Statin muscle-related adverse events

INTRODUCTION — Statins are the primary class of medication used to lower serum cholesterol concentration for both primary and secondary prevention of cardiovascular disease. (See "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease" and "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)

Statins are both effective and generally safe. Although muscle toxicity remains a concern, severe myonecrosis leading to clinical rhabdomyolysis is rare, affecting perhaps 0.1 percent of patients [1,2]. Muscle syndromes associated with statins include myalgias, myopathy, myositis, and muscle injury [3,4]. The clinical and distinct histopathological findings of these syndromes are presented in the table (table 1). Other statin side effects are discussed separately. (See "Statins: Actions, side effects, and administration".)

PATHOGENESIS — The mechanism by which statins cause muscle toxicity or statin-associated muscle symptoms (SAMS) is not well understood, and the term SAMS is used to imply that these symptoms are not always truly caused by statin use. Nevertheless, progress is being made in understanding the causal relationships, including genetic studies [5,6]:

●Candidate gene studies – Examples include genes that play a role in SAMS through their impact on statin metabolism, transport, or action. These genes include variation in cytochrome P450 genes including CYP3A4, CYP3A5, CYP2D6, and the vitamin D receptor gene.

●Genome-wide association studies – Examples include SLCO1B1 rs4149056 and other variants. The SLCO1B1 gene product is responsible for hepatic uptake of statins. Loss of function variant rs4149056 is associated with higher plasma levels of statins, in particular simvastatin and to a lesser extent atorvastatin, leading to greater systemic exposure including at the level of muscle.

●Human leukocyte antigen basis for statin-associated necrotizing myopathy – An example is the condition of statin-associated autoimmune myopathy that results from autoantibodies that recognize hydroxymethylglutaryl (HMG)-CoA reductase (HMGCR). These antibodies may have a direct effect on muscle tissue expressing HMGCR, resulting in myalgia, myopathy, myonecrosis (creatine kinase [CK] levels >1000 international units/L), and prominent myofiber necrosis on muscle biopsy [6].

●Multi-omic networks – These are studies of genes related to proteomics, lipidomics, etc, which contribute to the transcription, metabolism, and metabolite levels and which may be related to SAMS.

Individual statins may have distinct effects on the synthesis of Coenzyme Q10 (CoQ10, ubiquinone), which plays an important role in muscle cell energy production. It has been speculated that a reduction in ubiquinone in skeletal muscle may contribute to statin-induced muscle injury. Some studies have found that statins decrease skeletal muscle and plasma concentrations of ubiquinone [7-10]; however, other studies have not [11], and studies have come to different conclusions about whether statin treatment decreases levels of ubiquinone in skeletal muscle [9,12,13]. Long-term treatment with simvastatin (10 to 40 mg/day for >12 months) reduced ubiquinone content in skeletal muscles and decreased maximal mitochondrial oxidative phosphorylation capacity [14].

One study found increased levels of plant sterols in skeletal muscle in patients treated with high-dose statins [9]. Specifically, sitosterol was increased by approximately 50 percent. The authors of the study proposed that these increased cellular levels could contribute to the muscle toxicity of statins. Beta-sitosterol is an activator of AMP-activated protein kinase, which inhibits acetyl-CoA carboxylase. This results in reduced fat synthesis and increased beta-oxidation. Preliminary evidence suggests that statin-intolerant patients demonstrate increased fatty acid oxidation (FAO) in response to lovastatin, implicating an intrinsic FAO abnormality [15]. Statins increase the expression of mitochondrial carnitine acylcarnitine translocase, and this effect may contribute to the alteration in FAO [16].

Atrogin-1, a muscle-specific ubiquitin protein ligase, may play an important role in statin toxicity. Lovastatin induces expression of atrogin-1 in humans with statin myopathy and in several in vitro models; in the models, myopathy could be prevented by knockdown of atrogin-1 [17]. These and other proposed mechanisms require further experimental confirmation.

Among patients experiencing statin-induced myalgia, skeletal muscle gene expression data show that persistent myalgia may result from cellular stress that results from mechanisms of post-inflammatory repair and end-organ susceptibility. The genetic basis for SAMS is supported by an increased frequency of single-nucleotide polymorphisms that were found in patients with statin myalgia (figure 1) [18].

DEFINITIONS — Terminology around statin-associated adverse muscle events is variable and has changed over time [5,19]. In this topic, where possible, we use the categories of events defined by the 2014 National Lipid Association Statin Muscle Safety Task Force [3]:

●Myalgia – A symptom of muscle-discomfort, including muscle aches, soreness, stiffness, tenderness, or cramps with or soon after exercise, with a normal creatine kinase (CK) level. Myalgia symptoms can be described as similar to what would be experienced with a viral syndrome such as influenza.

●Myopathy – Muscle weakness (not due to pain), with or without an elevation in CK level.

●Myositis – Muscle inflammation.

●Myonecrosis – Elevation in muscle enzymes compared with either baseline CK levels (while not on statin therapy) or the upper limit of normal that has been adjusted for age, race, and sex:

•Mild – Three- to 10-fold elevation in CK

•Moderate – 10- to 50-fold elevation in CK

•Severe – 50-fold or greater elevation in CK

●Clinical rhabdomyolysis – Defined by the Task Force as myonecrosis with myoglobinuria or acute renal failure (an increase in serum creatinine of at least 0.5 mg/dL [44 micromol/L]).

EPIDEMIOLOGY — Information about muscle injury and statins has come both from large clinical trials of statin therapy and from observational studies of statins in clinical use [20]. Often, research definitions require that the muscle symptoms be accompanied by elevations in creatine kinase, which excludes the more common definition of myalgia and myopathy used in other trials [4].

Using a strict definition, a 2014 meta-analysis of 42 randomized trials of statins found little or no excess risk of myalgias, creatine kinase (CK) elevations, rhabdomyolysis, or discontinuation of therapy versus placebo [21]. A small increase in muscle symptoms was found in a 2022 meta-analysis of 19 large trials, in which 27.1 percent of participants treated with a statin reported at least one episode of muscle pain or weakness during a median of 4.3 years, compared with 26.6 percent of participants treated with placebo (rate ratio 1.03, 95% CI 1.01-1.06) [22]. There was also a small increase in muscle pain or weakness among those treated with more intensive versus less intensive statin treatment (ie, 40 to 80 mg atorvastatin or 20 to 40 mg rosuvastatin daily).

Experience in clinical practice suggests that muscle side effects are relatively common, including side effects requiring discontinuation of statin therapy. The explanation for this difference is uncertain, but it may relate to selection criteria in randomized trials that limit the ability to generalize their results to the side effect profiles seen in a broader population of patients [23].

Consistent with this, a 2013 six-month randomized trial in 420 healthy adults designed to examine the effects of statin therapy on muscle function found a higher incidence of myalgia in patients treated with atorvastatin 80 mg/day than with placebo (9.3 versus 4.6 percent) [24].

