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Statin Toxicity

Mechanistic Insights and Clinical Implications
Originally published Research. 2019;124:328–350


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

    Statins are a widely prescribed class of drugs to lower cholesterol. Their mode of action is primarily via inhibition of HMG-CoA (hydroxymethylglutaryl-coenzyme A) reductase, the rate-limiting enzyme in the cholesterol biosynthesis pathway.1 Despite the widespread use of statins to lower cholesterol and reduce cardiovascular morbidity and mortality, discontinuation and nonadherence to statin therapy remains an ongoing problem. The major reason for discontinuation of statin therapy is statin-associated muscle symptoms (SAMSs),2 which are the most well-documented side effect of statins, although there appears to be no unifying mechanism. In addition, other more serious adverse effects of statins may also occur, with the next most established being new-onset type 2 diabetes mellitus for which the mechanisms are far less clear. Other side effects include neurological and neurocognitive effects, hepatotoxicity, renal toxicity, and others (gastrointestinal, urogenital, reproductive), which currently have no established validity. This review focuses on the benefits of statins, the types of statins, and their mechanism of benefit, followed by discussion of the previously mentioned toxicities, with a focus on SAMS. Last, we will discuss the clinical implications and alternative treatment options.

    Benefits of Statin Therapy

    There is now overwhelming evidence to support reducing LDL-c (low-density lipoprotein cholesterol) to reduce atherosclerotic cardiovascular disease (CVD).3 Statins are the most widely prescribed and evidence-based lipid-lowering drug in the world for lowering LDL-c and reducing cardiovascular morbidity and mortality, both in primary and secondary prevention.4 Recent statistics demonstrate increasing statin use in adults aged ≥40 years5 and in patients with elevated atherosclerotic CVD risk.6 Meta-analysis highlights the benefits of LDL-c reduction, with every 1 mmol/L (38.7 mg/dL) reduction associated with a significant 22% relative risk reduction in major vascular and coronary events.7 This is supported by the Cholesterol Treatment Trialists Collaboration. In men and women with a wide spectrum of clinical characteristics, there was a consistent relative risk reduction in major vascular events per change in LDL-c level with no observed adverse events, suggesting that lowering beyond current targets would further reduce CVD risk.8 Legacy data from the WOSCOPS (West of Scotland Coronary Prevention Study) further supports the early and prolonged use of statins for primary prevention of CVD in men with LDL-c ≥4.92 mmol/L (≥190 mg/dL).9 More recent data from the FOURIER outcomes study suggests that LDL-c levels can be reduced to <1.03 mmol/L (<40 mg/dL) with statins and PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors, which was associated with a 15% reduction in the primary outcome, with no excess in safety events at 2.2 years.10 Furthermore, the recently released 2018 American Heart Association and American College of Cardiology Guideline on the Management of Blood Cholesterol recommends the use of statin therapy to reduce risk in a range of patient populations (clinical atherosclerotic CVD, diabetes mellitus, and hyperlipidemia), where the greater the LDL-c reduction, the greater the subsequent risk reduction, with recommendations to reduce levels by ≥50%.11 In addition to health-promoting behaviors, statins are the bedrock of all international guidelines on lipid management.

    Mechanism of Action

    Statins work by competitively blocking the active site of the first and key rate-limiting enzyme in the mevalonate pathway, HMG-CoA reductase. Inhibition of this site prevents substrate access, thereby blocking the conversion of HMG-CoA to mevalonic acid. Within the liver, this reduces hepatic cholesterol synthesis, leading to increased production of microsomal HMG-CoA reductase and increased cell surface LDL receptor expression. This facilitates increased clearance of LDL-c from the bloodstream and a subsequent reduction in circulating LDL-c levels by 20% to 55%.12 In addition to reducing LDL-c and cardiovascular morbidity and mortality, statins may have additional non–lipid-related pleiotropic effects. These include improvements in endothelial function, stabilization of atherosclerotic plaques, anti-inflammatory, immunomodulatory and antithrombotic effects, effects on bone metabolism, and reduced risk of dementia. These additional benefits are primarily thought to arise because of inhibition of the synthesis of isoprenoid intermediates of the mevalonate pathway.12

    Structural Characteristics and Pharmacokinetics of Statins

    The active component of statins is a modified 3,5-dihydroxyglutaric acid moiety, which is structurally similar to the endogenous substrate, HMG-CoA, and the mevaldyl CoA transition state intermediate. This active site binds to and inhibits HMG-CoA reductase activity in a stereoselective process that requires the statin to have a 3R,5R configuration. The molecular and clinical differences of statins arise from the ring that is attached to the active moiety, which can be a partially reduced naphthalene (lovastatin, simvastatin, pravastatin), a pyrrole (atorvastatin), an indole (fluvastatin), a pyrimidine (rosuvastatin), a pyridine (cerivastatin), or a quinoline (pitavastatin). The substituents on the ring define the solubility and pharmacological properties of the statin. Hydrophilicity (pravastatin and rosuvastatin) originates from the common active site plus other polar substituents, whereas lipophilicity (atorvastatin, lovastatin, fluvastatin, pitavastatin, simvastatin, and cerivastatin) arises because of the addition of nonpolar substituents.13,14

    Statins differ in their pharmacokinetic characteristics due in part to the form they are administered in and in part to their lipophilicity (Table 1). Simvastatin and lovastatin are administered as an inactive lactone form that is converted to the active form in the body. In contrast, atorvastatin, fluvastatin, pravastatin, rosuvastatin, and pitavastatin are administered in active acid form.15 Hydrophilic statins require carrier-mediated uptake into the liver, whereas lipophilic statins are able to passively diffuse through the cell membrane, which decreases their hepatoselectivity as they are also able to diffuse into other tissues. Lipophilic statins are generally cleared via oxidative biotransformation, whereas hydrophilic statins are excreted unchanged. Metabolism occurs primarily through CYP3A4 for simvastatin, lovastatin, and atorvastatin, whereas fluvastatin is metabolized mainly through CYP2C9. In addition, all statins are substrates of several membrane transporters.14–16

    Table 1. Statin Drug Characteristics

    Drug NameDerivativeSide RingSolubilityForm AdministeredMetabolismClearance
    AtorvastatinSyntheticPyrroleLipophilicActive hydroxy acidCYP3A4Hepatic
    Cerivastatin*SyntheticPyridineLipophilicActive hydroxy acidVarious CYP3AHepatic
    FluvastatinSyntheticIndoleLipophilicActive hydroxy acidCYP2C9Hepatic
    LovastatinFungalNaphthaleneLipophilicInactive lactoneCYP3A4Hepatic
    PitavastatinSyntheticQuinolineLipophilicActive hydroxy acidNon-CYP450 Limited CYP2C9/19Hepatic
    PravastatinFungalNaphthaleneHydrophilicActive hydroxy acidNon-CYP450Hepatic and renal
    RosuvastatinSyntheticPyrimidineHydrophilicActive hydroxy acidNon-CYP450 Limited CYP2C9/8Hepatic and renal
    SimvastatinFungalNaphthaleneLipophilicInactive lactoneCYP3A4Hepatic

    CYP indicates cytochrome.

    *Withdrawn from the market.

    Statin Toxicity

    Statin toxicity or intolerance most commonly presents as SAMSs.17,18 Other side effects of statin therapy, which can be more serious, include new-onset type 2 diabetes mellitus, neurological and neurocognitive effects, hepatotoxicity, renal toxicity, and other conditions.19 Currently, no universally accepted definition of statin toxicity/intolerance exists, with several groups attempting to define the condition (Table 2). The prevalence of statin intolerance is also widely debated, in part because of difficulties in identification and diagnosis, particularly with respect to muscle symptoms.18 Observational studies suggest it occurs in 10% to 15% of patients,21,24 with clinic data putting it as high as 30%.17,22 In randomized controlled trials, the incidence is thought to be 1.5% to 5% of patients, although this is believed to be an underestimation as most studies exclude patients with a history of statin intolerance either before randomization or during the run-in period.18,21,25,26 True diagnosis of the condition requires a systematic approach of dechallenge and rechallenge to assess causation, multiple statin challenges to support diagnosis, and elimination of other underlying causes of the described side effects.25,27 Despite the difficulties in identifying and diagnosing statin toxicity, however, several international organizations have identified statin intolerance to be of major clinical importance that warrants further research and investigation.20,28,29

    Table 2. Definitions of Statin Intolerance

    National Lipid Association202014Adverse effects relating to quality of life, leading to decisions to decrease or stop the use of an otherwise beneficial drug.
    International Lipid Panel212015An inability to tolerate a dose of statin required to reduce a person’s cardiovascular risk sufficiently from their baseline risk and could result from different statin related side effects, including; muscle symptoms, headache, sleep disorders, dyspepsia, nausea, rash, alopecia, erectile dysfunction, gynecomastia, and arthritis.
    European Atherosclerosis Society222015The assessment of the probability of SAMS being due to a statin take into account the nature of the muscle symptoms, the elevation in CK levels and their temporal association with statin initiation, discontinuation, and re-challenge.
    Canadian Consensus Working Group232016A clinical syndrome characterized by significant symptoms and biomarker abnormalities that is documented by challenge/de-challenge/re-challenge using at least 2 statins (including atorvastatin and rosuvastatin) that is not due to drug-drug interactions or untreated risk factors for intolerance.

    SAMS indicates statin-associated muscle symptoms.

    Clinical Presentations of Statin Toxicity and Their Proposed Mechanisms

    Although the only reliably confirmed adverse events caused by statins are said to be muscle-related, type 2 diabetes mellitus, and possibly hemorrhagic stroke,30,31 it is important to consider all of the clinical manifestations of statin toxicity and intolerance, which can significantly impact adherence to therapy and subsequent cardiovascular risk. Mechanistically, statin toxicity is thought to arise because of HMG-CoA reductase inhibition effects, direct cellular and subcellular effects, or a combination of both.5 Other possible causes include genetic factors, drug-drug interactions, vitamin D status, and other metabolic or immune effects (Figure 1).21 Regardless of the mechanistic pathway, the end result is a change in drug bioavailability and activity, which can lead to nonadherence and intolerance.32 Adverse side effects have generally been shown to be class, dose, time, age, sex, and comorbidity dependent; however, considerable variability exists. Although the mechanisms are varied and likely because of multiple pathways, age is considered the leading predisposing risk factor because of the likely presence of multiple comorbidities (renal or liver dysfunction), concomitant drug use that may interfere, decreased body mass, cognitive impairment, and a decreased resistance to other stressors.23

    Figure 1.

