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Addressing Statin Intolerance In Practice: Moving Beyond the Controversy

Low-density lipoprotein cholesterol (LDL-C) has been shown to be atherogenic and likely have a causal relationship for the development of atherosclerotic cardiovascular disease (ASCVD).¹ Thus, reducing LDL-C levels is imperative in decreasing the impacts of ASCVD, as demonstrated in several studies.² Since their introduction more than 30 years ago, statins, along with lifestyle modifications, have been the treatment of choice in lowering cholesterol. They decrease cholesterol by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA), a rate-limiting step in cholesterol synthesis.³ Multiple large outcomes trials have demonstrated the efficacy of statins in not only lowering LDL-C but more importantly, reducing major adverse cardiovascular events both in the primary and secondary prevention of ASCVD.⁴ Given the strength of evidence and the cost-effectiveness, statins remain the first-line treatment of patients with elevated LDL-C, which was also highlighted in the updated 2018 AHA/ACC cholesterol guidelines.²

However, a large gap remains between guideline recommendations and use of statins in actual practice, with studies showing that a large number of eligible patients are not on statin therapy, or are not adherent to therapy.^5-9 This includes patients at high-risk for primary or secondary events, including patients with diabetes or cardiometabolic risk, and statin underutilization and non-adherence can increase ASCVD morbidity and mortality.⁸ Even when patients are initiated on statins, many discontinue statin therapy within the year of starting it.⁶ Real-world studies have shown that less than 40% of patients persist in taking statins for primary prevention at the 3-year post-initiation mark, while these number is only 45% for secondary prevention.⁸ One of the many reasons that lead to discontinuation of statin therapy can be statin intolerance, which is most frequently attributed to muscle-related adverse events.10 Often patients will discontinue statins without consulting their physician, which increases their cardiovascular risk.¹⁰

“One of the reasons for statin underutilization is that patients frequently go on the internet and read the negative complications associated with statins and are afraid to take a statin therapy. Another reason is that hypercholesterolemia is a silent killer. One does not feel anything until something bad happens like a heart attach or a stroke, and it is always very hard to treat silent conditions. That is why, for example, blood pressure is hard to treat, and we still do a dismal job in controlling it” — Leslie Cho, MD, Professor of Medicine and Section Head of Preventative Cardiology and Rehabilitation at the Cleveland Clinic in Ohio – told Cardiometabolic Chronicle in an interview.

The prevalence of statin intolerance is still widely debated mostly due to difficulties in identification and diagnosis.¹⁰ “Statin intolerance is unfortunately very common, but when we look at randomized controlled studies, reported rates are as low as <1% of the study populations. Part of this is due to randomized studies enrolling healthier patients; also, patients that had statin-related adverse events during the run-in-period were excluded from the studies. Conversely, when we look at real-world registries, such as the French registry of primary care clinics¹¹ or US insurance database studies² , statin intolerance is around 5-10%” – Dr. Cho added.

Statin intolerance can lead to statin discontinuation or suboptimal therapy, thus it is crucial to identify patients that are exhibiting true statin-associated side effects, and address these symptoms accordingly. “The most important thing for identifying statin intolerance is obtaining a very thorough patient history. Statin intolerance or its symptoms can be induced by concurrent medications that the patients are taking; for instance, several cardiovascular drugs and antibiotics can interact with statins, leading to reduced statin elimination, and increasing the risk of statin intolerance. Also, patients on fenofibrates and statins, or with underlying muscle issues, are at an increased risk for statin-associated myalgia. We should ask patients how long after initiating statin therapy they experienced muscle aches or weakness; if they report pain after just one dose than most likely it is not true statin intolerance, but if the pain appears a month after starting statins, is persistent and affects the patients’ quality of life, then we may think about the possibility of true statin intolerance. Therefore, it becomes crystal clear that getting to know the medical history of the patient before stopping or modifying statin therapy is very crucial as there is no simple test or a questionnaire to determine statin intolerance. ” – said Dr. Cho.

Very frequently, in patients with statin intolerance, it may be advisable to change the dose, switch to a different statin, or try an alternate-day regimen.¹² “The lipophilicity and hydrophilicity of statins plays an important role, as hydrophilic statins such as rosuvastatin and pravastatin are less likely to cause muscle aches than lipophilic statins such as simvastatin and atorvastatin. In our clinic, we often start with rosuvastatin once a week with the lowest dose, if the patient can tolerate it, we go to twice a week usually Monday and Thursday and then escalate the dose or the frequency depending upon their performance” – said Dr. Cho, while further adding “in our own study at the Cleveland Clinic¹² of more than 1600 patients that were intolerant to two or more statins, intermittent dosing was effective to achieve LDL-C goals and keep patients on statins; 72.5% of them could tolerate some form of long-term statin therapy, with 63.2% on a daily regimen, and 9.3% on intermittent dosiing, while 27.5% were statin-intolerant. Remarkably, the GAUSS-3 trial¹³, which was a statin intolerance study with the PCSK9 inhibitor evolocumab, echoed our findings, reporting that about 40% of patients population had true statin intolerance.”

The risk of incident diabetes is another common concern with statin therapy, with several studies suggesting that statin treatment may significantly increase the risk of type 2 diabetes onset in patients with hypercholesterolemia.^{8, 14, 15} However, despite the increase in incident diabetes, the cardiovascular risk reduction with statins is similar in patients with diabetes and those without, and these benefits outweigh any potential risk, a view supported in clinical practice guidelines and position statements.^{2, 8, 16, 17}

“Absolutely, the statin cardiovascular and mortality benefits outweigh the diabetes risk. This was also shown in the JUPITER trial, ¹⁸ where high-intensity statin therapy (rosuvastatin 20 mg) did not increase diabetes in patients with no major diabetes risk factors, but it did accelerate the average time to diabetes diagnoses in predisposed patients with diabetes risk factors. Unfortunately, the harmful effects of statins are more popular and it is remarkable how much negativity about statins exists in the internet and media. This has caused a “nocebo effect” regarding statins, in which patients develop symptoms because of preconceived negative expectations from its treatment. Lifestyle modifications, including diet and exercise, are the cornerstone of hypercholesterolemia management, followed by statin therapy. Statins have been around for 40 years, are extremely beneficial, cost-effective, have important pleiotropic benefits, and are generally safe. We can be seduced by the latest and greatest therapies, but the therapy that has proven to reduce mortality, myocardial infarction, and cardiovascular event rates, has been this oral medicine that now is cheap to take, so I believe that statins will still have a huge role going forward” – concluded Dr. Cho

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