Statin Intolerance Overestimated—Only ‘Small Number’ Get Side Effects: Meta-analysis

Intolerance to statin therapy appears to be much lower than previous data suggest, with researchers reporting that less than one in 10 patients are unable to tolerate the guideline-recommended, LDL cholesterol-lowering therapy.

The prevalence remained consistent across several definitions of statin intolerance, including stricter, more-objective definitions designed to account for the nocebo effect.  

“Our main aim was to finally answer the question—what is the worldwide prevalence of statin intolerance?” senior investigator Maciej Banach, MD, PhD (Medical University of Lodz/University of Zielona Gora, Poland), told TCTMD. With 4,143,517 patients in 176 studies, the meta-analysis required an enormous amount of work, he said, but was worth it because the goal “was to have a very strong message” with respect to statin-associated side effects leading to drug continuation.  

In the analysis, published this week in the European Heart Journal, just 9.1% of patients had statin intolerance as determined by recognized international definitions, said Banach. Given that statins significantly reduce morbidity and mortality associated with atherosclerotic cardiovascular disease (ASCVD), “the thought to discontinue a statin should be the last one if there are some symptoms reported by the patient,” said Banach.

In studies published to date, the prevalence of statin intolerance ranges widely, from 5% to 7% in randomized clinical trials to as many as one-third of treated patients in cohort studies, according to the researchers. Nonadherence/drug discontinuation remains a clinical problem for physicians around the world, and the most common reason for stopping is muscle pain. However, it’s often difficult to determine if the drug is causing the problem as patients may attribute normal ageing-related aches and pains to statins. Different diseases, use of concomitant medications, and risk factors can also influence statin intolerance, say researchers.  

The thought to discontinue a statin should be the last one if there are some symptoms reported by the patient. Maciej Banach

Neil J. Stone, MD (Northwestern University Feinberg School of Medicine, Chicago, IL), lead author of the 2013 American College of Cardiology/American Heart Association (ACC/AHA) guidelines on the treatment of cholesterol, and vice chair of the writing committee for the 2018 edition, praised the meta-analysis, saying that it was needed to put the benefits and risks of statins in perspective.

“These are very effective drugs at reducing the rates of heart attack and stroke in people who are at risk,” Stone told TCTMD. “The meta-analysis tells us that the number of people who can’t take them is not a wildly high number—it’s a small number—and I don’t know of a medicine that doesn’t have the potential for side effects. Every drug does, but for some reason, there’s been a huge overestimation of who can’t tolerate a statin. Many of us have patients who can take statins beautifully for many years without problems.”

Stone said that some “real-world” estimates of statin intolerance put the percentage as high as 50%, though that is not his experience in clinical practice. “Roughly 5% to 10% of people may have problems tolerating a statin, and there are ways to manage that,” he said.    

Similarly, James Underberg, MD (NYU Langone Health, New York, NY), said he’s even reluctant to use the term “statin intolerance” because it implies the patient can’t take any statin at any dose. Most patients, he said, can tolerate a statin at a low dose, even if it’s not ideal for ASCVD risk prevention. Like Stone, Underberg said the meta-analysis is an important addition to the field.

“It solidifies the belief that the randomized, clinical trials may underestimate statin intolerance a little bit,” he said. “They often preselect for patients who are less likely to have it whereas real-world clinical practice, as evidenced by the cohort studies, overestimates the prevalence because there’s not defined criteria used in a lot of clinical practice. Often the patient won’t completely report the symptoms as they should, or doctors don’t investigate symptoms that might be from other causes.”

In terms of the prevalence observed in the meta-analysis, Underberg said it’s ultimately reassuring. “Basically, nine out of ten people should be able to take a statin,” he told TCTMD. 

Less Than One in 10 Patients

To get at the true prevalence of statin intolerance, the researchers identified 112 randomized controlled trials and 64 cohort studies of statin-treated patients followed for a mean of 19 months. The studies largely included White participants (81.1%), with Black (8.25), Asian (5.1%), and Hispanic (4.5%) patients being in the minority.