Clinically significant myonecrosis, defined as a serum CK elevation more than 10 times normal in association with muscle symptoms, occurred in less than 0.5 percent of patients in large clinical trials [25-28]. A review of one year of records for 1014 patients taking statins in a primary care practice found that 0.9 percent of patients had CK elevations more than five times normal, and none of these appeared to be related to statin use [29]. Fourteen patients (2.1 percent) had elevations 2.5 to 5.0 times normal, and of these two appeared to be potentially related to statin use.

In large clinical trials, massive rhabdomyolysis with acute renal failure was not seen in patients who did not have other risk factors. Rhabdomyolysis has primarily been seen when a statin is given concurrently with cyclosporine, gemfibrozil, or protease inhibitors [30-32] (see 'Concurrent drug therapy' below). In addition, there have been case reports of rhabdomyolysis in patients taking statins in combination with niacin, macrolide antibiotics, digoxin, antifungal medications, and warfarin [33,34].

One study examined claims data from 11 managed care plans that included 252,460 patients treated with lipid-lowering agents [2]. The average incidence of hospitalization for rhabdomyolysis was 0.44 per 10,000 patient-years (95% CI 0.20-0.84) for patients treated with atorvastatin, pravastatin, or simvastatin monotherapy. Although the study did not find a statistical difference in the incidence of rhabdomyolysis among these three statins, no cases of rhabdomyolysis were seen with pravastatin. The incidence was higher with cerivastatin monotherapy (5.34 per 10,000 patient-years), and this statin was ultimately withdrawn from the market.

Many individuals who are prescribed statins discontinue treatment due to perceived side effects [35]. An internet-based survey that included 10,138 respondents (88 percent current statin users, 12 percent former users) found that the primary reason for discontinuation of statin therapy was side effects [36]. Muscle-related side effects were reported by 60 percent of former users and 25 percent of current users. However, the study did not make it clear whether the temporal relation between symptoms and starting or stopping statin therapy was assessed, and it is uncertain whether the 25 percent of current users with muscle symptoms attributed those symptoms to their therapy. Concomitant use of medications that inhibit statin metabolism increased the risk for muscle symptoms and for discontinuation of statin therapy for such symptoms [37].

RISK FACTORS

Statin characteristics — The ability to cause muscle injury appears to vary among the different statins and according to statin dose.

The risk of myopathy appears to be lowest with fluvastatin, pravastatin, and pitavastatin [38,39]. Possible reasons are described below:

●These statins are not metabolized by cytochrome P450 3A4 (CYP3A4) and are thus less likely to be involved with drug interactions [4,40]. (See 'Drug interactions' below.)

●In the case of fluvastatin, the lower risk may be related to the much lower systemic exposure of the extended-release formulation [41].

The risk of muscle injury is substantially increased when taking statins extensively metabolized by CYP3A4 such as lovastatin, simvastatin, and atorvastatin.

For all statins, the risk of muscle injury is greater at higher doses. With simvastatin, for example, the incidence of myositis in clinical trials was 0.02 percent at 20 mg/day, 0.07 percent at 40 mg/day, and 0.3 percent at 80 mg/day [42]. (See 'Dose limitations' below.)

The safety of pravastatin (40 mg/day) was confirmed in an analysis of more than 112,000 patient-years of experience in three large trials [43]. The incidence of serum creatine kinase (CK) elevations was not different from placebo, and there were no cases of confirmed clinical myositis or rhabdomyolysis. In an observational study of over 7000 patients on high-dose statin therapy, fluvastatin had the lowest rate of muscle symptoms among the statins [38]. Pitavastatin is not catabolized by CYP3A4 and also has a low risk of muscle injury [39].

The safety of rosuvastatin was demonstrated in a trial in 17,802 apparently healthy adults, in which rates of muscle toxicity with rosuvastatin 20 mg/day were similar to placebo [44]. However, there have been reports of rhabdomyolysis with rosuvastatin, particularly in myopathy-prone patients treated with doses higher than those recommended by the US Food and Drug Administration (FDA) product labeling, and product labeling in Europe highlights this risk, particularly at the highest dose of 40 mg/day [45].

Preexisting neuromuscular disorders — Underlying neuromuscular disorders may interact with statin therapy. In some cases, statins can cause new neuromuscular disorders (see 'Neuromuscular disorders' below); however, others involve increased risk of toxicity in patients with known underlying neuromuscular disorders or the development of clinically apparent disease in patients who had likely had preclinical disease before statins were initiated.

Statins appear to have deleterious effects in patients with amyotrophic lateral sclerosis (ALS) and conditions that mimic ALS [46]. Cholesterol levels may play an important role, as dyslipidemia has been associated with prolonged survival in ALS [47]. ALS-associated hypermetabolism may require more cholesterol availability. Indeed, calorie restriction exacerbates motor symptoms and high fat intake improves survival in a mouse model of ALS [48]. Sterol bioavailability and cholesterol synthesis represent pivotal adaptive responses to extracellular stress [49]. Although the optimal lipid levels are unknown for patients with ALS, it is considered reasonable to withdraw statins and other hypolipidemics in patients who develop ALS.

For genetically based muscle disorders, statins are believed to trigger myogenic symptoms more readily than in healthy subjects due to a reduced ability to compensate for drug-induced myotoxicity. In such patients, myopathic symptoms often persist after statin withdrawal, and this is a clinical indicator for electromyography and, potentially, muscle biopsy. It seems likely that the diverse neuromuscular phenotypes associated with statin use reflect multiple mechanisms acting either singly or synergistically.

Reports of diseases that have become clinically apparent in patients on statins include myasthenia gravis [50,51], mitochondrial myopathy [52-54], McArdle disease [54-56], acid maltase deficiency [57], muscle phosphorylase b kinase deficiency [58], carnitine-palmitoyl transferase deficiency [59], rippling muscle disease (RMD) [60], myotonic dystrophy types 1 and 2 [54,61], cytoplasmic- and hyaline-body (myosin storage) myopathies [62,63], motor neuronopathies (eg, Kennedy disease [54] and ALS [46]), dermatomyositis/polymyositis, inclusion body myositis, carnitine palmitoyltransferase II (CPT2) deficiency, and myoadenylate deaminase deficiency [5].

Hypothyroidism, hypovitaminosis D, and other disorders — Enhanced susceptibility to statin-associated myopathy occurs in patients with hypothyroidism, acute or chronic renal failure, and obstructive liver disease. In one hypothyroid patient, the myopathy resolved promptly after discontinuation of pravastatin and before initiation of thyroid hormone replacement [64], but in a second case the myopathy persisted until thyroid hormone was replaced [65]. These reports suggest that hypothyroidism may predispose to the development of statin-associated myopathy and that use of statins may "unmask" hypothyroid myopathy (see "Hypothyroid myopathy"). Very low vitamin D levels have been associated with higher rates of myalgia and myopathy. Replenishing low vitamin D levels can be an effective approach to improving statin tolerance in some patients with prior statin-associated muscle symptoms (SAMS) [66-68].

