Several actions of lipid lowering therapy like reduction in myocardial ischemia, improvement of autonomic function, changes in protein channel function and inhibition of cardiac remodelling make them prospective agents for the treatment of arrhythmias2223. Chronically administered pravastatin was shown to reduce the incidence of ischemia-induced ventricular tachyarrhythmias in experimental models 2425. Early use of pravastatin in patients with acute myocardial infarction (MI) reduced the incidence of in-hospital ventricular arrhythmias irrespective of the lipid levels 26. The Anti-arrhythmia Versus Implantable Defibrillators (AVID) Study showed that lipid lowering therapy decreased the recurrence rate of ventricular arrhythmias in patients implanted cardioverter-defibrillator 27.

Statins have also been shown to have a role in the treatment of atrial arrhythmias. Inflammatory changes have been shown in atrial biopsy specimens of patients with lone atrial fibrillation (AF) 28. Furthermore, serum levels of C-reactive protein (CRP), a sensitive marker of systemic inflammation, were increased in patients with AF. Not only that, CRP levels were higher in patients with persistent rather than paroxysmal AF, and persistent AF is less likely to spontaneously revert to sinus rhythm 2930. These studies suggested that inflammation may induce, provoke and promote the persistence of AF. Statins may be potent anti-inflammatory agents 31 and have also been shown to reduce CRP levels 32.

Not surprisingly, statins were subsequently shown to prevent AF recurrence in patients with lone AF after successful cardioversion 33 and in patients with CAD34. Both these studies were retrospective. However, it is well known that results obtained in retropsective studies may not be replicated in clinical trials 35. Accordingly, in an open, controlled multicenter study, pravastatin did not reduce the recurrence rate of AF after electroversion36. Moreover, there has been an isolated case report of AF due to simvastatin37, which further limits their role in the management of arrhythmias.

The evidence available for the beneficial role of statins is largely from observational and experimental studies which is clearly insufficient to recommend them as primary or even adjunctive antiarrhythmic agents. Moreover, their role in prevention as well as treatment of arrhythmias remains to be clearly defined.

Initial experimental evidence indicated towards both potential harm and benefit of statins in heart failure. Statins modulate a variety of inflammatory and immune responses 383940. In animal models of heart failure, statins moderate abnormal collagen and β-myosin expression, attenuate increased matrix metalloproteinase activity, improve ventricular remodelling and systolic function, normalize sympathetic responses and improve survival 414243 Given the relation of systemic inflammation to morbidity and mortality in heart failure patients, it was hypothesised that statins may benefit patients with heart failure separately from or in addition to effects on cholesterol and coronary disease44.

In a report of 551 patients with systolic heart failure, statin use was associated with improved survival in patients with ischemic and non-ischemic heart failure45. After risk adjustment for age, gender, CAD, cholesterol, diabetes, medication, hemoglobin, creatinine and NYHA functional class, statin therapy remained an independent predictor of improved survival. Furthermore, in a randomised trial in 63 patients with heart failure, statin use improved NYHA class and ejection fraction when compared with placebo 46. Also, statin therapy reduced new onset heart failure in the 4S Study 47, but this may have been related to effects on recurrent myocardial infarction. Using data from the Prospective Randomised Amlodipine Survival Evaluation (PRAISE) trial, association of statin therapy with total mortality among 1,153 patients with severe heart failure was evaluated 48. Statin therapy was associated with a 62% lower risk of death. However, only 12% patients were receiving statin therapy. Moreover, the study results cannot be generalised as these patients participated in a clinical trial at a time when β blockers and spironolactone were not commonly used in severe heart failure.

There also is some evidence to the contrary; lower serum cholesterol predicts worse outcomes in heart failure 49, raising concerns regarding use of lipid lowering agents. Statins also reduce ubiquinone (enzyme Q-10) 50, which may adversely affect mitochondrial and cardiac muscle function.

Therefore, in lieu of conflicting experimental and clinical data, the routine use of statins in congestive heart failure will be premature.

In initial experimental studies, simvastatin was shown to induce regression of cardiac hypertrophy and fibrosis and improve cardiac function in a transgenic rabbit model of human hypertrophic CMP 51. Based on the knowledge that statins improve endothelial function 39 and suppress systemic inflammation 31, it was hypothesized that statins may improve cardiac function in patients with nonischemic dilated CMP 46. Fourteen weeks of treatment with simvastatin was shown to improve left ventricular ejection fraction, reduce plasma concentration of tumour necrosis factor-alpha, and brain natriuretic factor in patients with idiopathic dilated CMP52. The effect on patient outcomes was however not evaluated.