    Figure 1. Potential mechanisms for the development of statin toxicity. FPP indicates farnesyl pyrophosphate; GGPP geranylgeranyl pyrophosphate; GPP, geranyl pyrophosphate; and HMG-CoA reductase, hydroxymethylglutaryl-coenzyme A reductase.

    Statin-Associated Muscle Symptoms

    SAMSs are by far the most prevalent and important adverse event, with up to 72% of all statin adverse events being muscle related.33 These can present as myalgia, myopathy, myositis with elevated CK (creatinine kinase), or at its most severe, rhabdomyolysis, with some people reporting additional joint and abdominal pain.17,34 Other skeletal-related side effects include tendinopathies and tendon disorders, as well as arthralgias, although these are rarely evaluated in large randomized controlled trials.35 Since first reported in 2002, several groups have worked to provide a unified definition and diagnostic approach for SAMS.29,36

    SAMS Phenotypes and Clinical Presentation

    Regardless of the definition, SAMS usually presents as a symmetrical (bilateral) condition that affects the large proximal muscles, particularly of the lower extremities. Symptoms can occur at rest or shortly after exercise and usually occur within 1 month of initiation of therapy or an increase in dose.5,21 Phenotypically, 7 progressively worse statin-related myotoxicity phenotypes have been proposed. Beginning at asymptomatic CK elevation, they include tolerable and intolerable myalgia, myopathy, severe myopathy, rhabdomyolysis, and autoimmune-mediated necrotizing myositis.37 However, it is now recognized that muscle adverse events do not present as a continuum that begins with myalgia and progresses to more severe forms, thus requiring each event to be categorized using standard definitions.36 Defining SAMS is further compounded by no current consensus on the terminology to be used, with myalgia, myositis, and myopathy often used interchangeably.18,34 Furthermore, SAMSs can, and frequently do, occur without elevations in CK, which must also be considered in definitions.38 From a clinical viewpoint, SAMSs can be divided into 4 groups: (1) rhabdomyolysis characterized by high CK concentrations (>100-fold the upper limit of normal [ULN]), myoglobinuria, and renal impairment; (2) myalgia or mild hyperCKemia (<5× ULN); (3) self-limited toxic statin myopathy (CK levels between 10 and 100 ULN); and (4) myositis or immune-mediated necrotizing myopathy with HMG-CoA reductase antibodies and CK levels between 10 and 100× ULN.34 Additional classification includes 4 grades of hypercreatinine kinase expressed relative to baseline values, with further consideration for sex and ethnicity.23

    Muscle toxicity is classed as either toxic or immune related.5,19 Immune-related statin-induced muscle toxicity is driven by both inflammatory and noninflammatory pathways. Inflammatory myopathies, while rare, are characterized by large increases in CK levels, a myopathic pattern on electromyogram and inflammatory infiltrates on muscle biopsy.19 Inflammation mainly comprised macrophages; however, certain immune-related features, including endothelial membrane attack complex deposition in non-necrotic fibers and MHC (major histocompatibility complex) class I, are additional features.19,34 The condition usually resolves with discontinuation of statin therapy and immunosuppressive therapy19; however, it has been associated with a specific immunogenetic background, with adults often showing the HLA-DRB1 (DRB1 beta chain)*11:01 and children HLA-DRB1*07:01.34 This is thought to be because of the upregulation of HMG-CoA reductase, with overexpression of this enzyme thought to facilitate presentation of highly immunogenic HMG-CoA reductase autoantibodies by the leukocyte antigen. These may have a direct pathogenic effect on muscle tissue expressing the HMG-CoA reductase enzyme and trigger an autoimmune response that is maintained by a feed-forward loop of autoimmunity.34,39–41 The presence of these antibodies has been demonstrated to be associated with both CK levels and limb strength in statin-exposed patients, which were improved after immunosuppressive treatment.42 Interestingly, these antibodies seem to be more selectively expressed in regenerating myofibers coexpressing neural cell adhesion molecule, which is a marker of muscle repair and regeneration, supporting the notion that statins impact muscle repair processes. In contrast, some studies have reported the presence of these antibodies in statin-naive patients.23 Of further note is the strong association between statin-induced immune-mediated necrotizing myopathy and HLA-DRB1*11:01.40 Noninflammatory myopathy presents as muscle weakness/pain with elevated CK, but no inflammation on biopsy, and has been suggested to be caused by statin therapy exposing previously restricted epitopes and triggering an autoimmune response.19

    Pathological investigation of toxic myopathy reveals necrosis and regenerating muscle fibers, with a negative response to anti–HMG-CoA reductase autoantibodies.34 The precise mechanisms behind toxic myopathy are unknown but have been suggested to be aggravated by conditions that increase statin levels in the blood, such as concomitant medications that interfere with statin metabolism via the CYPP450 enzymes, glucuronidation, or other processes.19 This is particularly relevant as skeletal muscle is 40× more sensitive to HMG-CoA reductase inhibition than hepatocytes.5 A study in skeletal muscle–specific HMG-CoA reductase knockout mice was shown to exhibit postnatal myopathy with elevated CK levels, mitochondrial impairment, and necrosis. This was accompanied by upregulation of LDL receptor and SREBP2 (sterol regulatory element-binding protein 2) mRNA expression, suggestive of adaptations to sterol regulation. Supplementation with mevalonic acid rescued this phenotype, supporting the hypothesis that enzyme inhibition by statins contributes to skeletal muscle toxicity.43

    Prevalence and Risk Factors for SAMS

    The prevalence of SAMS differs between statin classes, with the highest risk associated with lipophilic statins such as simvastatin, atorvastatin, and lovastatin because of their ability to nonselectively diffuse into extrahepatic tissues such as skeletal muscle.19,21 In contrast, hydrophilic statins such as pravastatin and fluvastatin have less muscle penetration and therefore lower risk of SAMS.21 Some reports suggest that up to 60% of SAMS cases may be because of concomitant use of statins with drugs metabolized by the same hepatic cytochrome P450 isoforms.5 Others suggest that the strongest risk factor for SAMS is a history of myopathy with other lipid-lowering therapy, high-dose statin therapy, personal history of unexplained cramps, a history of CK elevation, family history of muscular symptoms with lipid-lowering therapy, and untreated hypothyroidism.44 Other risk factors include female sex, old age (>80 years), small body frame and frailty, multisystem disease (particularly, involving the liver and kidney), alcoholism, high consumption of grapefruit juice, major surgery, vitamin D deficiency, calcium disorders, Asian ethnicity, low body mass index, and excessive physical activity.21,28

    Proposed Mechanisms for the Development of SAMS

    Proposed mechanisms for SAMS include HMG-CoA reductase pathway-mediated effects, cellular and subcellular effects, genetic factors, and effects on skeletal muscle. These can alter muscle cell membrane stability, fluidity, as well as protein signaling and activity; impact mitochondrial function; and reduce membrane cholesterol content.5 Alterations to statin uptake or metabolism can also result in increased exposure of skeletal muscle to statins, which can lead to altered mitochondrial function, calcium signaling, and cell cycle pathways.45 Given the wide variation in the presentation of SAMS and the inconsistent evidence with respect to treatment of the condition, however, it is likely that >1 pathological mechanism contributes (Figure 2).5,46 More detailed description of these proposed mechanisms is discussed below.

    Figure 2.

    Figure 2. Potential mechanisms for the development of statin-associated muscle symptoms. AKT indicates protein kinase B; Ca+2, calcium; CYP, cytochrome P450; IGF-1, insulin-like growth factor 1; LPL, lipoprotein lipase; PI3K, phosphoinositide 3-kinase; and UGTs, UDP glucuronosyltransferases.

    HMG-CoA Reductase Pathway-Mediated Effects

    The highly conserved mevalonate pathway is an important metabolic pathway, which plays a key role in many cellular processes via the synthesis of sterol and nonsterol isoprenoids (Figure 1). The sterol isoprenoid cholesterol is an important precursor of bile acids, lipoproteins, and steroid hormones, whereas nonsterol isoprenoids such as dolichols and ubiquinone (coenzyme Q10) play important roles in the post-translational modification of proteins involved in intracellular signaling and are essential for cell growth and differentiation, gene expression, protein glycosylation, and cytoskeletal assembly.5,12 Specifically, dolichols promote protein N-glycosylation, and inhibition of their formation can result in impairment in both receptor expression and production of structural proteins.47 In addition, end products of the mevalonate pathway, which include farnesyl pyrophosphate and geranylgeranyl pyrophosphate, play a role in cell maintenance and growth and reducing apoptosis.19,45 These end products are also involved in activating regulatory GTP-binding proteins and the post-translational modification of GTPases and lamins, both of which play an important role in cell maintenance and chromatin organization. Dysprenylation of small GTPases has been shown to result in apoptosis, whereas dysprenylation of lamin results in fragile nuclear membranes, which induces apoptosis.47 Other compounds also affected by inhibition of the mevalonate pathway include prenylated proteins, electron transport proteins, and heme A, which can result in downstream effects that include impaired cell membrane stability and excitability, impaired signal transduction and intracellular trafficking, and compromised protein structure and function, all of which can lead to dysfunction of or a decrease in membrane receptors, channels and transporters, as well as reduced gene expression.5,47

    Inhibition of HMG-CoA reductase can lead to alterations to muscle protein signaling and activity can occur. These include impaired skeletal PI3k (phosphatidylinositol 3-kinase)/Akt (protein kinase B), resulting in inductions in ubiquitin and lysosomal proteolysis through upregulation of the FOXO (Forkhead box protein O) downstream target genes of muscle atrophy, which have been observed in cultured myotubes, zebrafish, and mouse studies.48,49 These include cathepsin-L mRNA, MuRF-1 (muscle RING finger-1) and MAFbx (muscle atrophy F-box), and dephosphorylation of the FOXO1 and FOXO3 transcription factors.50 In vitro studies have demonstrated upregulation of atrogin-1 (MAFbx) in muscle cells exposed to statins. This was prevented by geranylgeranol, although inhibitors of the transfer of geranylgeranol isoprene units caused muscle damage and atrogin-1 induction.51 Others have suggested that suppression of IGF-1 (insulin-like growth factor) signaling with statin treatment contributes as this also leads to FOXO dephosphorylation, nuclear localization, and transcription of the atrogin-1 gene.52 Furthermore, these signaling effects were accompanied by distinct morphological changes to the muscle, including fiber damage, which was prevented by overexpression of PGC-1α (peroxisome proliferator–activated receptor-γ coactivator), a transcriptional coactivator that induces mitochondrial biogenesis.49 This finding was also confirmed in an animal model of statin myopathy, where simvastatin administration impaired PI3K/Akt signaling and upregulated FOXO transcription factors and downstream gene targets known to be implicated in proteasomal- and lysosomal-mediated protein breakdown, muscle carbohydrate oxidation, oxidative stress, and inflammation. Interestingly, the statin-induced signaling effects preceded the evidence of myopathy or change in muscle protein to DNA ratio, implying the direct effect of the statin on this sequence of events.48 The effect on the Akt pathway was also associated with impaired phosphorylation of S6 kinase, ribosomal protein S6, 4E-binding protein 1, and FOXO3a, resulting in reduced protein synthesis, accelerated myofibrillar degradation and atrophy of myotubes, as well as activation of apoptotic caspases and PARP (poly (ADP-ribose) polymerase). In vitro studies suggest differing effects on these signaling cascades in response to different statins, with simvastatin and atorvastatin cytotoxic at lower doses (10 μmol/L) compared with rosuvastatin cytotoxicity at higher doses (50 μmol/L).53

