NLA Task Force on Statin Safety - 2014 Update

Journal of Clinical Lipidology (2014) 8, S1–S4

Executive Summary NLA Task Force on Statin Safety - 2014 update

Terry A. Jacobson, MD, FNLA, Chair, The NLA Task Force on Statin Safety - 2014 Update*

Department of Medicine, Ofﬁce of Health Promotion and Disease Prevention, Emory University, 49 Jesse Hill Jr Drive SE, Atlanta, GA 30303, USA

KEYWORDS: Statins; Statin drug; Statin muscle; Statin intolerance; Statin brain; Statin liver; Statin diabetes

Statins are the most widely prescribed class of medications classified into these risk categories. Although shocking, in the United States and their benefits for lowering low- these numbers do not even account for the hundreds of mil- density lipoprotein cholesterol (LDL-C) and reducing the lions of patients who qualify for statins because they risk for coronary heart disease (CHD) are well docu- already have ASCVD, diabetes mellitus, or extremely mented.1 Statins have been the cornerstone of pharmaco- high LDL-C levels. Therefore, the potential risks and ben- therapy for the management of high blood cholesterol efits of statin use are a major US and worldwide public levels virtually since their development. The American health concern. Heart Association /American College of Cardiology 2013 In 2006, the National Lipid Association (NLA) guidelines recently expanded the number of individuals convened a Statin Safety Assessment Task Force of experts eligible for statin therapy by recommending it for those who published their findings on specific questions related to with: (1) clinical atherosclerotic cardiovascular disease the muscle, liver, renal, and neurologic effects of statins.5 (ASCVD), (2) LDL-C $190 mg/dL, (3) type 2 diabetes In the period since the report from that Task Force, the and age between 40 and 75 years with LDL-C 70 to body of evidence for the benefits and potential risks of 189 mg/dL, and (4) an estimated 10-year risk of ASCVD statin use has expanded.6–8 Prompted by examination of $7.5% and age 40 to 75 years.2,3 Considering only those those data, in 2012, the US Food and Drug Administration who qualify according to their estimated 10-year risk of (FDA) made new labeling rules that included (1) removal ASCVD, it has been reported that of the 101 million people of the routine periodic monitoring of liver enzymes in pain the United States age 40 to 79 years who do not have car- tients taking statins, recommending instead that liver diovascular disease, 33 million have an estimated 10-year enzyme tests be performed before statin therapy, and as risk of ASCVD $7.5%, and another 13 million have a clinically indicated thereafter; (2) adding information about risk between 5% and 7.4%.4 Using crude global estimates, the potential for generally nonserious and reversible cogni- 920 million people worldwide would be expected to be tive side effects and reports of increased blood sugar and

* Corresponding author. Submitted March 6, 2014. Accepted for publication March 6, 2014. E-mail address: [email protected]

Evidence grading: Strength of recommendation* Grade Strength of recommendation A Strong recommendation There is high certainty based on the evidence that the net benefit** is substantial B Moderate recommendation There is moderate certainty based on the evidence that the net benefit is moderate to substantial, or there is high certainty that the net benefit is moderate C Weak recommendation There is at least moderate certainty based on the evidence that there is a small net benefit D Recommend against There is at least moderate certainty based on the evidence that it has no net benefit or that the risks/harms outweigh benefits E Expert opinion There is insufficient evidence or evidence is unclear or conflicting, but this is what the expert panel recommends N No recommendation for or against There is insufficient evidence or evidence is unclear or conflicting *The system was adapted as a hybrid of the National Heart Lung and Blood Institutes (NHLBI) rating system (NHLBI cardiovascular-based methodology) used in the new American Heart Association/American College of Cardiology cholesterol guidelines (Stone, 2013) and adapted from the original GRADE system of evidence rating (Guyatt, 2008). **Net benefit is defined as benefits minus risks/harms of the service/intervention. glycated hemoglobin associated with statin use; and (3) $12 months without evidence of muscle injury, and adding expansion of the contraindications and dose limitations new contraindications and dose limitations for simvastatin for lovastatin use.9 This followed an FDA-mandated label- with certain medicines.10 ing change in 2011 limiting the use of 80 mg simvastatin to These labeling changes have raised numerous questions only those patients who have been taking this dose for among clinicians regarding the benefits vs risks of statin