Patient characteristics — Genetic factors appear to increase the risk of statin myopathy [69]. A genome-wide association study found that common variants of the SLCO1B1 gene, which encodes the organic anion transporting polypeptide 1B1 (OATP1B1) that mediates hepatic uptake of most statins, substantially increased or decreased the risk of myopathy in patients treated with simvastatin [70]. A subsequent trial of statins found an association between a specific SLCO1B1 variant (SLCO1B1*5) and an increased risk of mild adverse events [71]. Testing for SLCO1B1 variants associated with statin myopathy is commercially available, but it seems unlikely that such a test would be clinically useful or worth the expense in most situations.

As discussed, it remains unclear whether lipid-soluble statins penetrate the muscle membrane more readily than water-soluble statins, leading to increased risk for myopathy (see 'Statin characteristics' above). The discovery that organic anion transport polypeptide 2B1 (SLCO2B1) is expressed on the sarcolemma and mediates uptake of statins into the myocyte argues against a significant pathogenic role for passive diffusion of the fat-soluble statins. In addition to SLCO2B1, the multidrug resistance-associated proteins MRP1, MRP4, and MRP5 are also present in skeletal muscle and function as statin efflux transporters [72]. Ongoing research may clarify additional risk factors for myopathy related to statin transport phenomena in and out of skeletal muscle.

Certain racial populations may be at increased risk for statin myopathy, at least with simvastatin. Simvastatin prescribing information recommends caution when doses above 20 mg/day are used in Chinese patients who are also receiving niacin and states that such patients should not be treated with simvastatin 80 mg/day in combination with niacin [73]. In a large randomized trial in which all patients were treated with simvastatin 40 mg/day, participants from China had a higher rate of myopathy than patients from Europe (1.3 versus 0.4 events per 1000 patients per year) [74]. This risk was increased further in Chinese patients randomly assigned to treatment with niacin/laropiprant rather than placebo (risk ratio [RR] 5.2 versus 1.5 in European patients). Of note, we suggest not treating any patients with simvastatin at doses above 40 mg/day even when used as monotherapy. (See "Statins: Actions, side effects, and administration", section on 'Potency'.)

Other patient factors associated with an increased risk of statin-associated adverse muscle events include advanced age (greater than 80 years), frailty, female sex, small body frame, acute or decompensated liver disease, and severe renal disease [75].

Concurrent drug therapy — The increase in susceptibility to myopathy is substantially greater in patients receiving concurrent therapy with a number of drugs, particularly those that inhibit CYP3A4 (table 2) [76], as well as with fibrates [77]. Furthermore, concurrent use of a drug or drug class that is independently considered a risk factor for myopathy (ie, glucocorticoids, cyclosporine, daptomycin, zidovudine, and colchicine) may further increase risk [34,78,79]. Although initial studies described cases of myopathy when niacin (nicotinic acid) was given with a statin [80], this complication appears to be uncommon [81-83].

The uptake, metabolism, and clearance of each statin differs, and therefore each statin is subject to different types of drug interactions.

Simvastatin, lovastatin, and to a lesser extent atorvastatin are metabolized by CYP3A4. Fluvastatin clearance is partly dependent upon CYP2C9 metabolism whereas rosuvastatin, pitavastatin, and pravastatin are cleared primarily by non-CYP450 transformations and affected by fewer significant interactions [84,85]. Hepatic uptake of rosuvastatin and pitavastatin is regulated by hepatocyte membrane transporters whose effect on statin concentrations can be altered by a smaller number of significant drug interactions.

●CYP3A4 drugs – Drugs and substances that inhibit CYP3A4 (table 2) can increase the risk of statin myopathy due to lovastatin, simvastatin, and to a lesser extent atorvastatin [84]. These include cyclosporine [25,86-89], macrolide antibiotics (eg, erythromycin) [90], systemic-azole antifungals [91], and HIV/hepatitis C virus (HCV) protease inhibitors including ritonavir-boosted regimens (table 2) [86,92-94] and cobicistat-enhanced regimens [94]. Drugs that do not inhibit CYP3A4 but are competitive CYP3A4 substrates may also have myopathic interactions with statins, as has been reported with myotoxicity with simvastatin and atorvastatin and colchicine and increased concentrations of simvastatin observed when taken with amlodipine [34,95].

•Calcium channel blockers – The non-dihydropyridine calcium channel blockers diltiazem and verapamil are moderate inhibitors of CYP3A4 metabolism. Manufacturer data indicate that, at a simvastatin dose of 20 to 80 mg/day, there is a 0.6 percent incidence of myopathy in patients also treated with verapamil (a value 10 times higher than seen in patients taking simvastatin without a calcium channel blocker) [42]. The risk is also increased when simvastatin is taken with amlodipine, which is metabolized by CYP3A4 [73,96].

•HIV and HCV protease inhibitors – HIV protease inhibitors and pharmacologic boosters (eg, ritonavir, cobicistat) and some HCV protease inhibitors (eg, simeprevir, paritaprevir) are potent inhibitors of CYP3A4. Thus, statins that are not highly dependent upon CYP3A4 for clearance (eg, pravastatin, pitavastatin) have been usual choices for patients receiving protease inhibitors who require statin treatment. When using statins that are metabolized by CYP3A4, low doses of atorvastatin and rosuvastatin are recommended. Simvastatin and lovastatin are contraindicated statins for patients treated with HIV protease inhibitors and cobicistat-containing coformulations. This practice is supported by manufacturer data and early case reports of myopathy and rhabdomyolysis in patients receiving lovastatin or simvastatin in combination with HIV protease inhibitors [97]. Of the newer statins, pitavastatin does not appear to interact with protease inhibitors, whereas rosuvastatin can interact with some HIV protease inhibitors by a non-CYP mechanism [98-100]. Between 2007 and 2015, cobicistat-containing antiretroviral regimens accounted for an increasing proportion of episodes of contraindicated statin use, based on analysis of pharmacy claims data [94]. Cobicistat interactions are common with atorvastatin, and the dosing of this agent should be restricted to 10 mg/day. Less important interactions in cobicistat-treated patients occur with rosuvastatin, which increases blood rosuvastatin levels by 18 percent [101].

•Amiodarone – Amiodarone and its metabolites can moderately inhibit CYP3A4 metabolism. Data from the manufacturer indicate that, at a simvastatin dose of 80 mg/day, there is a 6 percent risk of myopathy in patients also treated with amiodarone [42]. The risk of rhabdomyolysis in patients treated concurrently with amiodarone appears to be higher with simvastatin than with other statins [102].

•Grapefruit juice – Grapefruit juice inhibits intestinal CYP3A4. However, daily consumption of up to 8 oz (240 mL) of grapefruit juice or one-half of a grapefruit, is unlikely to increase the risk of an adverse interaction or muscle injury [103].

