PAD, fewer vascular events occurred in the atorvastatin group versus placebo (1.3% v. 7.9%). Mohler et al.¹⁵ attributed their findings to several potential mechanisms, including a reduction in plaque size associated with statins, which may improve blood flow in the large arteries of the legs, and an increase in endothelium-dependent vasodilation. 

In another randomized controlled trial, McDermott et al.¹⁶ demonstrated that, in persons with and without PAD, statin use is associated with superior leg functioning compared with no statin use, independent of cholesterol levels and other potential confounders. Their findings support the findings of the Scandinavian Simvastatin Survival Study (4S) which concluded that subjects randomized to simvastatin had a 38% reduction in new or worsening claudication compared with subjects randomized to placebo over a median follow-up of 5.4 years (p=0.008).¹⁷ 

The beneficial effects of statins in PAD may be attributed to increased production of nitric oxide in the endothelium, which has local vasodilatory properties in addition to antithrombogenic, antiproliferative, and leukocyteadhesion inhibiting effects.^18,19 Other mechanisms by which statins favorably influence lower limb ischemia include enhancement of endothelium-dependent relaxation, ²⁰ inhibition of platelet function,²¹ and inhibition of endothelin- 1, a potent vasoconstrictor and mitogen.²² Reduction of vascular inflammation may be an additional mechanism by which statins are associated with better functioning in patients with PAD. Statin-associated reduction of inflammatory cytokines could improve blood flow, regress atherosclerosis, or improve end-organ function (such as skeletal muscle).²³

The antiinflammatory properties of statins may confer greater benefit than just reducing the risk of AF. The results of a recently published randomized controlled trial by Node et al.²⁴ suggest that the antiinflammatory effects of statin therapy result in improved neurohormonal imbalance and cardiac function and may benefit patients with symptomatic, non-ischemic dilated cardiomyopathy. The study involved 63 patients (average age, 54 years) with symptomatic non-ischemic dilated cardiomyopathy [New York Heart Association (NYHA) class II-IV; left ventricular ejection fraction (LVEF) <40%] who were randomized to either simvastatin (5 mg/day, increased to 10 mg/day at 4 weeks; n=24) or placebo (n=27). Patients with a history or evidence of ischemic Loop-the-loop.pdf disease were excluded from the study.

Over the course of 14 weeks of treatment, the use of simvastatin was associated with significantly improved functional capacity compared with placebo (39.1% v. 16% of patients had an improved functional status; p<0.01). Reductions in NYHA class also translated into significant improvements in LVEF from baseline to follow-up (34%±3% to 41%±4%; p <0.05), which were predominantly due to a decrease in LV end-systolic volume. Investigators reported that there were positive correlations between changes in ejection fraction and reductions in circulating inflammatory cytokines, suggesting that “statins may improve cardiac function, in part, by modulating the inflammatory state.” 

These findings, according to investigators, indicate that statins may be therapeutically useful in patients with nonischemic congestive Loop-the-loop.pdf failure in whom statins may not otherwise be indicated.²⁴

Clinically, there is emerging evidence that statins have beneficial effects in patients with multiple sclerosis, Alzheimer’s disease, and ischemic stroke.²⁵ Recent studies indicate that statins have immunomodulatory properties.^25,26 Statins decrease the migration of leukocytes into the central nervous system, inhibit major histocompatibility complex class II and costimulatory signals required for activation of proinflammatory T cells, induce a T(H)2 phenotype in T cells, and decrease the expression of inflammatory mediators in the central nervous system, including nitric oxide and tumor necrosis factor alpha.²⁵ These immunomodulatory effects can either inhibit or reverse chronic and relapsing experimental autoimmune encephalomyelitis, a model of multiple sclerosis.^25,27,28 

Data from epidemiologic trials indicate that statins may have some protective effect against the development of Alzheimer’s disease.²⁹ However, at present, available evidence does not lend credence to the use of statins in the general non-demented population without hyperlipidemia. 