Evidence grading: Quality of evidence Type of evidence Quality rating* Well-designed, well executed RCTs that adequately represent populations to which the results are applied High and directly assess effects on health outcomes Well-conducted meta-analyses of such studies Highly certain about the estimate of effect; further research is unlikely to change our confidence in the estimate of effect RCTs with minor limitations affecting confidence in, or applicability of, the results Moderate Well-designed, well-executed nonrandomized controlled studies and well-designed, well-executed observational studies Well-conducted meta-analyses of such studies Moderately certain about the estimate of effect; further research may have an impact on our confidence in the estimate of effect and may change the estimate RCTs with major limitations Low Nonrandomized controlled studies and observational studies with major limitations affecting confidence in, or applicability of, the results Uncontrolled clinical observations without an appropriate comparison group (eg, case series, case reports) Physiological studies in humans Meta-analyses of such studies Low certainty about the estimate of effect; further research is likely to have an impact on our confidence in the estimate of effect and is likely to change the estimate. RCT, randomized controlled trial. This was the system used in the new American Heart Association/American College of Cardiology cholesterol guidelines3, which were published in the 2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults Report from the Panel members appointed to the Eighth Joint Na- tional Committee.21 Table reprinted with permission.21 *The evidence quality rating system used in this guideline was developed by the National Heart, Lung, and Blood Institute’s (NHLBI’s) Evidence-Based Methodology Lead (with input from NHLBI staff, external methodology team, and guideline panels and work groups) for use by all the NHLBI cardiovascular disease guideline panels and work groups during this project. As a result, it includes the evidence quality rating for many types of studies, including studies that were not used in this guideline. Additional details regarding the evidence quality rating system are available in the online Supplement. Jacobson Update on Statin Safety 2014 S3 use and have led to the desire by the leadership of the NLA compared with the general clinical population, which tends to convene a new Statin Safety Task Force to update the to have more comorbidity and frailty. Examples of 2006 review and provide expert panel opinion regarding the exclusions from recent statin RCTs are: pregnancy, reduced issues, which were reviewed in that report, as well as others renal or hepatic function, on drugs known to affect statin raised in the interim. In October 2013, a group of experts in metabolism (ie, cytochrome 3A4 inhibitors, cyclosporine, the fields of clinical lipidology, diabetes, neurology, fibrates, immunosuppressants), advanced age .75 years, hepatology, and myology participated in an NLA Statin uncontrolled diabetes mellitus, congestive heart failure, Safety Task Force meeting to discuss the available evidence dementia, cancer, substance abuse, history of noncompli- regarding statin safety. The moderators of the Task Force ance, and active rheumatologic or musculoskeletal condi- were Dr Terry A. Jacobson (Chair, Emory University, tions. Thus, patients who are more susceptible to adverse Atlanta, GA), Dr Harold Bays (Louisville Metabolic and events may be underrepresented in RCTs. Atherosclerosis Research Center, Louisville, KY), Dr Vera In assessing safety or harm of any therapy, going beyond Bittner (University of Alabama, Birmingham, AL), Dr John RCTs is thus very important. Evidence needs to be gathered R. Guyton (Duke University, Durham, NC), Dr Kevin C. from a broad range of sources, including observational and Maki (Midwest Center for Metabolic & Cardiovascular clinical epidemiologic studies, FDA adverse event report- Research, Chicago, IL), Dr Robert S. Rosenson (Icahn ing systems, meta-analysis of clinical trials, analysis of School of Medicine at Mount Sinai, NY, NY), and Dr Peter large health care databases (Veterans Administration, Kai- P. Toth (CGH Medical Center, Sterling, IL). After the full ser, Medicare, other claims databases), and case reports. In panel met, subpanels developed individual papers on the assessing harm or safety, the quality of study reports needs topics of statin use and (1) cognition, (2) glucose homeo- to be made explicit beforehand. High-quality studies that stasis and diabetes risk, (3) liver function, (4) muscle- assess harm generally prespecify the specific type of harm related signs and symptoms, (5) statin intolerance, and (6) to be investigated, use ‘‘active’’ vs ‘‘passive’’ inquiry interactions with other drugs. These articles were reviewed, methods about harm, use validated instruments for symp- edited, and approved by the entire panel. The recommen- tom ascertainment, and evaluate outcomes by a blinded dations represent a consensus of opinions of clinicians adjudication committee. Often there may be a discrepancy considered to be experts in the fields represented by these between the reporting of harm from the results of random- articles. ized clinical trials compared with that of observational Most of the evidence evaluated for this report, and, in studies. A good example is the low rate of reporting of fact, much of the published evidence for statins, in general, myalgia in clinical trials using statins vs placebo to that is in the form of clinical trials.6,8 The randomized clinical reported in observational studies. The reason for the trial is a useful study design for answering questions discrepancy is important and needs to be investigated. regarding efficacy, and is, in fact, considered to be at the Common reasons include distinct biases in study quality, top of the hierarchy of evidence grading.11,12 However, applicability (study population, setting), definition of the panel members acknowledge that clinical trials de- adverse events, selective reporting of outcomes, and pub- signed primarily to assess efficacy may not be ideal for lication bias. These can lead to either a positive or negative evaluating adverse effects and potential risks associated bias in determining the true incidence of a reported with use of a drug.13–17 This is particularly true for adverse symptom. effects that (1) occur at a substantially lower frequency than The Statin Safety expert panel was charged with the task the responses measured for efficacy, (2) may manifest over of addressing specific questions of clinical relevance and to a period of extended use (ie, a longer period than what is grade the evidence using a hybrid of the National Heart typically captured in clinical trials designed to examine ef- Lung and Blood Institutes (NHLBI) rating system (NHLBI ficacy), (3) occur in subsets of the population that are espe- cardiovascular-based methodology), which was adapted cially susceptible, and (4) that have multiple causes (other from the original Grading of Recommendations Assess- than statins) in the general population. Additionally, the ment, Development and Evaluation system of evidence methods used for evaluation of adverse events in clinical rating20 and the quality of evidence grading from the new trials may not be sensitive enough to capture some signs American Heart Association/American College of Cardiol- or symptoms. For example, angiotensin-converting enzyme ogy cholesterol guidelines,3 which were published in the inhibitor use is associated with a nonproductive cough in 2014 Evidence-Based Guideline for the Management of approximately 15% of those who take this class of medica- High Blood Pressure in Adults Report from the Panel mem- tion,18 but this association was not described until several bers appointed to the Eighth Joint National Committee.21 years after the first drug in this class was approved.19 Overall, the Statin Safety Expert Panel reaffirms the One of the major limitations of using randomized general safety of statin therapy. It is the belief of the Panel controlled trials (RCTs) for the evaluation of safety is members that in most patients requiring statin therapy that that the populations studied are very restricted in their study the potential benefits of statin therapy outweigh the poten- entry characteristics and often patients with multiple tial risks. In general terms, the number needed to treat in comorbidities and previous statin intolerance are excluded. preventing non-fatal myocardial infarction, revasculariza- Thus there is limited generalizability of patients in RCTs tion, stroke, and CVD mortality, far outweighs the number S4 Journal of Clinical Lipidology, Vol 8, No 3S, June 2014 needed to harm. Because the absolute benefit of statins is recommendations of the National Lipid Association Statin Safety related to an individual’s baseline risk, it is only in those Assessment Task Force. Am J Cardiol. 