Management Of Statin-associated Muscle Symptoms Research Articles

Decoding the Intricacies of Statin-Associated Muscle Symptoms.

Hyperlipidemia is the major cardiovascular morbidity and mortality risk factor. Statins are the first-line treatment for hyperlipidemia. Statin-associated muscle symptoms (SAMS) are the main reason for the discontinuation of statins among patients. The purpose of this review is to guide clinicians to recognize the difference between self-limited and autoimmune statin myopathy in addition to the factors that potentiate them. Finally, treatment strategies will be discussed. This review mostly focuses on new data in the past 3 years. Recent findings suggest that SAMS is a complex and multifactorial condition that involves mitochondrial dysfunction, oxidative stress, and immune-mediated mechanisms. Effective management of SAMS requires a thorough evaluation of the patient's symptoms, risk factors, and medication history, as well as consideration of alternative treatment options. While statins are effective in reducing the risk of cardiovascular events, their use is associated with a range of adverse effects, including SAMS.

Effect of statin treatment on metabolites, lipids and prostanoids in patients with 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).

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

Statin-associated muscle symptoms (SAMS) are the most common form of statin intolerance and are associated with increased risk of cardiovascular events that manifest from statin underutilization and discontinuation. The reported frequencies of SAMS are divergent in the literature. The writing group estimates the prevalence of SAMS, namely all muscle symptoms temporally related to statin use but without regard to causality, to be about 10% (range 5% to 25%), and the prevalence of pharmacological SAMS, specifically muscle symptoms resulting from pharmacological properties of the statin, to be about 1-2% (range 0.5% to 4%). In clinical practice, SAMS are likely to result from a combination of pharmacological and nonpharmacological effects, however this does not make the symptoms any less clinically relevant. Regardless of the etiology, SAMS need to be addressed in accordance with patients' preferences and experiences. This clinical perspective reviews the epidemiology and underlying pathophysiology of SAMS, and the cardiovascular consequences resulting from statin discontinuation. We present patient-centered clinical and communication strategies to mitigate SAMS and improve medication adherence and outcomes among statin users. Treatment strategies include 1) optimizing lifestyle interventions, 2) modulating risk factors that may contribute to muscle symptoms, 3) optimizing statin tolerability by dose reduction, decreased dosing frequency, or use of an alternate statin with more favorable pharmacokinetic properties, and 4) use of non-statins, emphasizing those with evidence for atherosclerotic risk reduction, either in combination with or in place of statin therapy depending on the patient's circumstances. The focus of this clinical perspective is sustainable lipoprotein goal achievement, which is important for cardiovascular risk reduction.

Step-by-step diagnosis and management of the nocebo/drucebo effect in statin-associated muscle symptoms patients: a position paper from the International Lipid Expert Panel (ILEP).

Statin intolerance is a clinical syndrome whereby adverse effects (AEs) associated with statin therapy [most commonly statin‐associated muscle symptoms (SAMS)] result in the discontinuation of therapy and consequently increase the risk of adverse cardiovascular outcomes. However, complete statin intolerance occurs in only a small minority of treated patients (estimated prevalence of only 3–5%). Many perceived AEs are misattributed (e.g. physical musculoskeletal injury and inflammatory myopathies), and subjective symptoms occur as a result of the fact that patients expect them to do so when taking medicines (the nocebo/drucebo effect)—what might be truth even for over 50% of all patients with muscle weakness/pain. Clear guidance is necessary to enable the optimal management of plasma in real‐world clinical practice in patients who experience subjective AEs. In this Position Paper of the International Lipid Expert Panel (ILEP), we present a step‐by‐step patient‐centred approach to the identification and management of SAMS with a particular focus on strategies to prevent and manage the nocebo/drucebo effect and to improve long‐term compliance with lipid‐lowering therapy.

The Relation of Vitamin D Blood Level with Statin-Associated Muscle Symptoms (SAMS)

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.

