Statin side effects are the result of negative expectations

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EDStatinsAn Imperial College London study suggests that common statin side effects of muscle pain and weakness are not a result of the drugs themselves, but rather patients’ negative beliefs about the medication – a phenomenon known as the nocebo effect.

Statins are typically prescribed to help lower levels of “bad cholesterol” – or low-density lipoprotein – in order to reduce the risk of a heart attack or stroke. But, reports The Guardian, despite their benefits, statins have been caught up in a storm of controversy, with critics questioning the safety and efficacy of the drugs after the UK’s National Health Service (NHS) guidelines advised that prescriptions should be extended to those at lower risk of heart attack.

The report says the new study suggests common side-effects of muscle pain and weakness are not a result of the drugs themselves, but rather patients’ negative beliefs about the medication – a phenomenon known as the nocebo effect. “You only get the muscle-related symptoms when you know you are taking the drug,” Peter Sever, lead author of the study from the national heart and lung institute at Imperial College London. He added that it was important to note that patients are not imagining their pains. “Patients genuinely get the symptoms,” he said. “But you cannot attribute that, in this case, to the drug.”

The report says the study echoes findings from other studies, which have also suggested the side-effects of statins are minimal, despite up to a fifth of patients reporting side-effects, chiefly muscle pain and weakness.

The researchers say they hope the latest research will finally quash the debate around statins, and reassure both doctors and patients that the benefits of the drugs outweigh concerns around side-effects. “Seldom in the history of modern therapeutics have the substantial proven benefits of a treatment been compromised to such an extent by serious misrepresentations of the evidence for its safety,” the authors write.

“There are people out there who are dying because they are not taking statins and the numbers are huge – the numbers are tens of thousands if not hundreds of thousands, and they are dying because of a nocebo effect, in my opinion,” said Sever.

While statins do have some potentially serious side effects, including a slightly raised risk of developing type II diabetes and, very rarely, a potentially fatal muscle condition known as rhabdomyolysis, Sever said in the report that the Medicines and Healthcare Products Regulatory Agency (MHRA) should remove warnings of side-effects including muscle pain and weakness, sleep disturbance, erectile dysfunction and problems with cognitive function.

The report says Sever also fiercely rebuked those who claim that high cholesterol is not linked to a risk of heart disease and stroke. “It is just like the MMR (scandal) – it is a small number of people getting up with opinions that are based on bad science,” he said.

Liam Smeeth, professor of clinical epidemiology at the London School of Hygiene and Tropical Medicine, who was not involved in the research, welcomed the study, saying that it highlights the danger of messages exaggerating the side-effects of statins. “I do think the MHRA advice could be toned down,” he added.

While the study and analyses received funding from Pfizer, the authors stress that the drugs company played no role in the research.

According to the report, researchers from the UK and Sweden describe how they carried out research between 1998 and 2004. More than 10,000 at-risk patients – predominantly white, male and over 60 – were randomly allocated to one of two groups, either taking statins or a placebo, and followed for more than three years. Neither the participants nor their doctors knew which group they belonged to.

In the second part of the study, 9,899 of the patients had the medication or placebo stopped, and both groups were then given the option of taking statins. The patients were then followed for more than two years.

“The uniqueness about the study was that these were the same patients who were followed throughout, they were seen by the same doctors, the same teams, the same way of recording the side-effects,” said Sever.

The team found that, when neither the patient nor the doctors were aware of whether statins were being taken, those taking the drugs reported similar rates of muscle problems and erectile disfunction to those taking a placebo. By contrast, when the patients and their doctors were aware of whether the patient was taking statins, reports of muscle-related problems were 41% higher among those who were taking statins.

The study also found that statins were linked to fewer sleep disturbances, but an increase in reports of needing to urinate at night and urinate more frequently, while there were too few reports of cognitive problems to draw any conclusions.

The results, say researchers, indicates that muscle-related problems linked to statins are largely the product of the “nocebo” effect. “If patients now begin to understand that actually this is not something that is specifically due to the chemistry of the drug then it may well be that your muscle aches and pains might get better,” said Sever.

While the authors admit that the dose of statins used in the study is low compared to levels currently prescribed, they stress that other studies have found no link between dose and severity of side effects. However only one type of statin, atorvastatin, was fully considered in the latest study, and it is not known if similar results would be seen among those of different ethnicities.