2006;97:89C–94C. individuals whose baseline risk is very low that the benefits 6. Mancini GB, Baker S, Bergeron J, et al. Diagnosis, prevention, and management of statin adverse effects and intolerance: proceedings of statin therapy may not outweigh the risk of adverse of a Canadian Working Group Consensus Conference. Can J Cardiol. events. However to date, based on the Cholesterol Treat- 2011;27:635–662. ment Trialists meta-analysis of 26 clinical trials and 7. Jukema JW, Cannon CP, de Craen AJ, Westendorp RG, Trompet S. 170,000 patients, a value for the concentration of LDL-C The controversies of statin therapy: weighing the evidence.JAm Coll Cardiol or for total CVD risk has not yet been defined that is . 2012;60:875–881. 1 8. Naci H, Brugts J, Ades T. Comparative tolerability and harms of indi- without relative benefit during statin therapy. vidual statins: a study-level network meta-analysis of 246 955 partic- In assessing any patients with real or perceived symp- ipants from 135 randomized, controlled trials. Circ Cardiovasc Qual toms related to statins, we first suggest that providers take a Outcomes. 2013;6:390–399. patient-centric approach. Any patient complaints related to 9. Food and Drug Administration. FDA drug safety communication: statins should be taken seriously and appropriately evalu- important safety label changes to cholesterol lowering statin drugs. Available at: http://www.fda.gov/drugs/drugsafety/ucm293101.htm. ated. It is important to remember that there are multiple Accessed November 6, 2013. causes of symptoms, particularly with musculoskeletal and 10. Food and Drug Administration. FDA drug safety communication: new cognitive complaints, and that a careful history and restrictions, contraindications, and dose limitations for Zocor (simva- physical examination is always essential. The true fre- statin) to reduce the risk of muscle injury. Available at: http://www. quency of statin intolerance in the population is unknown, fda.gov/drugs/drugsafety/ucm256581.htm. Accessed January 12, 2014. 11. Pocock SJ. Clinical Trials: A Practical Approach. Chicester, UK: John but may approach 10%. Real or perceived symptoms from Wiley & Sons; 1983. statins may be an underappreciated cause of nonadherence 12. Concato J. Observational versus experimental studies: what’s the evi- to therapy. Data from the cross-sectional Understanding dence for a hierarchy? NeuroRx. 2004;1:341–347. Statin use in America and Gaps in Patient Education 13. Vandenbroucke JP. What is the best evidence for determining harms of CMAJ (USAGE) study suggests that muscle symptoms may occur medical treatment? . 2006;174:645–646. 14. Levine M, Ioannidis J, Guyatt GH. Harm (observational studies). In: in up to 29% of patients initiated on statin therapy, and may Guyatt G, Rennie D, Meade MO, Cook DJ, editors. JAMA Evidence. be an important causal factor for statin discontinuation, Users’ Guides to the Medical Literature – A Manual for Evidence- statin switching, and statin nonadherence.22 According to Based Clinical Practice. 2nd ed. New York, NY: McGraw-Hill Global the Expert Panel on Statin Intolerance, ‘‘the decision on Education Holdings, LLC, 2008. statin intolerance is the patient’s decision, based on subjec- 15. Chou R, Aronson N, Atkins D, et al. AHRQ series paper 4: assessing harms when comparing medical interventions: AHRQ and tive feelings, preferences, and judgment,’’ but best when the effective health-care program. J Clin Epidemiol. 2010;63: guided ‘‘by evaluation and effective communication from 502–512. the clinician.’’ The importance of effective and empathetic 16. Department of Health and Human Services, Agency for Healthcare communication between patient and provider brings back Research and Quality. Methods Guide for Effectiveness and Compara- the sentiments of Francis Peabody who once said, ‘‘for tive Effectiveness Reviews, AHRQ Publication No. 10(12)-EHC063–EF2012. the secret of the care of the patient is in caring for the 17. Puhan MA, Singh S, Weiss CO, VaradhanR, Sharma R, Boyd CM. Eval- 23 patient.’’ uation of the benefits and harms of aspirin for primary prevention of cardiovascular events: a comparison of quantitative approaches. Methods Research Report. (Prepared by Johns Hopkins University Evidence-based Practice Center under contract No. 290-2007- References 10061-1). Department of Health and Human Services, Agency for Healthcare Research and Quality. AHRQ Publication No. 1. Cholesterol Treatment Trialists (CTT) Collaboration, Baigent C, 12(14)-EHC149-EF2013. Blackwell L, Emberson J, et al. Efficacy and safety of more intensive 18. Dicpinigaitis PV. Angiotensin-converting enzyme inhibitor-induced lowering of LDL cholesterol: a meta-analysis of data from 170,000 cough: ACCP evidence-based clinical practice guidelines. Chest. participants in 26 randomised trials. Lancet. 2010;376:1670–1681. 2006;129:169S–173S. 2. Goff DC Jr., Lloyd-Jones DM, Bennett G, et al. 2013 ACC/AHA 19. Sesoko S, Kaneko Y. Cough associated with the use of captopril.Arch Guideline on the Assessment of Cardiovascular Risk: a report of the Intern Med. 1985;145:1524. American College of Cardiology/American Heart Association Task 20. Guyatt GH, Oxman AD, Vist GE, et al. GRADE: an emerging Force on Practice Guidelines [e-pub ahead of print]. J Am Coll Cardiol. consensus on rating quality of evidence and strength of recommenda- 2013. http://dx.doi.org/10.1016/j.jacc.2013.11.005. Accessed March tions. BMJ. 2008;336:924–926. 14, 2014. 21. James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline 3. Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA Guide- for the management of high blood pressure in adults: report from line on the Treatment of Blood Cholesterol to Reduce Atherosclerotic the panel members appointed to the Eighth Joint National Committee Cardiovascular Risk in Adults: a report of the American College of (JNC 8). JAMA. 2014;311:507–520. Cardiology/American Heart Association Task Force on Practice 22. Wei MY, Ito MK, Cohen JD, Brinton EA, Jacobson TA. Predictors of Guidelines [e-pub ahead of print]. J Am Coll Cardiol. 2013. statin adherence, switching, and discontinuation in the USAGE sur- http://dx.doi.org/10.1016/j.jacc.2013.11.002 accessed March 14, 2014. vey: understanding the use of statins in America and gaps in patient 4. Ioannidis JP. More than a billion people taking statins? Potential impli- education. J Clin Lipidol. 2013;7(5):472–483. cations of the new cardiovascular guidelines. JAMA. 2014;311:463–464. 23. Oglesby P. The Caring Physician: The Life of Dr. Francis W. Pea- 5. McKenney JM, Davidson MH, Jacobson TA, Guyton JR. National Lipid body. Boston, MA: Francis A. Countway Library of Medicine; Association Statin Safety Assessment Task Force. Final conclusions and 1991. Journal of Clinical Lipidology (2014) 8, S5–S16

