The authors say muscle problems with statins are an example of the ‘nocebo’ effect.
A new study helps debunk the widespread belief that statins cause muscle-related pain and weakness in large numbers of patients. The “nocebo effect” may be the cause of the epidemic of muscle pain among statin users, say the study investigators and outside commentators.
There are few more broadly relevant and contentious questions in modern medicine than who should take statins. Observational studies and anecdotal reports indicate that adverse events in people taking statins are common. As many as 20% of people who take statins report some sort of problem. But in randomized controlled trials of statins reports of adverse events have been similar in the placebo and active treatment groups, suggesting little or no pharmacologic adverse effect. (All parties agree that statins can cause the rare and extremely serious adverse effect of rhabdomyolysis in about 1 in 10,000 patients, and that statins also cause a small increase in the risk of developing diabetes, though the clinical implications of the later finding are still unclear.)
Now a new report in the Lancet compares the rate of side effects in a group of patients both during and after their participation in a randomized controlled trial, the ASCOT-LLA trial. During the trial more than 10,000 patients were blinded to treatment assignment. After the trial was completed participants were invited to take part in a followup study in which they were offered open-label statin treatment.
During the randomized portion of the study there was no difference in the rate of muscle-related symptoms between the two groups: 2.03% per year in the atorvastatin group versus 2% in the placebo group. In the open-label followup study, in which about two-thirds of the patients were taking atorvastatin, there was a small but statistically significant larger percentage of patients in the atorvastatin group who reported muscle-related symptoms: 1.26% per year versus 1.00% per year (hazard ratio 1.41, CI 1.10–1.79, p=0.006).
“Just as the placebo effect can be very strong, so too can the nocebo effect.,” said Peter Sever (Imperial College London), lead author of the study, in a press release. “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.”
The authors speculated that they may have underestimated the nocebo effect, since ASCOT-LLA was performed between 1998-2005, “before claims that statin therapy causes high rates of side-effects had become as common as they are now.”
Statin critics have argued that adverse event rates in trials have been lower than real life because most trials have enrolled patients who have already been shown to tolerate statins. But, write Juan Pedro-Botet, Juan Rubiés-Prat (Barcelona), in an accompanying editorial, in ASCOT-LLA “no run-in period existed to exclude patients intolerant to therapy, and few patients had previously taken any statins.”
Rita Redberg (UCSF) doesn’t think that a nearly 20-year-old trial can address the situation today. She repeated her call for the Cholesterol Treatment Trialists (CTT) to release the patient-level data of their trials. “I think if they truly want to contribute to the discussion of the incidence of statin related adverse events in clinical trials, they should make the CTT held trial data publicly available, as Rory Collins said he would do two years ago, but has not happened.” Collins is a leader of the CTT and a co-author of the new Lancet paper.