Statin therapy: pharmacology, current uses and widening potential
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.
Key Points
- Statins inhibit the enzyme HMG-coA reductase, the rate limiting step in cholesterol biosynthesis.
- Statins reduce the circulating concentrations of the deleterious LDL-cholesterol and reduce cardiovascular events in virtually all populations studied, irrespective of the baseline cholesterol.
- Statins are generally well tolerated drugs. Hepatic and skeletal muscle toxicity are serious, but fortunately rare, safety concerns.
- Statins appear to have additional properties, typically anti-inflammatory, that may be beneficial across a range of degenerative, inflammatory and malignant diseases. These are currently the subject of much ongoing research.
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 myosit