    The upstream effects of statins on the HMG-CoA–mediated pathway relate to an increase in fatty acid synthesis. Early in vitro studies revealed that micromolar concentrations of lovastatin increased fatty acid synthesis and induced triacylglycerol and phospholipid accumulation in lipid droplets of cultured keratinocytes, which was associated with peroxisomal hyperplasia and increased catalase activity. These effects were prevented by coincubation with LDL-c or 25-hydroxycholesterol.54

    Direct Cellular and Subcellular Effects: Mitochondrial Toxicity and Calcium Signaling

    The direct effects on cellular and subcellular structures are predominately responsible for statin-related mitochondrial toxicity and calcium overload. These can result in increased oxidative phosphorylation, which can lead to a decrease in ATP levels, loss of mitochondrial membrane potential, activation of mitochondria permeability transition, decreased mitochondrial density and biogenesis, apoptosis, and calpain-mediated cell death. In addition, these effects can trigger massive calcium release either via the RYR (ryanodine receptor) in the sarcoplasmic reticulum or the permeability transition pore and sodium-calcium exchanger in the mitochondria.5,19 Impaired calcium signaling can then result in mitochondrial depolarization and calcium release, resulting in cytoplasmic calcium waves and subsequent caspase activation and apoptosis. Increased cytosolic calcium can also increase calcium and phospholipid-dependent PKC (protein kinase C) activity, which promotes the closing of the chloride-1 channel, resulting in membrane hyperexcitability.47

    In addition, muscle mitochondrial integrity is maintained by multiple signaling pathways, including the IGF-1/Akt pathways. In vitro studies have revealed that simvastatin-treated myotubes had reduced mitochondrial respiration that was associated with reduced Akt phosphorylation and rescued with IGF-1 treatment. In contrast, liver cells were not affected, with the IGF-1/Akt signaling maintained.55 Other in vitro studies have revealed that lactone forms of statins are more potent than their acid counterparts because of their increased passive transport across muscle membranes where they lead to decreased mitochondrial ATP production via direct effects on production machinery. Specifically, this appears to involve inhibition of the mitochondrial CIII complex at the Qo binding site and appears to be more significant with the hydrophilic lactones. These findings were confirmed in muscle biopsies from patients with statin-induced myopathy, which revealed significant decreases in CIII activity and ATP production.56 Simvastatin-treated patients were also found to have decreased muscle coenzyme Q10 content, which was accompanied by decreased mitochondrial oxidative phosphorylation capacity.57 More recent studies have demonstrated no major effects on mitochondrial function after 2 weeks of simvastatin treatment but an increase in mitochondrial substrate sensitivity, which may be indicative of early damage.58

    Mitochondrial effects can also result from a reduction in the formation of coenzyme Q10, an end product of the mevalonate pathway.5 Coenzyme Q10 is an important component of the electron transport chain of the inner mitochondrial membrane where it facilitates electron transport between complexes I and II during oxidative phosphorylation. Inhibition of this pathway results in abnormal mitochondrial respiratory function and subsequent mitochondrial dysfunction. Mitochondrial dysfunction, typically at complex I in the respiratory chain, increases mitochondrial NADH and the intracellular redox potential (NADH/NAD+ ratio), activates PDK (pyruvate dehydrogenase kinase), and inhibits flux via the PDC (pyruvate dehydrogenase complex).50 Interestingly, although most studies demonstrate a reduction in serum coenzyme Q10 levels with statin treatment, this is thought to be predominately because of a reduction in LDL-c, the main carrier of coenzyme Q10, with tissue levels largely unaffected.19 Moreover, studies that have examined the effect of coenzyme Q10 supplementation in patients with statin-induced muscle effects found no difference in muscle pain or plasma CK between the placebo or coenzyme Q10-treated groups.59

    Genetic Factors
    Organic Anion-Transporting Polypeptide 1B1 Influx Transporter

    SLCO1B1 encodes the OATP (organic anion-transporting polypeptide)1B1 influx transporter, expressed on the basolateral membrane of human hepatocytes.15,19 The transporter regulates the hepatic uptake of statins from portal blood, thus influencing their serum levels. Two common single-nucleotide polymorphism (SNP) variants of the SLCO1B1 gene; c.388A>G (p.Asn130Asp; rs2306283) and c.521T>C (p.Val174Ala; rs4149056) have been shown to affect OATP1B1 transport function, although these are dependent on their combination in individual haplotypes.15 When rs2306283 exists alone (≈25%–30% in whites, 4%–60% Asians, and 80% Africans/black), it is usually associated with increased OATP1B1 activity and lower plasma concentration of substrates. In contrast, rs4149056 reduces transport activity and increases plasma concentrations of the substrate, even when present in combination with rs2306283.15 Although all statins require hepatic transporters, the effect of SLCO1B1 polymorphisms appears to be dependent on the class of statin used and are particularly relevant for the lipophilic statins.15,19 The largest effect of rs4149056 is seen with simvastatin, followed by pitavastatin, atorvastatin, pravastatin, and rosuvastatin, with no effect observed for fluvastatin. This difference may be partly explained by varying contributions of other OATPs to hepatic uptake.15 Genome-wide scans have revealed strong associations between simvastatin-associated myopathy and the rs4363656 SNP.60 This appears to be because of a noncoding SNP in the SLCO1B1 gene that is in nearly complete linkage disequilibrium with the rs4149056 SNP, which was also associated with a slight reduction in the cholesterol-lowering efficacy of simvastatin.15

    Ryanodine Receptors

    RYRs are intracellular calcium release channels, expressed in a range of tissues. Three genes encode the different isoforms with RYR1 expressed predominately in skeletal muscle where it contributes to calcium signaling and muscle contraction. RYR3 expression has been shown to be upregulated in the skeletal muscle of patients with statin-associated structural muscle injury.61 In addition to variants in SLCO1B1, an intronic variant in RYR2 gene, rs2819742, was identified as being linked with rhabdomyolysis associated with cerivastatin, a drug that has now been withdrawn from the market.62

    Leukocyte Immunoglobulin-Like Receptor

    A variant in the leukocyte immunoglobulin-like receptor subfamily-B gene (LILRB5) has been associated with lower CK and lactate dehydrogenase levels, 2 common biomarkers that are released from injured muscle tissue. The T>C:Asp247Gly; rs12975366 variant was also associated with statin-intolerant phenotypes, defined as either elevated CK and nonadherence to therapy or intolerant to the lowest approved dose. It is postulated that this is via inhibition of immune-mediated repair and regeneration of skeletal muscles, specifically suppression of the accumulation of T regulatory cells, a process that is crucial in the repair of damaged skeletal muscle.63,64

    UDP Glucuronosyltransferase

    UDP glucuronosyltransferases convert the lactone form of statins to the acid form via a glucuronidation process. SNPs in the UGT1A gene (UGT1A1*28(TA)7) are associated with a reduction in the systemic exposure to the atorvastatin lactone, which has been associated with muscle toxicity.65

    Glycine Amidinotransferase

    Glycine amidinotransferase is an enzyme required for the synthesis of creatinine that is encoded by GATM. Phosphorylation of creatinine, the major downstream product of GATM (glycine amidinotransferase) activity, is a major mechanism of energy storage in muscle, which is mediated by CK, a biomarker of statin myopathy. Genome-wide eQTL analysis of lymphoblastoid cell lines from simvastatin-treated participants has revealed a possible link between GATM and statin-induced myopathy, as well as cellular cholesterol homeostasis and energy metabolism. Although the link between GATM and myopathy appears to be independent of CK levels, mechanistically, it is believed to be because of metabolic effects in the liver, including cholesterol depletion and subsequent effects on AMPK (5′ AMP-activated protein kinase) signaling.66 Despite this, however, a proposed protective SNP in GATM, rs9806699 G>A, has not been replicated in a case-controlled analysis of statin-induced myopathy.67

    Genetic Predisposition to Pain Perception

    A positive family history of statin myopathy is a common risk factor for statin intolerance and may relate to an inherited increased susceptibility to pain perception. Specifically, this may be because of a genetic variation in serotonergic receptors, supported by an early study looking at SNPs in genes related to serotonergic neurotransmission, widely implicated in pain detection and processing in the brain, spinal cord, and peripheral tissues. In hypercholesterolemic statin-treated patients, a significant association was observed between myalgia and 2 SNPs (rs2276307 and rs1935349) in the genes HTR3B and HTR7, which encode serotonin receptors. There was no association with CK levels, suggesting that statin myopathy may be a collection of independent syndromes encompassing various genetic pathways.68 This finding is also supported by clinic data, with statin myopathy commonly seen in association with personal or family history of nonspecific myalgia, higher scores on hospital anxiety and depression scales and fibromyalgia. Furthermore, patients with preexisting conditions associated with muscle symptoms, including fascioscapular muscular dystrophy, malignant hyperthermia, polymyositis and polymyalgia rheumatica, often report a worsening of symptoms with statin therapy.17

