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HMG-CoA reductase inhibitors (statins) are a widely used class of drug, and like all medications have potential for adverse effects (AEs). Here we review the statin AE literature, first focusing on muscle AEs as the most reported problem both in the literature and by patients. Evidence regarding the statin muscle AE mechanism, dose effect, drug interactions, and genetic predisposition is examined. We hypothesize, and provide evidence, that the demonstrated mitochondrial mechanisms for muscle AEs have implications to other nonmuscle AEs in patients treated with statins. In meta-analyses of randomized controlled trials (RCTs), muscle AEs are more frequent with statins than with placebo. A number of manifestations of muscle AEs have been reported, with rhabdomyolysis the most feared. AEs are dose dependent, and risk is amplified by drug interactions that functionally increase statin potency, often through inhibition of the cytochrome P450 (CYP)3A4 system. An array of additional risk factors for statin AEs are those that amplify (or reflect) mitochondrial or metabolic vulnerability, such as metabolic syndrome factors, thyroid disease, and genetic mutations linked to mitochondrial dysfunction. Converging evidence supports a mitochondrial foundation for muscle AEs associated with statins, and both theoretical and empirical considerations suggest that mitochondrial dysfunction may also underlie many non-muscle statin AEs. Evidence from RCTs and studies of other designs indicates existence of additional statin-associated AEs, such as cognitive loss, neuropathy, pancreatic and hepatic dysfunction, and sexual dysfunction. Physician awareness of statin AEs is reportedly low even for the AEs most widely reported by patients. Awareness and vigilance for AEs should be maintained to enable informed treatment decisions, treatment modification if appropriate, improved quality of patient care, and reduced patient morbidity.
HMG-CoA reductase inhibitors (statins) have been the best selling prescription drug class in the US and include atorvastatin, the best-selling prescription drug in the world – indeed in history.1-3 These drugs are perceived to have a favorable safety profile4-6 and have well documented benefits to cardiovascular disease in many groups, including persons who are younger and older, male and female, at moderate and high cardiovascular risk. In addition, benefits have been objectively shown to exceed risks on average for both total mortality and total morbidity (indexed by serious adverse events), specifically in clinical-trial equivalent middle-aged men who are at high cardiovascular risk.7-9 Although many people treated with statins do well, no drug is without potential for adverse effects (AEs). There is need for awareness of risks as well as benefits of all drugs, particularly those that, like statins, are used on a wide scale where even uncommon effects can translate to significant public health impact.
Statins inhibit the enzyme HMG-CoA reductase, at a stage early in the mevalonate pathway.10 This pathway generates a range of other products in addition to cholesterol, such as coenzyme Q10, heme-A, and isoprenylated proteins,10 which have pivotal roles in cell biology and human physiology and potential relevance to benefits as well as risks of statins.11-13 Additionally, cholesterol itself is not merely a final product (with its own range of vital roles) but also an intermediate to a suite of additional products of fundamental relevance to health and well-being, such as sex steroids, corticosteroids, bile acids and vitamin D, several of which have been shown to be affected with statin administration.14, 15 The biochemical influences of statins extend well beyond the lipid profile and its constituents (low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], and triglycerides), and even beyond the direct products of the mevalonate pathway, to include a wide swath of products and functions modified through these as well as nonmevalonate effects of statins, ranging from nitric oxide and inflammatory markers16 to polyunsaturated fatty acids,17 among many others.
This report reviews evidence related to statin induction of AEs and evidence for a dose-response relationship, and describes reported drug interactions. Muscle AEs are emphasized as they are the best recognized AEs of statins (liver AEs are perhaps second most recognized), and the AEs on which much of the information on mechanism, drug interactions, and dose-response has been obtained – information that, as we show, has relevance to other statin AEs.18, 19 Statins lead to dose-dependent reductions in coenzyme Q10,20-22 a key mitochondrial antioxidant and electron transport carrier that serves to help bypass existing mitochondrial respiratory chain defects.23-25 We review convergent evidence supporting a role for mitochondrial predispositions and mechanisms for statin muscle AEs. We seek to place other statin AEs in the context this evidence provides, proposing that mitochondrial dysfunction may underlie additional AEs reported on statins.
