Statin-associated muscle symptoms: Myth or reality?

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"tienePdf" => "es" "tieneTextoCompleto" => "es" "tieneResumen" => array:2 [ 0 => "es" 1 => "en" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "602" "paginaFinal" => "611" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Statin-associated muscle symptoms: Myth or reality?" ] ] "contieneResumen" => array:2 [ "es" => true "en" => true ] "contieneTextoCompleto" => array:1 [ "es" => true ] "contienePdf" => array:1 [ "es" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figura 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2215 "Ancho" => 2508 "Tamanyo" => 319616 ] ] "descripcion" => array:1 [ "es" => "Bases fisiopatológicas de la toxicidad muscular por estatinas. Se muestran los principales mecanismos fisiopatológicos que podrían explicar la toxicidad muscular de las estatinas. A) La disminución en la síntesis de los principales isoprenoides, el farnesil pirofosfato y el geranilgeranil pirofosfato, reduce la prenilación proteica favoreciendo la desprenilación de pequeñas GTPasas y lamininas, lo que podría provocar vacuolización de fibras musculares, degeneración de organelas y aumento de la susceptibilidad al estrés mecánico<a class="elsevierStyleCrossRef" href="#bib0595">32</a>. B) El uso de estatinas disminuye la concentración sérica de coenzima Q10, molécula que forma parte de importantes procesos fisiológicos como la producción de energía en las fibras musculares o la disminución del estrés oxidativo<a class="elsevierStyleCrossRef" href="#bib0600">33</a>. C) La disminución en la síntesis de escualeno reduce a su vez la síntesis de colesterol y su concentración en las membranas celulares de los miocitos, haciéndolas más susceptibles a la lisis<a class="elsevierStyleCrossRef" href="#bib0605">34</a>. D) Las estatinas favorecen el aumento de síntesis de atrogina-1, molécula que se ha relacionado con un aumento del catabolismo proteico en las fibras musculares en situaciones con pérdida de masa muscular. Su posible papel como efector en la toxicidad muscular por estatinas todavía no es del todo conocido<a class="elsevierStyleCrossRef" href="#bib0610">35</a>. E) Las estatinas alteran la homeostasis fisiológica del calcio aumentando su concentración intracelular en las fibras musculares por medio de la activación de receptores de rianodina<a class="elsevierStyleCrossRef" href="#bib0595">32</a>. Fuente: elaboración propia." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "A. Muñoz-Blanco, R. Gómez-Huelgas, J.F. Gómez-Cerezo" "autores" => array:3 [ 0 => array:2 [ "nombre" => "A." "apellidos" => "Muñoz-Blanco" ] 1 => array:2 [ "nombre" => "R." "apellidos" => "Gómez-Huelgas" ] 2 => array:2 [ "nombre" => "J.F." 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"apellidos" => "Gómez-Cerezo" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Servicio de Medicina Interna, Hospital Infanta Sofía, San Sebastián de los Reyes, Madrid, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Medicina Interna, Hospital Regional Universitario Carlos Haya, Málaga, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Sintomatología muscular asociada a estatinas: ¿mito o realidad?" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:9 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "Source: original work." "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2215 "Ancho" => 2508 "Tamanyo" => 321278 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Pathophysiological underpinnings of statin-associated muscle toxicity. The main pathophysiological mechanisms that could explain statin-associated muscle toxicity are shown. A) The decrease in the synthesis of the main isoprenoids, farnesyl pyrophosphate, and geranyl pyrophosphate reduce protein prenylation, favoring the deprenylation of small GTPases and laminins. This could cause vacuolization of muscle fibers, degeneration of organelles, and an increase in susceptibility to mechanical stress.<a class="elsevierStyleCrossRef" href="#bib0160">32</a> B) The use of statins decreases the serum concentration of the coenzyme Q10, a molecule that forms part of important physiological processes such as the production of energy in muscle fibers or the decrease of oxidative stress.<a class="elsevierStyleCrossRef" href="#bib0165">33</a> C) The decrease in squalene synthesis in turn reduces cholesterol synthesis and its concentration in the cellular membranes of myocytes, making them susceptible to lysis.<a class="elsevierStyleCrossRef" href="#bib0170">34</a> D) Statins favor the increase of atrogin-1 synthesis, a molecule which has been linked to an increase in protein catabolism in muscle fibers in situations of muscle mass loss. Its possible role as an effector in statin-associated muscle toxicity is still not fully described.<a class="elsevierStyleCrossRef" href="#bib0175">35</a> E) Statins alter the physiological homeostasis of calcium, increasing its intracellular concentration in muscle fibers by means of the activation of ryanodine receptors.<a class="elsevierStyleCrossRef" href="#bib0160">32</a>" ] ] ] "textoCompleto" => "IntroductionSince the first statins were introduced at the end of the 1980s, numerous studies linking their use to the onset of muscle symptoms have been published. The onset of these symptoms was initially called statin myopathy. In recent years, the use of “statin-associated muscle symptoms” (SAMS) has become widespread, which highlights the absence of true biochemical or clinical muscle damage in many cases.Despite the fact that this relationship has been the subject of study during the last 30 years, it remains controversial up until now. This review intends to clarify the reasons why it is still a subject of debate.EpidemiologyDespite the growing number of publications on the use of statins in the population and regarding their safety and possible side effects, we still do not have definitive data on its incidence and impact.