    Gene Array Analysis

    Analysis of gene expression in patients experiencing SAMS suggests an association with a molecular signature of mitochondrial stress, cell senescence, and apoptosis, including a host of differentially expressed genes with greater than expected enrichment in 5 canonical pathways. These pathways include IGF/PI3k/Akt signaling, cell cycle, nerve growth factor signaling, and cholesterol biosynthesis I and II. Specific genes within these pathways included upregulation of calmodulin (CALM1), a calcium sensor protein that interacts with RYR1 calcium channel to mediate calcium release during muscle contraction. In contrast, the inositol 1,4,5-trisphosphate receptor 2 (ITPR2), which triggers calcium release allowing mitochondrial calcium accumulation and cell senescence, was downregulated. Within the cell cycle pathway, genes that include the protein BARD1, thought to be involved in muscle wasting via apoptosis and protein degradation, and histone deacetylase, involved in muscle atrophy, were upregulated. Disruption of genes associated with cholesterol biosynthesis and related to downstream proteins of the mevalonate pathway were postulated to reflect a compensatory upregulation in response to statin-induced inhibition. Increased expression of these distal pathways is also suggestive of a complete blockade of the pathway because of increase statin exposure and sensitivity.45 The authors further suggest that persistent myalgia originates from cellular stress that affects the structural integrity and performance of skeletal muscle and its response to postinflammatory repair and regeneration.45

    Structural Effects of Statins on Skeletal Muscles

    Skeletal muscle consists of fast and slow twitch muscle fibers, which have different compositions and different responses to external compounds such as statins. Animal studies have consistently shown that statin treatment results in massive necrosis of muscle containing fast twitch, glycotic type IIB fibers, with the slow twitch oxidative type I fibers spared.5 These changes were accompanied by ultrastructural changes to the muscle mitochondria, including swollen mitochondria with disrupted cristae and increased vacuolation or degeneration resulting in vesicular bodies accumulating in the subsarcolemmal space.5 Human studies have also observed vacuolization of the T-tubular system in statin-treated patients.61,69

    Other structural effects may relate to an inability to replace damaged muscle protein via the ubiquitin pathways. A small study investigating the effect of atorvastatin and exercise on muscle damage observed differences in gene expression in the combination statin and exercise group compared with either treatment alone. Specifically, this combination had the greatest effect on genes related to transcription factors and those involved in the ubiquitin proteasome pathway, including protein folding and catabolism, which is responsible for the recognition and degradation of proteins in skeletal muscle.

    In addition, cholesterol is a key component of the structure and function of all cell membranes, including skeletal muscles. Increased sensitivity of skeletal muscle to HMG-CoA reductase inhibition can lead to a reduction in the cholesterol content in skeletal muscle cell membranes, rendering them unstable and altering fluidity and excitability of ion channels.5,19,35 This can modulate the function of sodium, potassium, and chloride channels, leading to myocyte damage and myopathy.47 Previous mouse studies have also demonstrated an increase in skeletal muscle mitochondria, cholesterol accumulation, and lipid droplets in statin-treated mice overexpressing lipoprotein lipase. This was also associated with increased plasma creatinine phosphokinase, indicative of muscle damage.70 More recently, statins have been shown to have toxic effects on immature muscle cells via multiple mechanisms. The lactone forms of statins significantly impaired complex III activity in C2C12 myoblasts, reducing mitochondrial respiration and inducing apoptosis. When investigated in a clinical setting, patients presenting with SAMS also had reduced complex II activity, which was most pronounced in those with rhabdomyolysis, the most severe form of muscle damage.56 Disturbances in the acid/base balance, for example, in the setting of acidosis and alkalosis can also affect the conversion of the inactive lactone forms of simvastatin and pravastatin to their active hydroxy acid form. Acidic environments appear to maintain the statins in their lactone form, facilitating greater uptake by C2C12 skeletal muscle cells because of the increased lipophilicity, which results in myotoxicity.71 This process was exacerbated in the presence of hyperlipidemia because of the enhanced association between simvastatin and nonpolar lipoprotein fractions and uptake via a lipoprotein lipase–mediated process.72 In addition, in vitro and animal studies have demonstrated that statin exposure can result in impaired muscle regeneration73 and cell cycle arrest.74

    Clinical Studies Investigating SAMS

    The PRIMO (Prediction of Muscular Risk in Observational) conditions study, a general practice survey in France, revealed that 10.5% of hyperlipidemic patients receiving high-dose statins (predominately simvastatin) reported mild-to-moderate muscle symptoms.44 In the United States, a large internet-based survey of current and former statin users (USAGE) reported muscle-related side effects in 60% of current and 25% of former users, with side effects the primary reason for statin discontinuation (62%).75 The STOMP (Effect of Statins on Skeletal Muscle Function) was a large randomized controlled trial assessing the effect of high-dose atorvastatin on muscle performance in healthy, statin-naive participants. Despite no effect on muscle strength or exercise performance after 6-month treatment, there was a significant increase in CK levels among both asymptomatic participants and those with myalgia after treatment with atorvastatin.76 The SEARCH (Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine) demonstrated a dose effect on development of myopathy, where 80 mg daily of simvastatin produced a 10-fold higher rate than a 20 mg dose77 or the 40 mg used in the HPS (Heart Protection Study), with risk higher when it occurred in combination with elevated CK levels.78

    A recent review has suggested that the excess rate of symptomatic muscle pain and other muscle-related problems is ≈10 to 20 cases yearly per 10 000 treated individuals, with only one of those cases associated with substantially elevated CK requiring cessation of statin treatment. Furthermore, treatment of 10 000 patients for 5 years with an effective regime (40 mg atorvastatin daily) has been suggested to yield 5 cases of myopathy of which one might progress to rhabdomyolysis if treatment was not stopped.30 Importance must be given, however, to how SAMSs are reported in studies, with a previous meta-analysis suggesting that only 62% of clinical trials report the frequency of muscle problems with only one of those studies systematically querying participants about muscle problems. Although the incidence of SAMS in the trials that reported these events did not differ between statin and placebo groups, 98% of the studies did not define muscle problems, nor did the majority of them enquire about muscle problems or report the effect of statin therapy on CK levels.79

    New-Onset Type 2 Diabetes Mellitus

    Incidence of new-onset type 2 diabetes mellitus with statin treatment appears to be more common in patients with preexisting risk factors, including elevated body massive index and glycated hemoglobin or impaired fasting glucose. It has been observed for both hydrophilic and lipophilic statins and appears to occur more frequently in older patients and those on high-dose statin therapy.21 Mechanistically, the incidence of new-onset type 2 diabetes mellitus is not known but may be related to both on-target and off-target action, including effects on body weight, body mass index, adipocyte differentiation, blood glucose homeostasis via gluconeogenesis and the insulin signaling cascade, changes in circulating free fatty acids or hormones such as adiponectin and leptin, as well as impaired β-cell function.16,23,80,81

    Proposed Mechanisms for Statin-Induced New-Onset Type 2 Diabetes Mellitus

    In the pancreas, insulin secretion is initiated by an increase in intracellular calcium controlled by voltage-gated calcium channels, with changes in these channels significantly affecting glucose homeostasis.16 In vitro studies have shown that simvastatin inhibited glucose-induced calcium signaling in rat pancreatic islet β-cells via direct blockage of L-type calcium channels, although this was not seen with pravastatin, suggesting that effects are related to lipophilicity.82 In addition, reductions in endogenous pancreatic cholesterol levels have also been proposed to contribute to impaired calcium channel function, either through incorrect sorting of membrane-bound lipid raft proteins or changes in the conformation of channel subunits.83 A recent in vitro study has also suggested that mitochondria isolated from rat pancreas and treated with statins had reduced complex II activity that was accompanied by oxidative stress, mitochondrial swelling, and reduced membrane potential.84

    Within adipose tissue and skeletal muscle, glucose uptake is facilitated by the GLUT4 (glucose transporter 4), which is initiated by insulin-receptor tyrosine kinase phosphorylation, facilitating recruitment of GLUT4 from intracellular storage to the plasma membrane.16 In vitro studies have shown an attenuation of adipocyte maturation and a decrease in GLUT4 expression in both differentiating and mature adipocytes with atorvastatin treatment because of inhibition in the formation of isoprenoids. In addition, a reduction in caveolin-1, an important plasma membrane protein associated with GLUT4 translocation, was observed. These findings were associated with impaired insulin sensitivity in mice with type 2 diabetes mellitus and elevated HbA1c (glycated hemoglobin) in a small patient population.85 Attenuation of the adipocyte differentiation process is also critical as preadipocytes do not secrete insulin-sensitizing hormones, a requirement for initiation of the signaling cascade. This inhibition is thought to be because of a decrease in the expression of 2 important transcription factors, PPARγ (peroxisome proliferator–activated receptor γ) and C/EBP (CCAAT/enhancer-binding protein).16 Other studies have shown that several statins decrease glucose uptake in skeletal muscle because of conformational changes in the glucose transporter GLUT1 or reduced GLUT4 expression.86

    The IRS-1 (insulin-receptor substrate) is also critical for insulin signaling, with its phosphorylation activating the PI3K pathway, Akt phosphorylation, and subsequent GLUT4 translocation.16 In vitro studies have demonstrated a reduction in the IRS-1–mediated signaling cascade and subsequent glucose uptake after treatment with atorvastatin. This effect was dose-dependent and due to inhibited lipid modification of various proteins involved in the signal cascade, as well as altered cellular distribution of some small G proteins.87

    Genome-wide association studies suggest that lipid fractions, including LDL-c, appear to have contrasting associations with CVD and diabetes mellitus.88 LDL-c–lowering genetic variants on or near the HMGCR gene have also been shown to be associated with a higher risk of type 2 diabetes mellitus, similar to the increased incidence observed in randomized controlled trials.89,90 Alleles that lower LDL-c via the HMGCR gene are also associated with increased body mass index and fasting insulin, suggestive of an effect on insulin resistance that is mediated via the LDL-c receptor.91 This is supported by cross-sectional analysis revealing a lower incidence of diabetes mellitus in patients with familial hypercholesterolemia compared with their unaffected relatives, with variability by mutation type revealing a lower prevalence in those with a LDL-c receptor gene mutation. This receptor-mediated effect has been hypothesized to be because of statin-induced increases in LDL receptors facilitating cholesterol entry into and damage of pancreatic cells.92