●Cyclosporine – Cyclosporine is an inhibitor of CYP3A4, CYP2C9, and the hepatocyte membrane efflux transporter organic anion transport protein (OATP), which regulates hepatic uptake of fluvastatin, rosuvastatin, and pitavastatin. Coadministration of cyclosporine can increase concentrations of fluvastatin twofold and rosuvastatin and pitavastatin by 3- to 10-fold or more [99,104-106]. Cyclosporine has been safely administered with fluvastatin doses of up to 40 mg/day [107]. Rosuvastatin and pitavastatin are dose-limited or contraindicated with cyclosporine, respectively.

●Fibrates – Fibrates are independently associated with muscle toxicity. An increased risk of muscle toxicity, as high as 1 to 5 percent, has been described with the administration of some statins (eg, lovastatin, simvastatin, and atorvastatin) with gemfibrozil [25,32,108,109]. (See 'Fibrates' below.)

●Colchicine – Myopathy is an infrequent adverse effect of colchicine treatment and several cases have been reported following its coadministration with a statin, particularly in the setting of renal insufficiency. Multiple mechanisms seem to be involved as the interaction has been reported with a variety of statins, including pravastatin [34,110].

●Fusidic acid – Several cases of rhabdomyolysis have been reported following coadministration of atorvastatin or simvastatin with fusidic acid, an antimicrobial available primarily outside the United States [111-117]. The interaction appears to cause significant elevation in levels of both the statin and fusidic acid and could be due to inhibition of glucuronidation, but the exact mechanism is unknown.

●Niacin – Early reports suggested an increased risk of myopathy with combination niacin and statin treatment [80], and this is reflected in longstanding warnings found in some of the statin drug labels [25,95]. This complication appears to be uncommon, and the risk of myopathy has seemed similar to that of either agent taken separately [81-83,118]. However, in a large randomized trial in patients receiving simvastatin, the combination of niacin and laropiprant increased the risk of definite myopathy (1.6 versus 0.4 events per 1000 patients per year; RR 4.4, 95% CI 2.6-7.5) [74]. The risk was particularly increased in participants from China (see 'Patient characteristics' above). It is uncertain whether niacin alone carries the same increased myopathy risk as niacin/laropiprant; however, this trial was much larger than prior studies and had the potential to have detected an interaction between niacin and statins that could have been missed in earlier smaller studies.

Management of these drug interactions, including choice of statin, dose limitations, and use of specific fibrates, is discussed below (see 'Drug interactions' below). For more detailed information about specific statin interactions, refer to the drug interaction program included in UpToDate.

Exercise — Studies offer conflicting results regarding the relationship between physical exercise and increases in muscle symptoms and CK elevations among statin users [119-122]. Exercise can induce rhabdomyolysis in patients with metabolic muscle disease, and vigorous unaccustomed exercise may be a risk factor for rhabdomyolysis in patients taking statins [123]. However, CK elevations and increases in muscle symptoms after exercise are typically mild and transient [3]. Such increases may not differ significantly between individuals with and without muscle-related symptoms prior to moderate-intensity exercise [122].

The mechanism for muscle injury in statin-exposed patients is uncertain [124] but ultimately, as is the case with exercise-induced muscle injury in general, relates to repeated tensile forces incurred by the sarcolemma mediated via the cytoskeletal components such as the costameres and intermediate filaments [125].

Combined risk factors — In an analysis of three prospective trials (Heart Protection Study, Heart Protection Study-2, and SEARCH) involving 58,390 participants treated with simvastatin, the effect of combined risk factors for simvastatin myopathy (defined as unexplained muscle pain or weakness with CK level >10-fold above the upper limit of normal) was explored [126]. Individual risk factors included higher simvastatin dose, female sex, being Chinese (versus European), older age, lower body mass index, medically treated diabetes, and concomitant use of niacin-laropiprant, verapamil, beta blockers, diltiazem, and diuretics. These risk factors were combined to form a weighted myopathy risk score, with a 30-fold difference in myopathy between the upper and lowest tertiles. The score was not associated with less severe myonecrosis (CK levels <10-fold above the upper limit of normal). Prior research has indicated that many of these risk factors have a higher risk of SAMS [4]. Weakness of this analysis includes a definition of “myopathy” that is restricted to severe myonecrosis with symptoms, an analysis restricted to the use of simvastatin, and the lack of a systematic approach to the identification of reproducible muscle symptoms identified in randomized, placebo-controlled, crossover trials [3,127].

CLINICAL FEATURES — Susceptible patients can have different constellations of statin-associated adverse muscle events (see 'Definitions' above), and these may not necessarily occur as a progression from less severe to more severe muscle injury in an individual patient (table 1 and figure 2) [3]. Muscle events result from distinct pathophysiological entities that may overlap in certain patients. The most hazardous myopathic consequence is rhabdomyolysis, associated with acute renal failure [86,128]. (See "Rhabdomyolysis: Clinical manifestations and diagnosis".)

Symptoms — Statin-induced myalgia and myopathy typically present as proximal, symmetric muscle weakness and/or soreness [129]. There may be muscle tenderness and there may be functional impairments such as difficulty raising the arms above the head, arising from a seated position, or climbing stairs; these symptoms are often described as fatigue or tiredness by the patient. Less often the discomfort is asymmetric. Other reported symptoms include cramping (including nocturnal cramping), stiffness [38,130,131], and tendon pain [129]. Some patients, but not all, have elevations in serum creatine kinase (CK). (See 'Diagnosis' below.)

Time course of muscle events — The onset of muscle symptoms is usually within weeks to months after the initiation of statin therapy but may occur at any time during treatment. As an example, a review of 44 cases of statin-associated myopathy found a mean duration of therapy before symptom onset of 6.3 months (range 0.25 to 48.0 months); approximately two-thirds of patients had onset of symptoms within six months of starting therapy [132].

Myalgias and weakness usually resolve and serum CK concentrations return to normal over days to weeks after discontinuation of the drug. In the above study, the mean time to resolution of symptoms in 43 patients who discontinued statin therapy was 2.3 months (range 0.25 to 14.0 months); 58 percent had resolution of symptoms within one month, and 93 percent had resolution within six months [132].

Exercise tolerance — There have been concerns about the effects of statin therapy on exercise tolerance even in the absence of other symptoms; however, data are conflicting [24,133]. Further study is needed to clarify whether some or all statins have important effects on aerobic and muscle fitness in response to exercise.

In some circumstances, exercise may increase the risk for muscle injury in patients taking statins. (See 'Exercise' above.)

Neuromuscular disorders — Statin therapy has been associated with a variety of neuromuscular disorders, including inflammatory myopathies such as polymyositis, dermatomyositis, and inclusion body myositis as well as immune-mediated necrotizing myopathy (IMNM) [134-142]. (See "Pathogenesis of inflammatory myopathies".)

Statin-associated IMNM and inflammatory myopathy may represent a pathophysiological spectrum rather than categorical entities [143].

Although IMNM is rare, the clinician must always be aware of the possibility of its presence whenever statin-associated muscle symptoms (SAMS) fail to resolve several weeks after statin discontinuation, in which case referral to a muscle specialist is needed. Further, immediate referral is warranted if SAMS worsens after statins are discontinued. Patients typically have mild to moderate symmetric proximal muscle weakness. Rarely, mild joint pain or rash may be present [6]; the rash may affect the face, chest, or dorsal hand and therefore resemble dermatomyositis [144]. Necrotizing myopathies can be idiopathic, paraneoplastic, or associated with a connective-tissue disorder.

