Behind The Medical Headlines

Statin therapy: pharmacology, current uses and widening potential

• Dr S Constable, Lecturer in Clinical Pharmacology and Therapeutics, Department of Pharmacology and Therapeutics, The University of Liverpool, Liverpool, England
• Professor M Pirmohamed, Professor of Clinical Pharmacology and Therapeutics, Department of Pharmacology and Therapeutics, The University of Liverpool, Liverpool, England

Summary

Cholesterol–lowering statins have become one of the most-widely used, and expensive, drugs of our time. Research has suggested that their use may go beyond that of preventing cardiovascular disease to providing benefit in a host of other disease areas. In this article Dr Simon Constable and Prof Munir Pirmohamed provide an overview on the current uses and widening potential of statins.

Declaration of interests: No conflict of interests declared

Introduction

The 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-coA) reductase inhibitors, commonly known as the ‘statins’, already have a prime place in current prescribing practice. Statins are at the forefront of strategies to manage dyslipidaemia and are pivotal in the primary and secondary prevention of cardiovascular disease – the scourge of the western world. They are now the most widely prescribed, and the most expensive, item on the NHS drugs bill. This is expected to increase as their use extends. The National Institute for Health and Clinical Excellence (NICE) specified in January 2006 that statins should be used for both secondary prevention and primary prevention in adults who have a greater than 20% 10-year risk of developing cardiovascular disease.¹ It is important to note that this is not dependent on the cholesterol concentration and is a potentially costly – but cost-effective – primary prevention strategy.

Recent findings that high-intensity statin therapy is associated with a regression in the extent of coronary atheroma² achieved front page headline status in much of the national and international press. The media spotlight naturally fuels speculation about statins as ‘miracle-cures’ and ‘wonder-drugs’. The name of the study in question, the acronym ‘ASTEROID’, does little of course to dampen down such positively ‘galactic’ expectations. In this short review we outline the pharmacology of the statins and how this relates to their widening therapeutic indications and safety.

The Pharmacology of Statins

Statins competitively inhibit HMG-coA reductase, the rate-limiting step in de novo cholesterol formation in the liver. As the cholesterol content of the hepatocyte (liver cell) is reduced, the expression of low density lipoprotein (LDL) receptors on the cell surface is enhanced, resulting in increased extraction of the deleterious LDL-cholesterol from the circulation. Five statins currently have marketing authorisations in the United Kingdom: atorvastatin, fluvastatin, pravastatin, rosuvastatin and simvastatin. In July 2004, simvastatin also became available as an over-the-counter (OTC) medicine in the UK, although interestingly this has not happened in the US. The Royal Pharmaceutical Society of Great Britain has issued guidance to pharmacists on the OTC sale of simvastatin, incorporating a risk assessment that must be satisfactorily completed before a sale on this basis can occur.

There is quite significant variability between the different drugs in terms of their chemistry and pharmacokinetics (Table 1) as well as in their safety.

Safety of Statins

Statins are well tolerated by most patients. The most common adverse effects are gastrointestinal disturbance and headache, are usually mild and transient. However, the pre- and post-marketing development of the statins has not been without significant safety issues. Hepatic and skeletal muscle toxicity are concerns, although these are fortunately quite rare.

a) Liver toxicity

Statins can cause increased activity in hepatic transaminases (as opposed to cholestatic abnormalities) in up to 3% of patients, and occasionally this may lead to symptomatic injury. The effect appears to be dose-related and comparable amongst the various statin drugs.³ Although liver function monitoring is recommended by both manufacturers and regulators, the value of this has been questioned given the relative rarity of serious liver dysfunction and the lack of evidence detailing the frequency of monitoring.⁴ Hence, the advice given to clinicians is often conflicting and confusing.

Prescribing advice in the setting of production information sheets indicates that all liver disease is a contraindication to statin therapy, although the necessity for this outside of decompensated cirrhosis or acute liver failure has been questioned.⁵ Isolated elevations in transaminase levels in the absence of increased bilirubin levels have not been linked clinically or histologically to acute or chronic liver injury.⁵ Moreover, a recent study has shown that patients with abnormal liver function tests prior to therapy are not at higher risk of statin-related liver dysfunction and should not be excluded from receiving statins.⁶ This is particularly relevant in the case of patients with non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH) who should be considered important targets for statin therapy because of their significantly increased cardiovascular risk. Pragmatic clinical management would however suggest that such patients should be investigated prior to the initiation of statin therapy, and be monitored closely thereafter, although defining a reasonable frequency of this is not evidence-based.

