Statin myopathy: navigating the maze

In addition to adopting a healthier life style, statin treatment is the foundation of cardiovascular disease (CVD) management. Statin therapy is generally well tolerated by most individuals. However, treatment is sometimes limited due to statins’ side effects, especially in the form of muscle symptoms. Indeed, statin associated muscle symptoms (SAMS) are the most frequent adverse events reported by statin treated patients¹. The risk of SAMS development became of increased scientific as well as general public interest in 2001, when cerivastatin was associated with severe muscle toxicity and was withdrawn from the market after 52 deaths from rhabdomyolysis².

The reported incidence of SAMS varies between different study types. Randomized controlled trials (RCTs) show a low prevalence of SAMS which is similar between statin and placebo users. Indeed, in the Heart Protection Study (n = 20,536) muscle symptoms were noted only in 0.5% in both the simvastatin and the placebo group³. Recently, the HOPE 3 study revealed a small difference in muscle symptoms between rosuvastatin and placebo (5.8% vs. 4.7% respectively, p = 0.005)⁴. However, there was no significant difference in the number of patients permanently discontinuing study treatment because of these symptoms (1.3% vs. 1.2% respectively). On the other hand, observational studies report a higher rate of SAMS (from 10% up to 29%) compared to RCTs^5,6. This discrepancy may be attributed to the carefully selected population of RCTs as these studies often exclude elderly individuals, patients with prior muscle-related symptoms or various comorbidities and comedications. Notably, severe statin toxicity (i.e. rhabdomyolysis) is overall rare in statin treated patients. Indeed, the average incidence of hospitalization for rhabdomyolysis with atorvastatin, pravastatin, or simvastatin was shown to be 0.44 per 10,000 patient-years⁷. Similarly, the US Food and Drug Administration Adverse Event Reporting System database reports rates of statin-induced rhabdomyolysis of 0.3–13.5 cases per 1,000,000 statin prescriptions⁸.

There are numerous definitions and categorizations of SAMS. This impedes the physician’s endeavor to catalogue muscle related symptoms reported by patients. Moreover, not all muscle symptoms in statin treated patients are SAMS. As a result, the physician comes against the challenging task of distinguishing SAMS from other entities. This diagnosis becomes even more difficult since the muscle reported symptoms are subjective, there is no “gold standard” diagnostic test nor a universally approved risk score in order to evaluate the presence of SAMS. Different expert panels have proposed various definitions as well as classifications of SAMS^9–12.

The National Lipid Association’s Muscle Safety Expert Panel proposed muscle adverse events to be defined as: (i) “myalgia” (muscle pain), (ii) “myopathy” (muscle weakness), (iii) “myositis” (muscle inflammation as determined by skeletal muscle biopsy and/or magnetic resonance imaging), (iv) “myonecrosis” (muscle injury based on the magnitude of serum creatine kinase [CK] elevation in comparison to the patient’s pre-statin CK level or an arbitrary normative upper limit adjusted for age, race, and sex), and (v) “myonecrosis with myoglobinuria or acute renal failure” or “clinical rhabdomyolysis” (increase in serum creatinine ≥0.5 mg/dL)¹¹. Moreover, this expert panel recommended a statin myalgia clinical index score based on the distribution of muscle complaints, temporal pattern of onset and improvement after statin withdrawal, and recurrence on rechallenge¹¹. The European Atherosclerosis Society (EAS) Consensus Panel suggested that assessment should be based on the presence of muscle symptoms as well as CK levels¹². According to the consensus, all reported muscle-related adverse events (i.e. pain, weakness, or cramps) should be categorized as “muscle symptoms” and then further subcategorized according to CK levels. Moreover, two additional categories include asymptomatic increases of CK levels. The probability of muscle symptoms being associated with statin use should be evaluated after examining the nature of muscle symptoms, the elevation of CK levels and their temporal association with statin initiation, discontinuation, and rechallenge. However, in view of the rarity of CK elevations during statin therapy, EAS does not recommend routinely monitoring CK levels¹². In a similar tone to the EAS suggestions is the position paper from the International Lipid Expert Panel⁹. According to their recommendations, SAMS include manifestations such as muscle aches or myalgia, weakness, stiffness, and cramps. Moreover, it is underlined that assessment of CK alone cannot adequately predict statin-associated myopathy. Recently, the Canadian Consensus Working Group released an update on statin adverse effects and intolerance¹⁰. It categorized SAMS based on the presence of symptomatic myopathy and CK levels. Myopathy is defined as muscle ache/weakness and is categorized as: i) ‘myalgia’ (without elevated CK levels) ii) “myositis” (with moderate increased CK levels or muscle biopsy) and “rhabdomyolysis” (with CK levels >10 times upper limit of normal [ULN]). Increased levels of CK are also categorized as: mild grade 1 (≤5 times ULN), mild grade 2 (5 times ULN < CK ≤10 times ULN), moderate (10 times ULN < CK ≤50 times ULN) and severe (CK >50 times ULN).

After the establishment of SAMS diagnosis comes the important step of its management before labeling a patient as statin intolerant. Most patients who develop SAMS can generally tolerate a different statin or at least an intermittent statin dosing strategy^13–15. All previous expert panels share a similar general core that every physician should follow^9–12. Initially, the presence of risk factors associated with SAMS should be evaluated. Indeed, comorbid conditions (e.g. hypothyroidism, genetic muscle defects), concomitant medications (e.g. gemfibrozil, azole antifungals) and high level of physical activity are some of the commonly found etiologies for the development of SAMS. Moreover, the need for statin treatment of the individual patient should be reassessed. Subsequently, patients unable to tolerate a statin should try a lower dose of an alternative statin. If the patient is still intolerant, a non-daily dose of statin is recommended (especially long acting statins) and lipid levels should be assessed between 4 and 12 weeks of therapy^9–12. The frequency and dosage of statin treatment should then increase as tolerated with the end target being the highest dose tolerated regardless of goal attainment as it has been demonstrated that even modest low-density lipoprotein cholesterol (LDL-C) reductions can improve long-term outcomes¹⁶. Finally, the use of complementary therapies (e.g. ubiquinone, vitamin D supplementation) is not recommended for SAMS management¹².