    Clinical Studies Investigating Statin-Induced New-Onset Type 2 Diabetes Mellitus

    The JUPITER trial (Justification for the Use of Statin in Prevention) revealed that participants with ≥1 diabetes mellitus risk factors randomized to 20 mg daily rosuvastatin were at increased risk (28%) of developing diabetes mellitus, despite reductions in LDL-c levels and cardiovascular events and mortality.93 The CARDS study found that low-dose (10 mg) atorvastatin caused small but significant glycemia progression in diabetic participants, but this did not increase with duration nor impact the CVD risk reduction.94 Meta-analysis has shown that intensive-dose statin therapy is associated with an increased risk of new-onset type 2 diabetes mellitus compared with moderate dose,95 whereas high-dose (80 mg) atorvastatin is associated with increased risk with baseline fasting glucose and metabolic syndrome features predictive of risk.96 Subsequent meta-analysis of 13 randomized controlled trials suggests that statin therapy is associated with a slightly increased risk of developing diabetes mellitus, but this risk is low when compared with the reduction in coronary events.97 A larger meta-analyses of 17 trials revealed different class, and doses of statins have differing effects on the incidence of diabetes mellitus. Pravastatin was associated with the lowest risk, and atorvastatin had an intermediate risk, whereas rosuvastatin was associated with a 25% increased risk.98 Increased risk with intensive dose statin compared with moderate dose was further confirmed in pooled analysis of 5 randomized controlled trials.95 More recent meta-analysis of observational trials confirms and reinforces the increased risk of diabetes mellitus with statin use.99 Although it has been suggested that treatment of 10 000 patients for 5 years with an effective regime (40 mg atorvastatin daily) would yield 50 to 100 cases of new-onset type 2 diabetes mellitus, this is far outweighed by the beneficial effects of statins on CVD, even among high-risk patients and those who already have diabetes mellitus.30,81

    Neurological and Neurocognitive Conditions

    Neurological conditions that have been associated with statin use include hemorrhagic stroke, cognitive decline, peripheral neuropathy, depression, confusion/memory loss and aggression, and personality changes.19 It is unclear whether these are because of the direct action of statins given the blood-brain barrier’s selective permeability to substrates and the brain’s self-sufficiency when it comes to endogenous cholesterol synthesis.81 Lipophilic statins are thought to have a higher risk because of their increased ability to cross the blood-brain barrier13; however, it should be noted that these effects may not be specific to statins per se and instead a result of low cholesterol levels.

    Proposed Mechanisms for Development of Neurological and Neurocognitive Conditions

    Several mechanisms for neurological effects have been proposed, most of which focus on the important role lipids play in brain function. Reductions in serum lipid levels have been proposed to negatively affect the formation of neuronal cell membranes, myelin sheath, and nerve synapses. Reduced cholesterol availability for neurons can then contribute to lower serotonin activity through reduced receptor expression, which can result in changes in behavior control and adverse psychiatric effects.100

    Clinical Studies Investigating Statin-Induced Ischemic and Hemorrhagic Stroke

    Observational studies suggest an inverse relationship between cholesterol levels and rates of hemorrhagic stroke, particularly at low concentrations of cholesterol in people with hypertension.30 The SPARCL trial (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) demonstrated a definite reduction in ischemic stroke with 80 mg daily of atorvastatin, but a probable increase in hemorrhagic stroke,101 which was confirmed in meta-analysis.102 Recent analysis of randomized controlled trials has suggested that treatment of 10 000 patients for 5 years with an effective regime (40 mg atorvastatin daily) would yield a probable 5 to 10 cases of hemorrhagic stroke.30 More recently, however, a large systematic review and meta-analysis has investigated statin use in patients with previous ischemic stroke or intracerebral hemorrhage. In patients with a previous intracerebral hemorrhage, statin use did not increase the risk of a recurrent event. In patients with a previous ischemic stroke, however, although statins reduced the risk of a recurrent ischemic stroke, they did nonsignificantly increase the risk of intracerebral hemorrhage. Irrespective of stroke type, statins did show clear benefits in reducing mortality and improving functional outcome, although these findings were predominately based on observational data, limiting their interpretation.103

    Clinical Studies Investigating Statin-Induced Dementia and Alzheimer Disease

    Both the PROSPER (Prospective Study of Pravastatin in the Elderly at Risk) and Heart Protection Studies demonstrated no effect of pravastatin or simvastatin on cognitive decline or impairment or the development of dementia.78,104 Similarly, no effect of statins on cognitive outcomes in patients with mild-to-moderate Alzheimer disease has been observed, with either atorvastatin105 or simvastatin.106 This is supported by a recent meta-analysis of 31 studies, which actually found a reduced risk of dementia with statin use.107 A population-based cohort study also observed a decrease in the risk of dementia in stroke patients who were receiving statin therapy, which was further enhanced with high-potency, lipophilic statins and a prolonged exposure time.108 In contrast, a recent population-based retrospective study observed an increased risk of Alzheimer disease in patients receiving fungus-derived statins compared with synthetic statins. Lipophilic statins were also associated with a higher risk compared with hydrophilic statins, whereas statin potency did not seem to have an effect.109 A recent systematic review and meta-analysis has also demonstrated that statin use may reduce the risk of all-type dementia, Alzheimer disease, and mild cognitive impairment, with no apparent effect on vascular dementia.110 A more recent community-based observational study has observed that older patients on long-term statin therapy (>5 years) showed no difference in neuroimaging biomarkers of Alzheimer disease compared with non–statin-treated (<3 months) adults. Long-term statin therapy was associated with a worse white matter structural integrity; however, this was thought to be reflective of the increased cerebrovascular and cardiovascular risk factor burden within this patient group. These results were not related to statin lipophilicity.111

    Clinical Studies Investigating Statin-Induced Psychiatric Effects

    There is some evidence to show that low cholesterol and statin use have been linked to neuropsychiatric effects including aggression, agitation, irritability, mood changes, violent ideation, sleep problems, and suicidal tendencies.112,113 A retrospective cohort study investigating depression in hydrophilic and lipophilic statin users found a nonsignificant increase in the risk of depression in patients taking lipophilic statins. These results were unchanged when patients were analyzed by subgroup, including patients initiating statin use for primary prevention, for secondary prevention, or in those with a history of psychiatric comorbidities. The highest incidence of depression was seen with simvastatin, followed by lovastatin, atorvastatin, pravastatin, and rosuvastatin, with the simvastatin group the only statin to reach statistical significance.114


    Early clinical trials of statins revealed elevations in aminotransferases in up to 2% of patients despite only rare observation of clinically apparent liver injury.115 Asymptomatic rises in hepatic enzyme activity, with elevated aminotransferase activity >3× the ULN, is a common side effect that normally resolves with dose reduction21 and is not associated with histopathology changes or liver toxicity in the absence of increased bilirubin or dysfunction. When combined with increased bilirubin, statin discontinuation and monitoring of liver function is necessary.23 More serious, but rare hepatotoxicity, may present as asymptomatic elevation in serum transaminases, hepatitis, cholestasis, and acute liver failure. Although liver function panels are recommended before commencement of statin therapy and at initial follow-up, further monitoring is only recommended if concerns emerge. In patients with chronic liver disease, including nonalcoholic fatty liver disease, chronic hepatitis, and primary biliary cirrhosis, follow-up of liver function is warranted, although these patients are not at higher risk of hepatotoxicity than patients with normal liver tests pretreatment.23,115 Current evidence suggests statin therapy to be safe in patients with nonalcoholic fatty liver disease and may confer more efficient treatment of viral hepatitis and reduced risk of cirrhosis and hepatocellular carcinoma.23

    Proposed Mechanisms of Stain-Induced Hepatotoxicity

    The mechanisms of statin-induced hepatocellular injury are unclear, although animal studies suggest that the reduction in mevalonate or one of its sterol intermediates may be associated with an elevation in liver enzymes. In addition, asymptomatic rises without histopathologic changes may result from changes in hepatocyte membrane lipid composition, leading to increased permeability and leaking of the liver enzymes.32 Statin-induced hepatotoxicity may also arise from extensive hepatic metabolism and lipophilicity, with a high oral daily dose associated with an increased risk of drug-induced liver injury.115 A recent study using the LDLr−/− mouse found that pravastatin can induce liver mitochondrial redox imbalance, which may also account for adverse hepatic effects. Interestingly, these effects were reversed with either coenzyme Q10 or creatine cotreatment, suggesting that the negative hepatic effects of statins are not solely because of inhibition of the mevalonate pathway.116

    Clinical Studies Investigating Statin-Induced Hepatotoxicity

    Recent data from the Spanish Hepatotoxicity Registry reveal that statins are the most frequent drug type associated with chronic liver injury.117 Atorvastatin appears to be the most implicated statin, although hepatotoxicity has also been observed in patients taking simvastatin, and to a lesser extent, fluvastatin, pravastatin, and rosuvastatin. Prognosis after statin discontinuation is generally favorable, with liver-related fatalities only having been observed in patients treated with atorvastatin and simvastatin.115 Three prospective studies have shown that most patients (87%) with statin-induced hepatotoxicity were symptomatic with hepatocellular rather than cholestatic or mixed liver injury. Cholestatic/mixed liver injury appeared to be more predominant in patients taking atorvastatin.115 Drug-induced autoimmune hepatitis has also been observed in statin users, particularly those receiving atorvastatin, with a similar clinical, biochemical, and histological pattern as non–drug-induced autoimmune hepatitis.115

    Renal Toxicity

    Controversy still exists about the effects of statins on renal function. With the exception of hydrophilic statins (pravastatin and rosuvastatin), other statins are metabolized by the liver and minimally cleared by the kidney.81 Mild transient proteinuria is sometimes seen with high-dose statin treatment, but this is not associated with impaired renal function.81

    Proposed Mechanisms for Statin-Induced Renal Toxicity

    Mechanistically, these effects are thought to be related to HMG-CoA reductase inhibition. Renal proximal tubule cells are responsible for the reabsorption of proteins, a process that involves receptor-mediated endocytosis and certain GTP-binding proteins. Inhibition of HMG-CoA reductase by statins results in reductions in isoprenoid pyrophosphates, which are required for the prenylation and normal function of GTP-binding proteins. In vitro studies have shown that statins inhibit the uptake of albumin via receptor-mediated endocytosis in a dose-dependent manner with no effects on cellular toxicity. The effects on uptake were associated with the degree of HMG-CoA reductase inhibition and related to depletion of mevalonate metabolites other than cholesterol.118,119

    Clinical Studies Investigating Statin-Induced Renal Toxicity

    A large Italian population nested cohort study revealed that high-potency statins were more likely to result in hospitalization for acute kidney injury at 6 months compared with low-potency statins, although there was no evidence for risk of chronic kidney disease.120 Retrospective cohort analysis revealed a higher crude incidence rate of severe renal failure (composite of hemodialysis, peritoneal dialysis, and kidney transplant) in high-potency statin initiators compared with low potency.121 Several meta-analysis, however, have revealed no change in the risk of acute renal impairment or increase in serious adverse renal events with statin therapy. In chronic kidney disease patients, there was no increase in disease progression or adverse events with statins.81 Statin therapy did not affect the risk of kidney failure events in adults not receiving dialysis, but was observed to modestly reduce proteinuria and decline in glomerular filtration rate.122 Interestingly, use of atorvastatin has been proposed to reduce inflammation and improve kidney function after transplantation.123

