Statin-associated muscle symptoms: impact on statin therapy—European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management

From prevention to plaque rupture and infarction.

Practical aspects in the management of statin-associated muscle symptoms (SAMS)

Between 5-10% of patients discontinue statin therapy due to statin-associated adverse reactions, primarily statin associated muscle symptoms (SAMS). The absence of a clear clinical phenotype or of biomarkers poses a challenge for diagnosis and management of SAMS. Similarly, our incomplete understanding of the pathogenesis of SAMS hinders the identification of treatments for SAMS. Metabolomics, the profiling of metabolites in biofluids, cells and tissues is an important tool for biomarker discovery and provides important insight into the origins of symptomatology. In order to better understand the pathophysiology of this common disorder and to identify biomarkers, we undertook comprehensive metabolomic and lipidomic profiling of plasma samples from patients with SAMS who were undergoing statin rechallenge as part of their clinical care. We report our findings in 67 patients, 28 with SAMS (cases) and 39 statin-tolerant controls. SAMS patients were studied during statin rechallenge and statin tolerant controls were studied while on statin. Plasma samples were analyzed using untargeted LC-MS metabolomics and lipidomics to detect differences between cases and controls. Differences in lipid species in plasma were observed between cases and controls. These included higher levels of linoleic acid containing phospholipids and lower ether lipids and sphingolipids. Reduced levels of acylcarnitines and altered amino acid profile (tryptophan, tyrosine, proline, arginine, and taurine) were observed in cases relative to controls. Pathway analysis identified significant increase of urea cycle metabolites and arginine and proline metabolites among cases along with downregulation of pathways mediating oxidation of branched chain fatty acids, carnitine synthesis, and transfer of acetyl groups into mitochondria. The plasma metabolome of patients with SAMS exhibited reduced content of long chain fatty acids and increased levels of linoleic acid (18:2) in phospholipids, altered energy production pathways (β-oxidation, citric acid cycle and urea cycles) as well as reduced levels of carnitine, an essential mediator of mitochondrial energy production. Our findings support the hypothesis that alterations in pro-inflammatory lipids (arachidonic acid pathway) and impaired mitochondrial energy metabolism underlie the muscle symptoms of patients with statin associated muscle symptoms (SAMS).

Background: The Consensus Statement from the European Atherosclerosis Society (EAS) Consensus Panel 2017 concludes on the basis of 3 different types of clinical studies that low-density lipoprotein (LDL) causes atherosclerotic cardiovascular disease (ASCVD). In Mendelian randomization studies, rare genetic mutations affecting LDL receptor function were found to cause higher or lower LDL-C levels, which are associated with correspondingly altered ASCVD risk. In prospective cohort studies and randomized controlled trials (RCTs) of statins, a remarkably consistent log-linear association was demonstrated between the absolute magnitude of LDL-C exposure and ASCVD risk. The EAS Statement proposes that any mechanism of lowering plasma LDL concentration should reduce the risk of ASCVD events proportional to the absolute reduction in LDL-C and the cumulative duration of exposure to lower LDL-C. However, as we explain, we do not find this conclusion acceptable. Summary: Our review points out that different interpretations are possible for the results of Mendelian randomization studies. As for prospective cohort studies, many inconsistent reports on the association of LDL-C and ASCVD were disregarded when drafting the Statement, reports with and without genetic factors related to LDL receptor function should be analyzed separately, and the term ASCVD in the Statement is used inappropriately because myocardial infarction and cerebral infarction differ in their association with LDL-C. As for RCTs, clinical reports on statins published before and after the implementation of new regulations affecting clinical trials (2004/2005) should not both be included in meta-analyses because the evaluated efficacy of statins changed markedly, and the irreversible adverse effects of statins need to be evaluated more rigorously now that their mechanisms have been elucidated. Key Messages: Apart from the EAS hypothesis that LDL causes ASCVD, recent pharmacological/biochemical studies, as summarized in this review and elsewhere, have revealed that atherosclerosis is caused by statins taken to lower LDL-C, as well as by warfarin and some types of vegetable fats and oils, in the absence of significantly elevated LDL-C levels. Thus, the promotion of statin treatment by the Statement is rather risky and we do not feel that the conclusions are justified for the prevention of ASCVD.