Again as in case of heart failure, although some evidence is available for the beneficial effect of statins in CMP, evidence to the contrary is also available. Lovastatin has been shown to significantly increase mortality in hamsters with cardiomyopathic heart due to reduction in ubiquinone supply53. Statins have been shown to decrease coenzyme Q levels in humans 54 and this coenzyme is indispensable for cardiac functions 55. In wake of such conflicting evidence, their use in ishemic/nonishemic CMP cannot be advocated.

In addition to microvascular complications, patients with type 2 diabetes are at an increased risk of developing CAD 56 Over a 7-year period, in patients with no history of CAD, the incidence of first MI was over five times greater for patients with diabetes compared with non-diabetic controls 57. Diabetes is now considered to be a cardiovascular disease and all diabetics, irrespective of history of CAD, are considered within the category of secondary CAD prevention. Diabetic dyslipidemia may exist in the absence of raised total serum cholesterol due to an increased proportion of the more atherogenic LDL particles. Moreover, dyslipidemia often exists with a number of other atherogenic co-factors in patients with diabetes (e.g. abdominal obesity and hyperinsulinemia) as a part of metabolic syndrome 58. The updated Adult Treatment Panel (ATP)-III guidelines have advocated the use of statins for diabetes with or without CAD 12. LDL lowering treatment when LDL-C is >100 mg/dL in diabetices without CAD and >70 mg/dL in diabetics with CAD has been recommended.

Since the appearance of the first report on the efficacy of statins in lowering lipid concentrations in patients with type 2 diabetes 59, clinical trial evidence has accumulated in their support as the primary lipid-lowering drugs for these patients. Subgroup analyses 60 of diabetic patients in the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT) 9, the MRC/BHF Heart Protection Study (HPS) 15, and the Anglo-Scandinavian Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA) 10 showed variable results of lipid lowering therapy on cardiovascular outcomes in diabetic patients. In ALLHAT-LLT 9 pravastatin did not reduce the incidence of non-fatal MI and CAD deaths in patients with diabetes. In the HPS trial 15 simvastatin significantly reduced the risk of CAD and total cardiovascular events in patients with diabetes, whether they already had CAD or not. In the ASCOT-LLA trial 10 atorvastatin did not reduce the risk of non-fatal MI and CAD death in patients with diabetes and hypertension who had no pre-existing CAD. Collaborative Atorvastatin Diabetes Study (CARDS) was carried out to evaluate the efficacy and safety of low-dose atorvastatin treatment in primary prevention of CAD in patients with type 2 diabetes at high-risk of CAD 61. CARDS Investigators conclude that statins should be used in all patients with type 2 diabetes unless the patient has sufficiently low risk of coronary heart disease.

However, generalization of CARDS results is debatable. For example, the risk of statin therapy might be increased in people older than 75 years of age in patients with chronic renal insufficiency or organ transplantation and in patients with very high triglyceride concentrations who are on fibrates 60. Moreover, the number needed to treat will be very high in patients in whom the baseline risk is low like those with type 2 diabetes who are younger than 40 years; in premenopausal women; and in those without any CAD risk factors 60.

Lipid lowering therapy with bezafibrate had earlier shown to improve plasma glucose levels and insulin response to 75 g oral glucose loading associated with hyperinsulinema 62. An analysis of patients enrolled in the WOSCOPS study had shown a 30% reduction in the hazard of becoming diabetic 63. The analysis was done post hoc and the levels of statistical significance was modest (p = 0.04). Additionally, by reducing the risk of CAD, the need for β-blocker use (and perhaps thiazides) was reduced. There is some evidence that β-blockers 6465 and thiazides 66 may be associated with an increase in the incidence of diabetes.

Although no effect of pravastatin on glucose levels was shown in another study, 67 the authors proposed that pravastatin might reduce the incidence of diabetes by a reduction in triglyceride (TG) levels. However, even this is unlikely because the effect of pravastatin on TG levels is only modest 68. A recent case control study from the UK based General Practice Research Database failed to show reduced incidence of development of diabetes 69.

There has been interest in link between serum lipids and retinal exudates for 40 years 70. A number of cross-sectional studies suggest that serum lipids may have a causative role in the formation of macular exudates 71727374. A cross-sectional study of Age-related Macular Degeneration (AMD) suggests that statin therapy does have a protective role against the development of macular degeneration 75.

Few studies have evaluated statins in diabetic retinopathy 7677. In one of these, an improvement in hard exudates was noted in all patients on statins 76. In another study, simvastatin was shown to improve fluoroscein angiographic picture and led to maintenance of visual acuity in all patients 78.

