Statin Intolerance: How Common Is It and How Do We Work With Patients to Overcome It?

Christopher P. Cannon


Eur Heart J. 2022;43(34):3224-3226. 

Graphical Abstract: Goals and approach to patient-provider discussion for statin intolerance.

Statin therapy is perhaps the most beneficial therapy in all of cardiology. In numerous large randomized trials, lowering low density lipoprotein cholesterol (LDL-C) with statins (or other agents) leads to reductions in both morbidity and mortality in those with or at risk of cardiovascular (CV) disease.[1] The Cholesterol Treatment Trialists Collaboration showed a 22% reduction in CV events for each mmol LDL-C reduction, that is similar across essentially all subgroups of patients.[1] As such, use of statins is first line in all our guidelines, including the 2019 European Society of Cardiology (ESC) dyslipidaemia guidelines.[2]

Yet, on the internet and in public perception, statins are perhaps best known for their side effects and often viewed with great scepticism. Whenever the topic comes up, patients will report themselves or knowing others who had side effects and 'couldn't take' statins. This has become known broadly as 'statin intolerance.' Real side effects do occur with statins, as with all medications. Muscle symptoms are the most common side effect, and the European Atherosclerosis Society reviewed the literature and developed an approach to evaluating statin-associated muscle symptoms.[3] The same consensus panel then went on to define other side effects, finding evidence for worsening glycaemia, but conversely no evidence supporting (and indeed strong evidence refuting) any adverse effect on cognitive function.[4]

The current report in this issue of the European Heart Journal by the Lipid and Blood Pressure Meta-Analysis Collaboration (LBPMC) Group and the International Lipid Expert Panel (ILEP) is a tour-de-force analysis looking at the prevalence of statin intolerance in >4 million patients from 176 studies.[5] They find that the incidence of statin intolerance based on standard definitions is 9.1%, with 95% confidence limits of 8–10%. There was not a difference by type of statin or whether it was prescribed for primary or secondary prevention. Some clinical factors were seen as associated with higher rates, such as increasing age, female sex, obesity, or diabetes.

The overall 9% incidence is a key number that we can all use in our discussions with patients. It shows that statin intolerance is real, but relatively uncommon. The risk is not 100% as many patients suspect after searching the internet. The rate is also not zero, as some have thought based on small crossover studies finding a 'nocebo' effect, where side effects are sometimes reported when a patient is taking a placebo but not when taking no pills.[6,7] Other larger crossover studies have found that 26% of patients with a prior history of statin intolerance reported muscle symptoms with placebo but not statin (suggesting these were more perceived side effects in these patients), while 42% patients have symptoms only with statin and not with placebo (more clearly documenting statin intolerance in a blinded fashion).[8] In this same study of patients with prior statin intolerance, 10% had biomarker elevations of creatine kinase elevations with myalgias, thus clearly documenting statin intolerance in some. As such, the rate of 'true' statin intolerance varies. With this new publication, having this rate of 9% based on the entire world's literature and >4 million patients is a strong starting point for an evidence-based discussion with patients.[5]

So, how do I approach the issue of statin intolerance? First, I open a discussion with the patient and accept their prior experience and aim to work together to find a lipid-lowering regimen for them. Next, I assess and share with them their CV risk—so that they understand the problem that we are working to overcome. If they have prior known atherosclerotic cardiovascular disease (ASCVD), I share with them the evidence, and their risk of subsequent events (20–30% risk over 10 years). If not, I discuss the10-year risk of CV events based on the ASCVD Risk score, and I often also share the 30-year or 'lifetime' risk that can be estimated. If there is any doubt about their risk, use of calcium scoring is very helpful in identifying signs of atherosclerosis, or a finding of 0 could lead to revisiting the need for statin therapy.[9] Then, I calculate what a 35–40% risk reduction when treating with a statin would mean for them in terms of a lower risk of events. I also discuss the cholesterol plaque and diagram it for patients—to show them what we are treating. Then, I review the data on lowering LDL-C—on both CV events[10,11] and the data from intrascular ultrasound studies showing that plaques are stabilized when the LDL-C is ~70 mg/dL, and that they modestly remodel and stabilize if we get the LDL-C to < 70 mg/dL, with the lower the better.[12] The goal is for them to really understand why we are prescribing them the lipid-lowering therapies.

For further evaluation, it is important to re-examine whether intervening medical conditions may have developed (e.g. hypothyroidism, vitamin D deficiency, or rheumatological conditions) or whether interacting drugs may have contributed to their symptoms. Then, we discuss treatment options. If a patient is on a regimen at present and complains of possible muscle symptoms, I propose a 1-month holiday—to see if the symptoms improve—but also then, to complete the experiment, I propose to have them restart it and see if the symptoms return. If not, then we both would see that the initial symptoms might have been caused by something else. If the symptoms return, I point out to them that we will then have clearly documented that that statin does give them side effects. Next, I explain how statin intolerance has been seen to be dose related, so I usually propose a trial of ultra-low dose statin, non-daily dosing (e.g. rosuvastatin 2.5 mg three times a week or equivalent for other statins). I point out that this dose is ~1/10 of a typical statin dose and, with the alternate day dosing, in our experience many patients can tolerate it.[13] If they do tolerate the ultra-low-dose statin, then I offer to move up slightly on the dose. If they do have muscle symptoms, then we move on to ezetimibe or other non-statins, that have all been shown not to have an increase in muscle symptoms in large randomized trials.[14–16] I work with the patient to get them to their goal [<55 mg/dL (1.4 mmol) for recent acute coronary syndrome or very high risk patients, <70 mg/dL (1.8 mmol) for stable ASCVD, and <100 mg/dL (2.6 mmol) for primary prevention].[2] I have found this 'shared decision-making' process gives the best chance to get effective lipid-lowering therapy for our patients.