Sir Nilesh Samani, medical director at the British Heart Foundation, said that the perception that statins cause significant side-effects, including muscle aches, memory loss, sleep disturbance and erectile dysfunction has clouded their use.

“However, these complaints are not uncommon in the general population for a whole variety of reasons,” he said. “Therefore when patients take a statin and develop such symptoms, these understandably attribute them to the statin when it may not be the cause. This study shows that this might indeed be the case.”

Background: In blinded randomised controlled trials, statin therapy has been associated with few adverse events (AEs). By contrast, in observational studies, larger increases in many different AEs have been reported than in blinded trials.
Methods: In the Lipid-Lowering Arm of the Anglo-Scandinavian Cardiac Outcomes Trial, patients aged 40–79 years with hypertension, at least three other cardiovascular risk factors, and fasting total cholesterol concentrations of 6·5 mmol/L or lower, and who were not taking a statin or fibrate, had no history of myocardial infarction, and were not being treated for angina were randomly assigned to atorvastatin 10 mg daily or matching placebo in a randomised double-blind placebo-controlled phase. In a subsequent non-randomised non-blind extension phase (initiated because of early termination of the trial because efficacy of atorvastatin was shown), all patients were offered atorvastatin 10 mg daily open label. We classified AEs using the Medical Dictionary for Regulatory Activities. We blindly adjudicated all reports of four prespecified AEs of interest—muscle-related, erectile dysfunction, sleep disturbance, and cognitive impairment—and analysed all remaining AEs grouped by system organ class. Rates of AEs are given as percentages per annum.
Results: The blinded randomised phase was done between February, 1998, and December, 2002; we included 101 80 patients in this analysis (5101 [50%] in the atorvastatin group and 5079 [50%] in the placebo group), with a median follow-up of 3·3 years (IQR 2·7–3·7). The non-blinded non-randomised phase was done between December, 2002, and June, 2005; we included 9899 patients in this analysis (6409 [65%] atorvastatin users and 3490 [35%] non-users), with a median follow-up of 2·3 years (2·2–2·4). During the blinded phase, muscle-related AEs (298 [2·03% per annum] vs 283 [2·00% per annum]; hazard ratio 1·03 [95% CI 0·88–1·21]; p=0·72) and erectile dysfunction (272 [1·86% per annum] vs 302 [2·14% per annum]; 0·88 [0·75–1·04]; p=0·13) were reported at a similar rate by participants randomly assigned to atorvastatin or placebo. The rate of reports of sleep disturbance was significantly lower among participants assigned atorvastatin than assigned placebo (149 [1·00% per annum] vs 210 [1·46% per annum]; 0·69 [0·56–0·85]; p=0·0005). Too few cases of cognitive impairment were reported for a statistically reliable analysis (31 [0·20% per annum] vs 32 [0·22% per annum]; 0·94 [0·57–1·54]; p=0·81). We observed no significant differences in the rates of all other reported AEs, with the exception of an excess of renal and urinary AEs among patients assigned atorvastatin (481 [1·87%] per annum vs 392 [1·51%] per annum; 1·23 [1·08–1·41]; p=0·002). By contrast, during the non-blinded non-randomised phase, muscle-related AEs were reported at a significantly higher rate by participants taking statins than by those who were not (161 [1·26% per annum] vs 124 [1·00% per annum]; 1·41 [1·10–1·79]; p=0·006). We noted no significant differences between statin users and non-users in the rates of other AEs, with the exception of musculoskeletal and connective tissue disorders (992 [8·69% per annum] vs 831 [7·45% per annum]; 1·17 [1·06–1·29]; p=0·001) and blood and lymphatic system disorders (114 [0·88% per annum] vs 80 [0·64% per annum]; 1·40 [1·04–1·88]; p=0·03), which were reported more commonly by statin users than by non-users.
Interpretation: These analyses illustrate the so-called nocebo effect, with an excess rate of muscle-related AE reports only when patients and their doctors were aware that statin therapy was being used and not when its use was blinded. these results will help assure both physicians and patients that most AEs associated with statins are not causally related to use of the drug and should help counter the adverse effect on public health of exaggerated claims about statin-related side-effects.

Ajay Gupta, David Thompson, Andrew Whitehouse, Tim Collier, Bjorn Dahlof, Neil Poulter, Rory Collins, Peter Sever

The Guardian report
The Lancet article summary

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