Reported muscle symptoms during statin treatment amongst Italian dyslipidaemic patients in the real-life setting: the PROSISA Study.

AimStatin‐associated muscle symptoms (SAMS) are a major determinant of poor treatment adherence and/or discontinuation, but a definitive diagnosis of SAMS is challenging. The PROSISA study was an observational retrospective study aimed to assess the prevalence of reported SAMS in a cohort of dyslipidaemic patients.MethodsDemographic/anamnestic data, biochemical values and occurrence of SAMS were collected by 23 Italian Lipid Clinics. Adjusted logistic regression was performed to estimate odds ratio (OR) and 95% confidence intervals for association between probability of reporting SAMS and several factors.ResultsAnalyses were carried out on 16 717 statin‐treated patients (mean ± SD, age 60.5 ± 12.0 years; 52.1% men). During statin therapy, 9.6% (N = 1599) of patients reported SAMS. Women and physically active subjects were more likely to report SAMS (OR 1.23 [1.10–1.37] and OR 1.35 [1.14–1.60], respectively), whist age ≥ 65 (OR 0.79 [0.70–0.89]), presence of type 2 diabetes mellitus (OR 0.62 [0.51–0.74]), use of concomitant nonstatin lipid‐lowering drugs (OR 0.87 [0.76–0.99]), use of high‐intensity statins (OR 0.79 [0.69–0.90]) and use of potential interacting drugs (OR 0.63 [0.48–0.84]) were associated with lower probability of reporting SAMS. Amongst patients reporting SAMS, 82.2% underwent dechallenge (treatment interruption) and/or rechallenge (change or restart of statin therapy), with reappearance of muscular symptoms in 38.4% (3.01% of the whole cohort).ConclusionsThe reported prevalence of SAMS was 9.6% of the whole PROSISA cohort, but only a third of patients still reported SAMS after dechallenge/rechallenge. These results emphasize the need for a better management of SAMS to implement a more accurate diagnosis and treatment re‐evaluation.

Statin-associated muscle symptoms: epidemiology, risk factors, mechanisms and treatment

Statins are widely prescribed and the risk of adverse drug reactions of lipid-lowering therapy is actively discussed, including muscle symptoms. This review synthesizes the knowledge about the clinical aspects of statin-associated muscle symptoms, which is important for the practitioner. Potential mechanisms of their development, risk factors, clinical manifestations, treatment and prevention are described. Timely detection the side effects of statins makes it possible to diagnose and eliminate, which is crucial for conducting lipid-lowering therapy for patients with atherosclerotic cardiovascular diseases. Management of statin-associated muscle symptoms requires altering (reduced dosages, use of another statin or alternative lipid-lowering drugs) or discontinuing the statin treatment.

Vitamin D Serum Levels in Patients with Statin-Induced Musculoskeletal Pain.

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 Toxicity.

There is now overwhelming evidence to support lowering LDL-c (low-density lipoprotein cholesterol) to reduce cardiovascular morbidity and mortality. Statins are a class of drugs frequently prescribed to lower cholesterol. However, in spite of their wide-spread use, discontinuation and nonadherence remains a major gap in both the primary and secondary prevention of atherosclerotic cardiovascular disease. The major reason for statin discontinuation is because of the development of statin-associated muscle symptoms, but a range of other statin-induced side effects also exist. Although the mechanisms behind these side effects have not been fully elucidated, there is an urgent need to identify those at increased risk of developing side effects as well as provide alternative treatment strategies. In this article, we review the mechanisms and clinical importance of statin toxicity and focus on the evaluation and management of statin-associated muscle symptoms.

Coenzyme Q10 as Treatment for Statin-Associated Muscle Symptoms-A Good Idea, but….