Challenging the premise that the use of statins increases the risk of depression, two recent studies have associated long-term use of statin with a reduced risk of depression in patients with CAD.^30,31 

Young-Xu et al.³⁰ assessed the psychological well-being of 590 patients with underlying CAD who were classified into groups according to frequency of statin use (continuous statin use (n=140), intermittent statin use (n=219), or no use of any cholesterol-lowering drugs (n=231).³⁰ The mean age at entry for the 3 groups was 64, 66, and 70 years, respectively. At study enrolment, the researchers recorded the patients’ sociodemographic, psychological, and clinical status. Patients completed annual follow-up questionnaires, including the Kellner Symptom Questionnaire, which is used to measure depression, anxiety, and hostility. 

After an average follow-up of 4 years (maximum followup, 7 years), comparison of psychometric scores between patients using statins continuously and patients not using cholesterol-lowering drugs showed that statin use was associated with lower risk of abnormal scores for depression, anxiety, and hostility. Investigators also noted that intermittent statin use was not associated with the same beneficial effects.In addition, the risk of mental illness continued to decline with each additional year of treatment. The progressive reduction observed in continuous statin users over the 7-year study period also seemed to be independent of the cholesterol-lowering effect of the drug or baseline cholesterol levels. Although it requires additional study, Young-Xu and colleagues hypothesize that the “penetration of the blood-brainbarrier by the lipophilic statins accounts for most of the observed impact on psychological well-being.”³⁰ 

The findings of another study yielded results similar to those reported by Young-Xu and colleagues. Yang and colleagues³¹ found that statin use was associated with reduced risk of depression, especially in long-term users and in patients with pre-existing CAD.³¹ These investigators identified patients with newly treated depression, who needed either hospitalization or referral, and patients with first-recorded diagnosis of suicidal behavior. They found that neither lipid-lowering therapy (LLT) nor untreated hyperlipidemia was associated with an increased risk of depression. In fact, the risk of depression actually decreased with statin therapy; risk of depression was 60% less in individuals using statins than in hyperlipidemic individuals not using LLT. The use of non-statin LLT yielded a similar, but weaker effect. In addition, the risk of suicidal behavior in individuals using statins did not differ significantly from the risk in other groups, according to the authors. 

The investigators observed that use of statin was inversely associated with depression but such an association was not likely to be directly causal because there is no known pharmacological mechanism for this effect. However, they suggested that a possible explanation could be an indirect effect of statins on the risk of depression through improved quality of life due to decreased incidence of cardiovascular events or more health consciousness and compliance among patients having longer lipid-lowering treatment.³¹ 

Statins and Cancer

Statins have been shown to inhibit proliferation and to induce apoptosis in a variety of tumor cells.³² They have also been found to display antitumor effects against melanoma, mammary carcinoma, pancreatic adenocarcinoma, fibrosarcoma, glioma, neuroblastoma, and lymphoma in animal tumor models resulting in retardation of tumor growth, and/or inhibition of the metastatic process.^32-34 In pre-clinical studies statins have also been demonstrated to potentiate the antitumor effects of some cytokines and chemotherapeutics.³² The molecular mechanisms underlying antitumor activity of statins have not been fully elucidated but interference with the function of Ras and Rho family GTPases, inhibition of the activity of certain cyclin-dependent kinases (CDK), and activation of CDK inhibitors, all seem to participate in this activity.³² phase I trials of statins in humans have demonstrated myotoxicity as their main dose-limiting toxicity, and phase II trials in various tumor types are ongoing to evaluate their efficacy.³⁵ 

Future directions in the development of the statins as anticancer agents include combinations with chemotherapeutic or other molecular-targeted agents, combinations with radiotherapy, maintenance therapy in minimal disease status, and as chemopreventive therapy.