These data, though important, do not permit us to draw a final conclusion as these studies were inadequately powered.

Claudication occurs when blood flow to the extremity fails to meet the metabolic demands of the skeletal muscle during exercise. It was hypothesised that statins, by improving endothelium dependent vasodilation at the arteriolar and capillary level 79, by their proangiogenic response independent of cholesterol reduction 80, and by inhibition of MMP-9 secretion by peripheral monocytes 81, could be beneficial in reducing claudication in patients with peripheral arterial occlusive disease (PAOD). Studies with lipid modifying therapies have demonstrated desirable effects in patients with PAOD 8283. A post-hoc analysis of the 4S data showed that new or worsening claudication was reduced in the group of patients receiving statins 84. High-dose, short-term therapy with simvastatin has been shown to improve walking performance, ankle-brachial pressure indices, and symptoms of claudication in hypercholesterolemic patients with PAOD 85. One-year treatment with atorvastatin improved pain free walking time and participation in physical activity in patients with intermittent claudication 86. However, maximal walking time did not change significantly. Similar benefit was shown with simvastatin on treadmill exercise time until the onset of intermittent claudication 87.

Despite the evidence from these studies suggesting benefit, well-designed long-term studies assessing primary and secondary prevention of PAOD with defined endpoints such as amputation or number of vascular events are required.

In an experimental model of encephalomyelitis, lovastatin treatment was shown to block disease progression and induction of inflammatory cytokines 88. Lovastatin treatment also attenuated the transmigration of mononuclear cells by downregulating the expression of leukocyte function antigen-1 (LFA-1), a ligand for intercellular adhesion molecule (ICAM), in endothelial-leukocyte interaction 88 and mononuclear cell infiltration into the CNS has been implicated in MS 89. Atorvastatin was shown to promote Th2 bias and reverse paralysis in a CD4(+)Th1-mediated experimental model of MS 90.

Therefore, statins were recognised as potential agents for future pharmacotherapy of MS 91. In the first clinical trial of statins in MS, 80 mg oral simvastatin for 6 months significantly reduced the number and volume of gadolinium enhancing lesions 92. However, immunological expression of surface markers on leukocyte cells or inflammatory cytokine profile showed no changes. Moreover, it was an uncontrolled, open label, small study with a baseline versus treatment comparison. Therefore, its results must be interpreted with caution. For instance, it is possible that reduction in the disease severity as measured with MRI could be due to regression to the mean. Moreover, since patients were included on the basis of the presence of gadolinium enhancement, this might have led to selection of patients with active disease who may subsequently have shown spontaneous reduction in disease activity anyhow. Additional factors like steroid use and unblinded assessment of MRI scans may have influenced the results. The exploratory immunological data in this study were also not found to be supportive.

Due to the paucity of evidence from adequately powered good quality clinical trials demonstrating the benefits of statins, any conclusive statement would be rather premature. Several trials are currently underway to address this question and we are also conducting a Double-blind, Randomised Evaluation of Atorvastatin in Multiple Sclerosis (DREAMS) trial in our institution.

Although cholesterol lowering is well known to decrease the risk of CAD, its association with decreased risk of stroke was demonstrated later 93. Meta-analyses done recently have shown statin use to be associated with reduced risk of stroke by 12 to 24% 9495.

Analysis of data from nine cohort studies showed a 15% decrease in thromboembolic stroke but a 19% increase in hemorrhagic stroke for a 1.0 mmol/l decrease in LDL concentration. The risk in those without a known cardiovascular risk factor was shown to be the same (6%) in clinical trials as that seen in cohort studies 91. Though the overall risk of non-fatal strokes was reduced, the risk of fatal strokes was not 96. Also, these results were obtained from studies which had stroke as their secondary endpoint. Moreover, in most of the included studies, incidence of stroke was very low, especially for primary prevention, reducing the power of comparison.

Addition of lovastatin to human HEK cells transfected with the amyloid precursor protein (APP) was shown to reduce intracellular cholesterol/protein ratios by 50%, and to inhibit cleavage of APP by beta-secretase 97. Non-demented individuals with heart disease have increased prevalence of AD-like beta-amyloid deposits in the neuropil and within neurons 98. In a cohort of patients taking lovastatin and pravastatin (but not simvastatin), a lower prevalence of diagnosed probable AD was noted 99. A case control study has also shown a lower risk of dementia among users of statins 100.

However, in a review done by the Cochrane Group, it was pointed out that no evidence in the form of controlled clinical trials was available to recommend the use of statins in AD 101. In a subsequent randomised, placebo controlled, double-blind trial, 26-week treatment with 80 mg simvastatin did not show any significant alteration in the cerebrospinal fluid levels of A-beta 40 and A-beta 42 102. Though the body of evidence for the beneficial effect of statins for AD is growing, due to the paucity of randomised controlled trials, no conclusions can yet be drawn 103.