Original Contribution An assessment by the Statin Cognitive Safety Task Force: 2014 update

Carlos H. Rojas-Fernandez, BSc(Pharm), PharmD*, Larry B. Goldstein, MD, Allan I. Levey, MD, PhD, Beth A. Taylor, PhD, Vera Bittner, MD, MSPH, FNLA

Schlegel–UW Research Institute for Ageing; School of Public Health and Health Systems; School of Pharmacy, University of Waterloo, 10 Victoria Street S, Room 7004, Kitchener, Ontario N2G 1C5, Canada (Dr Rojas-Fernandez); Michael G. DeGroote School of Medicine, Department of Family Medicine, McMaster University, University of Waterloo, Hamilton, ON, Canada (Dr Rojas-Fernandez); Duke Stroke Center, Duke University and Durham VAMC, Durham, NC (Dr Goldstein); Department of Neurology, Emory University, Atlanta, GA (Dr Levey); Department of Preventive Cardiology, Hartford Hospital & University of Hartford, Hartford, CT (Dr Taylor); and Division of Cardiovascular Disease, Preventive Cardiology Section, University of Alabama at Birmingham, Birmingham, AL (Dr Bittner)

KEYWORDS: Abstract: The National Lipid Association’s Safety Task Force convened a consensus conference of Statins; experts to develop a position statement on cognitive function to revise and update that published Cognition; originally by the Association in the 2006 assessment of statin safety by a panel of neurologists. Memory; The current expert panel was charged with addressing the speciﬁc issue of potential adverse cogni- Adverse drug effects; tive effects attributable to statins. Search strategies recently used in systematic reviews were used Iatrogenesis to identify relevant evidence using keywords and topics via Medline searches from 1966 to December 2013. Manual searches of bibliographies were also conducted. Panel members were asked to use the evidence to formulate answers to a series of questions of relevance to the subject matter. The strength of recommendations and quality of evidence were graded using accepted contemporary deﬁnitions and procedures. Recommendations to patients, health professionals, and researchers were put forth by the panel to aid in daily clinical decision making, and in future research endeavors. Ó 2014 National Lipid Association. All rights reserved.

Disclosures: The authors disclose that they have the following rela- (honoraria - Pharmacovigilance Advisory Board Amgen, Inc.); and Dr tionships with industry that might pose a potential conflict of interest(s): Vera Bittner (research support from Amgen, Bayer Healthcare, Glaxo- Dr Carlos Rojas-Fernandez (research grant support from Astra Zeneca, Smith-Kline, Pfizer, Roche, and Sanofi Aventis; and consultant for Amarin, Pfizer, Bristol Myers Squibb, Medisystems Pharmacy, and Remedy’s Rx Novartis, and the Federal Drug Administration). Pharmacies); Dr Allan Levey (research grant support from NIH [P50 * Corresponding author. AG025688], Merck, Eli Lilly, Lundbeck, and Neurovision; and consultant E-mail address: [email protected] for Genomind and Genentech); Dr Larry Goldstein (past consultant for Submitted February 27, 2014. Accepted for publication February 28, Pfizer and speaker at Pfizer-sponsored meetings); Dr Beth Taylor 2014.

Evidence grading: Strength of recommendation* Grade Strength of recommendation A Strong recommendation There is high certainty based on the evidence that the net benefit** is substantial B Moderate recommendation There is moderate certainty based on the evidence that the net benefit is moderate to substantial, or there is high certainty that the net benefit is moderate C Weak recommendation There is at least moderate certainty based on the evidence that there is a small net benefit D Recommend against There is at least moderate certainty based on the evidence that it has no net benefit or that the risks/harms outweigh benefits E Expert opinion There is insufficient evidence or evidence is unclear or conflicting, but this is what the expert panel recommends N No recommendation for or against There is insufficient evidence or evidence is unclear or conflicting *The system was adapted as a hybrid of the National Heart Lung and Blood Institutes (NHLBI) rating system (NHLBI cardiovascular-based methodology) used in the new American Heart Association/American College of Cardiology cholesterol guidelines1 and adapted from the original Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system of evidence rating.2 **Net benefit is defined as benefits minus risks/harms of the service/intervention.