The best recognized and most commonly reported AEs of statins are muscle AEs,26, 27 and include muscle pain, fatigue and weakness as well as rhabdomyolysis. While individual randomized controlled trials (RCTs) often fail to show an excess of muscle problems or symptoms, meta-analysis of randomized double-blind, placebo-controlled trials have shown increased myositis in patients receiving statins relative to placebo (odds ratio [OR] 2.56, 95% CI 1.12-5.85), with myositis there defined as creatinine kinase (CK) > 10 times the upper limit of normal with myalgia.28
In contrast to myositis, myalgia was not increased on average based on meta-analysis of RCTs that compared statins to placebo (relative risk [RR] 1.09, 95% CI 0.97-1.23).28 However, this does not necessarily mean that statins do not cause myalgia, and this point seems not to be uniformly appreciated. Rather, evidence has shown that statins reduce pain and improve walking distance in many individuals (for instance, but not confined to, persons with peripheral arterial disease),29 an effect that may arise through improved blood flow deriving from endothelial function benefits in persons with endothelial dysfunction.30 An overall null effect of statins on muscle pain in clinical trials may therefore indicate that, in the samples selected for these trials, statins caused muscle pain in approximately as many people as they relieved it.
In support of this view, triangulating evidence suggest that statins have a causal role in myalgia as well as muscle weakness in some people. For instance: A double-blind, placebo-controlled, crossover biopsy study showed partially reversible mitochondrial myopathy in persons reporting non-CK-elevating or minimally CK-elevating muscle symptoms on statins.31 In a family in which multiple members experienced statin-associated non-CK elevating muscle pain, objective investigation affirmed myopathic findings.32 Prior muscle symptoms on statins or other cholesterol drugs represent a predictor for future symptoms with statin rechallenge and may signal elevated risk for rhabdomyolysis on statins.33-36 Patients who experienced muscle symptoms on statins (typically with normal or slightly elevated levels of CK), that reverse with discontinuation, most often re-experienced muscle symptoms if rechallenged with an equivalent or higher expected potency statin based on calculated potency equivalencies; in contrast, those rechallenged with a lower potency statin re-experience problems significantly less frequently, p<0.01).37 These data support the view that muscle symptoms arising on statins and reversing with discontinuation are in many individual cases causally statin-associated, whether or not on average an increase in muscle symptoms occurs with statins.
This observation underscores a critically important point relevant to drug AEs in general, which merits emphasis and has relevance to other reported statin AEs. A significant increase in rates of a problem on drug vs placebo in RCTs supports a causal link between that drug and that AE, in some persons. However, absence of an average significant increase in a problem, or even presence of a significant average reduction in a problem, does not preclude causal occurrence of that problem in some individuals. Illustrating this point are the recognized occurrence of ‘paradoxical’ increases in blood pressure (BP) in some people with use of medicines designed to lower BP in most people, and ‘paradoxical’ increases in anxiety or aggression in some people who are given drugs designed to produce the opposite effect.38-45
In the case of statins, a potential basis for opposing effects occurring in muscle and in other organs can be identified. Evidence supports the proposition that antioxidant effects of statins underlie (or contribute to) many fundamental statin benefits – including benefits to flow and oxygen delivery46-48 and inflammation.49, 50 These effects may participate in improved walking distance in patients on statins, including benefits to muscle/walking in persons with and without peripheral artery disease.29 Yet a subset of people reproducibly exhibit increases in markers of oxidation on statins,51 and the occurrence of this increase has been tied to muscle pain on statins.52, 53
RCTs are important for evaluating average effects that may have relevance to use of a drug for treatment in a group overall. However, AEs are important to an individual even if they do not occur on average, and non-RCT data, including case-based data, have recognized importance in AE assessments.54-57 Bearing this in mind, Table I shows a range of additional muscle problems that have been reported on statins beyond the classical ‘myalgia’ and ‘myositis.’17, 29, 51, 58-78
Muscle effects arising on statins do not uniformly resolve fully with statin discontinuation.155 Crossover biopsy studies show a partially reversible mitochondrial myopathy in persons presenting with recurrent muscle pain on statins.31 Statins elevate the respiratory exchange ratio and do so even in asymptomatic persons, while persons who have been symptomatic on statins show an elevated off-statin respiratory exchange ratio.156-158 This altered cell respiratory function in persons with AEs may represent a cause (predisposing to statin myopathy) and/or a consequence of statin myopathy; the relative contributions of each awaits prospective study.