The development of SAMS in a patient does not necessarily translate to general statin intolerance. Therefore, great caution is required when labeling a subject as statin intolerant in order to avoid a misdiagnosis that can deprive a patient at CVD risk from statin treatment. Different descriptions of statin intolerance have been used in various clinical studies. Major expert panels have proposed their definitions of statin intolerance as well as management of these patients^9–12. The International Lipid Expert Panel defines statin intolerance as 1) the inability to tolerate at least two different statins – one statin at the lowest starting average daily dose and the other statin at any dose, 2) intolerance associated with confirmed, intolerable statin-related adverse effect(s) or significant biomarker abnormalities, 3) symptom resolution or significant improvement upon dose decrease or discontinuation, 4) symptoms changes not attributable to established predispositions such as drug–drug interactions and recognized conditions increasing the risk of statin intolerance⁹. The recent Canadian consensus also proposed a definition for goal-inhibiting statin intolerance: “A clinical syndrome characterized by significant symptoms and/or biomarker abnormalities that prevent long term use of and adherence to indicated use of statins as documented by challenge/de-challenge/re-challenge, when appropriate, using at least two statins, including atorvastatin and rosuvastatin, that is not due to drug–drug interactions or untreated risk factors for intolerance (e.g. untreated hypothyroidism), and leading to failure to maintain therapeutic goals as defined by national guidelines”¹⁰. The EAS panel avoided the use of the term “statin intolerance” in their SAMS statement on the basis that it is not specific for muscle symptoms¹². Similarly, no definition of statin intolerance is provided by the SAMS statement of the National Lipid Association¹¹.

Following the classification of a patient as statin intolerant, the physician is faced with the challenging decision of selecting the best alternative CVD management route. Currently there are several alternative treatment options for lipid lowering which have shown their efficacy in LDL-C reduction. However, their use is limited by their lack of beneficial CVD outcome data in contrast to statins. All major expert panels agree on a similar strategy in patients with statin intolerance^9–12. When the maximum tolerated statin dose cannot achieve therapeutic goals as monotherapy, adjunct therapy such as ezetimibe, niacin, resins, fibrates, PCSK9 inhibitors, microsomal transfer protein inhibitors or anti-sense oligonucleotide are recommended on top of statins. If the achieved LDL-C, after maximum tolerated statin dose, is no more than 20% higher than the patient's LDL-C goal, then ezetimibe is the preferred complimentary treatment of choice. This recommendation is based on the prospect that ezetimibe can achieve a 20% reduction of LDL-C when added on top of statin treatment while also having an established CVD risk reduction benefit¹⁷.

In the present issue of Current Medical Research & Opinion, a position paper from the Luso-Latin American Consortium is published regarding SAMS¹⁸. The authors present a comprehensive review of the current data regarding SAMS pathophysiology and describe muscle symptoms that are indicative of statin origin. The severity of SAMS is categorized into seven groups according to CK levels as well as symptom intensity and suggestions for handling each stage are provided¹⁸. The consortium offers a definition of statin intolerance as well as an algorithm for the management of these patients.

An interesting aspect of patient reported muscle symptoms during statin therapy is the role of the nocebo effect (i.e. a negative outcome caused by the suggestion or belief that something is harmful)¹⁹. Similar to the placebo effect, the nocebo effect reflects human neuropsychology rather than drug toxicity. Indeed, statin associated symptoms may be based on the patient’s misinformation through social media or even misinterpretation of the physician’s warnings regarding statin associated side effects²⁰. As a result, some patients may experience the nocebo effect associating unrelated symptoms with their statin use. This leads to poor treatment adherence or even statin discontinuation that is associated with higher CVD risk. Indeed, a meta-analysis showed low adherence patients had a 15% higher CVD risk compared with those with higher adherence²¹. Compliance becomes even more problematic as statin treatment targets the long term prevention of a possible future CVD outcome and not the resolution of currently present symptoms²².

Overall, although statins are well tolerated, physicians should be vigilant for any patient reported adverse effects with muscle symptoms being the most common. Initially, the potential causality of statin treatment should be evaluated and secondary causes of muscle symptoms explored in order to rule out false positives. Since the majority of patients with SAMS will be able to tolerate a statin even at intermittent dosing, an alternative statin based plan should be selected. Statins have proven their CVD reduction efficacy and therefore when possible should remain at the basis of CVD management with the augmentation of alternative lipid lowering therapies to achieve lower LDL-C levels if necessary.

In conclusion, the physician is tasked with establishing a trustful relationship with the patient requiring statin treatment. The patient should be made aware of possible statin associated side effects without establishing negative expectations. On the other hand, it is of great importance the patient understands the rationale for their statin treatment and that the expected CVD benefits vastly outweigh any possible adverse effect that may develop.

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This editorial was not funded.

Declaration of financial/other relationships

All authors have disclosed that they have no significant relationships with or financial interests in any commercial companies related to this article.

The CMRO peer reviewer on this manuscript has no relevant financial or other relationships to disclose.