The findings will likely reopen discussion of what to do when patients report muscle-related symptoms from statins.
The debate over statins has gone on for years. These inexpensive lipid-lowering drugs can markedly trim the risk of heart attacks or strokes, but some patients report muscle aches and refuse to take them. The uproar grew louder in late 2013, when the American Heart Association and the American College of Cardiology released guidelines that most experts said would greatly expand the pool of people advised to take statins.
Since then, the arrival of the PCSK9 inhibitors, a class of drugs that promises to reduce low-density lipoprotein (LDL) cholesterol even further, has added to the debate: are complaints about statins real, or are they all in patients’ heads?
A study published Tuesday in The Lancet adds a new wrinkle: after examining data on 26 side effects from 10,000 patients, researchers concluded that patients were more likely to report side effects when they knew they were taking statins. When they had no idea, there was no increase in muscle-related effects.1
This “nocebo” effect may explain the difference between patient reports in clinical trials, which have found little to no increase in side effects, and those in observational studies, where up to one-fifth of the patients report side effects.
“Just as the placebo effect can be very strong, so too can the nocebo effect,” Professor Peter Sever, senior author from the National Heart and Lung Institute, Imperial College London, United Kingdom, said in a statement. "This is not a case of people making up symptoms, or that the symptoms are ‘all in their heads.'"
Data were collected from 1998 to 2002 from 10,180 patients aged 40-79 who had hypertension and at least 3 other cardiovascular risk factors. Patients were from the United Kingdom, Ireland, and Scandinavia. They were randomly assigned to take 10 mg of atorvastatin or 10 mg or placebo and were followed for 3 years. This phase was a blinded randomized trial: neither the doctors nor the participants knew whether they were receiving the drug or a placebo.
At the end of the 3 years, the drug was shown to be effective and the same patients were offered the choice of taking a statin or not. During this unblinded phase of the trial, 9899 of the original participants were followed for another 2 years, and 65% stayed on a statin.
During the blinded phase, the rate of muscle-related symptoms was nearly identical whether patients took a statin (2.03%) or placebo (2%). But once patients knew they were taking a statin, muscle-related symptoms were 41% more likely among those taking statins compared with those who weren’t (1.26% vs 1%).
"Patients can experience very real pain as a result of the nocebo effect and the expectation that drugs will cause harm," Sever said. "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.”
Statins are well-studied and have both benefits and some limited risks; for every 10,000 people at high risk of a stroke or heart attack, lowering LDL cholesterol by 2 mmol/L by taking 40 mg of atorvastatin for 5 years could prevent 1000 incidents of heart attack, stroke, or the need for a coronary bypass. There is a smaller risk of developing type 2 diabetes (T2D); this occurs in 50 to 100 people out of 1000. Myopathy can occur at very high doses, but this is even less common.
The issue of whether muscle-related effects of statins has become a major issue for payers with the arrival of PCSK9 inhibitors, because they not only lower LDL cholesterol up to 60%, but they do so without reports of the side effects. But this comes at a cost—PCSK9 inhibitors list for $14,000 a year, and even with their limited US indication, reports show nearly three-fourths of all initial claims are denied.
Advocates for the use of these new drugs say they could bring relief to those patients who cannot tolerate statins, and some leading physicians say there are patients for whom statin-intolerance is real. FDA has not approved PCSK9 inhibitors in the United States for this indication, but the drugs have received this indication in Europe, where they are considerably cheaper.
The problem created by patients who perceive side effects from statins are real, according to an accompanying editorial. The phenomenon “can lead to poor treatment adherence or even statin discontinuation, which is associated with increases cardiovascular risk leading to higher rates of heart attacks, strokes, and cardiovascular mortality,” the editorial states.2
Sever said the Lancet results show that for the vast majority of patients who need to lower LDL cholesterol, statins are a viable, cost-effective option.
“Widespread claims of high rates of statin intolerance still prevent too many people from taking an affordable, safe and potentially life-saving medication,” he said.
1. Gupta A, Thompson D, Whitehouse A, et al. on behalf of the ASCOT investigators. Adverse events associated with unblinded, but not with blinded, statin therapy in the Anglo-Scandinavian Cardiac Outcomes Trial—Lipid-Lowering Arm (ASCOT-LLA): a randomised double-blind placebo-controlled trial and its non-randomised non-blind extension phase [published online May 2, 2017]. Lancet. 2017; http://dx.doi.org/10.1016/ S0140-6736(17)31075-9.
2. Statin-associated muscle symptoms: beware of the nocebo effect [published online May 2, 2017]. Lancet. 2017; http://dx.doi.org/10.1016/ S0140-6736(17)31163-7.