Assessment and management of statin-associated muscle symptoms (SAMS): A clinical perspective from the National Lipid Association

Statins represent an important class of cardiovascular drugs for the prevention of atherogenic complications. However, despite the effectiveness of statins, non-adherence and discontinuation of therapy with these drugs is a problem worldwide. Reasons for not using statins in patients at high CV risk include statin-associated muscle symptoms (SAMS), which are not usually associated with significant elevations of serum creatine kinase. SAMS are the most common side effects of statins: 3–5% in RCTs, 15–20% in observational studies, and 60% in patient surveys. This range is possibly due to misinterpretation of symptoms, as well as patients’ expectation of harm from statin treatment (“statin fear”). The article highlights the problem of studying the role of nocebo and drusebo effects for SAMS, presents differences in definitions and methods of detection. The concept of the drucebo effect was proposed by the International Lipid Expert Group (ILEP, 2018) as a harm to the patient, unrelated to the pharmacological action of the drug (negative effect of the drucebo). The results of studies and meta-analyses evaluating the effects of nocebo and drusebo for SAMS are presented, in which no difference was found in the frequency and severity of muscle symptoms between statin and placebo; the nocebo rate was 90% of the statin effect, and the contribution of the drusebo effect to SAMS and statin discontinuation ranged from 38 to 78%. Also presented are current international guidelines and principles of patient management aimed at preventing discontinuation of statin use in connection with SAMS.

Recently, the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) published a consensus paper giving guidance on the definition and management of statin-associated muscle symptoms (SAMS), as well as the use of proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors in very high-risk patients. The occurrence of SAMS can have a major negative impact on treatment adherence and, consequently, on the prognosis of cardiovascular diseases. In addition, both the ESC guidelines on the prevention of cardiovascular disease (CVD) in clinical practice with sections addressing global strategies to minimise the burden of CVD at population and individual levels, and the 2016 ESC/EAS guideline for the management of dyslipidaemias, focus on evaluation and treatment of SAMS. The release of these guidelines was a source of great interest to clinicians, as new emergent therapies, such as the PCSK9 inhibitors, have been approved for the treatment of dyslipidaemias: recently, both the US Food and Drugs Administration (FDA) and the European Medicines Agency (EMA) approved the use of PCSK9 inhibitors as add-ons for the treatment of hypercholesterolaemia in cases where low-density lipoprotein cholesterol (LDL-C) target levels could not be reached with maximum tolerated statin doses alone, or instead of statins in the event of SAMS. Because of the relatively high cost of these new therapies, physicians need to justify the use of PCSK9 inhibitors by demonstrating that their high-risk patients' LDL-C levels have remained high (1) despite a well-conducted, but insufficiently effective high-intensity statin therapy (e.g. rosuvastatin 10-20 mg or atorvastatin 40-80 mg), or (2) in the event of the patient developing side effects, in particular severe SAMS, during treatment with at least three statins. In addition to SAMS, the use of PCSK9 inhibitors may be considered in patients with documented atherosclerotic cardiovascular disease or in patients with familial hypercholesterolaemia and poorly controlled LDL-C under the combination of maximum tolerated stain and ezetimibe.