Statins are the most widely prescribed agents for bodies. Cognitive impairment may also be the result of treatment of dyslipidemia and are the most effective other conditions including infections and inflammatory or medicines to reduce low-density lipoprotein cholesterol vascular diseases. MCI/dementia may furthermore be the and lower the risk of cardiovascular and cerebrovascular result of a combination of primary and secondary causes.8 events.1 Statins are generally thought to be well tolerated, Although mixed dementias with primary and secondary and their use is infrequently the cause of major complica- causes are frequent, there is no gold standard for diagnosing tions in contemporary practice. Multiple case reports, and these disorders.9 Patients may also have cognitive deficits data from 2 randomized trials and 1 challenge- because of other conditions such as depression or metabolic dechallenge study; however, have suggested a potential as- disorders (the Differential Diagnosis section). It is also sociation between statins and cognitive impairment in some worth noting that there is variability in the clinical course individuals.4,5 In 2012, the US Food and Drug Administra- of dementing illnesses. Some dementias progress slowly, tion (FDA) expanded the warning section of the label for all some more rapidly, whereas others progress in spurts or in- statins to include a statement that statin use may contribute termediate rates. This variable course of illness progression to ‘‘.notable, but ill-defined memory loss or impairment makes it difficult to interpret case reports of putative statin- that was reversible upon discontinuation of statin therapy.’’6 induced cognitive adverse effects, as the duration and The FDA also stated that the data did not suggest these extent of follow-up vary across reports. cognitive changes are common or that they lead to clinically significant cognitive decline. Iatrogenic cognitive Assessing cognition impairment from pharmacotherapy is an important medical issue, potentially causing functional deficits and loss of The potential for cognitive side effects of statins poses quality of life. Because statin drugs are widely used, these very practical questions for clinicians: How should cogni- potential side effects need to be considered carefully and tion be assessed and what are signs and/or symptoms of put in the context of scientific evidence as well as the estab- statin-related cognitive deficits? There are various ways to lished benefits of statins. The potential to reduce the risk of assess cognition in practice, depending on the clinical death and disability from arterial disease as well as mild circumstances. The mini-mental status exam (MMSE) has cognitive impairment (MCI), dementia resulting from been among the most commonly used assessments, but stroke, and possibly Alzheimer’s disease with statin therapy does not evaluate executive function, which is most must be examined as well as any evidence that they might commonly affected in vascular cognitive impairment.10 induce mild cognitive impairment or more severe and per- Other limitations include floor and ceiling effects, insensi- manent forms of dementia. tivity to subtle cognitive deficits, and high sensitivity to educational levels (ie, those with high levels of education What is cognitive dysfunction? may score in the nonimpaired range despite underlying cognitive impairment, whereas those with low levels of ed- Cognition can be broadly described under 4 domains: ucation may score in the cognitively impaired range where executive function, memory, language, and visuospatial no such impairment exists). This test is now proprietary ability. The risk:benefit profile of statins in relation to with a licensing fee required for each administration intro- cognitive dysfunction is best considered with awareness of ducing a practical barrier to its use. the spectrum of cognitive disorders. Cognitive dysfunction The Montreal Cognitive Assessment (MoCA) addresses can be broadly defined as impairment in any of the some of the shortcomings of the MMSE, such as inclusion previously mentioned domains. MCI reflects a state of of items that are more sensitive for assessing executive cognitive dysfunction between normal cognition and de- function, language, and verbal memory. It is more sensitive mentia, the latter being defined as cognitive dysfunction than the MMSE for the detection of MCI and mild that involves 2 domains and is sufficiently severe to Alzheimer’s disease in the general population.11 The interfere with daily activities leading to a progressive loss MoCA is divided into 7 subscores evaluating visuospatial/ of independence.7 Clinically, individuals with MCI have executive function, naming and language, memory, atten- difficulty performing objective cognitive tasks that are not tion, abstraction, and orientation.12 The MoCA has been severe enough to impair instrumental activities of daily recommended as a screening instrument to assess cognition living. Because the demands of activities of daily living in patients with possible vascular disease because it in- vary considerably depending on age, occupation, family sit- cludes subtests of executive function, and unlike the uation, and other factors, the distinction between MCI and MMSE, is freely available. Although test-retest reliability dementia is often blurred. for the MoCA has been evaluated for some conditions, it When considering potential deleterious effects of statins, has not been established as useful for drug-related cognitive clinicians should remember that MCI and dementia are impairments.13 very common in individuals older than age 65 years and An important limitation for both the MMSE and MoCA can have a variety of causes including primary degenerative is the time required for administration, typically about 10 to conditions such as Alzheimer’s disease, frontotemporal 15 minutes, which is not practical, given that is the same as dementia, Parkinson’s disease, and dementia with Lewy the usual short duration of the entire office visit to most S8 Journal of Clinical Lipidology, Vol 8, No 3S, June 2014 primary care physicians.14,15 For this reason, briefer community-based samples, and 10% to 15% among screening instruments such as the Mini-Cog and Functional patients evaluated in specialty clinics.7 On follow-up, con- Activities Scale that have excellent sensitivity and speci- version rates to normal cognition were formerly thought to ficity for distinguishing MCI and dementia from healthy be in the range of 25% to 30%, although recent studies sug- cognitive aging have been developed.16 However, a limita- gest lower conversion rates for those with impairments in tion of all brief cognitive screening instruments is that very multiple cognitive domains or those with amnestic few, if any, clinical trials have evaluated the effect of MCI.22–25 Additional recent data suggest that conversion screening for cognitive impairment on clinician decision- of MCI to normal cognition may be almost nonexistent, making.17 and conversion to normal cognition does not preclude pro- Are there other cognitive instruments that may be useful in gression in the future.26 clinical practice? There are several, and as part of the new Determining a relationship between statins and cognitive Affordable Care Act, it is recommended that Medicare impairment is further complicated by the ‘‘worried well’’ patients receive an annual wellness visit that includes a (ie, patients who have subjective cognitive complaints in cognitive evaluation. Several different brief instruments are the absence of subtle or overt cognitive impairment).27 recommended including the MMSE, MoCA, and other very Although it was previously thought that these patients brief instruments suited for primary care practice such as the were not at risk for further cognitive impairment or demen- clock draw test or Mini-Cog.18 It is important to note that tia, studies suggest that this is not the case and that subjec- despite the wide range of available tests, they differ in their tive cognitive complaints are predictive for future sensitivity and specificity. Considering that adverse cognitive development of a dementing illness.28,29 The high fre- effects attributable to statins may be subtle and do not appear quency of cognitive complaints and cognitive disorders to have a predilection for specific cognitive domains, brief thus limits clear determination of a relationship between rather than very brief tests should likely be selected for the statins and cognitive impairment. purpose of documenting effects attributable to statins. Update on the 2006 Statin Safety Task Force Relevance of the epidemiology of Alzheimer’s report disease to issues of statin safety The 2006 Statin Safety Task Force report addressed the The Alzheimer’s Association reported that in 2013, 5.2 question, ‘‘Do statins impair memory or cognition in some million Americans, including 32% of those age 85 years or patients?’’ That Task Force concluded, based on findings older, have Alzheimer’s disease.19 In addition, MCI affects 7 from 4 randomized controlled trials, 2 of which were 10% to 20% of those age 65 years or older. If statins were studies assessing therapeutic effects of statins in patients to meaningfully impact the risk of cognitive impairment or with Alzheimer’s disease, that there was no evidence that dementia (either by increasing or decreasing risk), the poten- statins affected memory or cognition (confidence/level of tial public health implications could be enormous. Consid- evidence rating of 1B reflecting high confidence based on at ering the proportion of the population receiving statins, least 1 randomized controlled trial with a statistically uncommon adverse effects have the potential to impact a significant result or well-conducted epidemiological studies large number of people. For example, it was estimated that with adverse experiences as endpoints).30 Since 2006, addi- in 2002, 7.8% of the Canadian population was taking a 20 tional studies have been published that change our recom- statin. If the incidence of statin-associated cognitive mendations to providers. impairment were only 0.1%, it would currently affect about 2500 people in Canada. In the United States, between 2005 and 2008, approximately 41% of adults 451 years of age re- 2014 Questions ported using a statin, which represents approximately 126 million people (based on 2010 census).21 In turn, if 0.1% of 1. Should a baseline cognitive assessment be performed these users developed some form of cognitive adverse effect, before beginning a statin? it would affect 126,600 people. Based on the new American Heart Association/American College of Cardiology Guide- ANSWER: No. lines, the proportion eligible for statins will be even higher.1 STRENGTH OF RECOMMENDATION: E (expert Questions regarding potential cognitive side effects of statins opinion). need to be carefully reconciled with the high incidence and QUALITY OF EVIDENCE: Low. prevalence of cognitive impairment from other causes. EXPLANATION: Given the real possibility of statin- associated impairment of cognition, should clinicians MCI and conversion to dementia formally and routinely assess cognitive function using a standardized test such as the MMSE or the MoCA before Patients with MCI are at increased risk for developing initiating statin treatment? Although it may seem logical dementia; indeed, the annual incidence of dementia among to do so, it is unlikely that conducting these tests would those with MCI ranges from 5% to 10% among be useful owing to the clinical and practical issues reviewed Rojas-Fernandez et al Statins and cognition S9 in the preceding sections. In addition, it is uncertain that it had been investigating such reports for several years, whether such a test would have sufficient sensitivity to and that those affected often relate feeling fuzzy or unfo- detect the subtle types of cognitive deficits that have been cused in their thinking. The FDA indicated that the symp- reported to date with statins. Obtaining a baseline cognitive toms were not serious and were reversible within a few screening evaluation before beginning statin therapy would, weeks after discontinuation of statin therapy; it explicitly therefore, be logistically difficult and unlikely to be helpful, advised that patients should speak with their health care especially given the highly prevalent use of these medica- professional and not to stop taking a statin because the tions in practice. negative cardiac consequences could be far worse. Studies assessing potential relationships between statin 2. Are statins as a class associated with adverse effects on use and cognition include observational studies (case control, cognition? cohort, narrative, and systematic reviews), randomized trials, ANSWER: No. which have measured cognition as part of various outcome STRENGTH OF RECOMMENDATION: A (strong measures, and 1 dechallenge-rechallenge study.4,38–51 The recommendation). randomized trials are summarized in Table 1,34,38,39,52–62 QUALITY OF EVIDENCE: Low to moderate. whereas a summary of observational studies can be found EXPLANATION: The question of whether statins can in Table 2 of Rojas-Fernandez et al.4 Although all statins adversely influence cognition was initially raised in case have been implicated in cognitive dysfunction, in published reports, case series, 1 dechallenge-rechallenge study, and 2 case reports (cumulative N 5 83) the majority involve the randomized trials.5,31–39 These concerns have been recently more lipophilic statins (simvastatin, N 5 46 and atorvastatin, underscored by the FDA update on statins, which recog- N 5 32).31–33,35,36,63 The median time to symptom onset after nizes that cognitive impairment still continues to be restarting a statin was 60 days, but time to onset data were only ported sporadically in statin users in the FDA Adverse available for 30 cases.36 Case reports, however, generally Event Reporting System database.6 The FDA reported lack objective measures, do not indicate whether some cases