Statins have been linked to a reduction in the incidence of fractures in elderly patients.^36,37 In a recent study, Bauer et al.³⁷ analyzed statin use and fracture rates in 4 large prospective studies of older women taking statin therapy for hyperlipidemia (the Study of Osteoporotic Fractures, the Fracture Intervention Trial, the Heart and Estrogen/ Progestin Replacement Study, and the Rotterdam Study). They also conducted 2 cumulative meta-analyses consisting of data from 8 observational studies and 2 clinical trials that reported statin use and documented fractures.³⁷ 

The investigators found interesting, yet somewhat conflicting results. After adjusting for multiple factors, such as age, body mass index, and estrogen use among statin users in each of the 4 prospective studies, a trend toward fewer hip and non-spine fractures was observed. Similar reductions in risk were reported in the meta-analysis of observational studies; statin use was associated with an estimated 57% reduction in hip fracture, and an estimated 31% reduction in non-spine fracture. However, these proposed protective effects of statins were not observed in the meta-analysis of clinical trials. Based on their findings, investigators called for controlled trials specifically designed  to test the effect of statins on skeletal metabolism and fracture.³⁷

Age-related maculopathy (ARM) is the leading cause of irreversible vision loss among older adults in the Western world.³⁸ Based on the presence of similar risk factors, some suggest that the pathophysiologies of ARM and cardiovascular disease have similar causal pathways and, therefore, both groups of patients may benefit from the same drug treatment.³⁹ Two recent studies assessing the impact of statin therapy in patients with ARM draw opposing conclusions. 

Results from a nested case-control study suggest that statin use is associated with a significant risk reduction of ARM.³⁹ In their study, McGwin and associates³⁹ identified 550 incident cases of ARM and compared them to 5500 age-matched patients (controls). Compared with controls, ARM patients had a significantly higher incidence of diabetes, hypertension, cardiovascular and cerebrovascular disease; however, there were no differences between the 2 groups with respect to lipid metabolism disorders or arterial disease. Investigators found that 70% of ARM patients were less likely to have received and filled a statin prescription relative to controls, regardless of whether statin use was current or occurred more than 6 months before the ARM diagnosis. In addition, the results remained consistent after adjusting for other medical conditions, such as those listed above. Similar findings were noted when assessing nonstatin LLT. 

Compared with non-statin LLT, the use of only statins was associated with a significant risk reduction; the same results held true when statin and non-statin users were combined, but there was no significant association for nonstatin users alone. Interestingly, with the exception of cardiovascular and cerebrovascular disease, the riskreduction effects of statin therapy on ARM were stronger in the presence of an existing medical condition than in its absence. However, the investigators cautioned against presuming this association to represent a cause-and-effect relation; future research will also be required to address this issue. On the other hand, an earlier study conducted by van Leeuwen and colleagues⁴⁰ concluded that the use of LLT did not change a patient’s risk of developing ARM. Their conclusions were based on data collected from 4822 patients who were followed at mean intervals of 2.0 and 6.5 years. Of these patients, 457 used cholesterol-lowering drugs for >1 day, and 419 incident cases of ARM were identified throughout the course of the study. 

Compared with patients who had never used a cholesterol-lowering drug, the risk of ARM did not differ for those who had used cholesterol-lowering drugs at any time, be it for 1 month, 1-12 months, or > 1 year. Based on their findings the authors suggested that the lack of an association between LLT and ARM makes a protective effect of statins unlikely.

Statins are currently the most effective method to pharmacologically decrease total plasma cholesterol levels. Apart from the well known LDL and cholesterol lowering effect, statins have been postulated to exert beneficial effects due to so-called ‘pleiotropic’ or ‘non-lipid’ effects. However at present although the clinical implications of these beneficial ‘non-lipid’ effects seem promising yet properly designed, large, multi-center, prospective, controlled trials are needed to validate the use of statins for indications other than primary and secondary prevention of vascular diseases.

Dr Shahzad G Raja, 
Alder Hey Hospital, 
Liverpool L12 2AP, 
UK. 
e-mail: drrajashahzad@hotmail.com 

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