In necrotizing myopathy, scattered necrotic muscle fibers are present. This apparently histologically distinct noninflammatory statin myopathy is characterized by a macrophagocytic infiltrate engulfing necrotic muscle fibers, responds to immune therapy, and is presumably autoimmune [142,145,146]. Despite the lack of inflammation in the muscle itself, IMNM appears to be due to antibodies to hydroxymethylglutaryl (HMG)-CoA reductase (HMGCR) in regenerating muscle, and possibly other proteins [145,147,148]. In addition, intramuscular edema may be seen on magnetic resonance imaging (MRI) and inflammation of the surrounding fascia and subcutaneous tissue may be seen on biopsy [148]. (See "Pathogenesis of inflammatory myopathies", section on 'Immune-mediated necrotizing myopathy'.)

Other disorders that may have been induced by statin therapy include mononeuritis multiplex [149] and statin-induced extraocular muscle myopathy mimicking Graves' ophthalmopathy [150]. Additionally, patients who develop statin myopathy appear to be at increased risk for having malignant hyperthermia susceptibility [151,152]. (See "Susceptibility to malignant hyperthermia: Evaluation and management", section on 'Myopathies with ryanodine receptor abnormalities'.)

Treatment is discussed below. (See 'Immune-mediated necrotizing myopathy' below.)

DIAGNOSIS — The diagnosis of symptomatic and more severe myositis and myonecrosis with laboratory abnormalities (ie, increased serum creatine kinase [CK]) is typically straightforward and based on a temporal association for both onset with initiation of statin therapy and resolution with statin withdrawal.

However, many patients can have muscle symptoms from statin therapy without an elevation in serum CK. This issue was directly addressed in a crossover study in which 4 of 21 blinded patients who had muscle symptoms while taking a statin (aching, weakness, decreased exercise tolerance) could distinguish statin therapy from placebo because of reproducible muscle symptoms [52]. Strength testing confirmed muscle weakness during statin therapy that resolved during placebo treatment; unblinded review of muscle biopsies showed evidence of mitochondrial dysfunction that also reversed with cessation of therapy. Serum statin concentrations were not inappropriately increased.

There are many other common causes of muscle pain and weakness, including overuse and other injuries, and pain syndromes such as fibromyalgia and myofascial pain syndrome. (See "Overview of soft tissue musculoskeletal disorders" and "Clinical manifestations and diagnosis of fibromyalgia in adults" and "Differential diagnosis of fibromyalgia" and "Approach to the patient with myalgia".)

Distinguishing among these is typically based on a careful history and trials of cessation and reintroduction of statin therapy. Even with this, in some patients it will be difficult to be certain whether muscle symptoms are due to statin therapy, especially considering the variability in the timing of onset and offset of statin-associated muscle symptoms (SAMS) (see 'Time course of muscle events' above). A scoring system, the SAMS clinical index (SAMS-CI), was proposed for statin-associated symptoms [3] and later revised (figure 2) [153]. Validation of the scoring system showed that a low score <5 had a negative predictive value of 91 percent in correctly excluding patients with true statin myalgia [127] but the scoring system has not been evaluated for clinical utility. A general approach to patients with myalgia is discussed separately. (See "Approach to the patient with myalgia".)

The sensitivity and specificity of muscle biopsy for statin myopathy are unknown, and we do not typically use this test clinically, unless the muscle symptoms signs (eg, weakness, elevation of CK, etc) do not resolve upon statin discontinuation. Muscle biopsy obtained early in the course of rhabdomyolysis shows myonecrosis without vasculitis or significant inflammation. Biopsy later in the course may show some mononuclear cell infiltration suggestive of an inflammatory repair process [30-32].

Clinical judgment is necessary in interpreting increased CK levels in patients on statins. CK elevations can be related to hypothyroidism or muscle injury during sports (eg, running, hockey, impact or collision sports), and if a CK is to be measured in patients who engage in high-impact sports, it should be measured before engaging in exercise that day (see "Muscle enzymes in the evaluation of neuromuscular diseases"). In addition, there are differences in serum CK levels among racial groups (table 3) [154,155].

Some patients report pain with statin therapy after having been warned about the potential side effect, without a pattern that suggests typical statin myalgias. In some of these patients, the statins may not actually be causing physiologic pain, but instead concerns about side effects may be heightening patient perception of pain from other causes.

A study used n-of-1 trials in eight patients who developed pain within three weeks of initiating statin therapy and who had no clinically significant elevation in CK, a measure of myonecrosis, to examine whether statins were actually the cause of the myalgias [156]. Seven patients underwent three pairs of treatments and one patient underwent two pairs of treatments, with each treatment pair consisting of three weeks of therapy with statin (at the dose that had been used clinically in that patient) or placebo, a three-week washout period, and the opposite therapy (placebo or statin). None of the eight patients had a statistically significant difference in pain scores between statin and placebo treatment periods. Five of the eight patients resumed and tolerated open-label statin therapy after learning the results of their n-of-1 trials.

It is uncertain whether these results would apply to typical patients seen outside of recruitment for a study and where the diagnosis of statin myopathy is in doubt. Additionally, the total number of patients in the study was small. Although an editorial comment that accompanied the article suggested that n-of-1 trials could be clinically useful, patients in most clinical settings do not have simple access to such trials.

MONITORING — Despite the increased risk of myopathy associated with statin therapy, routine monitoring of serum creatine kinase (CK) levels is not recommended, based on a retrospective study of over 1000 patients in a primary care practice in which there were no significantly abnormal, and only two moderately abnormal, CK values potentially related to statin use [29]. However, it is useful to obtain a baseline serum CK before initiation of statin therapy for reference in case symptoms develop.

Patients treated with statins should be alerted to report the new onset of myalgias or weakness.

MANAGEMENT — No other treatment, aside from statin cessation, is necessary in most cases of statin-associated muscle symptoms (SAMS). Two notable exceptions are clinical rhabdomyolysis (urinary myoglobin with or without deterioration in kidney function), which always requires careful monitoring and supportive care, nearly always in an in-patient setting, and immune-mediated necrotizing myopathy, in which case immunosuppressive therapy is required. (See 'Neuromuscular disorders' above.)

Rhabdomyolysis — Patients with symptomatic or asymptomatic rhabdomyolysis from a statin should discontinue therapy immediately. Based on clinical experience, in the absence of clinical symptoms, a creatine kinase (CK) level >10 times the upper limit of normal that is felt to be due to a statin is an indication for discontinuing the medication. Patients should drink large quantities of fluids to facilitate renal excretion of myoglobin and to help prevent renal failure.