Aims: This work evaluates the vitamin D status in patients with statins- associated muscle symptoms.
 Study Design: A case control prospective study.
 Place and Duration of Study: Neurology Department, Mansoura University, Mansoura, Egypt, between June 2020 and May 2021.
 Methodology: Total of 85 participants included in this study, 60 participants of them have chronic Stroke and ischemic heart disease, treated by different kinds of statins and 25 participants were healthy controlled individuals. The 60 patients were 35 males (55%) and 25 females (45%), with age ranging from 40 to 70 years. The 60 participants were divided into two groups: The first group included (30 patients) treated with statins and they did not have Statin-Associated Muscle Symptoms (SAMS).The second group included (30 patients) also treated with Statin and they complained of SAMS. The third group is the control group, which contains the 25 participants who were healthy people. The control group included15 males (55%) and 10 females (45%) with age ranged from 35 to 65 years. Laboratory investigations were conducted on all participants in this study. The participants were subjected to total of 5 laboratory tests, which include: (1) Vitamin D (Enzyme immunoassay method), (2) Total CK (Enzymatic method), (3) Total Cholesterol and Triglycerides (Enzymatic method), (4)High density lipoproteins Cholesterol (Precipitation method), (4)Low density lipoproteins Cholesterol (Freid Wald equation), and (5) C – reactive protein (CRP: Latex Agglutination Method) was done beside elecetrophysiology study ( Needle electromyography (NEMG) was include).
 Results: Out of 60 patients the statistical readings of Vitamin D levels for the studied groups, demonstrating a significant statistical difference in Vitamin D levels between patients complaining of statin-associated muscle symptoms group (P≤0.001), and the other groups with lowest mean of (26.30 ±3.75), while patient without statin-associated muscle symptom group had the mean rating of (29.33 ±3.69), and the control group had the highest mean of (30.14 ±3.57).
 Conclusion: There is a positive relationship between vitamin D deficiency and statin-associated muscle symptoms. Vitamin D status may play an important role in diagnosis and management of SAMS. Further studies are needed to evaluate the relationship between vitamin D and SAMS.

In the last two decades, statin therapy has proved to be the most potent isolated therapy for attenuation of cardiovascular risk. Its frequent use has been seen as one of the most important elements for the reduction of cardiovascular mortality in developed countries. However, the recurrent incidence of muscle symptoms in statin users raised the possibility of causal association, leading to a disease entity known as statin associated muscle symptoms (SAMS). Mechanistic studies and clinical trials, specifically designed for the study of SAMS have allowed a deeper understanding of the natural history and accurate incidence. This set of information becomes essential to avoid an unnecessary risk of severe forms of SAMS. At the same time, this concrete understanding of SAMS prevents overdiagnosis and an inadequate suspension of one of the most powerful prevention strategies of our times. In this context, the Luso-Latin American Consortium gathered all available information on the subject and presents them in detail in this document as the basis for the identification and management of SAMS.

Introduction Statin-associated muscle symptoms are common side effects of statin therapy. These symptoms include myopathy, myalgia, and rhabdomyolysis. Vitamin D has been associated with musculoskeletal health; thus, its deficiency may produce detrimental effects in this tissue. Indeed, one symptom of vitamin D deficiency is myalgia, and the normalization of low vitamin D levels can relieve it. Patients and Methods This cross-sectional study examined 1210 statin-treated patients to assess vitamin D status. These patients were divided into two groups: 287 with statin-associated muscle symptoms (SAMS) and 923 control patients without SAMS. Results We have found a significant association between deficient and insufficient vitamin D status and statin-associated muscle symptoms (SAMS). Vitamin D deficiency (<30 nmol/L) presents 77% (95% C.I. 71.6% to 81.7%) sensitivity and 63.4% (95% C.I. 60.2% to 66.5%) specificity in diagnosing SAMS. Odds ratio analysis showed that this association is moderate-strong both for deficient and for insufficient status. Conclusion We found a correlation between vitamin D deficiency and SAMS. Therefore, vitamin D levels may be useful for the diagnosis and management of SAMS.

Statin-associated muscle symptoms and SLCO1B1 rs4149056 genotype in patients with familial hypercholesterolemia