A range of cases have now been reported in which statin use has “uncovered” previously clinically silent or clinically tolerated conditions, ranging from McArdle disease159, 160 to myotonic dystrophy159 to acid maltase deficiency161 to possible Kennedy disease.159 Statins have also exacerbated known muscle conditions, such as myasthenia gravis.78 In the case of mitochondrial myopathies, the relative degree to which statins have unmasked vs induced disease may not always be clear.159, 162
Rhabdomyolysis is among the best-recognized and most feared complications of statins; it occurs when muscle damage is severe, leading to a marked elevation of CK (e.g. in excess of 10 times the upper limit of normal) often accompanied by evidence of renal dysfunction and occasionally renal failure and death.81, 94, 163-166 Over 900 unique PubMed citations (as of January 2009) pair the keywords ‘rhabdomyolysis’ with terms referring to statins, i.e. ‘statins’, ‘HMG’, or each generic statin name individually. However, the recognition of rhabdomyolysis as a statin complication does not rest on randomized trial data, which even on meta-analysis do not support a significant increase (e.g. OR 1.59, 95% CI 0.54-4.70).28
A case report has suggested that misinterpretation of evidence-based medicine from RCTs on statin rhabdomyolysis may have fatal consequences – and perhaps has had.81 Underscoring the limitations of clinical trials for AE identification, cerivastatin was withdrawn from the market due to excess risk of rhabdomyolysis, although no cases of rhabdomyolysis occurred on cerivastatin in a meta-analysis of randomized trials.28 In contrast, observational studies of real-world use reported that rhabdomyolysis occurred with substantially higher frequency on cerivastatin than other statins,167, 168 particularly for cerivastatin in combination with fibrates (and specifically gemfibrozil).168 This was true for postmarketing surveillance data169 and for claims data.168 Illustrative of this, in one study, claims data rates per 10,000 person-years of treatment were 0.44 for simvastatin, atorvastatin or pravastatin alone (95% CI 0.20-0.84); 5.34 for cerivastatin (95% CI 1.46-13.68); 2.82 for fibrates (95% CI 0.58-8.24); and 0 for no lipid therapy (95% CI 0-0.48). With a modest number of total rhabdomyolysis cases, the difference approached but did not quite reach significance (p=0.056). Rates rose to 5.98 for statin (non-cerivastatin) combined with a fibrate (95% CI 0.72-216.0), and 1035 for cerivastatin-fibrate combinations (95% CI 389-2117).168
Emphasizing that figures for a larger group need not apply to subgroups within that group, per year of therapy the number needed to treat, to see one case of rhabdomyolysis was 22,727 for statin (monotherapy) overall, but 484 for older patients with diabetes mellitus treated with combined statin and fibrate, and 9.7 to 12.7 for patients who received cerivastatin plus fibrate.168 (As reviewed below, much of the excess in cases is attributable to high potency resulting specifically from gemfibrozil-cerivastatin interaction effects.170, 171)
In the setting of statin rhabdomyolysis, other organs may also be severely affected. Renal failure is well recognized and is a consequence of the rhabdomyolysis, but concurrent heart,96, 109, 110 pancreas,96, 105 liver,96, 106-108, 172 bone marrow,96, 173, 174 respiratory,96, 98 and CNS toxicity96, 112 – or all of the above96 – are also reported.