Moreover, excessive lipid lowering may be detrimental as too little cholesterol in neural membranes has been shown to increase the vulnerability of neural membranes to dysfunction 104. Low serum cholesterol concentrations have been shown to be associated with cognitive decline in prospective studies of aging American twins 105 and elderly Finns 106.

Two observational studies showed that long-term statin use is associated with a reduced risk of depression in patients with CAD 107108. After an average follow up of 4 years, comparison of psychometric scores between users and nonusers of statins showed that statin use was associated with lower risk of abnormal scores for depression, anxiety and hostility 107. Authors have attributed the findings to a possible direct effect of statins on psychological well being. Similar reduced risk of depression was noted with statins in patients with hyperlipidemia 108. A more plausible possibility of reduced risk of depression due to an improvement in the overall quality of life was suggested in this study.

On the other hand, lowering of serum cholesterol may be associated with an increased incidence of depression and suicides 109110111112113. To sort of neutralize the evidence, some randomised, placebo controlled trials of statins have shown that depression was neither more nor less common among those taking active treatment 114115116.

Statins were shown to inhibit LFA-1, which is known to play an important role in the pathophysiology of inflammatory and autoimmune diseases 117. Statins also led to significant suppression of collagen-specific Th 1 humoral and cellular immune responses, reduction of anti-CD3/anti-CD28 proliferation and IFN-gamma release from mononuclear cells derived from peripheral blood and synovial fluid 118. Based on these findings, a putative role for statins in RA was suggested.

A preliminary study done in 15 patients with RA who were receiving methotrexate as a single disease modifying agent with no satisfactory responses, showed improvement after eight weeks of treatment with 40 mg simvastatin 119. Recently, in a randomized placebo controlled trial 120, atorvastatin 40 mg was shown to significantly improve disease activity score after 6 months of therapy although the effects were modest. The use of disease modifying anti-rheumatic drugs was rather heterogeneous among the treatment groups in this study, with more patients receiving methotrexate in the atorvastatin group. Other limitations were a small study group and a direct effect of statins on hepatic CRP synthesis, which could exaggerate the impression of disease modification.

The biologic effects of statins on bone metabolism have been reported in literature 121. Statins were shown to be potent stimulators of bone formation in vitro. Statins were shown to stimulate the bone morphogenic protein-2 (BMP-2) promoter in an immortalized osteoblast cell line 121. BMP-2 is known to enhance osteoblast differentiation 122. Further supporting evidence for its beneficial role came from osteoporosis observational studies 123124125126. However, in these studies, no adjustment for weight was made and part of the protective effect of statins could be because of reduction in weight.

By contrast, the Women's Health Initiative Observation Study found no relationship between statins and hip/wrist/arm/non-spine fracture rates after adjusting for weight and other potential confounders 127. Lack of benefit of statins in reducing hip and non-spine fracture was also reported in a case control study from the General Practice Research Database 128. In the first placebo-controlled trial specifically designed to assess bone turnover, statin treatment did not show any difference in rates of bone formation 129. Other uncontrolled studies have been conflicting; both increased 130 and decreased 131132 rates of bone formation have been reported. In spate of high optimism, it has been suggested that increasing the bioavailability of statins to the bone may lead to better results 133. As of now, keeping in mind lack of a consistent response with statins in various studies, it will be inappropriate to conclude that statins have a meaningful benefit for patients with osteoporosis.

Similar to most of the above mentioned indications, the action of statins in cancer has been bi-fold with arguments and evidence both in favour and against having been published.

It was suggested, nearly a decade ago, that cholesterol inhibition could inhibit tumour cell growth and possibly prevent carcinogenesis 134. Recently, statin use was shown to be associated with a reduced risk of breast 135 and colorectal 136 carcinoma. However, these findings need confirmation as they were based on a small number of events. Statin use has been associated with a 20% reduction in colon cancer, if used for more than 4 years and if more than 1350 defined daily doses were taken 136.

Evidence to the contrary has also grown simultaneously. Epidemiological studies in the early 1990s had shown a rise in non-cardiovascular mortality, particularly cancer deaths in people with low cholesterol concentrations 137. Similar conclusions have been drawn from results of early trials of cholesterol lowering 138. Some researchers have shown that lipid-lowering drugs, including statins, increase the occurrence of several types of cancer in rodents 139. In the CARE trial 6, incidence of female breast cancer and in the PROSPER trial 8 in elderly, incidence of all cancers increased in patients given pravastatin.