    Other Statin-Mediated Adverse Events

    Other statin-mediated adverse events include cataracts, gastrointestinal effects, urogenital health effects, gynecomastia, and reproductive effects, most of which have been purported to be as a result of reduced production of intermediate and end products of the mevalonate pathway. Thyroid disease, while not thought to be because of statin toxicity per se, may contribute to statin intolerance, particularly with respect to SAMS.23 Although it remains debatable as to the role statins play in these proposed adverse effects, meta-analysis has revealed no significant effect of statins or cholesterol lowering with a statin on the development or prevention of cataracts.124 Indeed, in vitro studies have shown that atorvastatin promotes phagocytosis and reduces inflammation in retinal pigment epithelium, which may protect against the development of age-related macular degeneration.125

    Statins may be associated with reductions in androgens as they inhibit production of the substrate required for local synthesis. An early meta-analysis highlighted the testosterone-lowering effect of statins in both men and women,126 whereas a recent case-control study has revealed an increased risk of developing gynecomastia with statin use.127 Fetal exposure to statins may also result in adverse effects, and this is particularly relevant when considering patients with familial hypercholesterolemia who require lipid-lowering therapy from an early age. A recent cohort analysis of pregnant women found that statin exposure during the first trimester was associated with an increased risk of fetal ventricular septal defect, and there was a higher incidence of congenital cardiac abnormalities in pregnancies exposed to statin therapy.128 Of further potential clinical importance is a recent animal study, which revealed significant adverse effects of atorvastatin, but not pravastatin, on cardiac muscle integrity, which effected cardiac mitochondrial structure and function, as well as cardiac cytoarchitecture.129

    Off-Target Statin-Induced Effects

    Genetic Variants

    Common and rare genetic variants may contribute to statin toxicity via mutations in genes that encode proteins regulating statin pharmacokinetics (drug receptors, transporters, and metabolizing enzymes) and pharmacodynamics (muscle enzymes).23 These can include polymorphisms or mutations in genes encoding the CYP450 (cytochrome P450) enzymes, coenzyme Q, myophosphorylase, glycine amidinotransferase, UDP glucuronosyltransferase, palmitoyltransferase 2, myoadenylate deaminase, ATP-binding cassette sub-family B, multidrug resistance protein 1, and multidrug resistance–associated protein 2 efflux transporters.15,19,23,41,65 Genetic differences in the activity of CYP450 enzymes can affect statin interactions with other drugs, whereas genetic differences in membrane transporters can alter first pass hepatic uptake and thus residual circulating concentrations and peripheral tissue exposure.81 In addition, mouse studies have revealed that statin therapy may also alter gene expression, including hepatic genes related to lipid and glucose homeostasis, such as Pparα, Trib3, and Slc2a2, which may also contribute to their adverse side effects.130

    The importance of the HMG-CoA pathway–mediated effects can also be inferred from Mendelian randomization studies. Such analysis, which constructs a genetic score that mimics the action of statins by targeting variants in the HMG-CoA reductase gene (HMGCR), reveals that individuals with higher scores have lower LDL-c levels and a reduced risk of myocardial infarction or death from coronary heart disease. This was additive when combined with high scores for variants in the PCSK9 gene.90 Other studies, which have investigated over 50 genes that are associated with lower LDL-c, are also associated with a lower risk of coronary heart disease.3 In contrast, a high HMGCR score was associated with an increased risk of diabetes mellitus, which appeared to be dose dependent, additive when combined with a high PCSK9 score, and higher in those with an impaired fasting glucose at baseline.90

    Drug-Drug Interactions

    Drug-drug interactions occur when the pharmacokinetic or pharmacodynamics of 1 drug is altered by prior or concomitant administration of another drug, resulting in an effect different from the expected effects of each drug given alone. This can result in a change in drug efficacy or toxicity for one or both drugs in an additive, synergistic, or antagonistic fashion, as well as alterations to absorption, distribution, metabolism, or excretion of a drug. Most clinically significant drug-drug interactions are pharmacokinetic in origin and often because of induction or inhibition of drug-metabolizing enzymes and transporters.131 Most statins undergo extensive microsomal metabolism by the CYP450 isoenzymes in addition to being recognized by drug transporters in the liver, gut, and kidney.131 The risk of statin toxicity is increased by drug interactions that increase the concentration of statins in the plasma, with up to 50% of statin-mediated adverse events thought to be because of drug-drug interactions.23,132 These interactions are dependent on the pharmacokinetic profile of the statin prescribed and can occur because of competing metabolism with CYP3A4 or the (OATP)1B1 transporter.132 Inhibitors of (OATP)1B1 can decrease the hepatic uptake and therapeutic index of many statins. Potent inhibitors of CYP3A4 can significantly increase the plasma concentration of the active forms of atorvastatin, simvastatin, and lovastatin. Fluvastatin, which is metabolized by CYP2C9, is less prone to pharmacokinetic interactions, whereas pravastatin, rosuvastatin, and pitavastatin are not susceptible to any CYP450 inhibition.133 In addition, genetic variations in hepatic, gut, and muscle transporters may also contribute to drug-drug interactions through alterations to statin bioavailability, metabolism, and clearance, as well as tissue concentration.15

    ABC (ATP-binding cassette) transporters including ABCB1 (ATP-binding cassette subfamily B member 1) are expressed on the canillicular membrane of hepatocytes and are thought to mediate the excretion of statins into the bile. Variation in the ABCB1 gene, which encodes the P-glycoprotein MRP2 (multidrug resistance protein), has been associated with myalgia.41,134ABCG2, which encodes the ABCG2 (ATP-binding cassette G2) efflux transporter, is expressed in the apical membranes of intestinal epithelial cells, hepatocytes, renal tubule cells, and the endothelial cells of the blood-brain barrier. Most statins are substrates of the ABCG2 transporter, and it is thought to limit intestinal absorption and tissue penetration as well as enhance renal and hepatic elimination of its substrates.15 Mutations in the ABCG2 gene impact plasma concentrations of statins, with carriers also reported to have increased risk of statin-associated adverse drug reactions.41,134 One relatively common SNP is c.421C>A (p.Gln141Lys; rs2231142), which reduces the transport function of ABCG2, predominately affecting rosuvastatin, followed by the inactive form of simvastatin, atorvastatin, and fluvastatin. It appears to have no effect on atorvastatin or pitavastatin. The SNP results in an increase in the plasma concentration because of increased bioavailability as a result of decreased intestinal efflux.15 More recently, the rs717620 (-24C>T) SNP in the ABCC2 gene, which encodes a transmembrane transporter, has been shown to alter response to simvastatin and atorvastatin. Interestingly, female Chinese patients carrying this SNP appeared to have a reduced benefit from simvastatin, whereas male patients did not. In contrast, Chilean male but not female patients had an attenuated response to atorvastatin with this SNP, highlighting the contribution of both gender and ethnicity.135,136

    The most common drugs associated with statin drug interactions are glucocorticoids, antipsychotics, HIV protease inhibitors, azole antifungal agents, immunosuppressive drugs, macrolides, calcium channel blockers, and lipid-modifying drugs like gemfibrozil. Additional interactions can also occur with alcohol, opioid, and cocaine abuse.5 Despite this, variation in the disposition of statins, including the role of metabolizing enzymes and transporters, as well as interindividual variations in the activity of CYP450 enzymes and transport proteins, makes predicting statin drug-drug interactions difficult.131

    Vitamin D Status

    Vitamin D is a steroid hormone that plays an important role regulating the body’s levels of calcium and phosphorus, as well as in bone mineralization. Vitamin D is produced when 7-dehydrocholesterol (synthesized from cholesterol) is converted to cholecalciferol by UV B light.137 Low vitamin D is associated with many disease states, including muscle weakness and myopathy.138 Skeletal muscle contains vitamin D receptors and the molecular mechanisms of vitamin D within this tissue are both genomic and nongenomic. The genomic pathway effects are initiated by the binding of bioactive vitamin D (calcitriol) to its nuclear receptor, resulting in alterations in gene transcription and subsequent protein synthesis. This can have effects on muscle calcium uptake, phosphate transport across muscle cell membranes, as well as muscle cell proliferation and differentiation. Vitamin D is also known to regulate calcium uptake through modulation of calcium pump activity, which then affects intracellular calcium levels and subsequent muscle contraction, relaxation, and function. Effects on phosphate transport can impact cell structure and ATP availability, whereas proliferation effects can alter the synthesis of certain cytoskeletal proteins.137

    It remains debatable whether vitamin D insufficiency leads to statin-induced myalgia or statins contribution to vitamin D deficiency. There is speculation that insufficient vitamin D status may complicate and confound the adverse effects of statins, possibly because of a preferential shunting of the CYP3A4 enzyme toward hydroxylation of vitamin D, reducing the enzyme’s availability for statin metabolism and thus increasing circulating statin levels.32,137,138 Conversely, high vitamin D status may also cause enhanced CYP450 activity, increasing statin metabolism and reducing drug bioavailability.138

    Although the exact interaction between vitamin D and statins is unclear, vitamin D status does appear to play a role in the lipid-lowering response to statins, with vitamin D–deficient patients having no response to low (10–20 mg) or high-dose (40–80 mg) atorvastatin.139 Interestingly, supplementation with vitamin D was shown to enhance the effects of atorvastatin, which is unexpected given both are metabolized by CYP3A4.138 Biopsies of skeletal muscle in adults with vitamin D deficiency show type II muscle fiber atrophy with enlarged interfibrillar spaces and infiltration of fat, fibrosis, and glycogen granules.140 Retrospective, cross-sectional, and meta-analysis reveal an association between low vitamin D levels and myalgia in patients on statin therapy,141–143 although normalization of serum vitamin D levels has been shown to facilitate successful statin rechallenge in ≈88% of patients previously intolerant because of SAMS.144 A recent secondary analysis trial has shown that monthly vitamin D supplementation results in improved adherence to statin medication in older adults on long-term statin therapy.145

