In the vast majority of people who experience muscle pain or weakness while taking a statin, those symptoms are not related to the statin, a new individual patient data meta-analysis of randomized controlled trials shows.
The Cholesterol Trialists Collaboration meta-analysis examined 19 large randomized double-blind trials that compared statin therapy with placebo and involved almost 124,000 patients.
"Our results show that in people who experience muscle symptoms in the first year of taking a statin, those symptoms are actually due to the statin in only 1 of 15 of those people. For the other 14 of the 15 people who experience muscle symptoms in the first year of taking a statin, that muscle pain is not due to the statin," lead investigator Colin Baigent, MD, said.
After the first year, there was no difference in muscle symptoms between patients taking a statin or those taking placebo.
Baigent, who is director of the Population Health Research Unit at the University of Oxford, United Kingdom, presented the data on August 29 at the European Society of Cardiology (ESC) 2022 Congress.
It was also simultaneously published online in the Lancet.
Baigent explained that statins very rarely cause serious muscle adverse effects with biochemical evidence of cellular damage, such as myopathy (which occurs in less than 1 in 10,000 patients per year) and rhabdomyolysis (which occurs in about 0.2 per 10,000 patients per year).
The effect of statins on other less serious muscle symptoms without biochemical evidence of cellular damage is less clear, but misinformation about the risks have arisen from nonrandomized studies, with social media and press reports suggesting that the risk for muscle symptoms with statins is extremely common, Baigent said.
In response to this, the Cholesterol Trialists Collaboration put together a new program of data collection, validation, and analysis to provide reliable information from large double-blind randomized trials that are free from bias and confounding.
"Overall, when we look at all these data, we find there is about a 3% relative increase in the risks of experiencing muscle pain or weakness with a statin versus with placebo," Baigent reported.
Muscle pain or weakness was reported by 16,835 of 62,028 patients taking a statin, (27.1%), compared with 16,446 of 61,912 patients taking placebo (26.6%), for a rate ratio of 1.03 (95% CI, 1.01 - 1.06).
In absolute terms, the results show a rate of 166 reports of muscle symptoms per 1000 patient-years in those taking a statin, compared with 155 per 1000-patient-years in those taking placebo in the first year. This gives a rate ratio of 1.07 and an excess of 11 cases of muscle pain or weakness per 1000 patients in the first year of statin therapy.
"The very small excess of muscle symptoms in the statin patients were generally mild, with most patients able to continue treatment," Baigent added.
After the first year, the rate of muscle pain or weakness was exactly the same in the statin and placebo groups, at 50 per 1000 patient-years.
"Therefore, for the vast majority of people who experience muscle pain or weakness on a statin, those symptoms are not due to the statin itself. It is due to something else, which could be ageing, thyroid disease, or exercise," Baigent said. "After the first year of taking a statin, there is no excess risk of muscle pain or weakness at all."
"To summarize, the excess risk of muscle pain or weakness with statin use is tiny, and almost nonexistent after the first year," he added.
"Muscle pain is very common in the general population, and it was very common in both patients taking a statin and those given placebo in these randomized trials. We can only detect a difference by looking at all the data combined in this enormous study. And we now know for sure that over 90% of cases of muscle symptoms experienced by people taking a statin are not due to the statin."
The researchers also looked at statin intensity and found that the more intense statins tend to cause slightly more muscle pain. "There was also some evidence, although this was not very clear, that the muscle pain with the more intensive statins may persist for longer than 1 year," Baigent said.
But in terms of different moderate-intensity and high-intensity statins, there was no evidence of differences in muscle pain between the individual statin brands, he added.
Better Patient Information Needed
Baigent called for better information in statin package inserts about the real risk for muscle symptoms with these drugs.
"We need to do a better job of communicating the real risk of muscle symptom to patients who are taking statins and to their doctors. At the moment, doctors often stop statins if patients complain of muscle pain, but our data show that in 14 out of 15 times, they would be wrong for doing that. Stopping the statin is nearly always a mistake," he commented.
"At present, the package inserts include a whole load of rubbish from observational studies, which are completely unreliable," he added. "This is of no value to patients. They go through this information and find several symptoms they are experiencing, which they attribute to the drugs. We really need to divide up the information into the evidence that we really know for sure and then the more speculative stuff."
Baigent also highlighted the large benefits of statins compared with the small risk for muscle symptoms.
"While statins may cause 11 patients per 1000 to experience some mild muscle pain in the first year of taking these drugs, and this was reduced to none in subsequent years, statins, when used for the primary prevention of cardiovascular disease, prevent 25 cardiovascular events per 1000 patients every year they are taken. And for secondary prevention this rises to 50 events prevented per 1000 patients each year," he noted.
The individual participant data meta-analysis involved 23 trials with information on almost 155,000 patients. All trials included at least 1000 patients and at least 2 years of scheduled treatment. Adverse-event data were collected for all individual participants in 19 large randomized double-blind trials comparing statin therapy with placebo (123,940 patients) and in four randomized double-blind trials comparing more-intensive with less-intensive statin therapy (30,724 patients).
In the four trials of more-intensive versus less-intensive statin therapy, high-intensity regimens (atorvastatin 40 mg to 80 mg daily or rosuvastatin 20 mg to 40 mg daily) resulted in a larger relative increase in the rate of muscle pain or weakness than moderate-intensity regimens, with rate ratios of 1.08 (95% CI, 1.04 - 1.13) and 1.02 (95% CI, 1.00 - 1.05), respectively.
Discussant of the study at the ESC Hotline session, Erin Bohula, MD, Brigham and Women's Hospital, Boston, said this new analysis had many strengths and used a rigorous approach to look at the issue of muscle symptoms with statins.
She pointed out some challenges, including the fact that the definition of adverse muscle events has changed over time and differed in the various trials, with heterogeneous data capture across trials. "So, this was a Herculean task to harmonize this very complicated dataset."
Bohula concluded: "I think this is a very significant undertaking, resulting in a rich dataset that enhances our understanding of muscle symptoms related to statin use. The take-home for me is that muscle symptoms are a common complaint in the general population but are very rarely attributable to statins. This is very reassuring to me and I hope it is reassuring to patients and can help us encourage them with adherence, given the clear cardiovascular benefits of statins."
Chair of the ESC Hotline session at which the study was presented, Gabriel Steg, MD, Hôpital Bichat, Paris, asked whether some statin patients who experienced muscle symptoms with the drugs in active run-in periods in the trials may have been excluded from the main trials, so that this information might not have been captured, but Baigent replied that they also examined those data, which had been accounted for in the analysis.
"That's really good news," Steg commented. "This study is going to be one more tool in our response to statin skeptics and I think, as such, this work is a really a service to public health."
The meta-analysis was funded by the British Heart Foundation, the UK Medical Research Council, and the Australian National Health and Medical Research Council.
European Society of Cardiology (ESC) Congress 2022. Presented August 29, 2022.
Lancet. Published online August 29, 2022. Full text
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