With such conflicting evidence available there is a need for exercising cautious scepticism for a potential beneficial role of statins for cancers.

Hyperlipidemia induced by antiretroviral treatment is observed frequently and can cause an increase in cardiovascular risk in HIV patients 139. Moreover, HIV infection itself induces pro-atherogenic lipid changes, which may lead to an increased cardiovascular risk but are partly reversed by antiretroviral regimens 140. Statins, given to patients with HIV infection and hyperlipidemia, effectively reduced total cholesterol (27%) and triglycerides (15%) 141. In the first double-blind, placebo-controlled study of the effects of statin therapy on lipids, lipoprotein subfractions, and endothelial function in HIV patients taking protease inhibitors, pravastatin reduced concentrations of atherogenic lipoproteins 142. Similar beneficial effects of statins were shown in a cohort of 245 patients 143. However, in all these studies the decrease in total cholesterol, LDL and triglycerides was only modest, and a significant number of patients did not achieve their NCEP goals. Moreover, the risk of rhabdomyolysis with concomitant use of statins in patients receiving highly active anti-retroviral therapy needs to be carefully evaluated in future studies.

Statins have been shown to have a direct effect on HIV infection itself 144145. In in vitro studies, 9 days after viral loading, lovastatin inhibited both sterol synthesis and viral multiplication in Human H9 lymphocytic cell line 144. Rho-guanosine triphosphatase (GTPase) activity is required for HIV infectivity into the cells 145. Statins block Rho-A activation induced by HIV-1 binding to target cells and also inhibited entry of HIV-1 pseudotyped viruses. These data are only experimental and considerable work will need to be done before any speculations for anti-retroviral potentials of statins are made.

Some of the other uses for which statins are being evaluated are drug-induced dyslipidemia following transplantation 146147, for causing immunosuppression in patients undergoing organ transplantation 148, promotion of fracture healing in vascularised bone allograft 149, sickle cell anemia 150151, idiopathic pulmonary fibrosis 152153, sensorimotor recovery after experimental intra-cerebral haemorrhage 154, sepsis 155156157, and glomerulonephritis 158. However, only limited, preliminary data are available to support routine use of statins in most of these indications and no recommendations can be made at present.

One cannot ignore the safety concerns with statin use; besides the well known side effects of myopathy, procarcinogenesis potential 159160, nerve damage 161162, short temper 163, cognitive decline 164, memory loss 165, teratogenic potential 166167, and more recently loss of libido 168 are some of the other concerns.

There is no doubt that statins have become one of the most commonly utilized drugs in cardiac patients not only in developed 169 but also in developing nations 170. It is also obvious that their use will be intensively promoted in many non-cardiac conditions discussed above although the tremendous promise seen in some experimental and initial clinical studies failed to be sustained in clinical trials or if it did the effect was only modest. For others the initial conflicting results continue to exist.

Recent years have shown a kind of contagiousness being demonstrated in research. Foremost among these have been the case of COX-2 inhibitors. After the discovery of COX-2 isoenzyme, almost every pathophysiological process showed involvement of COX-2 171172. Selective inhibition of COX-2 was thought to be the answer to a number of problems in therapeutics. A large number of studies giving evidence to the contrary or addressing adverse effects of COX-2 inhibitors got overshadowed (or were suppressed) in the hype created over COX-2 inhibitors 173174. Rofecoxib and some other selective COX-2 inhibitors are being withdrawn for their adverse effect profiles as their discoverer companies gear up for payments of compensation claims made by sufferers. Many other molecules have suffered similar fate and we hypothesized that statin research may also be on decline.

To test this hypothesis we searched Medline using the MeSH term "statins", "statins AND cancer (as well as other indications one by one)" for overall and yearwise extraction of citations. A total of approximately 11,000 citations were found out of which about 50% have appeared in only the past 4 years (since our last review 2). An analysis of yearly trends showed some interesting details. The first study on statins was reported in 1975 175. Subsequently, there was a steady increase in the publications until pleiotropism of statins was suggested in the mid-90s 176 and since then (especially since 2000), a steep rise in publications for various indications with a peak around 2002–2003 can be noticed. It is interesting to note that a trend towards a decline in the number of these studies can already be seen for statins in general (Fig 1) and in many indications specifically (Fig 2). This declining trend is probably due to failure to establish any definite benefit in majority of the indications for which their use was proposed.

Therefore, our hypothesis which appeared quite implausible initially may not have been altogether wide of the mark. Consequently, it remains to be seen whether statins can withstand the test of time or will sink into oblivion like many of the other molecules.