Statin Intolerance: Myths and Facts

Ulrich Laufs; Berend Isermann

Disclosures

Eur Heart J. 2020;41(35):3343-3345. 

Statin-associated muscle symptoms (SAMS) remain a highly controversial topic. Patients frequently complain about muscle symptoms that they associate with statin treatment while the large randomized statin trials do not report more frequent muscular symptoms compared with placebo.[1,2] There are few other topics with such a striking discrepancy between the experience during patient care and the results of high quality clinical research.

One important explanation for this phenomenon relates to the challenges of diagnosing SAMS and the differentiation from nocebo effects. The vast majority of patients with SAMS have normal serum creatine kinase (CK) concentrations, and a specific lab test is lacking. Imaging technologies, even in combination with muscle stress tests, or tissue biopsies have not yet been conclusive. The clinical presentation and the pathology are very heterogeneous and potentially multifactorial. This is reflected by the variety of definitions that can be found in the literature.[2] According to current consensus, the diagnosis SAMS is based on (i) the exclusion of (the large number) of potential alternative causes of muscle symptoms and (ii) the diagnostic strategy of stopping statin treatment, observation and assessment of symptoms, followed by re-exposure to different statin at low doses.[2] The term 'SAMS', as used, has disadvantages, as it does not differentiate between harmless muscle symptoms of various origin and potentially life-threatening muscle injury with the risk of rhabdomyolysis. The accuracy and the success of this time-consuming diagnostic process needed to differentiate the different forms of SAMS depend on the motivation and the skills of the treating physician (Figure 1). 'SAMS' are not measurable. Partially to overcome these limitations, the term 'statin intolerance' has been used in several randomized trials. It is defined by the inability to tolerate at least two statins, one at a pre-defined low dose, due to a prior adverse event that started during statin therapy and resolved when statin therapy was discontinued.[3] However, the terminology 'statin intolerance' is not specific for muscular symptoms and has negative connotations suggesting an end-stage condition without options for management or reversibility (e.g. as in 'zero tolerance'). Several colleagues believe that this term may be misused to promote the sale of new drugs and that the high prevalence of SAMS may be primarily driven by talking about this problem (nocebo effect). Both terms, 'SAMS' and 'statin intolerance', do not include information on risk/prognosis. There is need for international consensus on a clinically meaningful terminology that includes an actionable risk stratification, for example one could envisage a staged definition of SAMS such as stage 1 (no CK elevation, treatment with low-dose statin possible, excellent safety), SAMS stage 2 (no CK elevation, any form of statin treatment not possible, excellent safety), and SAMS stage 3 [CK >10× upper limit of normal (ULN)], increased risk of rhabdomyolysis, need to stop statin, monitoring].

Figure 1.

Flow-chart for management of patients with statin-associated muscle symptoms and normal creatine kinase. Following the EAS consensus, the first step is the exclusion of other causes of muscular–skeletal symptoms.2,14 Take time for the patient; a significant part of SAMS can be addressed by listening and reaching consensus on long-term risk reduction and safety. The next step is a 3–4 week break of statin treatment. If symptoms persist, non-statin causes of muscle symptoms have to be identified. Statin-induced muscle symptoms are reversible.2,9 The next step is re-exposure to statins. Re-starting with another statin provides an opportunity for a fresh start. Starting with a very low dose and increasing very slowly, the highest tolerable dose is established. If the individual LDL chlolesterol goal is not reached, new options for evidence-based combination therapy have become available. Based on the IMPROVE-IT trial, the EAS recommends ezetimibe as the first combination partner for statins.2 Bempedoic acid (BA) inhibits hepatic cholesterol synthesis upstream of statins. BA is an oral prodrug activated by a specific enzyme that is present in hepatocytes but not in skeletal muscle.15 BA lowers LDL-cholesterol, especially on the background of low-dose or no statin and in combination with ezetimibe.3,16 BA is being tested in the CLEAR outcomes trial on ~12 000 patients with 'statin intolerance' (NCT02993406). Positive outcome data are already available from several studies with anti-PCSK9 (proprotein convertase subtilisin/kexin type 9) antibodies that lower LDL cholesterol by ~50% irrespective of background therapy. The outcome trial with the PCSK9 small interfering RNA inclisiran is ongoing (ORION 4, NCT03705234). BA, PCSK9 antibodies, and PCSK9 small interfering RNA did not differ from placebo with regard to muscular symptoms and are well tolerated by patients with SAMS.

Novel and important information on this complex problem is provided by Hopewell and colleagues in this issue of the European Heart Journal. The authors provide data from three large trials (HPS, SEARCH, and HPS2-THRIVE) reporting on 58 390 individuals treated with simvastatin for a mean of 3.4 years.[4] In these trials, 'myopathy' was prospectively defined as otherwise unexplained muscle pain or weakness with CK >10× ULN and adjudicated in 171 cases (0.3%). New unexplained muscle pain or weakness that was not associated with a diagnosis of 'myopathy' (within 28 days) was defined as 'other muscle symptoms' and occurred in 15 208 individuals (26%). The analysis reveals independent risk factors for 'myopathy', namely higher simvastatin dose, Chinese ethnicity, female sex, higher age, lower body mass index (BMI), diabetes mellitus treated with hypoglycaemic agents, and concomitant use of niacin–laropiprant, verapamil, beta-blockers, diltiazem, and diuretics. These risk factors predicted a >30-fold risk difference between the top and bottom thirds of a novel 'myopathy risk score' derived from the combination of these factors by the authors. Despite the strong association with 'myopathy', this score was not associated with the 'other muscle symptoms'. The authors report that 'myopathy' in male Europeans only occurred in diabetics with a BMI <25 that are treated with a beta-blocker and diuretics. In Caucasians females, 'myopathy' was limited to a BMI of ~20. These data clearly demonstrate the extremely low absolute risk of simvastatin-related 'myopathy' and provide criteria to identify individuals at low and at higher risk. Validation and comparison of this risk score in independent future studies is required to prove its utility and clinical value.[5] Another interesting aspect requiring future work-up is the observation that almost two-thirds of the affected individuals developed SAMS after 6 months or later, when a steady-state can be assumed. What are the events triggering SAMS in these patients?