Patients with a history of statin-induced rhabdomyolysis should generally not be treated with another statin because of the risk of recurrence [123]. In some cases, however, it may be reasonable to retry statin therapy after the resolution of an acute reversible event that contributed to muscle toxicity (eg, undetected hypothyroidism, acute renal failure, biliary obstruction, use of other medications that increase statin levels).

The clinical presentation, diagnosis, and management of rhabdomyolysis are discussed separately. (See "Rhabdomyolysis: Clinical manifestations and diagnosis" and "Prevention and treatment of heme pigment-induced acute kidney injury (including rhabdomyolysis)".)

Immune-mediated necrotizing myopathy — Management of this condition includes immediate statin discontinuation. In addition, treatment with oral steroid, methotrexate, intravenous immunoglobulin (IVIG), and/or rituximab appears to be reasonable and safe, and these agents are commonly used. The severity of the weakness coupled with the CK elevation guides the selection and dosing of these potential agents. The European Neuromuscular Centre (ENMC) has produced a guidance document to assist the clinician in the treatment of these patients [157,158]. (See 'Neuromuscular disorders' above.)

Other muscular toxicity

General approach — If a patient requires a statin and experiences muscle symptoms (other than rhabdomyolysis), we suggest the following approach:

Administer the SAMS clinical index (SAMS-CI) (figure 2) to determine the likelihood that muscle symptoms are due to statin use.

●For patients with a low SAMS-CI score (2 to 4):

•Discontinue the statin.

•Evaluate for other causes of symptoms, including depression and anxiety or medication-related side effects.

•Wait for symptom resolution.

After symptom resolution:

•If patient was not on a high-intensity statin, restart the same statin at a lower dose.

•If patient was on a high-intensity statin, switch to an alternative high-intensity statin (atorvastatin, rosuvastatin) and address concerns about side effects. If the patient experiences adverse muscle symptoms on the alternative high-intensity statin, we recommend switching to fluvastatin, pravastatin, or pitavastatin.

•If the patient was already on a low daily dose of a statin, consider alternate-day dosing [4]. (See 'Alternate-day dosing' below.)

●For patients with a high SAMS-CI score (5 to 11):

•Discontinue the statin.

•Assess for drug interactions, including those related to addition of a new medication or a change in administration of a long-term medication that may account for symptoms.

•Assess for comorbidities which may account for or exacerbate symptoms (vitamin D deficiency, hypothyroidism, acute or chronic renal failure, or obstructive liver disease). Correct hypothyroidism or low vitamin D level if present.

After symptom resolution:

•If patient was not on a high-intensity statin, restart the same statin at same or lower dose. If patient was already on the lowest dose, consider alternate-day dosing, although this may result in lower efficacy. (See 'Alternate-day dosing' below.)

•If patient was on a high-intensity statin, switch to an alternative high-intensity statin (atorvastatin, rosuvastatin) and address concerns about side effects. If the patient experiences adverse muscle symptoms on the alternative high-intensity statin, we recommend switching to fluvastatin, pravastatin, or pitavastatin.

•Readminister the SAMS-CI between 4 and 12 weeks.

•If the SAMS-CI score is still high, switch to a statin with different pharmacokinetic properties (table 4) and/or consider non-statin low-density lipoprotein (LDL) cholesterol-lowering therapy.

-If switching statin therapy to an agent with a different pharmacokinetic profile is unsuccessful [153], initiate alternate-day (or less frequent) dosing with careful monitoring. (See 'Alternate-day dosing' below.)

•If SAMS-CI score is low, consider and evaluate for non-statin-associated conditions or therapies that may be causing symptoms.

•If symptoms persist, discontinue all statin therapy and consider non-statin cholesterol-lowering therapy.

Vitamin D — If a patient with statin myopathy is known to be vitamin D deficient, it is reasonable to assess vitamin D status and, in patients with vitamin D deficiency, administer vitamin D replacement therapy and then rechallenge with statin therapy. Low vitamin D levels are associated with myopathy in statin-treated patients [66]. (See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment", section on 'Summary and recommendations'.)

Some studies, but not all, have suggested that low vitamin D levels may be associated with statin myopathy [159]. Case reports, case series, and some small, inadequately controlled studies have reported improvement in symptoms of statin myopathy in patients supplemented with vitamin D [159,160]. Although vitamin D deficiency might be a cause of statin myopathy, it may instead be a marker for other factors for myopathy (such as other nutritional deficiencies).

Switching statins — As discussed above, pravastatin, fluvastatin, and pitavastatin appear to have much less intrinsic muscle toxicity than other statins (see 'Statin characteristics' above). Thus, in patients who have developed statin myopathy (other than rhabdomyolysis) on a statin other than pravastatin, pitavastatin, or fluvastatin, an option is to switch to one of those medications once symptoms have resolved off statin therapy.

Alternate-day dosing — Daily dosing of statins is preferred whenever possible, since daily regimens are the ones that have been studied and proven to reduce clinical events. Clinical experience suggests that alternate-day dosing may improve the tolerability of statins in patients experiencing myalgias, and this strategy appears to have equal LDL cholesterol-lowering efficacy [161] and can reasonably be tried in patients unable to tolerate daily statin therapy.

However, it is possible that alternate-day dosing, especially of shorter-acting statins, may result in decreased efficacy. Alternate day-dosing presumes that LDL cholesterol levels are as well controlled between doses as when the statin is given daily. This may be the case with longer-acting statins (eg, rosuvastatin, atorvastatin) but is less likely with shorter-acting statins (eg, simvastatin, fluvastatin, pravastatin, lovastatin) whose half-lives are less than six hours. We prefer to use alternate-day dosing only with long-acting statins. However, if alternate-day dosing with a shorter acting statin is chosen, we would measure the LDL cholesterol at the nadir of the dosing regimen to ensure adequate lowering of the LDL cholesterol level. We do not use regimens that extend the dosing interval beyond every other day, such as once-weekly regimens, as these are very unlikely to control LDL cholesterol levels adequately. (See "Statins: Actions, side effects, and administration", section on 'Alternative dosing regimens'.)

Therapies of uncertain benefit

Coenzyme Q10 — We suggest not administering Coenzyme Q10 (CoQ10) to try to improve or prevent statin-associated muscle events. As discussed above, CoQ10 depletion that reduces skeletal muscle ubiquinone concentrations may play a role in statin myopathy (see 'Pathogenesis' above). However, there is little published evidence showing benefit of CoQ10 supplements for the treatment of myalgia or myopathy [3].

The American Heart Association (AHA) statement on statin safety concluded that CoQ10 is not helpful in SAMS [162].

In our view, the best available evidence is from a small randomized double-blind, placebo, crossover trial that found no benefit of CoQ10 at a dose of 600 mg/day in patients with simvastatin-induced myalgia [163]. In this trial, participants were tested prior to enrollment for the presence of a true statin myalgia by being randomized to simvastatin or placebo for eight weeks and then crossed over to the other therapy. Symptoms were measured in each phase, and only 35.8 percent of participants were categorized as having true statin myalgia (ie, symptoms on the statin but not on the placebo) and allowed to continue in the trial. Among the other participants, 29.2 percent experienced symptoms on placebo but not on simvastatin, and 17.5 percent experienced pain on both simvastatin and placebo. These results highlight the fact that many patients are likely to have symptoms that are not a true statin myalgia, and this information diminishes our confidence in the patient selection for other trials without this pre-testing.