Table 1 Summary of placebo-controlled clinical trials of statins and cognition Population, Randomized Study Statin(s) sample size Duration study? Effects on cognition? Harrison et al.52 Sim 40 Healthy 4 wk Y None Prav 40 N 5 25 Kostis et al.53 Lov 40 N 5 22 6 wk Y None Prav 40 Cutler et al.54 Sim 20 N 5 24/arm 4 wk Y None Prav 40 (crossover) Gengo et al.55 Lov 40 N 5 24/arm 4 wk Y DSST better for statins vs placebo Prav 40 (crossover) Santanello et al.56 Lov 20 N 5 431 6 mo Y None Lov 40 Muldoon et al.38 Lov 20 N 5 209 6 mo Y None Gibellato et al.57 Lov 40 N 5 80 4 wk DK None Prav 40 Muldoon et al.39 Sim 10 N 5 308 6 mo Y Placebo improved on Elithorn mazes Sim 40 and recurrent words, whereas Sim did not; no difference on Grooved Pegboard, Digit Vigilance, or Mirror tracing; 4-word memory test showed detrimental effects with sim Golomb et al.58 Prav N 5 1016 6 mo Y None Sim Parale et al.34 Ator 10 N 5 55 6 mo N Positive Summers et al.59 Ator 10 N 5 57 12 wk Y None Berk-Planken et al.60 Ator 10 N 5 30 30 wk N Positive Ator 80 Shepherd et al.61 Prav N 5 5804 3.2 y Y None 70–82 y Collins et al.62 Sim 40 N 5 20,536 5.3 y Y None Ator, atorvastatin; DK, don’t know; DSST, digit symbol substitution testing; lov, lovastatin; N, no; prav, pravastatin; sim, simvastatin; Y, yes. S10 Journal of Clinical Lipidology, Vol 8, No 3S, June 2014