    Microbiome-Mediated Effects

    The microbiome plays an important role in our physiology, immune system development, digestion, and overall health.146 While extremely dynamic, the microbiota composition and structure can be influenced by a number of factors including medication. Recent studies have demonstrated a role for statins in modulating microbiome composition, with statin therapy resulting in profound remodeling of the gut microbiota, hepatic gene deregulation, changes in bile acid pool size and composition, as well as metabolic alterations in mice through a pregnane X receptor–dependent mechanism.130 Hypolipidemic response to rosuvastatin has also been shown to be dependent on microbiome composition, diversity, and taxa,147,148 whereas simvastatin has been shown to influence gut-derived metabolites which may impact response to the drug, as well as the development of adverse events.149

    Stem Cell–Mediated Effects

    Statin effect on stem cells is another potential mechanism contributing to their adverse effects. Mesenchymal stem cells isolated from adipose tissue and exposed to physiologically relevant doses of statins have been shown to experience increased cell senescence and apoptosis via upregulation of p16, p53, and various caspases. Accompanying this was impaired expression of DNA repair genes as well as impaired differentiation ability.150 In vitro and animal studies have also demonstrated a reduced proliferative capacity of stem cell–derived mesodermal precursors after statin exposure.151

    Cardiovascular Sequelae of Statin Intolerance From Observational and Trial Data

    Statins are commonly prescribed to reduce total and LDL cholesterol levels, and their clinical benefits are widely accepted in both primary and secondary prevention.7 Meta-analysis has highlighted the benefits of LDL-c reduction, with every 1 mmol/L (38.7 mg/dL) reduction associated with significant reductions in major vascular and coronary events.7 The Cholesterol Treatment Trialists Collaboration has demonstrated a consistent relative risk reduction in major vascular events per change in LDL-c level to as low as 0.5 mmol/L (21 mg/dL) with no observed adverse events, suggesting that lowering beyond current targets would further reduce CVD risk.8 As a result, statin discontinuation and nonadherence represents a significant clinical problem. Estimates suggest that 40% to 75% of patients discontinue their statin therapy within 1 year of initiation, with rates higher for primary versus secondary prevention, in older patients (>75 years), in women, in patients taking concomitant medication, and in patients with higher medication copayments.152 Data from the National Cardiovascular Data Registry suggest that among coronary artery disease outpatients, over one-third fail to receive their optimal combination of secondary prevention medication, including statins.153 More recent analysis suggests that more than half of all stable coronary artery disease patients are still considered at extreme risk with only ≈5% achieving recommended LDL-c targets (<55 mg/dL).154 Reports from the United Kingdom reveal only 79% of patients with established CVD were reported to be receiving statins, with only 31% of those receiving high-dose statins as recommended by clinical guidelines.155

    In primary prevention, retrospective analysis reveals that patients with ≥90% statin adherence over 1 year had significantly fewer nonfatal coronary artery disease events compared with those who were <90% adherent with their statin.156 In patients with a prior acute myocardial infarction, the risk of mortality was significantly increased in low adherence statin users compared with high adherence users (24% versus 16%).157 Retrospective cohort analysis revealed that statin intolerance was also associated with a 36% increase in recurrent myocardial infarction and a 43% increase in coronary heart disease events compared with high statin adherence patients.158 Meta-analysis of secondary prevention statin trials revealed large variability in the reduction of lipoprotein levels with statin therapy. Furthermore, >40% of patients failed to reach guideline-recommended LDL-c targets despite high-dose statin therapy. Those who did achieve very low LDL-c levels had significantly lower risk of cardiovascular events than those who achieved moderately low levels.159

    Reinitiating Statin Therapy: More Than Just Reducing Cardiovascular Risk

    Meta-analysis reveals several sociodemographic, medical, and healthcare utilization characteristics, including sex, income level, out-of-pocket costs, and level of lipid testing as factors that impact statin adherence.160 The economic significance of this also needs to be considered, as patients with hyperlipidemia already have substantial economic and clinical burden from cardiovascular events up to 3 years after their first event, which continues to increase with subsequent events.161,162 A decrease in the use of statin therapy, either in primary or secondary prevention, can arise as a result of several issues. First, statin underuse may be because of a physician’s failure to initiate or intensify treatment or a patient’s reluctance to initiate treatment because of concerns about toxicity. Second, it may be due to the development of statin resistance, which occurs when a patient has a substantially lower response to a given dose of statin than what would be predicted. Third, due to statin intolerance, when a patient cannot tolerate statin therapy either at a necessary dose or at all, and finally statin nonadherence because of poor patient compliance with statin medication.152 A recent survey of US adults prescribed statins revealed that provider-patient communication about statin therapy is inadequate, which may play a pivotal role in statin adherence.163 Retrospective analysis of statin reattempt after an adverse event revealed that the nature and timing of the adverse event, medical history, and the medication prescribed, including adverse reactions to nonstatin therapy, all affect the success rate of reattempting statin therapy, supporting the need for a patient-centered approach when attempting to restart statin treatment.164

    The REGARDS study (Reasons for Geographic and Racial Differences in Stroke) found that 15% of those surveyed reported stopping their statin treatment. Within this group, the major reasons for discontinuation included statin side effects (66%), perceived lack of need for a statin (31%) and cost (3%). Overall, 37% of patients who had ceased statin treatment were willing to reinitiate statin therapy, with this being highest in the group who reported cost as the primary reason for discontinuation. Those with elevated LDL-c and reported side effects were less willing, highlighting the need for health providers to discuss the benefits of statin treatment with respect to long-term cardiovascular risk reduction.165 A large retrospective study of >100 000 patients found that after discontinuation, most patients (92%) could be rechallenged with a new statin that was tolerated for ≥12 months, suggestive of a reversible pattern of statin toxicity in most cases.166 It is therefore important that when a patient presents with statin intolerance and other causes have been ruled out, a step-by-step approach to future treatment, including that reinitiating statin therapy is essential. This must include an accurate clinical assessment, listening to patient concerns, reviewing past adverse events and possible contributing factors, providing evidence-based counseling about the potential for adverse events as well as the cardiovascular benefits of statin therapy, and shared decision making with the patient when reintroducing therapy.18,33 Treatment and management algorithms have been developed to aid both diagnosis and management of SAMS in a bid to standardize nomenclature and phenotypes, as well as the type of data that should be collected from each patient.37 Development was based on 2012 Therapeutic Guidelines: Cardiovascular and 2016 European Society of Cardiology/European Atherosclerosis Society Guidelines for the management of dyslipidemias, with input from experts (Figure 3).23,29,36

    Figure 3.

    Figure 3. Statin-associated muscle symptoms (SAMS) management algorithm. CK indicates creatinine kinase; LDL-c, low-density lipoprotein cholesterol; LLT, lipid-lowering therapy; and ULN, upper limit of normal. Figure derived from and 2012 Therapeutic Guidelines: Cardiovascular and 2016 European Society of Cardiology/European Atherosclerosis Society Guidelines for the management of dyslipidemias.23,29,36

    Recently released 2018 American Heart Association and American College of Cardiology Guidelines for the Management of Blood Cholesterol recommend a comprehensive approach to patients who experience statin-associated symptoms, with the clinician reassessing, rediscussing, and encouraging rechallenge as the initial approach unless side effects are severe. Reassessment and rechallenge should be addressed by modified dosing regimen, an alternate statin or in combination with nonstatin therapy to achieve a maximal LDL-c–lowering effect. Ongoing communication is seen as integral to patient care, along with regular monitoring to check for adherence, adequacy of response, new associated symptoms, and reaffirmation of clinical benefits. Measurement of CK is only recommended for those who experience severe SAMS or objective muscle weakness. Coenzyme Q is not recommended for either routine use or the treatment of SAMS. Patients with increased risk of type 2 diabetes mellitus are recommended to continue statin therapy with added emphasis given to net clinical benefit and adoption of lifestyle changes including increased physical activity, a healthy diet, and moderate weight loss. If hepatotoxicity symptoms are present, liver transaminases, total bilirubin, and alkaline phosphatase are recommended. In patients with stable liver disease (including nonalcoholic fatty liver disease), statins can be used after obtaining baseline measurements and determining a safety monitoring schedule.11

    Biomarkers of Statin Toxicity

    The lack of universal definitions of statin toxicity, particularly with respect to SAMS, means potential biomarkers identifying either risk of developing adverse events or confirming their presence have not been identified. In extreme cases of necrotizing myopathy, patients do present with significantly elevated CK levels (>1000 IU/L) and prominent myofiber necrosis on biopsy, whereas patients with autoimmune myopathy will also present with anti–HMG-CoA reductase autoantibodies. However, less severe SAMS do not always include a pathogenic response and, in some instances, can include normal CK levels. Further investigation of the STOMP trial revealed no association between CK levels and skeletal muscle function, nor did CK predict muscle complaints after high-dose atorvastatin treatment.167 Conversely, elevated CK levels can also be observed in the absence of myopathy, such as after strenuous exercise, further confounding the problem.5,41,81

    The National Lipid Association has developed guidelines for both diagnosing and managing SAMS.36 Recently renamed the SAMS Clinical Index to reflect the diversity of symptoms, the score aims to define the spectrum of statin-associated muscle events to include, in increasing order of severity, myalgia (described as flu-like symptoms), myopathy (muscle weakness), myositis (muscle inflammation), myonecrosis (muscle enzyme elevation or increase in CK), and clinical rhabdomyolysis.168 SAMS clinical index uses 4 scales relating to location, pattern, timing of symptom onset, and timing of improvement after statin withdrawal (Table 3).169 Although this index appears to confirm true SAMS in a small study of statin myopathy, its use still requires validation in larger, long-term studies.29

    Table 3. Statin-Associated Muscle Symptom Clinical Index36,170

    Clinical SymptomsScore
    Regional distribution/pattern
     Symmetrical hip flexors/thigh aches3
     Symmetrical calf aches2
     Symmetrical upper proximal aches2
     Nonspecific asymmetrical, intermittent1
    Temporal pattern
     Symptom onset <4 wk3
     Symptom onset 4–12 wk2
     Symptom onset >12 wk1
     Improves upon withdrawal <2 wk2
     Improves upon withdrawal 2–4 wk1
     Does not improve upon withdrawal >4 wk0
     Same symptoms reoccur upon rechallenge <4 wk3
     Same symptoms reoccur upon rechallenge 4–12 wk1
    Statin myalgia clinical index score