<a class="elsevierStyleCrossRef" href="#bib0005">1</a>Clinical experience points to the fact that muscle symptoms arising from the use of statins is common, causing early treatment abandonment.<a class="elsevierStyleCrossRef" href="#bib0010">2</a> The difference in the incidence of SAMS in observational studies, which ranges from 5% to 10% of cases, compared to clinical trials, which ranges from 1% to 5%, is noteworthy.<a class="elsevierStyleCrossRef" href="#bib0015">3</a>A meta-analysis that included 42 clinical trials which analyzed muscle symptoms produced by various statins did not find differences in the frequency of these symptoms compared to a placebo.<a class="elsevierStyleCrossRef" href="#bib0020">4</a> Of note is a recent systematic review that included 62 randomized trials on the use of statins in primary prevention. In this review, despite the fact that the rate of muscle symptoms was higher compared to the placebo, there were no differences in the onset of clinically significant muscle disease. The authors of this review concluded that on most occasions, the potential benefit of cardiovascular risk (CVR) reduction with the use of statins is greater than the possible side effects arising from their use.<a class="elsevierStyleCrossRef" href="#bib0025">5</a>These differences and those found in other publications, which are mainly observational studies, could be explained by variations in the definition of muscle symptoms used.<a class="elsevierStyleCrossRef" href="#bib0030">6</a> In a clinical trial by the ASCOT group, the rate of adverse effects with atorvastatin was compared to that of a placebo. After two or three years of follow-up, no differences were found during the blinded phase of the study, but in the later open-label phase, the rate of muscle side effects with atorvastatin was significantly higher than that of the placebo.<a class="elsevierStyleCrossRef" href="#bib0035">7</a>It has been proposed that the apparently contradictory results of these studies could be explained by the strict inclusion criteria of clinical trials, which may limit the extrapolation of the results to the general population.<a class="elsevierStyleCrossRef" href="#bib0040">8</a>However, observational studies are subject to a greater number of biases, which could limit the validity of their results.<a class="elsevierStyleCrossRef" href="#bib0045">9</a> In any case, this is an issue of great importance for patients’ health, as statins have been demonstrated to decrease CVR, with lower levels of LDL cholesterol,<a class="elsevierStyleCrossRef" href="#bib0050">10</a> and the lack of treatment adherence with statins acts as an independent prognostic factor of cardiovascular mortality.<a class="elsevierStyleCrossRef" href="#bib0055">11</a>In recent years, the possible involvement of a nocebo effect on the rate of side effects associated with statin use has gained importance. This effect—known in the field of medicine as when a patient experiences negative phenomena arising from a treatment because the patient is aware they may occur—has been analyzed in a recent study that included 60 patients who, for one year, received 12 packages with a monthly medication. Four of the packages contained 40 mg atorvastatin tablets, four contained a placebo, and four were empty.The ratio of the nocebo effect (defined as the quotient of the differences between the intensity of symptoms with the placebo and statins minus the intensity of symptoms without treatment) was 0.90, indicating that the majority of symptoms caused by statins were secondary to this effect. In addition, no differences were found between atorvastatin and the placebo in the intensity of symptoms at the start of treatment or in the alleviation of symptoms after stopping treatment.<a class="elsevierStyleCrossRef" href="#bib0060">12</a>When the definition is limited to muscle necrosis, understood as a marked elevation of creatine kinase (CK), the relationship is even more controversial. A retrospective study published in 2003 with data obtained after one year of treatment with statins did not find differences in the frequency of CK increases compared to the general population.<a class="elsevierStyleCrossRef" href="#bib0065">13</a>Regarding the onset of rhabdomyolysis with acute renal failure, a retrospective study of 252,460 patients in treatment with statins for at least six months showed a mean incidence per 10,000 person-years of 0.44 for monotherapy with atorvastatin, pravastatin, or simvastatin. This means that the number needed to treat would be 22,727 patients to find one case of rhabdomyolysis. This incidence increases to 5.98 if they are combined with fibrates.<a class="elsevierStyleCrossRef" href="#bib0070">14</a>Genetic underpinningsPolymorphisms in the genes SLCO1B1, RYR2, LILRB5, CLCN1, and GATM; polymorphisms in genes related to the cytochrome CYP450; polymorphisms in genes related to vitamin D; and polymorphisms in genes related to the ABC transporter family receptors have been linked to an increase in the risk of side effects arising from the use of various statins.<a class="elsevierStyleCrossRefs" href="#bib0075">15–18</a>Polymorphisms in the genes SLCO1B1 and LILRB5 show the most evidence. SLCO1B1 and its posterior synthesis product are those in charge of statin uptake in the liver. Presence of the rs4149056 mutation entails less statin clearance, increasing the risk of muscle toxicity.