Table 2 Examples of drugs commonly associated with adverse effects on cognition Mechanism Common examples* Anticholinergic Antimuscarinic bladder relaxant drugs: oxybutynin, tolterodine, darifenacin Some tricyclic antidepressants: amitriptyline, imipramine Antimuscarinic drugs for Parkinson’s disease: benztropine, trihexylphenidyl Other antidepressants: paroxetine, mirtazapine First-generation histamine H1 antagonists Chlorpheniramine, hydroxyzine, diphenhydramine, dimenhydrinate, promethazine GABAergic Any benzodiazepine receptor agonist: diazepam, lorazepam, clonazepam Opioids Codeine, morphine, hydromorphone, oxycodone, hydrocodone Mixed mechanisms Some antipsychotics: chlorpromazine, olanzapine, quetiapine, thioridazine GABA, gamma aminobutyric acid. *Not an exhaustive list. were incompletely reversible, and are limited by various con- A cohort study found that statin use was associated with founders and other forms of bias, rendering it impossible to nonsignificant improvements on the Trail Making B Test of draw conclusions regarding severity, timing, and reversibility cognitive performance compared with statin nonusers of symptoms when a medication is stopped. With regard to (11.0 seconds difference, P 5 .05).44 A second cohort study the balance of the observational evidence, 3 studies selected found that modified MMSE scores were significantly higher patients with dementia at the time of analysis and compared among postmenopausal women with coronary disease tak- statin exposure with nondemented controls.40–42 These ing statins compared with non-statin users (93.7 6 6.1 vs studies showed a beneficial effect of statins on dementia in 92.7 6 7.1, respectively, P 5 .02); statin users also had a study subjects. In 1 study, patients using statins were less trend toward a lower likelihood of cognitive impairment likely to have dementia based on a composite definition (OR 0.67, 95% CI 0.42–1.05).45 In a third retrospective (odds ratio [OR] 0.23, 95% confidence interval [CI] 0.1– cohort study, statins were found to have a beneficial effect 0.56); Alzheimer’s disease (OR 0.37, 95% CI 0.19–0.74); on lifelong cognitive change (F 5 5.78, P 5 .017, partial or, vascular dementia subtypes (OR 0.25, 95% CI 0.08– eta-squared 5 0.013).46 This was measured as significant 0.85).40 This study also found improved MMSE scores improvements in IQ between ages 11 and 80 among statin among statin users compared with a decline in controls users compared with nonusers. A cross-sectional cohort (OR for no change or improvement 2.81, 95% CI 1.02– study found that statin users performed better on verbal 8.43, P 5 .045) and higher scores on the Clock Drawing fluency, naming tests, immediate free recall, and word Test (difference of 1.5 6 0.1, P 5 .036).40 In a nested case- accentuation test compared with nonuser controls; however, control study, 284 patients with dementia were compared these differences disappeared when the data were adjusted with 1080 controls without dementia with regard to statin for potential confounders.47 use.41 Statin users were found to have a lower risk of devel- Conversely, 2 observational studies have noted potential oping dementia compared with nonusers (adjusted relative cognitive impairment with statin use. In a large, retrospec- risk 0.29, 95% CI 0.13–0.63, P 5.002). Rockwood et al. con- tive cohort study, patients taking statins before elective ducted a case control study and observed a protective effect surgery were noted to have a 30% (95% CI 15–47%) higher of statins for all types of dementia in patients younger than risk for postoperative delirium compared to those not 80 years of age (OR 0.24, 95% CI 0.07–0.80), but this protec- taking statins.64 In this study, 1.1% of the study population tive effect was not significant in those older than 80 years of was found to have delirium, which is far below the ex- age (OR 0.43, 95% CI 0.11–1.58).42 pected rate of 15% to 25%, making it likely that only a mi- Other observational studies have likewise observed nority of cases were identified because of the low (35%) potential or actual improvement among various groups. In sensitivity of the database to the presence of delirium.65 a longitudinal observational study at Alzheimer’s Disease This low detection of the outcome of interest increases Centers in the United States, elderly research volunteers the risk of residual confounding and bias that cannot be with normal cognition at baseline (N 5 1244 statin users, fully addressed by the methods used in that study. A N 5 2363 nonusers) and with MCI at baseline (N 5 763 population-based, national cohort study in the United States users, N 5 917 nonusers) were followed annually with assessed cognition in 7191 participants using statins and detailed cognitive and functional assessments.43 Detailed 17,404 participants not using statins.66 Cognitive impair- neuropsychological testing of subjects with either normal ment was observed in 8.6% of statin users compared with cognition or with MCI showed that statin users had signif- 7.7% of nonusers (P 5 .014); however, after adjustment icantly better cognition compared with nonusers; this effect for potential confounders the association was not signifi- was observed across multiple cognitive domains in subjects cant (OR 0.98, 95% CI 0.87–1.10). with MCI. Moreover, statin users with normal cognition at In addition, in a survey-based study, participants baseline had significantly slower annual decline, suggesting (N 5 714) from the University of California San Diego a possible protective effect of statins on cognition. (UCSD) Statin Effects Study who had reported potential Rojas-Fernandez et al Statins and cognition S11 statin-related problems (via a general patient-targeted recall (P 5 .03). Differences in performance change be- questionnaire submitted through mail or email) were asked tween the 2 groups were significant for tests of attention to complete a second survey to further characterize these (z score 0.18, 95% CI 0.06–0.31) and for tests of psycho- symptoms.37 Of 714 patients, 422 (59%) reported cognitive motor speed (z score 0.17; 95% CI 0.05–0.28), indicating and/or memory problems, with or without other symptoms greater improvement in the placebo group. The investiga- (eg, gastrointestinal problems, neuropathic, muscle-related) tors noted that these effects were small and that such and these patients were invited to complete the additional changes in neuropsychological performance would not be survey. Of these 422 patients, 181 (43%) completed the sur- considered clinically significant. The small adverse effects vey, 10 of whom were excluded from analysis: 1 whose that were noted were primarily an absence of practice ef- symptoms were exclusively related to disturbing dreams, fects rather than an absolute decline in performance. It 6 whose surveys were incomplete, and 3 who cited no should also be noted that there was no a priori hypothesized cognitive concerns on the questionnaire, leaving 171 pa- effect in this study, nor were adjustments made for multiple tients for analysis (representing 24% of the original cohort comparisons. Muldoon et al. also conducted another study and 40% of those who reported cognitive symptoms). Using (N 5 308), which found a potentially detrimental effect a modified Naranjo adverse drug reaction probability scale, of simvastatin on cognition in a sample of middle-aged patient-reported adverse drug reactions for cognitive symp- men and women with hypercholesterolemia.39 There were toms were classified as definite in 12% (N 5 20) of the no deficits in memory, and the detrimental effect consisted cases, probable in 63% (N 5 108), and possible in 25% of a possible impairment in learning, reflected by a (N 5 43). Onset of cognitive symptoms ranged from reduction in the expected improvement in performance on 1 day to about 10 years. Statin discontinuation led to retesting for selected domains. These domains included improvement of symptoms in 90% of patients and complete psychomotor speed, attention, and short-term memory resolution in 32% of patients. (assessed by the Elithorn maze test, recurrent words, and It should be stressed, however that all of these studies are 4-word memory test, respectively). The findings for the subject to the usual limitations of observational studies. recurrent words test were confounded by baseline differ- Moreover, the observational studies have been conducted in ences in this test; furthermore, the statistical difference patient populations that vary substantially by baseline for the 4-word memory test was equivocal (P 5 .05). Other cognitive status (ie, healthy vs patients with MCI, dementia, limitations should be considered when assessing these find- and/or Alzheimer’s disease) making it difficult to separate the ings. When used in the current context, these neuropsycho- influence of statins on preventing or treating cognitive logical tests are generally poor outcomes given expected impairment from their independent effect on cognition. practice effects. Assuming that differences in practice ef- Last, 2 narrative reviews and 4 meta-analyses (1 in subjects fects at 2 time points reflect cognitive impairment in the without baseline cognitive dysfunction, the other in subjects group with observed lower practice effect may be an over- with or without dementia) have recently also reported no interpretation of observed effects. Findings that tests such adverse effects of statins on cognition.4,48–51 The systematic as the digit-symbol (or the Stroop or trails tests) did not review by Richardson et al. provides additional intriguing in- demonstrate an adverse effect from statins argue against a sights.50 The investigators conducted an independent anal- cogent biologically plausible mechanism given the sensi- ysis of the FDA postmarketing surveillance database and tivity of these tests to diffuse neurologic deficits. Last, reported that during the marketed lifetime of statins, losartan, the tests, which the authors term ‘‘statin sensitive,’’ also and clopidogrel, rates (per 1 million prescriptions) of cogni- appear to involve many different cognitive abilities that tive adverse events were 1.9, 1.6, and 1.9 for statins, losartan, are required and assessed by the so called ‘‘statin insensi- and clopidogrel, respectively (see Table 2 in Richardson tive’’ effects. Overall, the clinical significance of Muldoon et al.50). It is noteworthy that the latter 2 drugs have not et al.’s 2004 study39 is therefore uncertain. In addition to been previously associated with cognitive impairment, nor the above findings, a small (N 5 18), 12-week prospective have studies suggested an association of these drugs with open-label study was conducted to evaluate the impact on adverse cognitive effects. cognition of statin discontinuation and rechallenge in pa- Among the 14 randomized, controlled trials, (cumulative tients with Alzheimer’s disease.5 Patients underwent a 6- N 5 20,536), 2 studies reported potential adverse effects of week withdrawal phase followed by a 6-week rechallenge, statins on cognition.38,39 In the first trial, Muldoon et al.38 with MMSE and Consortium to Establish a Registry for sought to study the potential psychological effects of lova- Alzheimer’s Disease as primary and secondary cognitive statin by randomizing 209 patients to placebo or lovastatin outcomes, respectively, measured at baseline, after 6 weeks and conducting a variety of neuropsychological tests at without statin therapy (visit 1), and again 6 weeks (visit 2) baseline and after 6 months of lovastatin therapy (before after restarting statin therapy. The baseline MMSE score testing, patients attended a practice session to be familiar- was 22.1, which increased to 24 at visit 2, then decreased ized with test materials and instructions). At 6 months’ to 22.1 at visit 3 (P 5 .018, repeated measures analysis follow-up, placebo-treated patients improved significantly of variance). Total Consortium to Establish a Registry for on all cognitive measures (P , .05), whereas patients Alzheimer’s Disease scores were unchanged, but differ- receiving lovastatin improved only on tests of memory ences were noted favoring verbal memory improvement S12 Journal of Clinical Lipidology, Vol 8, No 3S, June 2014 with statin withdrawal (P 5 .04) and an improvement of stopping the statin should be assessed. Based on the language with statin rechallenge (P 5 .01). Limitations of individual patient characteristics, the statin dose could be this study included lack of a control group, open-label lowered or the statin could be stopped to assess for design, small sample size, study duration, and inconsistent reversibility of symptoms. If the statin is stopped, an cognitive findings. alternative statin should be considered, preferably a statin The question remains regarding plausible neurobiolog- that may be less likely to enter the brain (eg, pravastatin, ical explanations for the reported cognitive effects. As the rosuvastatin). great majority of cholesterol in the central nervous system STRENGTH OF RECOMMENDATION: E (expert (CNS) is produced by de novo synthesis, a commonly cited opinion). theory posits that reduced cholesterol synthesis in oligo- QUALITY OF EVIDENCE: Low. dendrocytes below a critical level, leading to inhibition of EXPLANATION: Subjective patient complaints of myelination in the CNS, may cause the observed neuro- cognitive symptoms should not be dismissed nor mini- cognitive deficits.67,68 This position has been supported by mized. Indeed, if a patient who is taking a statin reports animal studies showing that statins inhibit remyelination in cognitive difficulties, which he or she perceives as related mice after chemically induced demyelination.69,70 to statin use, then the clinician should evaluate this Although such suggestions are intriguing, there is cause complaint in detail, including a systematic search for other for skepticism regarding such a mechanism because animal potential causes or contributors to cognitive impairment, models are difficult to generalize to humans (with or including appropriate laboratory investigations (Fig. 1), and without dementia) for multiple reasons, not the least of a thorough investigation of other iatrogenic sources of which is that the effect of statins on remyelination was as- cognitive impairment (Table 2).71 It would be reasonable sessed after chemically induced neuronal damage, a sce- to consider using the MoCA or another cognitive screening nario quite different from the clinical situation of patients measure to document the affected cognitive domains and taking statins.69,70 In addition, as previously noted, cogni- magnitude of impairment. The patient should also be asked tive symptoms appeared anywhere from 1 to 60 days after to detail specific types of cognitive problems noted, their patients began taking statins.36,37 The rate of cholesterol frequency, and severity. If a statin is suspected of contrib- turnover in the brain is very low (estimated half-life of uting to cognitive symptoms independent of other causes, about 8 months), further bringing into question putative it is reasonable for the drug to be discontinued for 1 to adverse effects of statins via alterations in CNS choles- 2 months before considering a rechallenge. The patient terol.67 A plausible neurobiological mechanism for possible should be reassessed frequently (eg, every 1-2 months) statin effects on cognition thus remains elusive. Overall, with the same cognitive screening measure that was used there is a lack of consistent quality evidence of an effect to document the affected cognitive domain(s) until he or of statins on cognition (adverse or beneficial). she no longer reports cognitive difficulties before a rechallenge. A repeat assessment may be useful to document 3. What should the provider do if a patient reports cogni- improvement and/or a normal result. An important excep- tive symptoms after beginning a statin? tion to discontinuing statins are patients who have had a ANSWER: Cognitive testing should be conducted, other recent stroke, because statin withdrawal in the acute setting potential contributors should be ruled out, and the risk of increases the risk of recurrence and poorer outcomes.72–74