A range of sources support a dose relation for statin AEs (Table II37, 167, 170, 171, 175-184), although there may exist AEs that are not dose dependent. Meta-analyses of RCTs comparing lower vs higher potency statins are of greatest relevance among the clinical trial data because these examine similar patients (within the same study) placed on drugs of different potencies.176, 178 Results of these meta-analyses have supported more total AEs with statin vs placebo175 (although this may not be equally true in all settings), more total AEs with intensive vs nonintensive statin use,176 and more AEs leading to dropouts with intensive vs nonintensive statin use.176 (Dropout rates are not, however, necessarily greater for lower intensity statin use vs placebo in clinical trial samples.28) In addition, CK elevations and liver function test (LFT elevations) occur more frequently with higher dose vs lower dose statins.176, 178
Rechallenge data also support dose-related effects. This study design examines muscle symptom recurrence in persons with prior statin AEs. Patients rechallenged with same-or-higher potency statins (relative to the potency of the statin on which problems originally arose) usually re-experienced the problem, and did so significantly more frequently than those rechallenged with lower potency statins.37 Examination of rechallenge data provides a highly efficient study design because at-risk patients are selected for, and by comparing subjects to themselves, erosion of power arising from cross-subject variability is reduced.
Although some investigators promote very low LDL-C targets, proposing that lower is better and no LDL-C is too low,191-193 the US FDA has stated that “all statins… should be prescribed at the lowest dose that achieves the goals of therapy (e.g. target LDL-C level).”180 Intensive statin treatment in RCTs does not improve mortality, even in patients with heart disease, relative to less intensive treatment (although it may do so in the setting of acute coronary syndrome).194 Moreover, intensive treatment comes at the cost of an increased risk of adverse outcomes.176, 194
Fibrates, particularly gemfibrozil, amplify the risk of rhabdomyolysis on statins (most powerfully for cerivastatin170, 171), and are present in many statin rhabdomyolysis reports,82, 99, 105, 109, 195-221 likely due to their effect of impeding statin metabolism and perhaps their additional lipid-modifying effects. (Other cholesterol-lowering drugs have also been implicated in muscle toxicity222 and in statin rhabdomyolysis cases, although less frequently.223-225) However, lipid-lowering drugs are not the sole drug class that may increase risk of statin rhabdomyolysis and other statin AEs (see Table III,105 155, 169-171, 179, 195-199, 202, 210, 223-233).
Drug interactions arise when drugs inhibit metabolic pathways of statins, compete for metabolism with statins, or cause similar or interacting toxicity. Additionally, apparent interactions may arise when drugs serve as markers for existing problems that signal vulnerability to statin AEs.
Several widely used statins – atorvastatin, simvastatin, and lovastatin (and previously cerivastatin, now off the market) – are metabolized by the cytochrome P450 (CYP)3A4 pathway.318 (Simvastatin acid is also metabolized by CYP2C8; fluvastatin is primarily metabolized by the CYP2C9 pathway, while pravastatin and rosuvastatin are not metabolized by these systems.318) Concurrent administration of statins with CYP3A4 inhibitors may raise statin concentrations and risk of toxicity, including rhabdomyolysis.185 The CYP3A4 pathway is inhibited by a variety of agents including cyclosporin, erythromycin, azole antifungals, and antiretrovirals such as ritonavir.318, 319 (Antiretrovirals may also cause lipids to rise, thus creating both the need for lipid therapy and the setting in which it is more toxic.302) Some agents, such as calcium channel blockers, are considered weaker CYP3A4 inhibitors and appear to increase statin rhabdomyolysis risk, perhaps to a lower degree.186, 318, 320 However, interaction effects vary dramatically among statins as well as among subjects for a single statin. Regarding the former, increases in simvastatin concentrations may be several times greater than in atorvastatin concentrations with concurrent CYP3A4 inhibitors.321 Regarding the latter, one study of 12 subjects showed more than tenfold interindividual variation in the extent of interaction between simvastatin and both erythromycin and verapamil as indexed by these drugs' effect on simvastatin concentration.322 Of note, in a large study using administrative claims data, statin-associated muscle disorders including rhabdomyolysis were six-fold elevated in persons on concurrent CYP3A4 inhibitors.167
Grapefruit juice and perhaps pomegranate juice inhibit CYP3A4 and have been presumptively linked to statin rhabdomyolysis.230, 323 (Combined rosuvastatin-ezetimibe therapy was involved in the report involving pomegranate juice.230) Although some urge caution only with consumption of greater than a quart of grapefruit juice a day,94, 324, 325 far smaller quantities of grapefruit juice can pose a potential risk in vulnerable subjects: less than a cup daily of grapefruit juice for three days, consumed prior to subjects' simvastatin dose, reportedly increased simvastatin concentrations by four-fold on average (range: ~two-fold to nine-fold, p<0.01).326
The CYP3A pathway has a prominent role in drug metabolism in liver and intestine327 and approximately half of prescription drugs are metabolized by CYP3A4.328 For this reason polypharmacy may lead to competition for a common metabolic pathway. This competition may increase statin concentrations and the risk of dose-related statin AEs.
