Only Very Small Risk of Muscle Symptoms With Statins: CTT Collaboration

BARCELONA, Spain—There is only a very small risk of developing muscle symptoms with statin therapy, and the majority of muscle-related side effects that are reported are not attributable to the treatment, a new meta-analysis shows.

Across a large number of randomized, placebo-controlled trials, more than one-quarter of patients taking a statin reported muscle pain or weakness, but so did a similar number of patients who were treated with placebo. And while the increased risk of developing muscle symptoms with statin therapy is real, that risk is very small, say investigators.

“Statins are one of the most effective medicines in our armamentarium,” said Colin Baigent, BMBCh (University of Oxford, England), who led the new analysis on behalf of the Cholesterol Treatment Trialists’ (CTT) Collaboration. Their value, however, is being limited because patients are either stopping the medication, or are not willing to start it, because of concerns about muscle pain, he added.

The new analysis, which was presented today during a Hot Line session at the European Society of Cardiology (ESC) Congress 2022 and published simultaneously in the Lancet, showed that patients taking statins had a 3% relative higher risk of muscle pain or weakness with statin therapy versus placebo but the risk was no longer evident in those taking the drugs for more than a year.

“It’s a tiny increase in the risk of experiencing muscle pain or weakness,” said Baigent.  

Manesh Patel, MD (Duke Clinical Research Institute, Durham, NC), who wasn’t involved in the study, told TCTMD that one of the biggest opportunities to help patients reduce their risk of atherosclerotic cardiovascular disease (ASCVD) is to reduce their LDL-cholesterol levels with statin therapy. While statins are effective, inexpensive, and widely available, that doesn’t mean it’s easy.

“One of the hardest things to do in medicine is to prescribe a medicine and have a patient stay on it,” he said.

In clinic, patients will express concerns about statin-related muscle symptoms before they’ve even started treatment, because that information is widely available online, said Patel. However, the randomized, controlled trial data, including the new CTT Collaboration analysis, show that the real risk of developing muscle symptoms is quite small.

Statins are not generally the cause of muscle pain in people that are taking them. Colin Baigent

“We emphasize and ask patients to watch out for these symptoms and side effects with the medication,” said Patel. “If you look on the internet, these are the symptoms that are commonly reported. There’s a lot of input about these symptoms, but these data should make people feel comfortable that those symptoms often are not related to the medication.”

Maciej Banach, MD, PhD (Medical University of Lodz, Poland), who is part of the International Lipid Expert Panel that recently published a step-by-step guide to diagnosing and managing patients with statin-associated muscle symptoms, as well as managing the nocebo/drucebo effect, said these new data are important because they will promote better adherence to therapy, which will translate into better clinical outcomes.

“On the one hand, we can’t say that statin intolerance doesn’t exist,” he told TCTMD. “It would mean it’s not a problem at all. That’s not true—it is a problem. On the other hand, we shouldn’t say that it’s a large problem. We already have a lot of people—patients, physicians, cardiologists—who are afraid of statins. They’re thinking about possible side effects before they’ve even started therapy.” 

Banach, who wrote an editorial accompanying the Lancet paper, emphasized that physicians shouldn’t fixate on possible statin-related side-effects when starting treatment. Instead, they should focus on patient risk so that they can deliver optimal medical therapy.

“That’s the most important thing,” he said. “If and when statin intolerance appears, we know how to proceed because we have strict guidelines from the International Expert Lipid Expert Panel or the National Lipid Association. If you follow those guidelines, you’ll still be able to treat 95% or more of your patients with statins. But don’t think about statin intolerance at the beginning, because it’s one of the most important causes of physician inertia.”  

Most Symptoms Not Statin-Related

As part of the CTT analysis, researchers collected individual participant data on all recorded adverse events from 19 randomized, double-blind trials comparing statins versus placebo and four randomized trials comparing intensive versus less-intensive statin therapy.

The placebo-controlled trials included 123,940 participants in 4S, WOSCOPS, CARE, AFCAPS/TexCAPS, HPS, ASCOT, JUPITER, and HOPE-3 among others, while the trials of differing statin intensity included 30,724 patients randomized in PROVE-IT, A to Z, TNT, and SEARCH. The median follow-up was 4.3 years in the placebo-controlled trials, 4.9 years in the statin-intensity trials, and 4.4 years in the 23 trials combined.

