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

A meta-analysis that includes individual patient data is an extraordinary collaboration that provides a higher quality of information than most meta-analyses, which use aggregated data from individual studies. In this regard, we are grateful to the Cholesterol Treatment Trialists' Collaboration, which has previously provided us with detailed information on the protective effects of statins in cardiovascular prevention and on some side effects (myopathy, diabetes mellitus), whose importance is far outweighed by the unquestionable benefits of lipid-lowering treatment in patients with high cardiovascular risk.

Several placebo-controlled studies report that most of the alterations attributed to statins are based on the “nocebo effect”, which is the mirror image of the placebo (subjective harm/benefit to the patient independent of the actual pharmacological effect of the treatment). In other words, the apparent discomfort or side effects of statins have no real pathophysiological or pharmacological basis. Paradoxically, the detailed description of possible side effects in the information contained on statin packaging (technical data sheet) potentially reinforces the “nocebo” effect. Who does not experience some discomfort over the years, whether or not they are taking medication?

Once it has been confirmed that there is no objective basis in clinical trials for many of the disorders attributed to statins, a note of caution should be added. Clinical trials are not real life; the use of statins is widespread, including in patients who are usually excluded from pivotal clinical trials: the elderly, ethnic minorities, patients with concomitant diseases and polypharmacy... Therefore, individual assessment of each patient with their doctor is essential.

Fortunately, we can reassure patients by pointing out that the primary (protective) and secondary (harmful) effects of statins have been extensively evaluated, and that hundreds of thousands of people currently take them and have taken them for decades with unquestionable cardiovascular protective effects.

If, after explaining all this, the patient considers that any of their discomfort is attributable to statins, we can agree with the patient to briefly suspend treatment (in most cases disproving the relationship with the drug) and, if the patient continues to consider that there are problems with the treatment, fortunately we have lipid-lowering treatments used specifically in statin-intolerant patients or with completely different mechanisms of action (ezetimibe, iPCK9), which have demonstrated cardiovascular benefits and can provide effective and safe alternatives for reducing cardiovascular complications by controlling hypercholesterolaemia.

Unfavourable press reports about statins are not irrelevant, as they are associated with a decline in their use and an increase in cardiovascular disease, so providing reassuring news has significant and undeniable public health value.

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!

I find this to be a high-quality study with a very robust methodology, using exclusively data from each participant in all large randomized clinical trials comparing different statins, at varying doses, against placebo or other controlled comparators (such as another statin or a different dose). This type of design represents the methodological gold standard for understanding the causal effects of treatments. Furthermore, the study was conducted by a broad academic consortium of experts whose analyses are not directly influenced by the pharmaceutical industry, which strengthens its credibility.

The results, in fact, confirm much of what we already knew. Essentially, they corroborate the risk of liver toxicity and muscle discomfort, as well as the increased risk of developing diabetes in predisposed individuals when using high doses of statins, referring the evidence of direct muscle damage (myopathy or rhabdomyolysis) to previous studies.

However, the study rules out other risks that had been subsequently attributed in observational or pharmacovigilance studies, such as tendon or joint damage, or neuropsychiatric effects like cognitive impairment, depression, or insomnia.

[Regarding potential limitations] The very advantages of the design, based exclusively on randomized clinical trials, also constitute a significant limitation. These studies typically exclude higher-risk individuals—such as elderly patients with multiple comorbidities—as well as women and minorities. Therefore, it cannot be ruled out that these groups may experience additional risks associated with statin use that could be detected in pharmacovigilance studies. However, as the authors themselves point out, establishing causality is more problematic in this context.

Furthermore, this type of trial limits the analysis of drug interactions, which are more frequent in real-world clinical practice and in patients who are not usually represented in clinical trials. Therefore, it cannot be entirely ruled out that they may produce more side effects than those reported. In any case, I believe the overall assessment of the study reaffirms the safety of statin use despite certain scientific or media noise.

Finally, the article does not delve into the evidence of direct muscle damage, which the same group has already demonstrated in the past and which attracted considerable media attention and has been used as an argument to promote the use of other lipid-lowering drugs or to recommend lower doses of statins.