In a meta-analysis of 12 placebo-controlled randomized trials (n = 575 patients) assessing the effects of CoQ10 supplementation on SAMS and plasma CK, CoQ10 supplementation ameliorated SAMS such as [164]:

●Muscle pain (weighted mean difference [WMD] -1.60, 95% CI -1.75 to -1.44)

●Muscle weakness (WMD -2.28, 95% CI -2.79 to -1.77)

●Muscle cramp (WMD -1.78, 95% CI -2.31 to -1.24)

●Muscle tiredness (WMD -1.75, 95% CI -2.31 to -1.19)

There was no meaningful difference in the plasma CK levels. Although symptoms were reduced, there was substantial heterogeneity among trials, and most did not attempt to identify patients with true statin myalgia.

The evidence for CoQ10 for prevention of muscle events is even more limited. (See 'Use of coenzyme Q10 for prevention' below.)

Red yeast rice — Red yeast rice (Monascus purpureus) is a nutraceutical that lowers LDL cholesterol levels by 20 to 30 percent. The LDL cholesterol-lowering effect of red yeast rice is due to the presence of monacolin K, a compound similar to lovastatin. Although red yeast rice lowers LDL cholesterol similar to a low-efficacy statin and may be tolerated by some patients who have discontinued statin therapy for muscle side effects, this therapy is not recommended due to lack of clinical outcomes data, variable drug bioavailability [165], and possible toxic effects from contaminants. Red yeast rice may also induce muscle complaints because of its statin-like content [166-168]. (See "Lipid management with diet or dietary supplements".)

PREVENTION

Choice of statin — As discussed above, pravastatin, fluvastatin, and pitavastatin appear to have much less intrinsic muscle toxicity than other statins (see 'Statin characteristics' above). All of these agents are relatively lower efficacy statins; however, whenever they are adequate for the clinical situation, we suggest treating with one or the other to reduce the risk of statin myopathy.

As discussed below, the choice of statin is also important in dealing with potential drug interactions. (See 'Drug interactions' below.)

Drug interactions — Certain drug interactions are discussed below. Additional detail about specific statin interactions and management suggestions for avoiding increased myopathy risk is available by using the drug interactions program.

CYP3A4 drugs — As discussed above, the risk of muscle injury is substantially increased when taking the combination of statins extensively metabolized by cytochrome P450 3A4 (CYP3A4; lovastatin, simvastatin, atorvastatin) and drugs that inhibit CYP3A4 (table 2) (see 'Concurrent drug therapy' above). Pravastatin, fluvastatin, and pitavastatin are preferred when concurrent therapy with a strong inhibitor of CYP3A4 cannot be avoided.

The importance of using a statin that is not extensively metabolized by CYP3A4 when administering a CYP3A4 inhibitor is illustrated by the moderate CYP3A4 inhibitor cyclosporine. Regular-dose lovastatin (40 to 80 mg/day) and simvastatin (20 mg/day) are associated with an appreciable risk of myositis (as high as 13 to 30 percent) in cyclosporine-treated patients [25,86,87]. Lovastatin levels much higher than the therapeutic range have been noted in patients with rhabdomyolysis who were treated with cyclosporine [25]. Although the data are limited, myositis has also been described when cyclosporine is given with atorvastatin, which is metabolized by CYP3A4 [88,89]. By contrast, pravastatin and fluvastatin, which are not extensively metabolized by CYP3A4, do not appear to increase the risk of myopathy when given concurrently with cyclosporine [87,169-171].

The safety of pravastatin in such patients was illustrated in an open-label study that compared pravastatin (40 mg/day) with simvastatin (20 mg/day) in 87 cardiac transplant recipients [87]. Rhabdomyolysis or myositis occurred only with simvastatin therapy (13.3 percent). A similar lack of muscle toxicity was noted in a placebo-controlled trial in which none of 50 cardiac transplant recipients treated with pravastatin (40 mg/day) developed myalgia or myositis during one year of therapy [169].

The safety of fluvastatin (20 and 40 mg/day) taken with cyclosporine in hypercholesterolemic renal transplant patients has been demonstrated in several small trials in which mean serum trough levels of cyclosporine were not significantly altered [107,172,173].

Although pitavastatin and rosuvastatin are not significantly metabolized by CYP3A4, manufacturers' pharmacokinetic data show they can interact with cyclosporine, apparently by a non-CYP mechanism [99,106]. Hepatic uptake of pitavastatin and rosuvastatin is regulated by hepatocyte membrane transporters, known as organic anion transport proteins (OATPs), whose effects can be inhibited by certain drugs (ie, cyclosporine, erythromycin, clarithromycin), causing increased levels of pitavastatin or rosuvastatin [174,175]; there is some evidence that clarithromycin can increase the risk of rhabdomyolysis even in patients taking statins that are not metabolized by CYP3A4 [176].

Fibrates — The concomitant use of fibrates and statins can increase the risk of muscle injury, including rhabdomyolysis [2]. The effect is due to an increase in statin levels and varies according to the fibrate and statin. Toxicity can be minimized by the choice of fibrate and by using statins at relatively low doses [177-179]. The lowest risk is with the use of fenofibrate and either fluvastatin, pravastatin, or pitavastatin at the lowest effective dose.

Fenofibrate is the preferred fibrate in patients who require combined therapy with a statin due to minimal risk of increase in statin levels [180]. It appears to be safer than gemfibrozil due to a differential effect on statin excretion [181,182].

The relative safety of fenofibrate has been demonstrated in meta-analyses and individual trials, in which there has been no increase in muscle-related adverse events in patients taking fenofibrate plus a statin compared with a statin alone [183-185].

Gemfibrozil has a greater potential to increase plasma levels of statins and risk for muscle toxicity, especially when used with lovastatin, simvastatin, or atorvastatin [25,32,108,109]. Fluvastatin and pravastatin are the safest statins in this situation [177,186-191] and can be considered for use with gemfibrozil if the benefit is likely to outweigh the risk.

Niacin — Although the overall increase in risk of statin-associated muscle symptoms (SAMS) with concurrent use of niacin with statins appears to be small, niacin seems to increase the risk of myopathy in patients receiving simvastatin and perhaps other statins (see 'Concurrent drug therapy' above). This increased risk may be a particular concern in patients from China (see 'Patient characteristics' above), and we suggest avoiding the combination of simvastatin and niacin in Chinese patients and only using niacin with caution in patients receiving other statins.

Dose limitations — Manufacturer recommendations for simvastatin, and also for lovastatin, state that the medications are contraindicated in patients treated with most strong CYP3A4 inhibitors (table 2) and that there are dose limitations or recommendations to avoid these statins when used in conjunction with a number of other medications, including limiting simvastatin to 20 mg/day when taken with amlodipine [73,96].