b) Skeletal muscle toxicity

Statins can also produce a variety of skeletal-muscle problems; the severity is variable and ranges from myalgia to myositis and the most severe form, rhabdomyolysis. The latter can lead to renal failure and multiple metabolic abnormalities. Death can result from cardiac arrhythmias attributable to hyperkalaemia, and from disseminated intravascular coagulation. Although all statins can cause muscle toxicity, the incidence varies with the different drugs. Cerivastatin has been associated with the highest incidence of muscle problems, and this led to its withdrawal from the market in 2001. Cerivastatin-induced rhabdomyolysis has been associated with approximately 100 fatalities, the death rate being as much as 80 times greater than observed with the other statins. Of the statins currently on the market, rosuvastatin, presumably because of its potency and its licensing in the post-cerivastatin era, has been subject to a high degree of regulatory scrutiny with regards to potential muscle toxicity. Reporting bias is a problem – although, in a recent study taking this into consideration, adverse event reporting patterns with rosuvastatin have been comparable to those seen with other statins.⁷ Moreover, they did not resemble cerivastatin.

The mechanism(s) of skeletal muscle toxicity remains unknown. Depletion of cholesterol from skeletal muscle cell membranes (with associated membrane instability) or effects on metabolic intermediates (such as ubiquinone) have been proposed as potential mechanisms.⁸ It is also suggested that statins may enhance apoptosis, or programmed cell death. Identification of patients at risk of myopathy is problematic, although pharmacokinetic interactions may plays a crucial role. The high bioavailability, lipophilicity (fat solubility) and potency of cerivastatin may at least partially explain its high myotoxicity rate. However, an interaction with gemfibrozil through inhibition of both glucuronidation and cytochrome P450-mediated oxidation is also thought to be relevant. Indeed, inhibition of both P450 and transporters may be responsible for the higher rate of myotoxicity in individuals co-prescribed ciclosporin and statins.

It is important, however that myopathy is extremely uncommon and rhabdomyolysis causes 0.15 deaths per 1 million prescriptions. Therefore, although prescribers should be vigilant, the risk-benefit analysis is definitely in the patient’s favour.

Lipid Lowering and Cardiovascular Events

Numerous clinical trials have demonstrated that cholesterol-lowering with statins substantially reduces morbidity and mortality from cardiovascular events in virtually all groups studied and at virtually all baseline levels of cholesterol. The statin era truly started in 1994 with the Scandinavian Simvastatin Survival Study (4S),⁹ and since then the population expected to benefit from statin therapy has widened considerably. The largest statin study to date, the Heart Protection Study (HPS), randomised 20,536 patients with coronary heart disease (CHD) to either 40mg simvastatin per day or placebo.¹⁰ Treatment with simvastatin significantly reduced all-cause mortality by 13% (p=0.0003) and there were reductions of approximately 25% in relative risks of non-fatal myocardial infarction (MI), death through CHD (p<0.0001) and revascularisation procedures (p<0.0001).

Advocates of the “lower the better” cholesterol hypothesis surrounding highly intensive lipid-lowering therapy may have been cheered by the recent ASTEROID study. High intensity statin therapy with rosuvastatin 40mg daily for 2 years achieved an average low density lipoprotein cholesterol (LDL-C) of 1.6 mmol/L and increased high density lipoprotein cholesterol (HDL-C) by 14.7%, with a significant regression of atherosclerosis, as measured by intravascular ultrasound.² Disease regression is not something that has been convincingly shown in previous studies. However, this effect on the underlying lesion of coronary artery disease has yet to be supported by long-term data with rosuvastatin on key clinical outcome measures such as cardiovascular and all-cause mortality. This may well be demonstrated in the near future, and would be consistent with the data shown for other statins. The PROVE-IT, TNT and IDEAL trials have already compared the effects of achieving different LDL-C concentrations with 80mg atorvastatin daily versus 40mg pravastatin, 10mg atorvastatin or 20mg/40mg simvastatin respectively, and the results are in favour of the high dose “intensive” statin therapy.^11,12,13

Beyond Cholesterol?

Aside from in vitro studies and work in animal models, several landmark clinical trials have indicated that statins have additional cardiovascular protective activity that may function independently of their ability to lower serum cholesterol¹⁴. Indeed, the majority of cardiovascular events occur in patients without hypercholesterolaemia. Moreover, for example, in the West of Scotland Coronary Prevention Study (WOSCOPS), when the event rates between the pravastatin- and placebo-treated groups with the same LDL-cholesterol level were compared, the cardiovascular risk was found to be lower in the pravastatin group.¹⁵

The non-lipid lowering effects of statins have been highlighted in many other studies. For instance, intensive therapy with atorvastatin is associated with an early clinical benefit in patients with an acute coronary syndrome^11,13. This rapid effect is unlikely to be due to lipid lowering. It has been suggested that this may be due to atherosclerotic plaque stabilisation which may occur through modulation of macrophage activation as well as antiplatelet, antithrombotic and anti-inflammatory actions. Statins also have an effect on endothelial function via enhanced availability of nitric oxide, and reduced levels of intermediates from the cholesterol biosynthetic pathway which molecules play key roles in cell growth and signal transduction. Dietary cholesterol is a stressor, at least in part because it initiates a hepatic inflammatory response, leading to a state of chronic sub-clinical inflammation which drives the process of atherosclerosis and other metabolic conditions. This leads on to the possibility of using statins for indications in which this pathophysiology is relevant. Peripheral vascular disease and stroke are logical therapeutic targets.