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are extremely well tolerated but are associated with a range of mild-to-moderate statin-associated muscle symptoms (SAMS). Estimates of SAMS incidence vary from <1% in industry-funded clinical trials to 10-25% in nonindustry-funded clinical trials and ∼60% in some observational studies. SAMS are important because they result in dose reduction or discontinuation of these life-saving medications, accompanied by higher healthcare costs and cardiac events. The mechanisms that produce SAMS are not clearly defined. Statins block the production of farnesyl pyrophosphate, an intermediate in the mevalonate pathway, which is responsible for the production of coenzyme Q10 (CoQ10). This knowledge has prompted the hypothesis that reductions in plasma CoQ10 concentrations contribute to SAMS. Consequently, CoQ10 is popular as a form of adjuvant therapy for the treatment of SAMS. However, the data evaluating the efficacy of CoQ10 supplementation has been equivocal, with some, but not all, studies suggesting that CoQ10 supplementation mitigates muscular complaints. This review discusses the rationale for using CoQ10 in SAMS, the results of CoQ10 clinical trials, the suggested management of SAMS, and the lessons learned about CoQ10 treatment of this problem.

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

Background and aimsStatin-associated muscle symptoms (SAMS) frequently cause statin non-adherence, switching and discontinuation, contributing to adverse cardiovascular (CV) outcomes. Therefore, the management of SAMS is key in the effective treatment of patients with cardiovascular disease (CVD), through achievement of maximum-tolerated statin dosing and other practical aspects. The aim of this article is to provide practical, focused advice for healthcare professionals on the management of patients with SAMS. MethodsAn expert working group combined current evidence, published guidelines and experiences surrounding a number of topics concerning SAMS to provide recommendations on how to best assess and manage this condition and reach the highest tolerated dose of statin for each individual patient. ResultsThe group collaborated to provide guidance on definitions in the SAMS field, psychological issues, re-challenging and switching treatments, as well as interpretation of current guidelines and optimal treatment of SAMS in different patient populations. An algorithm was developed to guide the management of patients with SAMS. In addition, the expert working group considered some of the more complex scenarios in a series of frequently asked questions and suggested answers. ConclusionsThe expert working group gave recommendations for healthcare professionals on the management of SAMS but highlighted the importance of tailoring the treatment approach to each individual patient. Evidence supporting the role of nutraceuticals and complementary therapies, such as vitamin D, was lacking, however the majority of the group favoured combination therapy with ezetimibe and the addition of PCSK9 inhibitors in high-risk patients.

New concepts in the management of dyslipidaemiaa.

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.

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

Statin-associated muscle symptoms (SAMS) are one of the principal reasons for statin non-adherence and/or discontinuation, contributing to adverse cardiovascular outcomes. This European Atherosclerosis Society (EAS) Consensus Panel overviews current understanding of the pathophysiology of statin-associated myopathy, and provides guidance for diagnosis and management of SAMS. Statin-associated myopathy, with significant elevation of serum creatine kinase (CK), is a rare but serious side effect of statins, affecting 1 per 1000 to 1 per 10 000 people on standard statin doses. Statin-associated muscle symptoms cover a broader range of clinical presentations, usually with normal or minimally elevated CK levels, with a prevalence of 7–29% in registries and observational studies. Preclinical studies show that statins decrease mitochondrial function, attenuate energy production, and alter muscle protein degradation, thereby providing a potential link between statins and muscle symptoms; controlled mechanistic and genetic studies in humans are necessary to further understanding. The Panel proposes to identify SAMS by symptoms typical of statin myalgia (i.e. muscle pain or aching) and their temporal association with discontinuation and response to repetitive statin re-challenge. In people with SAMS, the Panel recommends the use of a maximally tolerated statin dose combined with non-statin lipid-lowering therapies to attain recommended low-density lipoprotein cholesterol targets. The Panel recommends a structured work-up to identify individuals with clinically relevant SAMS generally to at least three different statins, so that they can be offered therapeutic regimens to satisfactorily address their cardiovascular risk. Further research into the underlying pathophysiological mechanisms may offer future therapeutic potential.