GUADALAJARA, Mexico — The US Food and Drug Administration (FDA) defines statin intolerance as “the inability to tolerate at least two statins at the lowest approved doses due to musculoskeletal symptoms,” recalled Francisco López-Jiménez, MD, a cardiologist in the Department of Cardiology at the Mayo Clinic in Rochester, Minnesota, during his presentation at the Annual Congress of International Cardiology (CADECI) 2023.
“A very recent meta-analysis that included data from 176 cohort studies, clinical trials, and case series with more than 4 million patients showed that statin intolerance is present in approximately 9% of statin-treated patients,” said López-Jiménez.
The study identified risk factors for statin intolerance, including female sex (47.9%), obesity (30.6%), hypothyroidism (37.6%), diabetes (26.6%), use of antiarrhythmics (31.2%), alcohol use (22%), exercise (23.2%), chronic liver disease (24.3%), chronic kidney failure (25.2%), use of calcium channel blockers (35.5%), and use of high-dose statins (37.5%).
There were also some factors that were not related to statin intolerance, such as smoking, high blood pressure, duration of statin treatment, being White or Hispanic, and the use of warfarin.
López-Jiménez recalled that when statins first began to be used, the concept of intolerance to the drug did not exist. “It was not accepted that there were musculoskeletal symptoms that could be attributed to the statin.”
However, to clarify this situation, a study was conducted that compared statin intolerance in two phases of the same clinical trial. The first was a double-blind phase, where intolerance or muscle symptoms were present in 2% of patients treated with statins and placebos. The second was an open-label phase.
Participants treated with “statins had a 40% greater risk of symptoms, compared to those who took placebo, which suggests the so-called nocebo (opposite of placebo) effect, where the patient believes and is convinced that a treatment will harm them, so they will feel the harmful symptoms even if the drug does not cause anything,” explained López-Jiménez.
He noted that the most important study to demonstrate the existence of statin intolerance is the Effect of Statins on Skeletal Muscle Function and Performance (STOMP) study, published in Circulation.
“This was a double-blind clinical trial of atorvastatin 80 mg versus placebo specifically designed to assess the difference in muscle symptoms and muscle strength, as well as exercise capacity,” said López-Jiménez. He pointed out that the study of only 420 patients with a 6-month follow-up found that statin intolerance due to musculoskeletal symptoms occurred in 9% of patients taking atorvastatin versus 4% of those taking placebo.
Meanwhile, in the GAUSS-3 study, all participants had a history of statin intolerance, and those who took atorvastatin had a higher incidence of muscle pain compared with those who took placebo. “However, about 60% of patients taking placebo developed intolerance.”
Lastly, to confirm the presence of intolerance and the proportions of patients who are truly intolerant and tolerant, a meta-analysis of 123,000 patients was performed. This study included data from controlled clinical trials comparing statin or placebo or a high versus low dose.
“They found that 27% of the participants developed intolerance at the 4-year follow-up, yet the absolute difference between those taking statins and those taking placebo was only one case per 1000 patient-years. In practical terms, it was concluded that only one in 15 cases reporting musculoskeletal symptoms attributed to statins was real,” said López-Jiménez.
He said that some practical recommendations for the diagnosis of statin intolerance are measuring the enzyme creatine phosphokinase and evaluating the level of certainty that relates the symptoms to statins by means of causality rules.
When symptoms start 5 years after taking statins, intolerance is unlikely “because usually when it is real it starts in the first few weeks, maybe even in 1 or 2 months. When the symptoms start the same day the statin was taken, surely there is no intolerance,” he said.
Regarding the management of statin intolerance when there is evidence that the patient has related symptoms, López-Jiménez recommended “asking oneself whether the drug is really necessary. Most of the time the answer will be positive, but in other cases not. In primary prevention, coronary calcium should be used not only to find patients at risk but also to move the needle to the other side. That is, if calcium is not found in patients considered to be at moderate or high risk, it is advisable to lower their risk level, and they probably no longer need statins.”
Another important aspect is the assessment of risk perceptions. “If we teach the patient that the risk of a serious event, death, hospitalization, or serious complications with statins is less than 1 in 3 million individuals on treatment, they can go away fearing the rare event and not focusing on the risk of the actual event. Thus, make it clear that the risk of not taking a statin is much higher, especially in patients with coronary disease,” he noted.
López-Jiménez also recommended avoiding the initiation or increase of exercise exactly when a patient starts or changes statin doses. “When the patient leaves the medical office with their statin prescription and is motivated to do exercise, it is inevitable that their muscles will ache, and they will not attribute it to the exercise they started to do, but to the statins,” the clinician concluded.
López-Jiménez has disclosed no relevant financial relationships.
Follow Pablo Hernández Mares of Medscape Spanish Edition on Twitter @pablohmares
This article was translated from the Medscape Spanish Edition.
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