The SLCO1B1 (solute carrier organic anion transporter family member 1B1) is a transporter that takes up statins into hepatocytes. The SLCO1B1 polymorphism (c.521T>C, p.V174A) is associated with increased statin blood levels. Heterozygous carriers of the genetic variant exhibit a 4.5-fold and homozygous carriers a 17-fold increased risk of 'myopathy' with simvastatin.[6] The analysis by Hopewell and colleagues reports on a high number of genotyped participants (n = 9109). Although SLCO1B1 genotype was associated with 'myopathy', carriers of the C allele of SLCO1B1 had the same risk of muscle pain or weakness under simvastatin treatment compared with the TT genotype (odds ratio per C allele: 0.97, 95% confidence interval 0.88–1.05, P = 0.43).[4] The data confirm that genotyping of SLCO1B1 has a very low specificity and a very low positive predictive value for SAMS. The lack of association of the 'myopathy risk score' and the SLCO1B1 variants with 'other muscle symptoms' suggests that these conditions are not necessarily part of one continuum. Hopewell and colleagues indeed conclude that 'The lack of association of the myopathy risk score with other muscle symptoms reinforces randomized placebo-controlled evidence that statins do not cause the vast majority of reported muscle symptoms'.

Every important study has some limitations. Different protocols to monitor CK were used in the studies considered. The analysis is focused on simvastatin, but the data, especially on SLCO1B1, may not apply to other statins. Simvastatin has several disadvantages compared with atorvastatin and rosuvastatin in addition to the lower potency. In 2011, the Food and Drug Administration (FDA) recommended limiting the use of simvastatin 80 mg because of increased risk of muscle damage and recommended not to exceed 10/20 mg simvastatin in combination with drugs such as amiodarone, verapamil, diltiazem, and ranolazine due to the potential interaction at the cytochrome P450 3A4 system (http://www.fda.gov/Drugs/DrugSafety/ucm256581.htm). For these reasons, simvastatin is not the first choice. The proposed 'myopathy risk score' is limited by the inclusion of niacin, laropiprant, and the early-generation calcium blockers diltiazem and verapamil that are contra-indicated in the majority of patients. Finally, the report of the genetic analysis of SLCO1B1 does not consider other variants associated with SAMS such as the leucocyte immunoglobulin-like receptor subfamily B5 locus.[7] In the light of the extremely high variability ( >40-fold) of statin plasma levels reported for patients taking the same dose, the clinical significance of the transporter gene variants is still unclear.[8]

From a practical perspective, Hopewell and colleagues recommend that patients on statins with elevated CK levels should be monitored and patients without CK elevation should be encouraged to continue taking their statin therapy because 'these commonly reported muscle symptoms are not part of a continuum with simvastatin-related myopathy, but instead represent a nocebo effect'. Based on the trial evidence and from clinical experience, this conclusion applies to the majority of patients with SAMS.[2] However, despite their indisputable importance and very high quality, HPS, SEARCH, and HPS2-THRIVE may under-represent groups with increased risk of SAMS such as individuals with previous muscle symptoms, rare genic causes of myopathy, frailty, arthritis, thyroid disorders, alcohol consumption, high level of physical activity, and history of poor statin tolerance in the past. Importantly, mild muscle symptoms may have escaped adjudication but may be highly relevant for patients and their medication adherence. The STOMP trial, one of the very rare prospective studies specifically addressing skeletal muscle function and performance, documented a rate of statin-related muscle complications of ~5% after accounting for the nocebo effect. This was accompanied by an average increase of CK by 21 U/L but no effect on muscle strength or exercise performance.[9] This is in agreement with the clinical experience that the vast majority (~90%) but certainly not 100% of 'other muscle symptoms' are nocebo effects. Statin discontinuations are frequent and dangerous because of their association with atherosclerotic cardiovascular (ASCVD) events.[10,11] The likelihood of a patient complaining of muscle symptoms, which are believed to be caused by a statin, to stay on the medication for the long term is low. The most important finding of the elegant study by Hopewell and colleagues is the reassurance on the safety of statins. Their data are very helpful as background information to keep patients on statin medication. Irrespective of CK and of the highly prevalent nocebo effects, each patient reporting with SAMS requires attention and time—not for reasons of safety but in order to support medication adherence and to reach LDL cholesterol goals. The issue of SAMS has to be fully resolved for each individual patient. In the majority of patients presenting with SAMS, therapy can be continued.[12,13] However, even after careful work-up (Figure 1), some patients cannot tolerate a sufficient dose of a statin. For these selected individuals, combination therapy has emerged as a successful strategy with additional treatment options on the horizon.

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