Individuals may differ in their response to individual statins, in terms of both efficacy and tolerability, due to pharmacogenomic differences, including those that affect statin hepatic uptake, clearance, and CYP pathways.329-332 Differences in these pathways may also lead to differential vulnerability to drug interactions.
Fibrates have special relevance to statin AEs, and as noted above, gemfibrozil, in particular, interferes with statin metabolism (an effect that was found to be singularly powerful in combination with cerivastatin170, 171). Additionally, fibrates themselves may be linked to rhabdomyolysis.168 Finally, fibrates may serve as markers for a population at risk for statin AEs – persons with high triglycerides and impaired fatty acid oxidation (those most likely to receive fibrates) may also be at amplified risk of statin AEs.94, 155, 333
In addition to dose and drug interactions, a multitude of other factors have been associated with an increased risk of statin AEs. Reported risk factors and corresponding citations are delineated in Table IV.36, 37, 51, 52, 94, 163, 176, 178, 180, 186, 191, 192, 283-288, 300, 325, 334-340
Most risk factors depicted can be viewed as sharing one or both of two primary mediating pathways: increased statin exposure (e.g. dose, drug interactions, genetic variants or other factors that affect clearance or hepatic uptake) or mitochondrial derangement or vulnerability (with factors producing mitochondrial problems or serving as a marker for existing ones). Reduced concentrations of coenzyme Q10 are particularly a problem in the setting of existing mitochondrial dysfunction because ample coenzyme Q10 can bypass a range of respiratory chain defects,23-25 fostering adequate ATP production and improving the redox state. Additionally, toxicity of certain interacting drugs may be mediated through mitochondrial mechanisms (as Table III shows), and mitochondrial-relevant genetic defects have been disproportionately found in patients who experience statin myopathy (reviewed below), strongly supporting mitochondrial vulnerability. Metabolic syndrome factors, particularly hypertension, are linked to increased risk of statin AEs; and these factors, including obesity, hypertriglyceridemia, hyperglycemia and particularly hypertension, have been linked to mitochondrial dysfunction and mitochondrial DNA defects.377
While a medley of potential mechanisms may cause or contribute to statin AEs (and these merit more full review in another venue), mitochondrial mechanisms have been repeatedly implicated in muscle AEs. Mitochondrial defects predispose to problems on statins (as shown in the second to last entry of Table IV, ‘Genetic mutations associated with mitochondrial dysfunction’). Additionally, statins predispose to mitochondrial defects (Table V,22 31, 32, 112, 155, 158, 162, 397, 406-414) – in all users and, to a greater degree, in vulnerable individuals. Dose-dependent reductions in coenzyme Q1020-22 can reduce cell energy, promote oxidation,362, 415 promote apoptosis, and unmask silent mitochondrial defects.23-25, 362, 415-418 The mevalonate pathway, which statins inhibit, also produces heme-A, which has it own central involvement in mitochondrial electron transport.419
Statins reduce20-22 and coenzyme Q10 supplementation increases420-422 serum coenzyme Q10 levels. The ability to demonstrate tissue changes in coenzyme Q10 with administration of either agent is more variable; however, irrespective of changes in tissue coenzyme Q10 levels, changes in tissue mitochondrial and respiratory function clearly occur (improved with coenzyme Q10, impaired with statins).25, 156-158, 407, 423 Indeed, a range of study types have shown mitochondrial and metabolic predispositions to statin AE vulnerability, and mitochondrial and metabolic effects of statins in animals317, 347, 424-428 as well as humans, with mitochondrial effects in humans arising in all users or selectively in those who express AEs (Tables TablesVV and andVIVI).
