Reacción a "Statins cause almost none of the side effects listed in their package inserts, according to a meta-analysis"

The article is of unquestionable scientific quality. Randomised, double-blind clinical trials were selected, comparing a statin with a placebo or a statin at different doses, with more than 1,000 cases in each study and a follow-up period of more than two years. It is not a conventional meta-analysis; the authors used the individual data of the patients included in each study. In total, individual data from 123,924 cases included in 19 studies with an average follow-up of 4.5 years were analysed. The analysis methodology was correct.

The main objective of the study was to analyse potential side effects, especially those included in the product information lists. The hypothesis was that the lists of side effect warnings indicated in the “package insert” documentation are not based on scientific evidence, but rather on isolated observations or those described in general follow-up observational studies.

The evidence provided is devastating. Only four of the 66 side effects listed by the various regulatory agencies showed a statistically higher incidence in the statin group compared to the placebo:

• Muscle discomfort.
• New diagnosis of diabetes.
• Abnormal urine tests (0.03% excess per year compared to placebo (not significant in the text of the results, but it does appear in Figure 1).
• Abnormal liver function tests (0.13% excess per year compared to placebo).

The figures are excellent in terms of information, but they can be difficult to understand if you do not know anything about statistics. In any case:

• Side effects are more common with high doses of statins.
• The incidence of excess side effects compared to placebo is very low.

The study does not seek to compare with previous evidence, but rather with the “popular” perception of safety (among many doctors, patients and the general population). And, above all, with the warnings of regulatory agencies.

[Regarding possible limitations] All studies have limitations. In this study, they are the usual ones in clinical trials and are not significant enough to cast doubt on the results and conclusions. In this case:

• All statins are mixed together and the side effects may be different.
• For protection, people included in clinical trials are selected using inclusion criteria that exclude potential contraindications and comorbidities (other associated diseases), i.e. it is a population with a lower risk of complications and it is not known what happened to patients who did not qualify for inclusion in the studies. Those who are excluded fare worse and may have more complications.
• In all clinical trials, patients receive more medication than the study drug or placebo. They receive multiple medications for their diseases. Some of the medications may have similar side effects or additional benefits. To exclude the influence of other concomitant diseases and the potential effect of other medications, special statistical analyses are necessary to determine more accurately whether the effect of the study drug is independent of other factors (other diseases and medications). With such a high number of cases, it is unlikely that this type of analysis would yield different results, and it is not usually performed in the first evaluation.
• The analysis was done on an intention-to-treat basis, but there are patients on statins who stop taking the medication and patients assigned to placebo who start treatment with statins.

The patients included in the clinical trials analysed were selected based on safety criteria. Regulatory agencies consider all available information, including study data, safety observations, publications of isolated cases with significant complications, etc. Therefore, it is understandable that regulatory agencies are more restrictive and go beyond the safety conclusions demonstrated in clinical trials. In any case, agencies must change the information provided to patients (in package inserts) or they will be misleading consumers and healthcare professionals.

The results of this work should be considered a very important contribution to the safety of statins, which patients, doctors and regulatory agencies should be aware of and consider. But this study does not end with this publication. The database built with data from all the studies is immense and will provide more information: benefits, subgroups, etc.

My congratulations to the group of researchers who carried out the work, starting with the most difficult part: agreeing to pool the individual patient data from each study and obtaining authorisation to do so from the owners of the databases for each study, generally the commercial companies sponsoring the clinical trials. Bravo!