Statins: benefits and risks
- Medicines and Healthcare products Regulatory Agency
- 11 December 2014
- Therapeutic area:
- Cardiovascular disease and lipidology
Statins (HMG-CoA reductase inhibitors) are widely used medicines for patients with lipid disorders and in the primary and secondary prevention of heart attack and stroke.
Article date: May 2014
The statins currently available in the UK are simvastatin, atorvastatin, pravastatin, fluvastatin, and rosuvastatin.
Evidence from large clinical trials1 2 3 4 shows that statins can reduce heart attacks and the need for bypass surgery, and can save lives in certain patient groups. Meta-analysis of randomised trial data shows that if patients with a 10-year cardiovascular risk of at least 20% take statins for 5 years, it would prevent at least 450 heart attacks, strokes, or vascular deaths per 10,000 treated patients.3
The importance of statin safety data from clinical studies and clinical practice
Large clinical trials1 2 3 4 also showed that statins are generally well tolerated by most people who take them. Safety was carefully monitored in these trials by comparing statin side effects with those reported for placebo treatment. However, these trials were generally aimed at establishing efficacy. Specific suspected side effects were not investigated as the main outcomes of these trials, so this data is not enough to establish the safety profile of statins. Some side effects only become apparent when medicines are used in the community:
- by many people (because of the rarity of some side effects)
- for a long time (because of the slow onset of some side effects)
- when high doses are used more frequently than in clinical trials
- by people who are not typically included in clinical trials because they have multiple medical conditions, use other medicines, have differences in genetic make-up or lifestyle, or are younger or older than those included in trials (all these factors might affect the risk of side effects)
Data from clinical practice can help identify side effects occurring in these situations. However, clinical practice data are subject to other limitations, including the stimulated reporting of side effects (for example due to media interest); under-reporting of side effects; and possible contribution of concomitant medications, the underlying disease, and patient characteristics and lifestyle.
Muscle-related side effects of statins
All effective medicines can cause side effects in some patients and a small proportion of patients taking statins will inevitably experience side effects. Although they may be distressing to the individual concerned and limit that individual’s willingness or ability to tolerate statin use, statin-related side effects are generally mild and not medically serious.
Muscle-related problems are the most frequently reported side effect of statins. The following statin side effect incidences have been estimated based on randomised trial data, cohort studies, published case reports and spontaneous reports:5
- mild muscle pain: 190 cases per 100,000 patient years
- myopathy: 5 cases per 100,000 patient years
- rhabdomyolysis: 1.6 cases per 100,000 patient years
Recent studies from electronic medical record databases6 7 have found similar rates. The risk of myopathy is increased with all statins and is known to be dose dependent. Myopathy risk also increases when certain medicines are used together with statins, either because both medicines can cause myopathy or because the second medicine increases the blood plasma concentration of the statin (mimicking the effects of a higher statin dose). The prescribing information and patient leaflets for each statin advises on how to minimise the risk of side effects, including:
- which medicines to avoid taking with statins
- when to use a lower statin dose
- when to interrupt or stop statin treatment.
Certain genetic profiles may increase the risk of statin-induced myopathy
Recent studies6 8 have highlighted that some people’s genetic make-up may make them more prone to experiencing myopathy while taking certain statins. The gene SLCO1B1 encodes for OATP1B1, one of a family of uptake transporters which controls statin uptake from the blood into liver cells. Simvastatin is primarily taken up via the OATP1B1 transporter. Other statins are taken up by additional or different transporters, so the blood plasma concentration of those statins is less susceptible to changes in OATP1B1 function than that of simvastatin (see table). Inherited variations in the SLCO1B1 gene affect the ability of this transporter to metabolise statins. People can be grouped into one of three statin-metabolising genotypes:
- normal metabolisers of statins (those who carry two copies of the standard gene, or T/T)
- intermediate metabolisers (those who carry one copy of the standard and one copy of the variant gene, or T/C)
- poor metabolisers (those who carry two copies of the variant gene, or C/C).
People who are poor metabolisers (C/C) have reduced OATP1B1 transporter function and experience higher blood plasma levels of simvastatin for the same administered dose compared with normal metabolisers (T/T) or intermediate metabolisers (T/C). As a consequence people who carry a C variant gene are at higher risk of developing myopathy with simvastatin (especially if they have two copies of it) than people who carry a T variant.
Where a person’s SLCO1B1 genotype is known or can be tested, this should be taken into consideration before prescribing high doses of simvastatin. As a test is not yet readily available in the UK, alternative statins which are less affected by this genetic subtype should be considered (see table). There is no need for anyone who has been using simvastatin without any problems to stop taking it on the basis of this information.
Table: Effect of SLCO1B1 genotypes on the systemic exposure of various statins9
|Percentage increase in AUC for SLCO1B1 CC versus SLCO1B1 TT|
AUC = area under the plasma concentration-time curve
Things to consider when prescribing statins
Advise patients to seek prompt medical attention if they experience muscle problems while taking statins. Myopathy may not be clinically serious to start with, but can rarely progress to potentially fatal rhabdomyolysis. Review statin treatment if muscle problems occur. For some patients, stopping statin treatment may be appropriate. If statin treatment must be continued despite muscle problems, consider using a lower statin dose or switching to a different statin. Take into account the severity of the myopathy, the degree of hypercholesterolaemia, and the patient’s medical history.
Patients and prescribers should also be aware that other side effects have also been reported in association with statins.10 11 These are listed in the summary of product characteristics and patient information leaflet of each statin.
The benefits of using any statin in its licensed indication outweigh the risks in most patients. As with all medicines, the MHRA constantly reviews the safety of statins and will inform prescribers and patients when new important information becomes available. In deciding whether to offer statin therapy, carefully consider both the potential benefits and harms for each patient.
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Published: 11 December 2014
Therapeutic area: Cardiovascular disease and lipidology