Background: Statins are the cornerstone pharmacotherapy for lowering LDL-C and reducing risk of ASCVD. However, statin initiation and adherence are limited by statin-associated muscle symptoms (SAMS), posing significant clinical and public health dilemmas. Mobile health (mHealth) tools offer novel ways to assess real-time symptom data and share them back with patients to facilitate shared decision-making. Objective: To assess the feasibility and usability of an automated, text-message-based SAMS symptom-tracking platform to longitudinally track SAMS in patients who previously experienced muscle symptoms while on statin therapy. Methods: We enrolled 19 patients from 2 clinics at a single health system (Johns Hopkins; Baltimore, MD) and recorded baseline demographics, statin history and indication, perceptions of SAMS, and technology use via an online survey. Quantitative SAMS scores were gathered via daily text messages, and qualitative symptom data were collected in weekly text messages. Monthly symptom reports were sent to select participants via email on study days 30, 60 and 90. Upon study completion, participants reported perceptions of the study, the mHealth platform, and study measures via an online exit survey. Results: A total of 18 patients (aged 59.3 [SD 14.5] years, 67% women) collected data, and 15 patients completed the 90-day study protocol. Overall response rate to text messages was 91.5% (92.2% for daily SAMS messages, 86.0% for weekly muscle symptom prompts). Patients reported a statin adherence of 70%. Nine patients reported intolerable muscle symptoms at least once during the study, and intolerable symptom scores represented 3% of all reported symptom scores. Patients reported overall satisfaction with the study and found the SAMS scores helpful. Conclusions: Patients with previously reported SAMS successfully engaged with a text-message-based symptom-tracking platform with high interactivity and acceptability. This study demonstrates the feasibility and usability of an automated mHealth platform for longitudinally tracking SAMS in patients on statin therapy, and may provide a means for improving shared decision making to tailor statin therapy and improve adherence.

Background Statin-associated muscle symptoms (SAMS) are the major side effects reported for statins. Data from previous studies suggest that 7–29% of patients on statin had associated muscle symptoms. In the UK, there is a lack of corresponding data on SAMS and factors associated with the development of SAMS. Objective This analysis is aimed at establishing the prevalence of SAMS and identifying major contributory risk factors in patients attending a lipid clinic. Methods Clinical records of 535 consecutive patients, who visited the lipid clinic in the University Hospitals of Leicester, were studied retrospectively between 2009 and 2012. SAMS were defined by the presence of muscle symptoms with two or more different statins. Patients who reported muscle symptoms to statin with one or no rechallenge were excluded. The association of SAMS with clinical characteristics such as age and BMI, sex, smoking, excess alcohol, comorbidities, and medications was tested for statistical significance. A binomial logistic regression model was applied to adjust for risk factors significantly associated with SAMS. Results The prevalence of SAMS was found to be 11%. On unadjusted analysis, the mean age of patients who had SAMS was significantly higher than those without SAMS (59.4 ± 10.5 years vs. 50.3 ± 13.4 years, respectively, P < 0.001). Nonsmokers were more likely to develop SAMS in comparison to active smokers (P = 0.037). Patients taking antihypertensive medications were more likely to develop SAMS (P = 0.010). In binomial logistic regression analysis, only age was positively and significantly associated with SAMS after adjusting for other risk factors (β = 0.054, P = 0.001). Conclusion To the best of our knowledge, this study is the largest cohort of patients with SAMS in the United Kingdom. Our data suggest that the prevalence of SAMS is 11% and increased age is a risk factor associated with the development of SAMS in our cohort of patients.

Pleiotropic effects of metformin to rescue statin-induced muscle injury and insulin resistance: A proposed mechanism and potential clinical implications

Adherence to hydroxymethylglutaryl-CoA reductase reductase inhibitor (statin) therapy correlates with cardiovascular mortality. Muscle symptoms are the most significant side-effects of statin therapy. This review article summarizes the current concepts of the diagnosis and clinical work-up of patients with statin-associated muscle symptoms (SAMS). SAMS represent a major barrier to maintain long-term persistence to statin treatment. SAMS reduce the quality of life and rare complications may extend to rhabdomyolysis. The molecular pathology of SAMS is heterogeneous. After exclusion of other causes of muscle symptoms the main principle of treatment is re-exposure to very low dose of statin and slow uptitration until the maximally tolerated dose is established. Using this approach the vast majority of patients can be treated with statins long term. For patients with SAMS that are not at low-density lipoproteins (LDL) goal with their maximally tolerated dose of statin combination therapy with ezetimibe and proprotein convertase subtilisin/kexin-9 inhibitors are available. Time and care is needed to address SAMS because they impair drug adherence. For most patients it is possible to continue the statin therapy. However, combination therapy is wanted if the maximally tolerated statin dose is not sufficient to reach LDL targets.