When using the National Lipid Association (NLA) criteria—intolerance defined as an adverse effect that limits quality of life and leads to a decision to decrease or stop the medication—the prevalence was 7.0%. The International Lipid Expert Panel (ILEP) uses a similar definition for statin intolerance, and when it was used, the prevalence was 6.7%. The European Atherosclerosis Society (EAS) uses a somewhat stricter definition of statin intolerance by focusing specifically on statin-associated muscle symptoms (SAMS), elevations in creatine kinase (CK) levels, and their temporal association between statin initiation, discontinuation, and rechallenge. With the EAS definition, the prevalence of drug intolerance was 5.9%.

Banach said that diagnosing statin intolerance with a definition that includes challenging and rechallenging patients with different drugs and/or doses, and also looks at the timing of muscle pain or CK elevations, helps exclude or minimize the nocebo effect.  

The number of people who can’t take them is not a wildly high number—it’s a small number—and I don’t know of a medicine that doesn’t have the potential for side effects. Neil J. Stone

In a meta-regression analysis, age as a continuous variable was associated with a higher risk of statin intolerance, as was older age (> 65 years). Asian and Black patients were also at higher risk of statin intolerance, while women had a 47% higher relative risk of being drug intolerant compared with men.

Additionally, there was a positive association between several clinical indices and statin intolerance, among them, obesity, diabetes mellitus, hypothyroidism, chronic liver disease, and chronic liver failure. Exercise, alcohol, use of calcium channel blockers, and use of antiarrhythmic agents also were linked to statin intolerance, as was the prescription of a higher dose upon statin initiation.

“It’s a strong message for physicians,” said Banach. “You need to try to optimize treatment of these diseases, like diabetes, chronic kidney disease, and chronic liver disease, because you can decrease the risk of statin intolerance. If the disease is well controlled, you have a greater chance of the patient staying on the statin without any safety issues.”

Stone said that the decision to start a statin always begins first with a discussion, with the physician explaining to the patient why the drug is needed. Simply saying it’s for high cholesterol is not as effective as a conversation that details the patient’s risk profile and why the statin is needed for them at this time. In 2013, for example, the ACC/AHA guidelines began to emphasize the importance of that discussion before initiating statin therapy.

“You need to know the patient you’re talking to, and you need to manage their expectations,” said Stone. “Also, you need to understand their beliefs and concerns about medications.” He tells his patients that most people do very well on treatment. “And if they don’t, they can always stop the statin and find another statin that they can better tolerate. I have some patients that have hit the right statin on the second or third try.” 

Physician Inertia

Banach said that while patient nonadherence is an issue, physician inertia with statin therapy can be a problem, too. When a patient has symptoms shortly after starting a statin, there might be a tendency to give up on treatment too easily.

Physicians need to be diligent determining the characteristics of the muscle pain and when it first appeared, he said. SAMS will usually occur in the first few months after starting treatment, or with dose escalation. If the patient has been on therapy for a while, side effects might be related to the interaction between another newly started medication, such as an antiarrhythmic drug or calcium channel blocker, or possibly to uncontrolled diabetes or another medical condition, said Banach.

“It’s so important to take a full view of the patient,” he said. “Don’t ignore the whole situation because it’s so easy to then say, ‘OK, discontinue statin therapy.’” Even relatively short interruptions in statin therapy place high-risk patients at a significant risk of adverse cardiovascular events, he added. 

Basically, nine out of ten people should be able to take a statin. James Underberg

To TCTMD, Underberg said it’s likely a combination of clinicians and patients giving up a bit too easily when the first signs of side effects emerge. Trying different statins, or different doses, requires time and energy in the form of follow-up and callbacks but persistence matters. “I think the 9% to 10% rate [of intolerance] is something physicians can hold onto,” he said. “They can say, ‘Look, the likelihood of this happening to you is not high.’”

It’s been 20 years since the ACC, AHA, and National Heart, Lung, and Blood Institute published a clinical advisory on some potential risk factors that might influence statin safety. That advisory, Banach said, was based largely on expert opinion and there’s been no attempt to validate those risk factors in clinical trials or observational studies. This meta-analysis provides some data on patient characteristics and clinical conditions that are linked with statin intolerance, he said, and can help physicians address some of those issues instead of abandoning the LDL cholesterol-lowering drugs.