<a class="elsevierStyleCrossRefs" href="#bib0095">19,20</a> This increase in risk is more evident in cases with more severe muscle manifestations<a class="elsevierStyleCrossRef" href="#bib0105">21</a> and varies according to the type of statin; simvastatin is associated with the greatest toxicity.<a class="elsevierStyleCrossRefs" href="#bib0110">22,23</a> The rs12975366 mutation of the gene LILRB5, whose synthesis product is a receptor related to innate immunity expressed by various cells,<a class="elsevierStyleCrossRef" href="#bib0120">24</a> has been linked to higher CK levels, even in patients who do not take statins.<a class="elsevierStyleCrossRefs" href="#bib0125">25,26</a> This seems to indicate that its effect could be independent of their use.The haplotype DRB1**11:01 has also been related to an increase in the risk of statin-associated autoimmune myopathy<a class="elsevierStyleCrossRefs" href="#bib0135">27,28</a> mediated by anti-HMG-CoA reductase, especially in the African American population. However, these studies must be interpreted with caution, mainly due to their small sample size.<a class="elsevierStyleCrossRef" href="#bib0145">29</a>A recent study demonstrated different genetic expression in patients with muscle pain attributed to the use of statins who received treatment these agents again.<a class="elsevierStyleCrossRef" href="#bib0150">30</a> Various pathways, such as those related to mitochondrial stress, cellular senescence, and apoptosis, were abnormal, which could mean that patients with SAMS could be genetically predisposed to present with statin intolerance.In regard to the pathophysiological mechanisms, various mechanisms of muscle damage have been described. However, the specific processes and their possible links have not been definitively established and are not able to explain on their own the different degrees of clinical compromise in patients.<a class="elsevierStyleCrossRef" href="#bib0155">31</a><a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a> shows a summary of the main mechanisms described to date.<a class="elsevierStyleCrossRefs" href="#bib0160">32–35</a><elsevierMultimedia ident="fig0005"></elsevierMultimedia>Risk factorsDespite sharing a mechanism of action, the biochemical characteristics of statins are different and the risk of developing muscle symptoms depends on the statin used and its dose.<a class="elsevierStyleCrossRef" href="#bib0180">36</a> It seems that statins metabolized by the cytochrome P450 3A4 (lovastatin, simvastatin, atorvastatin) would have a greater risk of interaction with other drugs and would reinforce their toxic effect.<a class="elsevierStyleCrossRef" href="#bib0185">37</a> Among these, simvastatin has demonstrated the greatest incidence of muscle toxicity in clinical trials. What’s more, a higher incidence of myositis at high doses has also been found.<a class="elsevierStyleCrossRef" href="#bib0190">38</a>The estimated risk of muscle toxicity is lower when pravastatin, fluvastatin, or pitavastatin are used.<a class="elsevierStyleCrossRef" href="#bib0195">39</a> In a study on more than 100,000 patients in treatment for at least five years with 40 mg of pravastatin, no cases of rhabdomyolysis or elevations greater than ten times the normal value were reported.<a class="elsevierStyleCrossRef" href="#bib0200">40</a> Regarding fluvastatin, the PRIMO study, published in 2006, is of note. It analyzed the data from 7924 patients in treatment with high potency statins (fluvastatin 80 mg, pravastatin 40 mg, atorvastatin 40–80 mg). The fluvastatin group presented with the lowest incidence of muscle symptoms (5.1% of patients).<a class="elsevierStyleCrossRef" href="#bib0205">41</a> The use of rosuvastatin merits special mention, given that despite having conducted a study which did not show an increase in the incidence of myopathy compared to the placebo,<a class="elsevierStyleCrossRef" href="#bib0210">42</a> cases of rhabdomyolysis with doses greater than 20 mg/day have been reported.<a class="elsevierStyleCrossRef" href="#bib0215">43</a>There is evidence of a worsening or revealing of various underlying myopathies after starting treatments with statins.<a class="elsevierStyleCrossRefs" href="#bib0220">44–47</a> However, the causal relationship has not been entirely established and it is difficult to know if the muscle symptoms are secondary to starting treatment or if it is the natural course of the disease.<a class="elsevierStyleCrossRef" href="#bib0240">48</a>There are data regarding a possible increase in myopathy risk in patients with underlying hypothyroidism.<a class="elsevierStyleCrossRef" href="#bib0245">49</a> However, a study demonstrated that suspending the statin had no beneficial effects on patients’ muscle symptoms and the myopathy did not resolve until thyroid hormone levels normalized.<a class="elsevierStyleCrossRef" href="#bib0250">50</a> Other possible associations that increase the risk of myopathy are vitamin D deficiency<a class="elsevierStyleCrossRef" href="#bib0255">51</a> and liver or kidney failure, with the latter in turn being an independent risk factor for rhabdomyolysis.There are no conclusive data regarding age, although studies have been published which link a greater risk of muscle toxicity and falls with the use of statins in older adult patients.<a class="elsevierStyleCrossRef" href="#bib0260">52</a>Studies have been published which associate an excess of physical exercise with an increased risk of presenting with muscle toxicity due to statins.<a class="elsevierStyleCrossRef" href="#bib0265">53</a> However, the causal mechanism<a class="elsevierStyleCrossRef" href="#bib0270">54</a> is still not known exactly and the results of said studies have not been corroborated in other publications. It has been demonstrated that performing progressive physical exercise could protect muscle fibers from the potential oxidizing effects of statins.