    Genome-wide association studies have identified several genetic variants associated with statin toxicity; however, these are suggestive and their associations have not always been widely replicated. Furthermore, this type of investigation predominantly looks at common variants in the genome and may not detect rare variants.41 In addition, it is unknown whether statins play a causal role in unmasking a phenotype or whether development of an adverse event is a natural progression of the underlying condition, indicating that further understanding of the molecular mechanisms underlying statin toxicity is required. This is particularly relevant with SAMS, given the diverse nature of muscular conditions that are reported. Pharmacogenomics of statin therapy has generally focused on genes involved in pharmacodynamics and pharmacokinetics (SLCO1B1 and CYP3A4) or those linked to lipoprotein metabolism pathways (HMGCR, LDLR, APOE, APOB, PCSK9). In general, these common genetic variations do not appear to be a major determinant of statin response, with relatively modest effect sizes and inconsistent replication in larger studies. The exception to this is SLCO1B1 and risk of myopathy, with SLCO1B1 521C clinically relevant to simvastatin-induced myopathy.170,171

    Animal studies have revealed increased serum and urinary excretion of 1- and 3-methylhistidine in response to cerivastatin-induced mytotoxicity.172 Elevated skeletal muscle phosphodiesters are also related to muscle disorders, and these have been observed to be higher in statin users compared with nonstatin users,173 although further work is required to establish a link between either of these markers and muscle function and myopathy. Other potential biomarkers include lactate/pyruvate ratio, which may reflect a dysfunction in the mitochondrial respiratory chain and myotoxicity. An early study revealed higher lactate/pyruvate ratios in statin-treated hypercholesterolemic patients compared with untreated patients or healthy controls.174 In contrast, a study in healthy subjects treated with simvastatin observed statin-induced mitochondrial dysfunction compared with those treated with placebo, with no difference observed for lactate/pyruvate ratio.175

    The Nocebo Effect: Is Statin Toxicity All in the Mind?

    The issue of statin toxicity, particularly with respect to the development of SAMS, remains a contentious issue. Randomized controlled trials suggest a low incidence (<5%) of statin toxicity; however, some feel this is an underestimation as most studies exclude patients with a history of statin intolerance either before randomization or during the run-in period. Furthermore, patients more likely to develop statin intolerance are often underrepresented in trials, those enrolled in trials often underreport side effects, and there is a lack of valid questionnaires, standard definitions, relevant biomarkers, and toxicity outcomes included in trial design.5,19 Others maintain that randomized controlled trials do not reflect clinical practice and thus fail to reliably assess adverse effects.176

    A much debated topic is the so-called nocebo effect, caused by negative expectations about the effects of treatment because of information provided by clinicians, drug package inserts, the media, and a patient’s own internet searches about possible side effects, leading to higher than expected adverse event reporting.21,81,177 Both the placebo and nocebo effect reflect normal human neuropsychology and not drug efficacy or toxicity.178 Two large-scale trials have observed development of SAMS in statin-intolerant patients randomized to either PCSK9 inhibitors or ezetimibe, drugs that operate via mechanisms distinct to statins and thus do not offer plausible mechanisms for the presentation of this side effect.179,180 The GUASS-3 trial of PCSK9 inhibitors in statin-intolerant patients reported muscle problems in 42.6% of participants during atorvastatin treatment and in 26.5% of participants during placebo treatment, with 9.8% reporting symptoms during both and 17.3% having no symptoms with either treatment.181 Furthermore, both GUASS-3 and ODYSSEY ALTERNATIVE had limited reporting of muscle problems in statin-intolerant participants who were receiving atorvastatin in a blinded manner.180,181 More recently, the drucebo effect has been proposed, which relates to the beneficial or harmful effects of a drug (as opposed to an inert substance) that are because of expectations rather than the pharmacological actions of a drug. A recent study investigating this phenomenon suggests a substantial increase (38%–78%) in the incidence of SAMS with open-label therapy compared with when participants are blinded to treatment.182 Interestingly, the Lipid-Lowering Arm of the Anglo-Scandinavian Cardiac Outcomes Trial suggests that muscle-related adverse events are reported only when the patient and their doctor were aware statins were being used.183 Regardless, it is important to consider the nocebo/drucebo effect when comparing the rates of statin intolerance between observational studies, randomized trials and the clinic. Although the true prevalence of statin intolerance remains debatable, downplaying its clinical implications is unwise, particularly given the significant long-term cardiovascular benefits of statin treatment.184

    Several studies have also reported that negative statin-related news stories are associated with early statin discontinuation, particularly in patients already receiving statins, and this results in increases in CVD events.185–187 A study within the Danish population found that early statin discontinuation increased with negative statin-related news stories, with the opposite seen for positive statin-related new stories.185 British reports reveal that media coverage of statins is substantially influenced by publication of national guidelines and clinical studies in medical journals. The press coverage was reported as being predominately negative and included questions about the balance between medication use and lifestyle management, adverse effects of treatment, and the reliability of research.188

    Alternative Treatment Options

    Lifestyle should be both the first and concomitant therapy adopted for reduction of LDL-c and CVD risk, including consumption of a heart healthy diet, maintaining a normal weight, avoiding tobacco products, and regular exercise. The initial pharmacological step in treating statin intolerance is discontinuation and rechallenge with the same or a different statin, followed by a switch in statin type, step-by-step reduction in dose and intermittent/alternate day statin dosing, as per the proposed management algorithms (Figure 3).189 If unsuccessful, ezetimibe treatment becomes next-line therapy. Ezetimibe treatment offers significant LDL-c reduction, although its extended half-life and flat dose-response allow for lower doses to be used. Second after this are bile acid resins, which although generally safe and offer additional LDL-c reduction, are limited by the need for separate administration times, poor palatability and acceptance, worsening hypertriglyceridemia, and insurance coverage restrictions on some brands. PCKS9 inhibitors markedly reduce LDL-c levels and are well tolerated and with less frequent dosing requirements. However, their high cost limits their use to high-risk patients unable to meet lipid targets on maximal medication regimes.33 However, recent news on Regeneron/Sanofi plans to reduce the cost of Praluent (alirocumab) from $14 600 to $4500 to $8000, as well as Amgen plans to lower the acquisition cost of Repatha (evolocumab) by 60% to $5850, may facilitate more widespread use, including in patients who cannot tolerate statin therapy.190,191

    Nutraceuticals are food components or derivatives that offer a safe and generally well-tolerated alternative for statin-intolerant patients. Their role is chiefly in lowering LDL-c levels as monotherapy or in combination with low-dose statin regimes or nonstatin therapy. They may also have additional properties including directly targeting myopathic processes and as analgesics, although their mechanisms of action are not fully understood nor have they been demonstrated to have any effect on long-term CVD outcomes.2 Berberine, red yeast rice (containing monacolin K or lovastatins), and plant sterols all have moderate potential as lipid-lowering agents, with other nutraceuticals such as marine-derived omega-3 polyunsaturated fatty acids, policosanols, polyphenols, flavonoids, and fibers offering some further benefit.189,192 Individual and combination nutraceuticals, including the patented Armolipid Plus, have been demonstrated to provide modest reductions in total cholesterol and LDL-c in statin-intolerant patients, including those treated with ezetimibe, with limited reporting of adverse effects.2,33,192,193 More recently, an International Lipid Expert Panel has reviewed the clinical benefits of various nutraceuticals, either alone or in combination with other nutraceuticals or ezetimibe. These nutraceuticals have been shown to have both LDL-c lowering properties as well as other nonlipid beneficial effects, including improvements in vascular function, as well as anti-inflammatory and antioxidant activities. Although there is still insufficient evidence about their long-term safety and effectiveness, these nutraceuticals may offer alternative treatment options in the management of statin intolerance.194

    Conclusions and Future Directions

    Although the true prevalence of statin intolerance remains debatable, discontinuation and nonadherence to statin therapy remains a significant and ongoing clinical problem. Despite a range of potential mechanisms being proposed for the development of statin toxicity and intolerance, true identification of the condition remains hampered by a lack of clear definitions and biomarkers. Given the widespread use of statins for reducing cholesterol and subsequent cardiovascular morbidity and mortality, both in primary and secondary prevention, further research on this condition is warranted. In addition to potential biomarkers identifying either the risk of developing adverse events or confirming their presence, there is an urgent need for alternative treatment strategies for people who remain unable to take statins. Although various pharmacological (ezetimibe, PCSK9 inhibitors) and nonpharmacological (nutraceuticals) treatment options exist, these can also be limited in their use because of side effects, cost, as well as lack of long-term safety and efficacy data. One potential new treatment option is bempedoic acid, which has already been demonstrated to reduce LDL-c in statin-intolerant patients.195 Further investigation into the effect of this drug on major cardiovascular events in statin-intolerant patients with or at high risk of CVD is currently being investigated in the CLEAR OUTCOMES trial. Of paramount importance is acknowledgement and discussion between clinician and patient on the existence of statin intolerance, the risks associated with discontinuation of statin therapy, as well as strategies for reinitiating therapy, particularly in high-risk individuals.

    Nonstandard Abbreviations and Acronyms


    ATP-binding cassette


    protein kinase B


    5′ AMP-activated protein kinase


    CCAAT/enhancer binding protein


    creatinine kinase


    cardiovascular disease


    cytochrome P450


    Forkhead box protein O


    glycine amidinotransferase


    glucose transporter




    insulin-like growth factor


    insulin receptor substrate-1


    Justification for the Use of Statin in Prevention


    low-density lipoprotein cholesterol


    muscle atrophy F-box


    major histocompatibility complex


    multidrug resistance protein


    muscle RING-finger protein-1


    organic-anion-transporting polypeptide B1


    poly (ADP-ribose) polymerase


    proprotein convertase subtilisin/kexin type 9


    pyruvate dehydrogenase complex


    pyruvate dehydrogenase kinase


    peroxisome proliferator–activated receptor-γ coactivator


    phosphoinositide 3-kinase


    protein kinase C


    peroxisome proliferator–activated receptor


    Prediction of Muscular Risk in Observational


    Prospective Study of Pravastatin in the Elderly at Risk


    ryanodine receptor


    statin-associated muscle symptoms


    Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine


    single-nucleotide polymorphism


    Stroke Prevention by Aggressive Reduction in Cholesterol Levels


    Effect of Statins on Skeletal Muscle Function


    UDP glucuronosyltransferases


    upper limit of normal


    West of Scotland Coronary Prevention Study


    *These authors are joint senior authors.

    Correspondence to Gerald F. Watts, DSc, MD, PhD, School of Medicine, University of Western Australia, GPO Box X2213, Perth WA 6847, Australia, Email
    Robert H. Eckel, MD, University of Colorado Denver, Anschutz Medical Campus, Mail Stop 8106, 12801 E 17th Ave, Aurora CO 80045, Email


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