Muscle is highly aerobically dependent and selectively vulnerable to mitochondrial pathology.430 But given the evidence for mitochondrial vulnerability and pathology related to statin AEs, it merits note that other organs – including brain, liver, heart and kidney – can be affected by mitochondrial pathology as well,430 and we suggest mitochondrial mechanisms may also be involved in a range of nonmuscle statin AEs. The occurrence of failure of other organs in concert with rhabdomyolysis is noteworthy in this regard, and multiple organ injury or failure has been reported in the context of statin rhabdomyolysis.81, 91, 96, 98, 100, 105, 107-109, 112, 431
Cognitive problems are second only to muscle problems among patient reports of statin AEs.432 Brain tissue shares with muscle tissue a high mitochondrial vulnerability as both are postmitotic tissue with high metabolic demand.433-437 Muscle has a very high dynamic range of demand; and the brain, while reflecting only about 2-4% of (nonobese) body mass, accounts for approximately 20% of oxygen438 and 50% of glucose utilization.439 Muscle and brain are the organs most classically affected in mitochondrial disease (mitochondrial myopathy and encephalomyopathy are classical manifestations of respiratory chain diseases). For instance, mitochondrial encephalomyopathy resulting from heritable coenzyme Q10 deficiency classically produces fatigue, muscle symptoms, and cognitive problems,440 although the cases referred for analysis are often relatively severe.429, 441 Gastrointestinal26 and neurological symptoms,432, 442 psychiatric symptoms,443-446 sleep problems,444, 447 glucose elevations,182 and a range of other symptoms reported on statins also arise in mitochondrial dysfunction.379, 448-457
Table VII,28 31, 108, 172, 178, 181, 458-481 shows those AEs for which there is RCT support in some subject groups (and provides, in some cases, additional non-RCT evidence). Randomized trials have recognized limitations for AE detection, due in part to selection considerations.482 Even among RCTs, studies that differ in selection criteria are expected to differ in expression of, and power for, AE occurrence due to effect modification. (This issue is not specific to statins, but is germane to assessment of risks and benefits for all drugs.)
When the average effect (of drug on outcome) is harmful in RCTs, then it can be concluded that adverse consequences to that outcome occur in at least some individuals. However, when average effects are not harmful, AEs to that outcome are not on that basis excluded. Recall that randomized trials seek to determine the overall or average impact of a drug on an outcome (in the selected sample), in order to assess whether the drug may be used to benefit that outcome on average. It is worth re-emphasizing that harms in an individual are important even if benefits occur on average.
Case reports coupled with triangulating evidence can represent an important source of evidence regarding occurrence of specific AEs, and case reports and case series are reportedly the primary grounds upon which label changes with drugs occur.54-57 For identification of AEs in an individual, the experience of the individual is the most relevant since average effects need not apply to an individual, whether average effects are determined by RCT or observational designs. Table VIII,15 369, 444, 538-560 characterizes reported AEs that do not have identified RCT support.
Effect modification – leading to statins producing different effects on the same outcome in different individuals – is recognized in the context of statin (and other lipid-lowering drug) effects on lipids,881, 882 and has previously been discussed in relation to statin muscle effects (benefits to walking occur in some,29 while detriments occur in others113). As Table VII shows, a similar theme pervades other statin effects, with statins reported to benefit and worsen proteinuria and to benefit and worsen arrhythmia, cardiac function, and an array of other outcomes. We speculate that a common source of effect modification underlies many of these reported benefits and harms – with statin-induced antioxidant effects and improved flow benefiting many organs in some individuals; and statin-induced pro-oxidant effects and mitochondrial dysfunction adversely affecting a range of organs and outcomes in other individuals. Indeed, even RCT evidence has differed for the same outcome in different subject groups, generally along the lines this proposition predicts.
