Study finds statin nocebo effect

People who know they are being given statins are more likely to report side effects than those who don’t know they’re taking them, a new study has found

Published in The Lancet, the study found that when patients knew they were taking a statin, they were more likely to report symptoms.

But when patients were unaware they were taking statins, there was no increase in muscle-related side effects.

These results are consistent with the ‘nocebo effect’, where patients report negative effects on their health because they have negative expectations of the treatment they’re being given, say the authors.

The study looks at data on 26 side effects from a trial of around 10,000 patients and suggests that cases of muscle pain and weakness are unlikely to be directly caused by statins, but may instead be due to the nocebo effect

Known side effects of statins include an increase in the risk of diabetes (50-100 new cases per 10,000 people), haemorrhagic strokes (5-10 per 10,000) and myopathy (5 per 10,000), the authors say; what’s less certain is the rate of muscle pain and weakness, with observational studies in general practice finding that up to a fifth of patients report symptoms, with little to no increase identified in randomised trials.

Professor Peter Sever, lead author from the National Heart and Lung Institute, Imperial College London, UK, says: “Just as the placebo effect can be very strong, so too can the nocebo effect.

“This is not a case of people making up symptoms, or that the symptoms are ‘all in their heads’. Patients can experience very real pain as a result of the nocebo effect and the expectation that drugs will cause harm.

“What our study shows is that it’s precisely the expectation of harm that is likely causing the increase in muscle pain and weakness, rather than the drugs themselves causing them.

“We know that statins can prevent a significant number of heart attacks and strokes. We know there is a small increase in the risk of diabetes, and at high doses there is a very small increase in myopathy, but overall the benefits greatly outweigh the harms.

“Widespread claims of high rates of statin intolerance still prevent too many people from taking an affordable, safe and potentially life-saving medication.”

The first phase of the trial was conducted in 1998-2002 and included 10,180 patients aged 40-79 with hypertension and at least three other cardiovascular risk factors from the UK, Ireland and Scandinavia.

Patients were randomly assigned to receive atorvastatin 10mg or placebo and were followed for three years. This phase was a blinded randomised trial.

At the end of the three years, the drug was shown to be effective and the same patients were offered the choice of taking a statin or not, in the non-blinded, non-randomised phase of the trial. Of the original group, 9899 participants were followed for a further two years and two-thirds (65%) of these chose to use a statin.

During the blinded phase of the study, the rate of muscle-related symptoms was similar whether patients received a statin or placebo (2.03% per year versus 2% respectively).

However, during the non-blinded phase of the study, muscle-related symptoms were 41% more common among people taking statins compared to those who weren’t (1.26% vs 1% per year respectively).

In total, the analysis looked at 26 types of side effects including erectile dysfunction, sleep disturbance and cognitive impairment. These four side effects had previously been identified as possible side effects by the Medicines and Healthcare Products Regulatory Agency and Food and Drug Administration, on the basis of observational studies.

The randomised, blinded phase of the trial found no difference between the statin and placebo groups for erectile dysfunction (1.86% vs 2.14% per year). Sleep disturbance was lower in the statins group compared to placebo (1.00% vs 1.46%) and there was an increase in renal and urinary side effects in the statins group compared to placebo (1.87% vs 1.51%), both of which require further investigation.

Too few cases of cognitive impairment were reported to provide reliable data, and no other differences in the other adverse events was identified.

The authors highlight that the trial was conducted in 1998-2004, before claims that statin therapy causes high rates of side effects were as widespread as they are today. They note that this may mean the strength of the nocebo effect is likely underestimated in this trial.

Participants were prescribed atorvastatin at a daily dose of 10mg, and only a few people in the non-blinded phase used simvastatin. This dose would now be considered a low dose, but the authors note that randomised trials of higher doses have not found that statins cause an increase in muscle-related symptoms, other than the very small increase in myopathy.

In a linked comment, Dr Juan Pedro-Botet, Hospital del Mar, and Dr Juan Rubiés-Prat, Universitat Autònoma de Barcelona, Barcelona, Spain, write: “Muscle-related adverse event rates are often argued to be low in randomised controlled trials owing to patient selection.

“Thus, the strengths of Gupta and colleagues’ study lie in the fact that these were the same patients, no run-in period existed to exclude patients intolerant to therapy, and few patients had previously taken any statins.

“Additionally, the atorvastatin dose typically used in the non-blinded phase was the same as in the blinded phase.

“Given that statins are among the best evidence-based lipid-lowering tools available and suitable for many patients, prevention of intolerance is paramount.

“Thus, physicians should alert their patients to possible statin-associated side-effects without raising negative expectations. Furthermore, they should encourage patient understanding of the rationale for statin treatment, which could optimise and facilitate shared decision making on statin therapy.”

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