<a class="elsevierStyleCrossRef" href="#bib0275">55</a> In any case, the CK elevations associated with physical exercise tend to be mild or moderate and do not tend to cause treatment suspension.<a class="elsevierStyleCrossRef" href="#bib0280">56</a>InteractionsStudies have shown that the risk of presenting with muscle damage is greater when statins are combined with certain drugs. Statins are mainly metabolized by the cytochromes CYP3A4 (lovastatin, atorvastatin, and simvastatin) and CYP2C9 (fluvastatin, pitavastatin) and to a lesser extent by the cytochromes CYP2C19 (rosuvastatin) or CYP3A4 (fluvastatin).<a class="elsevierStyleCrossRefs" href="#bib0285">57–59</a> The use of other agents metabolized by these cytochromes can result in a decrease in statin clearance and an increase in their toxicity.<a class="elsevierStyleCrossRef" href="#bib0300">60</a> Other mechanisms are related to the use of the same transporters, such as organic anion transporting polypeptides<a class="elsevierStyleCrossRef" href="#bib0305">61</a> or the strengthening of muscle toxicity produced through different pathways, such as in the case of fibrates.<a class="elsevierStyleCrossRef" href="#bib0310">62</a>Likewise, it has been verified that statins can interact with certain foods, such as grapefruit juice or cranberry juice. These juices contain particular compounds (such as bergamottin in the case of grapefruit juice) which could deactivate the CYP3A4 cytochrome and thus reduce the degradation of the metabolized statins.<a class="elsevierStyleCrossRef" href="#bib0315">63</a><a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> shows a summary of the main drugs that interact with statins.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>SymptomsThe term SAMS is very broad, encompassing everything from muscle weakness or myalgias which can be accompanied by varying degrees of muscle fiber necrosis to potentially lethal cases such as rhabdomyolysis accompanied by acute kidney failure.The most common symptom is muscle pain, which is also the main reason for interrupting treatment with statins.<a class="elsevierStyleCrossRef" href="#bib0320">64</a> The pain tends to be mainly proximal and symmetrical and can be accompanied by varying degrees of weakness that limit patients’ functionality. It is not common for it to be accompanied by CK elevation, which is not a very sensitive marker for the diagnosis of SAMS.<a class="elsevierStyleCrossRef" href="#bib0325">65</a>On this matter, the outcomes of two clinical trials are of note. The first compared the incidence of adverse liver and muscle effects in more than 20,000 patients with 40 mg of simvastatin per day or a placebo. Only 11 (0.1%) of patients in the simvastatin arm presented with CK elevation: four of them with values greater than ten times the upper limit of normal. CK values normalized in all patients after suspending treatment.<a class="elsevierStyleCrossRef" href="#bib0330">66</a> The second trial compared the toxicity of 20 mg of lovastatin per day compared to a placebo. No differences were found in the frequency of CK elevations above ten times the normal limit between the two, with a frequency of 0.6% in each group. It is noteworthy that none of the patients with said elevation presented with associated muscle symptoms. However, patients in the lovastatin arm presented with a greater incidence of CK elevations less than five times the normal limit, which normalized during follow-up without needing to suspend treatment.<a class="elsevierStyleCrossRef" href="#bib0335">67</a> No data on the frequency of said elevation in the patients of this trial were recorded.The interval from the start of treatment with statins to the onset of symptoms tends to be short—between four and six weeks—although a study has been published which found an approximate mean of six months from starting treatment.<a class="elsevierStyleCrossRef" href="#bib0340">68</a> After stopping statins, the disappearance of symptoms also tends to occur in the first two months. Other symptoms include muscle cramps and joint or bone pain.<a class="elsevierStyleCrossRef" href="#bib0345">69</a> Rhabdomyolysis secondary to the use of statins is not a common clinical scenario. Its presentation does not differ from when it is secondary to other etiologies and it can be asymptomatic in some cases.The use of statins has been linked to the onset or worsening of myopathies of various natures. Special mention should be made of the association between the use of statins and the onset of immune-mediated necrotizing myopathy, which occurs in approximately two to three cases out of every 100,000 inhabitants.<a class="elsevierStyleCrossRef" href="#bib0350">70</a> This entity, characterized by the presence of anti-HMG-CoA reductase,<a class="elsevierStyleCrossRef" href="#bib0355">71</a> muscle infiltration by macrophages and lymphocytes, and extensive necrosis of muscle fibers, does not resolve following the suspension of treatment with statins and requires long-term immunosuppressive treatment in most cases.<a class="elsevierStyleCrossRef" href="#bib0360">72</a> It occurs early after starting treatment with myalgias and varying degrees of proximal muscle weakness. It is also associated in some cases with arthralgias or the presence of a maculopapular rash in varying locations.