Observational and limited randomized trial data variably suggest partial (though incomplete) benefit of coenzyme Q10 supplementation to muscle symptoms; and to other AEs of statins (observational data).883-886 Additional studies are required to better understand the role of coenzyme Q10 supplementation in prevention and mitigation of statin AEs. It merits note that preparations of coenzyme Q10 vary widely in their bioavailability.887
Randomized trial evidence has little to offer in understanding recovery profiles for statin AEs, although some evidence is beginning to emerge. While one study reported uniform recovery of statin muscle AEs,888 a larger statin myopathy clinic including more objective data noted that recovery is often incomplete when objective measures are used.889 Other evidence supports this, noting for muscle AEs that “variable persistent symptoms occurred in 68% of patients despite cessation of therapy.”155 Incomplete resolution in some subjects has been reported for other AEs. Thus, in an analysis of data, presented in the Australian Adverse Drug Reaction Bulletin, it was noted that “Statin-associated peripheral neuropathy may persist for months or years after withdrawal of the statin… In two ADRAC (Adverse Drug Reactions Advisory Committee) cases of persistent peripheral neuropathy, motor and sensory conduction tests showed minimal recovery 4 and 12 months, respectively, after discontinuation of simvastatin, despite clinical improvement.”561
As others have observed, “finding potential drug-safety problems requires skillful observation by clinicians who are attuned to the possibility of drug-related adverse events.”890 and (according to FDA officials) “physicians need to think ‘adverse drug reactions’ when encountering unexpected symptoms in their patients.”891
Even for the most commonly reported AEs involving statins, patients state that physicians often dismiss the possibility that their AE may be statin related.432 Failure to recognize drug AEs can prevent needed reassessment of the risk-benefit profile for statin treatment – and where appropriate, modification of the treatment regimen, in the face of possible or probable statin AEs. This may reduce quality of patient care, reduce medication compliance relative to a modified regimen, and place patient safety in peril both for morbidity and mortality from not only the AEs, but also perhaps from the conditions the medication is designed to treat.
The converse is also true: awareness of statin AEs is vitally important as it may improve recognition of these effects when they arise, enable more informed treatment decisions by patient and provider, improve the quality of patient care – and reduce patient suffering and morbidity.
It has been observed that “as more information is learned through the results of clinical trials, LDL-C goals become more stringent and difficult to attain. Large doses of high-potency statins, sometimes given in combination with other lipid-lowering agents, are frequently necessary to achieve these goals. As a result, the frequency of AEs from statin therapy may be expected to increase, and less common AEs may occur more often.”734 This increases the importance of recognition of statin AEs.
As reviewed here, AEs on statins may signal a mitochondrial vulnerability, which may alter or perhaps even reverse an otherwise favorable impact of statins on cell energetics. And AEs may signal occurrence of a net prooxidant rather than antioxidant effect of statins53 with possible unfavorable implications for a range of statins' proposed pleiotropic effects.892
When possible side effects arise in a patient on any drug, the risk-benefit balance of treatment should be reassessed. Statins are a linchpin of current approaches to cardiovascular protection: however, AEs of statins are neither vanishingly rare nor of trivial impact. For statins, as for all medications, vigilance for potential AEs is imperative. Recognition of potential statin AEs is needed and may be fostered by an improved awareness both of relevant literature and of its limitations.
The authors have no conflicts of interest to report. Work that contributed to this paper was funded by a Robert Wood Johnson Generalist Physician Faculty Scholar award to Dr Golomb. The study sponsor did not participate in study design; in the collection, analysis, or interpretation of data; in the writing of this report; or in the decision to submit this paper for publication. The authors would like to thank Hanh Nguyen and Jersey Neilson for kind assistance securing articles; and Sabrina Koperski for excellent editorial and administrative assistance.