Common statin side effects explain poor compliance

The systematic review by DeVera et al. 1 found that poor adherence to statin pharmacotherapy increases cardiovascular events, but gave no consideration to the possibility that poor compliance may be due to side effects. Statin side effects have been under-estimated in recent studies, which do not include statin intolerant patients. However, more than 50% of patients discontinue statin therapy 1 and side effects are likely to be the main reason for doing so. Independent audit 2 and earlier randomized clinical trials show that side effects are relatively common and include fatigue, myopathy, liver dysfunction, cerebral haemorrhage, subtle cognitive impairment, neuropathy, renal failure, diabetes mellitus and cataracts. Side effects are dose related 2–4, often appear before cardiovascular benefits are obtained 4,5, impair quality of life, but are difficult to model and weigh against the benefits of pharmacotherapy 6. Insofar as side effects impede compliance, cardiovascular events may increase 1.

Highly significant reductions in mortality and around 25% reduction in total cardiovascular events were seen with just 20-40 mg of simvastatin in landmark earlier trials (4S 7 and the Heart Protection Study, HPS 8). This is about three-fold the dose required to lower low density lipoprotein (LDL)-cholesterol by 50% of maximum, the ‘effective dose (ED)₅₀’, which in a comprehensive meta-analysis of statins and doses 5 is about 12 mg for simvastatin. By comparison, the mean statin dose prescribed in a recent large Japanese audit 9 was equivalent to about 24 mg simvastatin or 6 mg of atorvastatin daily 5, very similar to the statin doses used in 4S 7 and HPS 8. This may prove to be the effective standard defined daily dose (DDD) for statins, but higher doses may be indicated in high risk patients, lower doses in smaller, elderly patients or those with liver impairment or side effects.

Commonly promoted higher doses of the newer more potent statins, such as 80 mg atorvastatin 3 are over 25-fold the ED₅₀, do not reduce mortality 3,4 and side effects can be markedly increased 2–4, liver dysfunction up to six-fold 3. Given the lifelong requirement for therapy, side effects are likely to compromise compliance. Closer attention to smoking, weight and blood pressure reduction is likely to reduce cardiovascular risk more effectively and safely. We suggest that lower statin dosing is very effective and may improve outcomes because reduced side effects will increase statin adherence.

Competing Interests

The authors have completed the Unified Competing Interest form at http://www.icmje.org.coi_discolosure.pdf (available on request from the corresponding author) and declare no support from any organization for the submitted work, no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years and no other relationships or activities that could appear to have influenced the submitted work.