<a class="elsevierStyleCrossRef" href="#bib0365">73</a> The symptoms persist or even worsen after suspending statins. In more than 90% of cases, this entity progresses with a CK elevation greater than ten times the normal range that does not normalize after suspending treatment.DiagnosisThe diagnosis of this disease is clinical. A diagnosis is made when there is a temporal association, generally of weeks, between the onset of muscle symptoms and starting statins, with or without an associated CK elevation. Given the low specificity of the symptoms and the absence of markers sensitive enough for a diagnosis, this can be complex. The main tool we have available is a clinical evaluation after suspending treatment and its later reintroduction.<a class="elsevierStyleCrossRef" href="#bib0370">74</a>The number of attempts that should be made in order to diagnose SAMS has not been established, although in most studies, the onset of symptoms after two or more attempts with different statins has been used as a criterion. Therefore, two is the most accepted number.<a class="elsevierStyleCrossRef" href="#bib0375">75</a>A scale has been proposed to facilitate a diagnosis (SAMS Clinical Index or SAMS-CI). It is based on the clinical characteristics of patients after two or more attempts at statins treatment.<a class="elsevierStyleCrossRef" href="#bib0280">56</a> This scale, which was revised in 2017,<a class="elsevierStyleCrossRef" href="#bib0380">76</a> has a scoring system which classifies cases as unlikely, possible, and probable (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). It has shown good performance mainly for ruling out unlikely cases (negative predictive value of 91% for cases with a score less than 5).<a class="elsevierStyleCrossRef" href="#bib0385">77</a> However, it must be taken into account that at present, this scale has not been validated for use in clinical practice.<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Very few biopsies have been conducted and thus, information on histological findings is scarce. Among the cases of rhabdomyolysis, findings that are indistinguishable from those caused by other etiologies have been found.<a class="elsevierStyleCrossRef" href="#bib0390">78</a>One particular case is immune-mediated necrotizing myopathy. In this disease, it can be useful to perform an electromyogram, in which myopathic changes can be observed such as the presence of activity at rest and low potential in the motor units. In addition, performing imaging tests such as muscle magnetic resonance imaging can identify the muscle edema present in this illness.<a class="elsevierStyleCrossRef" href="#bib0345">69</a> A muscle biopsy is necessary in these patients. The characteristic presence of necrosis and regenerative muscle fibers can be observed in the results, as can infiltration predominantly by macrophages and, to a lesser extent, infiltration mediated by CD4+ and CD8+ lymphocytes, CD123+ lymphocytes, and plasmacytoid dendritic cells.<a class="elsevierStyleCrossRef" href="#bib0395">79</a> A test for detecting anti-HMG-CoA reductase should always be performed in these patients, given that its presence robustly supports the diagnosis and its absence should lead us to consider other etiologies.<a class="elsevierStyleCrossRef" href="#bib0350">70</a>ManagementThe first step in patients with symptoms compatible with SAMS is to rule out possible interactions with concomitant medication and exclude other potential causes of the patient’s symptoms.<a class="elsevierStyleCrossRef" href="#bib0400">80</a> If, after this step, we conclude that the patient could present with statin toxicity, the principal SAMS management guidelines concur that for later decision-making, serum CK levels and the indication for treatment according to the patient’s CVR should be jointly considered.<a class="elsevierStyleCrossRef" href="#bib0405">81</a>In general, if the CK elevation is mild or moderate (less than six times the upper limit of normal) and CVR is low, a healthy lifestyle should be promoted, ensuring good control of the rest of CVR factors and evaluating the potential benefits of the use of statins versus the severity of symptoms. In cases with CK values greater than ten times the normal value, it is recommended to suspend treatment due to risk of rhabdomyolysis and closely monitor until the normalization of these levels can be verified.<a class="elsevierStyleCrossRef" href="#bib0280">56</a> Once normalized, restarting treatment with a statin different from the initial one or other lipid-lowering agents could be evaluated. In cases of established rhabdomyolysis, restarting treatment with statins is not recommended due to the possible risk of recurrence,<a class="elsevierStyleCrossRef" href="#bib0410">82</a> although there is currently no data in this regard.In the cases in which the benefit of treatment with statins outweighs the risks (for example, in patients with high or very high CVR), the current recommendations are to carry out a treatment washout period, which can vary from two to six weeks according to the degree of CK elevation, and then to conduct a personalized assessment regarding treatment options together with the patient. Several options are currently available: maintaining the same treatment at a lower dose, changing to another statin, intermittently administering treatment, or the combination of other lipid-lowering agents apart from statins<a class="elsevierStyleCrossRef" href="#bib0410">82</a> (ezetimibe, anti-PCSK9 antibodies, or bempedoic acid).Regarding intermittent administration, studies have shown favorable outcomes in terms of tolerance and effectiveness, including in weekly administrations.<a class="elsevierStyleCrossRef" href="#bib0415">83</a> However, the long-term prognosis of patients is still not established. In these cases, it would be recommendable to use statins with a longer half-life, such as rosuvastatin or atorvastatin.At present, there is no evidence that the periodic measurement of muscle damage markers is beneficial for patients.