Given high rates of myopathy with simvastatin 80 mg/day [192] and the availability of rosuvastatin and generic atorvastatin, we suggest not treating patients with doses of simvastatin above 40 mg/day. Additionally, clinicians should strongly consider switching even patients who are currently tolerating simvastatin 80 mg/day to one of these other statin options. (See "Statins: Actions, side effects, and administration", section on 'Potency'.)

For more detailed information about dose limitations, refer to the individual drug monographs included with UpToDate.

Use of coenzyme Q10 for prevention — Some clinicians recommend that patients taking statins take Coenzyme Q10 (CoQ10) to try to prevent myopathy, and a few case reports have noted benefit with doses of 30 to 250 mg/day [193]. Further, a meta-analysis of several small clinical trials suggests benefit [164]. Nonetheless, we feel that there is inadequate evidence to recommend CoQ10 supplementation for prevention of statin-induced muscle toxicity based on a randomized, double-blind placebo-controlled crossover trial [194].

Exercise

Approach to exercise for patients on statins — Although exercise may trigger SAMS and increases in CK levels [130], patients who are taking statins should not avoid exercise. Statin-related injury from exercise is typically mild and subclinical [3]. Moreover, a graduated exercise program may mitigate the risk of muscle injury from unaccustomed vigorous exercise.

Rationale for graduated physical training — Graduated physical training may protect skeletal muscles from exercise-induced muscle injury. Graduated physical training induces mitochondrial biogenesis and upregulates antioxidant defense mechanisms. This may increase the oxidative capacity of skeletal muscles and thereby protect skeletal muscle fibers from the pro-oxidant effects of statins [195].

Holding statin prior to intensive exercise is usually not necessary — In individuals who have done endurance training, statins can potentiate muscle injury from prolonged vigorous exercise. For example, one study showed greater increases in post-marathon CK levels in individuals receiving statins, and older runners receiving statins exhibited more susceptibility than younger runners [196]. Nonetheless, CK elevations were mild and subclinical, which suggests that most trained individuals need not discontinue statin therapy prior to a race.

SUMMARY AND RECOMMENDATIONS

●Epidemiology – Statin muscle-related adverse events are relatively uncommon. Myalgias and myopathy occur with a frequency of 2 to 11 percent. However, severe myonecrosis and clinical rhabdomyolysis are much rarer (0.5 percent and less than 0.1 percent, respectively). Patients can experience statin-induced myalgias without an elevation in serum creatine kinase (CK) concentration. (See 'Epidemiology' above.)

●Risk factors – Several risk factors have been identified, including the following (see 'Risk factors' above):

•Choice of statin – The risk of muscle injury is substantially higher when taking a statin that is extensively metabolized by cytochrome P450 3A4 (CYP3A4; lovastatin, simvastatin, atorvastatin) together with a drug that interferes with CYP3A4 (table 2). Pravastatin, fluvastatin, rosuvastatin, and pitavastatin are preferred when given to a patient receiving another drug that is a strong inhibitor of CYP3A4. (See 'CYP3A4 drugs' above.)

•Patient characteristics – Enhanced susceptibility to statin-associated myopathy occurs in patients with neuromuscular disorders, acute or chronic renal failure, obstructive liver disease, and hypothyroidism. (See 'Patient characteristics' above.)

•Concurrent drug therapy – The increase in susceptibility to myopathy is substantially greater in patients receiving concurrent therapy with a number of drugs, particularly those that inhibit CYP3A4 (table 2). (See 'Concurrent drug therapy' above.)

●Clinical features – Muscle symptoms and/or signs usually begin within weeks to months after starting statins. Myalgias, weakness, and serum CK concentrations usually return to normal over days to weeks after drug discontinuation, although in a few cases they may require months to resolve. (See 'Time course of muscle events' above.)

●Diagnosis – The diagnosis of symptomatic statin myopathy with laboratory abnormalities (ie, increased serum CK) is typically straightforward and based on a temporal association for both onset with initiation of statin therapy and resolution with statin withdrawal. However, some patients can have muscle symptoms from statin therapy without an elevation in serum CK, and it can then be difficult to be certain whether muscle symptoms are due to statin therapy. (See 'Diagnosis' above.)

•Clinical judgment is necessary in interpreting increased CK levels in patients on statins. CK elevations can be related to hypothyroidism or muscle injury during sports (eg, running, diving for a volleyball, hockey), and patients who engage in high-impact sports should be advised to have any CK measurements done before engaging in exercise that day. (See 'Diagnosis' above.)

●Evaluation – In patients who develop evidence of muscle toxicity while on statin therapy, we use the statin-associated muscle symptoms clinical index (SAMS-CI) to determine the likelihood of statin involvement. We assess for drug interactions and check a vitamin D level and thyroid function. We use a step-wise approach to decisions regarding continuing, switching, or discontinuing statin therapy. (See 'Concurrent drug therapy' above and 'Hypothyroidism, hypovitaminosis D, and other disorders' above and 'Vitamin D' above and 'General approach' above.)

●Limited role for lab monitoring – We suggest not routinely monitoring serum CK levels in patients on statin therapy (Grade 2C). It is useful to obtain a baseline CK level for reference purposes prior to starting statin therapy. Patients treated with statins should be alerted to report the new onset of myalgias or weakness. (See 'Monitoring' above.)

●Management

•Rhabdomyolysis – Patients with symptomatic or asymptomatic rhabdomyolysis from a statin should discontinue therapy immediately. (See 'Rhabdomyolysis' above.)

•Immune-mediated necrotizing myopathy – Management of this condition includes immediate statin discontinuation. (See 'Immune-mediated necrotizing myopathy' above.)

•Switching statins – Pravastatin, pitavastatin, and fluvastatin appear to have much less associated muscle toxicity than other statins. Thus, in patients who have developed statin myopathy (other than rhabdomyolysis) on a statin other than pravastatin, pitavastatin, or fluvastatin, we suggest switching to one of these medications once symptoms have resolved off statin therapy (Grade 2B). (See 'Switching statins' above and 'Statin characteristics' above.)

•Alternate-day dosing – In patients who are unable to tolerate daily dosing of pravastatin, fluvastatin, or pitavastatin, we suggest a trial of alternate-day or less frequent dosing (one to two times weekly) of statin therapy (Grade 2C). (See 'Alternate-day dosing' above.)

•Limited role for coenzyme Q10 – We suggest not administering coenzyme Q10 (CoQ10) for treatment or prevention of statin myopathy (Grade 2C). However, there may be a subset of patients who may derive benefit, and there is little to no risk of harm in use of this nutraceutical. (See 'Coenzyme Q10' above and 'Use of coenzyme Q10 for prevention' above.)

●Prevention – Strategies for prevention include choice of statin and management of existing or potential drug interactions. (See 'Prevention' above.)

•Fibrates – In patients who require combined therapy with a fibrate and a statin (including pravastatin or fluvastatin), we suggest fenofibrate rather than gemfibrozil (Grade 2B). (See 'Fibrates' above.)