The role of statins in the management of coronary artery disease and its sequelae is now clear. Interestingly, there is now increasing evidence that statin therapy may be beneficial in patients with cardiac failure not attributable to ischaemia, improving cardiac function by modulating the inflammatory state.¹⁶ Given that statins may be anti-inflammatory, there has been interest in their use in high grade inflammatory conditions such as rheumatoid arthritis, systemic lupus erythematosus or inflammatory bowel disease. However, emerging data from double-blind placebo controlled studies are not particularly impressive. Alongside a more general interest in cancer prophylaxis and treatment, statins are also under investigation in as myeloma and lymphoma, alongside conventional chemotherapy, as they induce apoptosis in vitro, inhibiting myeloma and lymphoma cells in a dose- and time-dependent manner.

Whilst statins in vascular dementia would seem entirely logical, the potential neuroprotective effects of statins on cognitive impairment could be beneficial in Alzheimer’s disease, both for prophylaxis and/or treatment. Clinical trials are underway, but firm conclusions have yet to be established. Statins are also attracting interest in osteoporosis and multiple sclerosis.

These broader indications are still very much under investigation, and are some time from being licensed uses of statin therapy. There has been debate about combination pharmacotherapy in the form of a “polypill” consisting of a statin amongst other agents. Statin-fortified drinking water has also been mooted by the more provocative commentator. Undoubtedly, the statin era has yet to reach maturity, and there is every reason to be optimistic about the future potential of this class of drug. The question is: will we be able afford them?

References

1. National Institute for Health and Clinical Excellence. Technology Appraisal 94: Statins for the prevention of cardiovascular events. NHS, January 2006.
2. Nissen SE, Nicholls SJ, Sipahi I, et al; ASTEROID Investigators. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA 2006; 295: 1583-4.
3. Farmer JA, Torre-Amione G. Comparative tolerability of the HMG-CoA reductase inhibitors. Drug Safety. 2000; 23: 197–213.
4. Pirmohamed M, Ferner RE. Monitoring drug treatment. BMJ. 2003; 327: 1179-81.
5. Cohen DE, Anania FA, Chalasani N; National Lipid Association Statin Safety Task Force Liver Expert Panel. An assessment of statin safety by hepatologists. Am J Cardiol 2006; 97: 77C-81C.
6. Chalasani N, Aljadhey H, Kesterson J, Murray MD, Hall SD. Patients with elevated liver enzymes are not at higher risk for statin hepatotoxicity. Gastroenterology 2004; 126: 1287-1292.
7. Davidson MH, Clark JA, Glass LM, Kanumalla A. Statin safety: an appraisal from the adverse event reporting system. Am J Cardiol. 2006; 97: S32-43.
8. Thompson PD, Clarkson P, Karas RH. Statin-associated myopathy. JAMA. 2003; 289: 1681-1690.
9. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994; 344: 1383-1389.
10. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002; 360: 7-22.
11. Cannon CP, Braunwald E, McCabe CH et al, for the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 Investigators. Intensive versus Moderate Lipid Lowering with Statins after Acute Coronary Syndromes. N Engl J Med 2004; 350: 1495-1504.
12. LaRosa JC, Grundy SM., Waters DD, et al, for the Treating to New Targets (TNT) Investigators. Intensive Lipid Lowering with Atorvastatin in Patients with Stable Coronary Disease. N Engl J Med 2005; 352: 1425-1435.
13. Pedersen TR, Faergeman O, Kastelein JJP, et al, for the Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) Study Group High-Dose Atorvastatin vs Usual-Dose Simvastatin for Secondary Prevention After Myocardial Infarction: The IDEAL Study: A Randomized Controlled Trial. JAMA 2005; 294: 2437-2445
14. Schwartz GG, Olsson AG, Ezekowitz MD et al, for the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study Investigators. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA. 2001; 285: 1711-1718.
15. Shepherd J, Cobbe SM, Ford I, et al, for the West of Scotland Coronary Prevention Study Group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med. 1995; 333: 1301-1307.
16. Leite-Moreira AF, Castro-Chaves P. Heart failure. Statins for all? Heart. 2006 Apr 10; [Epub ahead of print]