Baigent said the patient-level meta-analysis was a “huge effort,” one that took 7 years to complete and involved the collection of 38 million records and 840 datasets.

There is 10 times more information on the internet about the harmful effects of statins than the beneficial effects. Maciej Banach

In the placebo-controlled trials, 27.1% of participants assigned to statin therapy and 26.6% of placebo-treated patients reported at least one episode of muscle pain or weakness during follow-up (RR 1.03; 95% CI 1.01-1.06). In the first year, statin therapy was associated with a 7% relative increase in muscle pain or weakness compared with placebo, but there was no increased risk seen beyond that point. There was no evidence that the risk varied among the different statins. The relative risk for muscle pain or weakness was higher for women than for men (RR 1.09; 99% CI 1.03-1.16 vs RR 1.00; 95% CI 0.97-1.04). While the test for heterogeneity was positive by sex, they didn’t see any difference in risk between men and women in studies of differing statin intensity, suggesting it may be a play of chance, said Baigent.

The increased relative risk during the first year of treatment translates into an absolute excess of 11 events per 1,000 person-years. Based on reports of muscle pain or weakness in the placebo group, just one in 15 reports of muscle symptoms in the first year are caused by the statin, say investigators.

“In the rest of [reported muscle symptoms]—14 out of 15, or more than 90%—the muscle pain was not due to the statin,” said Baigent. That muscle pain is attributable to another cause, whether it’s normal aging, a thyroid disorder, or exercise, he said. 

Compared with moderate-intensity statin therapy, there was an increased risk with higher-intensity statins (RR 1.05; 95% CI 0.99-1.11), a risk that was fairly consistent across studies comparing more- versus less-intensive statin therapy. Creatinine kinase information accompanied very few reports of muscle pain or weakness, but concentrations were less than three times the upper limit of normal (ULN) in 97% of cases. Statin therapy resulted in a “small, clinically insignificant increase” in median CK values of approximately 0.02 times the ULN, report investigators.

To TCTMD, Banach cautioned that while statin intolerance is overdiagnosed, these new data from the CTT Collaboration shouldn’t be mistaken as documenting its prevalence. These were very well monitored patients within a randomized, controlled trial setting. For most of the trials, statin-intolerant patients were excluded before the trial started or were excluded during the washout period.

Earlier this year, Banach published a detailed meta-analysis showing that the prevalence of statin intolerance in more than 4.1 million people was approximately 9%, a number that varied according to the definition and patient population. In randomized trials, the prevalence of statin intolerance was roughly 5%, but it went as high as 17% in cohort studies.

In the Clear After a Year

In clinic, Patel advises patients to stay active but return if they develop any muscle symptoms, so that they can discuss these side effects. If necessary, there are numerous options for doctors, such as trying a different statin, or a lower dose, to see if symptoms are alleviated. “When we start therapy, I try to make sure they understand the relative risks and benefits of every therapy,” he said. “With statins, it’s pretty clear that patients get a broad long-term benefit by bringing their LDL cholesterol down.”

Nonadherence to statin therapy can be as high as 60% after 2 years and is associated with a significantly higher risk of ASCVD events, added Banach.

Debates about statin-related side effects have been ongoing for nearly 2 decades even though the data from randomized trials, cohort studies, and registries is reassuring, he said. The problem isn’t the absence of data, but rather the pervasive and vocal anti-statin movement on the internet. This had led to the proliferation of inaccurate reports of the adverse effects of statins.  

“When we discuss [statins] with patients, there is a lot of fear,” said Banach. “There is 10 times more information on the internet about the harmful effects of statins than the beneficial effects.”

Baigent agreed that there is a lot of misinformation in some media and circulating online. Given the new findings, he’d like to see two things happen: first, physicians need to find better ways than stopping the medication in patients who report muscle pain, and second, medication package inserts and other educational material needs to be updated to convey the real risks of muscle pain/weakness about statin therapy.

“Statins are not generally the cause of muscle pain in people that are taking them,” said Baigent said, “We need to do a better job of communicating that fact to patients who are taking statins and to their doctors. What’s happening at the moment is that people are experiencing muscle pain and the doctors eventually get them to stop it.”