<a class="elsevierStyleCrossRef" href="#bib0015">3</a> The principal guidelines stress the importance of explaining the possible side effects arising from statin use to patients so that they report them if they present with them.<a class="elsevierStyleCrossRef" href="#bib0420">84</a> Only in the case of presenting with severe symptoms attributable to statin use should the physician proceed to measure markers.In regard to the onset of rhabdomyolysis, its treatment is no different from when it is produced by other causes and is mainly based on the administration of fluids; the administration of bicarbonate in order to alkalinize urinary pH remains controversial.The presence of immune-mediated necrotizing myopathy requires the immediate suspension of statin treatment at the time of diagnosis. The main action guidelines we have at present are from the European Neuromuscular Centre. They mainly consist of combining systemic glucocorticoids, methotrexate, intravenous immunoglobulins, or rituximab.<a class="elsevierStyleCrossRef" href="#bib0425">85</a>There is currently no evidence of the benefit of dietary supplementation with coenzyme Q10 or red yeast rice.<a class="elsevierStyleCrossRef" href="#bib0410">82</a>New therapiesAt present, the lipid-lowering effect of ezetimibe and anti-PCSK9 antibodies is well known, as is its safety profile in patients with high CVR.<a class="elsevierStyleCrossRef" href="#bib0015">3</a> In the last ten years, the lipid-lowering effects of bempedoic acid and its safety in patients with high CVR have been demonstrated.<a class="elsevierStyleCrossRef" href="#bib0430">86</a> It is a prodrug which, after being activated thanks to the ACSVL1 enzyme, inhibits the ATP citrate lyase enzyme, which is necessary for the transformation of citrate into acetyl-CoA, the direct precursor to HMG-CoA reductase. One study demonstrated that it is effective for reducing LDL cholesterol levels in patients with prior intolerance to statin treatment, with no differences with respect to a placebo in the incidence of muscle symptoms.<a class="elsevierStyleCrossRef" href="#bib0435">87</a> Unlike statins, bempedoic acid is a prodrug that is not activated in the skeletal muscle, which could explain the absence of muscle toxicity compared to statins.The future introduction on the market of this non-statin lipid-lowering agent could be of great use for the management of dyslipidemia in patients with these intolerances.ConclusionSAMS is a clinical entity with a varying incidence that can be a true challenge in both its diagnosis and treatment in patients with an indication for lipid-lowering treatment. Until now, multiple elements have been proposed to attempt to explain its pathophysiological basis. However, we still do not have a unified theory that is able to explain the wide variability of its presentation in patients and which allows us to identify those at greater risk of presenting with muscle toxicity with treatment. This variability is demonstrated in the wide range of clinical manifestations that patients may experience and the fact that although the vast majority are mild and cease with the suspension of treatment, they can be severe and potentially lethal.Despite the introduction of scales for facilitating a diagnosis, the main tool available at present to classify these patients continues to be a clinical evaluation with the suspension and reintroduction of treatment with statins. The elevation of muscle damage markers only occurs in a minority of patients and is not sensitive or specific enough for diagnosing SAMS in and of itself.The management of these patients is mainly based on substitutions between statins with different pharmacokinetic properties or formulation changes, although the introduction of new lipid-lowering treatments other than statins, such as bempedoic acid, may expand the number of treatment options.One special, rare case is statin-associated immune-mediated necrotizing myopathy. It should be suspected in patients whose symptoms do not stop despite the suspension of statin treatment and who also present with elevated CK markers. Unlike the rest of SAMS manifestations, with this disease, it can be useful to perform additional tests aimed at detecting direct muscle damage, such as an electromyogram, magnetic resonance imaging test, or a muscle biopsy. Its pathophysiological basis seems to be of autoimmune origin, defined by the presence of anti-HMG-CoA reductase. Its management requires treatment with classical immunosuppressants, rituximab, or intravenous immunoglobulins.FundingNo funding of any type has been received for this review.Conflicts of interestThe authors have no conflicts of interest in the creation of this review." "textoCompletoSecciones" => array:1 [ "secciones" => array:17 [ 0 => array:3 [ "identificador" => "xres1816584" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1585938" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1816583" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1585939" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Epidemiology" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Genetic underpinnings" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Risk factors" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Interactions" ] 9 => array:2 [ "identificador" => "sec0030" "titulo" => "Symptoms" ] 10 => array:2 [ "identificador" => "sec0035" "titulo" => "Diagnosis" ] 11 => array:2 [ "identificador" => "sec0040" "titulo" => "Management" ] 12 => array:2 [ "identificador" => "sec0045" "titulo" => "New therapies" ] 13 => array:2 [ "identificador" => "sec0050" "titulo" => "Conclusion" ] 14 => array:2 [ "identificador" => "sec0055" "titulo" => "Funding" ] 15 => array:2 [ "identificador" => "sec0060" "titulo" => "Conflicts of interest" ] 16 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2022-02-01" "fechaAceptado" => "2022-03-29" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1585938" "palabras" => array:4 [ 0 => "Statins" 1 => "Statin-associated muscle symptoms" 2 => "Miopathy" 3 => "HMG-CoA reductase" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1585939" "palabras" => array:4 [ 0 => "Estatinas" 1 => "Síntomas musculares asociados a estatinas" 2 => "Miopatía" 3 => "HMG-CoA reductasa" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Statin-associated muscle symptoms is an entity that encompasses a constellation of various clinical manifestations of variyng severity. Since the introduction of the first statins, numerous studies have been published regarding its incidence, pathophysiology, diagnosis and treatment; however, to this day these aspects are still controversial. With the progressive increase in the use of statins in the general population, notifications of adverse reactions related to its use have multiplied, particularly those related to muscular toxicity. Nevertheless, the differences between the published studies, both in methodology and in the results obtained, make this relationship a complex issue of great interest for clinicians and patients. The integration of the evidence that we currently have can help us understand better this entity and facilitate its management in clinical practice." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "La sintomatología muscular asociada con estatinas es una entidad que engloba una constelación de diversas manifestaciones clínicas de distinta gravedad. Desde la introducción de las primeras estatinas se han publicado numerosos estudios acerca de su incidencia, fisiopatología, diagnóstico y tratamiento; sin embargo, a día de hoy estos aspectos siguen generando controversia. Con el aumento progresivo del uso de estatinas en la población general se han multiplicado las notificaciones de reacciones adversas relacionadas con su uso, particularmente las relacionadas con la toxicidad muscular. No obstante, las diferencias existentes entre los estudios publicados tanto en metodología como en resultados obtenidos hacen de esta relación un tema complejo y de gran interés para el clínico y los pacientes. La integración de la evidencia de la que disponemos actualmente puede ayudarnos a comprender mejor esta entidad y facilitar su manejo en la práctica clínica." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Muñoz-Blanco A, Gómez-Huelgas R, Gómez-Cerezo JF. Sintomatología muscular asociada a estatinas: ¿mito o realidad? Rev Clin Esp. 2022. https://doi.org/10.1016/j.rce.2022.03.013" ] ] "multimedia" => array:3 [ 0 => array:9 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "Source: original work." "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2215 "Ancho" => 2508 "Tamanyo" => 321278 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Pathophysiological underpinnings of statin-associated muscle toxicity. The main pathophysiological mechanisms that could explain statin-associated muscle toxicity are shown. A) The decrease in the synthesis of the main isoprenoids, farnesyl pyrophosphate, and geranyl pyrophosphate reduce protein prenylation, favoring the deprenylation of small GTPases and laminins. This could cause vacuolization of muscle fibers, degeneration of organelles, and an increase in susceptibility to mechanical stress.<a class="elsevierStyleCrossRef" href="#bib0160">32</a> B) The use of statins decreases the serum concentration of the coenzyme Q10, a molecule that forms part of important physiological processes such as the production of energy in muscle fibers or the decrease of oxidative stress.<a class="elsevierStyleCrossRef" href="#bib0165">33</a> C) The decrease in squalene synthesis in turn reduces cholesterol synthesis and its concentration in the cellular membranes of myocytes, making them susceptible to lysis.<a class="elsevierStyleCrossRef" href="#bib0170">34</a> D) Statins favor the increase of atrogin-1 synthesis, a molecule which has been linked to an increase in protein catabolism in muscle fibers in situations of muscle mass loss. Its possible role as an effector in statin-associated muscle toxicity is still not fully described.<a class="elsevierStyleCrossRef" href="#bib0175">35</a> E) Statins alter the physiological homeostasis of calcium, increasing its intracellular concentration in muscle fibers by means of the activation of ryanodine receptors.<a class="elsevierStyleCrossRef" href="#bib0160">32</a>" ] ] 1 => array:9 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "Source: original work." "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0010" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:1 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Drug \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Mechanism of interaction \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Statins with greater risk of interaction \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Protease inhibitors \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CYP3A4 and OATP1B1 transporter inhibitors \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">All \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " rowspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Macrolides</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CYP3A4 inhibitors</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Atorvastatin \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Simvastatin \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Lovastatin \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " rowspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Azoles</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CYP3A4 and CYP2C9 inhibitors</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Atorvastatin \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Simvastatin \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Fluvastatin \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pitavastatin \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " rowspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Non-dihydropyridine calcium channel blockers</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CYP3A4 inhibitors</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Atorvastatin \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Simvastatin \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Lovastatin \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " rowspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Antidepressants</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CYP3A4 inhibitors</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Atorvastatin \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Simvastatin \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Lovastatin \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cyclosporine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CYP3A4 inhibitor and OATP1B1 transporter \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">All \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " rowspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Amiodarone</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CYP3A4 and CYP2C9 inhibitor</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Atorvastatin \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Simvastatin \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Fluvastatin \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pitavastatin \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " rowspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cranberry or grapefruit juice (at lease 250 mL per day)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CYP3A4 inhibitors</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Atorvastatin \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Simvastatin \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Lovastatin \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Fenofibrate</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CYP2C9 inhibitor</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Fluvastatin \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pitavastatin \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Gemfibrozil \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Glucuronidation inhibitors \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">All \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] ] ] ] "descripcion" => array:1 [ "en" => "Drugs associated with a greater risk of muscle toxicity in combination with statins according to the mechanisms of interaction." ] ] 2 => array:9 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "Source: modified from Rosenson et al.<a class="elsevierStyleCrossRef" href="#bib0380">76</a>" "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0015" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "InterpretationTotal score: probability that the patient’s symptoms are secondary to statin use:2–6: unlikely7–8: possible9–11: probable" "tablatextoimagen" => array:1 [ 0 => array:1 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Score \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">A. Regional distribution/pattern of muscle symptoms (in case of presenting with more than one category, include the one with the higher score) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Symmetrical hip flexors/thighs \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Symmetrical calves \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Symmetrical upper proximal limb \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Asymmetric, intermittent, or non-specific \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">B. Time from the introduction of the statin to symptoms onset \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Less than 4 weeks \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">From 4 to 12 weeks \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">More than 12 weeks \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">C. Time since suspension of the statin to symptoms improvement \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Less than 2 weeks \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">From 2 to 4 weeks \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No improvement after 4 weeks \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">D. Time since reappearance of muscle symptoms following starting a new statin therapy (the new regimen can be the same previous statin and dose) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Less than 4 weeks \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Between 4 and 12 weeks \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">The symptoms do not reappear after more than 12 weeks \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] ] ] ] "descripcion" => array:1 [ "en" => "Statin-associated Muscular Symptoms Clinical Index (SAMS-CI)." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:87 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Statin toxicity" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "N.C. 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