Figure 1 Evaluation of the patient with cognitive symptoms. CSF, cerebrospinal ﬂuid; HIV, human immunodeﬁciency virus; MCI, mild cognitive impairment; MS, multiple sclerosis; OTC, over the counter. Rojas-Fernandez et al Statins and cognition S13

It should then be determined and discussed with the evaluated, including undertaking appropriate neuropsycho- patient whether rechallenge with a statin is appropriate logical testing in patients whose symptoms persist despite based on patient characteristics, expected benefits from statin discontinuation. If no other causes of cognitive reinstituting statin therapy, and patient preferences. The dysfunction are identified, discontinuation of the medica- issue of which statin to use is an important consideration. tion should be considered after a careful review of the The pharmacokinetics of statins in the brain are not well benefit:risk ratio. delineated, and controversy exists regarding whether hydrophilic drugs such as pravastatin can enter the brain.75 Recommendations to patients Some lipophilic statins such as lovastatin and simvastatin cross the blood-brain barrier via passive diffusion, whereas Patients should know that although cognitive symptoms others (pravastatin) rely on transport systems with low af- have been reported by some statin users, information from finities. Mixed data for CNS penetration of atorvastatin such case reports cannot be considered to be reliable, is not and cerivastatin have been reported. Yet an additional conclusive, and has not been proven in a cause-and-effect mechanism that may facilitate CNS penetration of atorvas- manner. Patients should understand that many other causes tatin and simvastatin is their peripheral lactonization.76,77 of memory complaints exist, including normal aging, the Animal data suggest that brain levels of some statins corre- effect of many commonly used medications (eg, sedative- spond, at least in part, to their lipophilicity in the rank order hypnotics, over-the-counter antihistamines, pain medica- of simvastatin . lovastatin . pravastatin.78–81 Data also tions), and the effects of many medical conditions (eg, suggest that rosuvastatin, as with pravastatin, has limited anxiety, depression, sleep apnea). If patients have a concern potential to penetrate the blood-brain barrier.82 In addition, about their memory or other symptoms, they should first statins appear to be rapidly eliminated from the brain, but discuss this with their health care provider before consid- mechanisms remain elusive, and different statins may be ering discontinuing their statin. eliminated via different transporters such as P-glycoprotein (statins are ligands for P-glycoprotein).75 Overall, exact Recommendations for future research clinical predictions regarding CNS penetration of statins remains a complex issue, nevertheless it is possible that some Further research is needed to elucidate the impact of statins (eg, pravastatin, rosuvastatin) are less likely to pene- statin type, dose (especially high dose), effects of comor- trate the CNS.80 bidities and concomitant medications as well as other If the patient and prescriber agree to reinitiate a statin, putative predisposing factors on cognition. Such studies clinicians should use the lowest dose to achieve the would ideally be conducted in patients representative of treatment goal and may wish to use a statin, which may those in whom statins are commonly used, would use theoretically be less likely to contribute to central effects instruments sensitive to subtle cognitive deficits, would be (ie, a statin such as pravastatin or rosuvastatin).4,83 Howev- of sufficient duration to also address potential effects over er, there is insufficient evidence at this time to definitively time, and would more rigorously assess clinical signifi- recommend substitution of hydrophilic over lipophilic sta- cance. It should also be noted that designs involving tins in this setting. Persistent cognitive symptoms should individual patients with dechallenge and rechallenge are prompt search for another etiology and possible referral favored for assessment of harm, although admittedly, the to a specialist. clinical significance for cognitive effects remains unclear in light of previously mentioned practice effects.84 In addi- Recommendations from the cognitive expert tion, because there are no long-term studies investigating how statin use over many years may affect cognition, devel- panel oping a patient database with appropriate repeat cognitive testing and reports of statin-associated cognitive side ef- Recommendations to clinicians fects is critical for addressing this gap in the literature, given the increasing numbers of adults who are treated As a class, statins have important health benefits in with statins across the lifespan. patients at risk of cardiovascular events that far outweigh Another issue to consider is whether cognitive function risks of cognitive dysfunction as a side effect. Although should be assessed as part of all clinical trials, especially cognitive side effects of statins may occur in rare in- considering the associations between vascular risk factors dividuals, the medical evidence supporting a causal effect is and dementia and the possibility of effects from new weak or nonexistent. The true incidence of these side treatments (beneficial or adverse). It may be argued that effects cannot be determined with currently available data. all trials involving vascular risk factor modification (ie, Nonetheless, because of the serious nature of cognitive stroke, diabetes, dyslipidemia, hypertension, atrial fibrilla- dysfunction, the widespread use of statins, and the high tion, coronary artery disease, and heart failure) via prevalence of cognitive dysfunction due to any number of pharmacological intervention should include such mea- causes—particularly with aging—patient complaints about sures. The Vascular Cognitive Harmonization Statement cognition should be taken seriously and appropriately provides direction in this regard, as it includes a 60-minute S14 Journal of Clinical Lipidology, Vol 8, No 3S, June 2014 protocol that could be used in studies that require cognition 12. Gill DJ, Freshman A, Blender JA, Ravina B. The Montreal cognitive to be assessed in the 4 domains of executive function/ assessment as a screening tool for cognitive impairment in Parkinson’s . Mov Disord activation, language, visuospatial, and memory.9 How to disease . 2008;23:1043–1046. 13. Hoops S, Nazem S, Siderowf AD, et al. Validity of the MoCA and best balance the added burden of such detailed assessments MMSE in the detection of MCI and dementia in Parkinson disease. to the overall cost and feasibility of clinical trials remains Neurology. 2009;73:1738–1745. to be determined. 14. Gottschalk A, Flocke SA. 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Starr JM, McGurn B, Whiteman M, Pattie A, Whalley LJ, Deary IJ. statin type and cognitive performance: analysis of the reasons for Life long changes in cognitive ability are associated with prescribed geographic and racial differences in stroke (REGARDS) study. Clin medications in old age. Int J Geriatr Psychiatry. 2004;19:327–332. Cardiol. 2010;33:280–288. 47. Benito-Leon J, Louis ED, Vega S, Bermejo-Pareja F. Statins and 67. Saher G, Simons M. Cholesterol and myelin biogenesis. Subcell Bio- cognitive functioning in the elderly: a population-based study. J Alz- chem. 2010;51:489–508. heimers Dis. 2010;21:95–102. 68. McGuinness B, O’Hare J, Craig D, Bullock R, Malouf R, Passmore P. 48. Jukema JW, Cannon CP, de Craen AJ, Westendorp RG, Trompet S. Cochrane review on ’Statins for the treatment of dementia’. Int J Ger- The controversies of statin therapy: weighing the evidence.JAm iatr Psychiatry. 2013;28:119–126. Coll Cardiol. 2012;60:875–881. 69. 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77. Jacobsen W, Kuhn B, Soldner A, et al. Lactonization is the critical ﬁrst 81. Saheki A, Terasaki T, Tamai I, Tsuji A. In vivo and in vitro blood- step in the disposition of the 3-hydroxy-3-methylglutaryl-CoA reduc- brain barrier transport of 3-hydroxy-3-methylglutaryl coenzyme A tase inhibitor atorvastatin. Drug Metab Dispos. 2000;28:1369–1378. (HMG-CoA) reductase inhibitors. Pharm Res. 1994;11:305–311. 78. Johnson-Anuna LN, Eckert GP, Keller JH, et al. Chronic administra- 82. Nezasa K, Higaki K, Matsumura T, et al. Liver-speciﬁc distribution of tion of statins alters multiple gene expression patterns in mouse cere- rosuvastatin in rats: comparison with pravastatin and simvastatin. bral cortex. J Pharmacol Exp Ther. 2005;312:786–793. Drug Metab Dispos. 2002;30:1158–1163. 79. Thelen KM, Rentsch KM, Gutteck U, et al. Brain cholesterol synthesis 83. Schachter M. Chemical, pharmacokinetic and pharmacodynamic prop- in mice is affected by high dose of simvastatin but not of pravastatin. erties of statins: an update. Fundam Clin Pharmacol. 2005;19: J Pharmacol Exp Ther. 2006;316:1146–1152. 117–125. 80. Tsuji A, Saheki A, Tamai I, Terasaki T. Transport mechanism of 3- 84. Guyatt G, , Evidence-Based Medicine Working Group. Users’ guides hydroxy-3-methylglutaryl coenzyme A reductase inhibitors at the to the medical literature: a manual for evidence-based clinical prac- blood-brain barrier. J Pharmacol Exp Ther. 1993;267:1085–1090. tice. 2nd ed. New York: McGraw-Hill Medical; 2008. Journal of Clinical Lipidology (2014) 8, S17–S29

Original Contribution An assessment by the Statin Diabetes Safety Task Force: 2014 update

Kevin C. Maki, PhD, FNLA*, Paul M Ridker, MD, MPH, W. Virgil Brown, MD, FNLA, Scott M. Grundy, MD, PhD, FNLA, Naveed Sattar, MD, PhD

Midwest Center for Metabolic & Cardiovascular Research and DePaul University, 6323 North Avondale Avenue, Suite 103, Chicago, IL 60631, USA (Dr Maki); Brigham and Women’s Hospital and the Harvard Medical School, Boston, MA, USA (Dr Ridker); Emory University School of Medicine, Atlanta, GA, USA (Dr Brown); The University of Texas Southwestern Medical Center, Dallas, TX, USA (Dr Grundy); and University of Glasgow, Glasgow, UK (Dr Sattar)

KEYWORDS: Abstract: Statin therapy reduces the risk of myocardial infarction, stroke, and cardiovascular death by 25% National Lipid to 30% in primary as well as secondary prevention patients. Thus, statins are the pharmacologic therapy of Association; choice for the management of high blood cholesterol levels. Prompted by examination of clinical trial data Lipid; suggesting a modest, but statistically significant, increase in the incidence of new-onset type 2 diabetes Type 2 diabetes mellitus; mellitus with statin use, the US Food and Drug Administration in 2012 added a statement to the labels Statin; of statin medications indicating that increases in glycated hemoglobin (HbA1C) and fasting glucose levels Coronary heart disease have been reported with statin use. This labeling change has raised questions among clinicians regarding the relative benefits and risks of statin use, both among patients with diabetes mellitus and among those with diabetes risk factors. This 2014 report from the Diabetes Subpanel of the National Lipid Association Expert Panel on Statin Safety reviews the published evidence relating statin use to the hazard for diabetes mellitus or worsening glycemia, examines potential mechanisms that may mediate the relationship between statin use and diabetes mellitus risk, and suggests future research efforts. Given the well- established benefits of statin therapy in the primary and secondary prevention of cardiovascular events among those with indications for treatment, no changes to clinical practice are recommended other than the measurement of HbA1C or fasting glucose in those deemed to also be at elevated diabetes risk after initiating statin therapy, and potentially before initiation in selected patients considered to be at elevated risk of developing diabetes. The panel advocates following recommendations from the American Diabetes Asso- ciation, or other relevant guidelines if outside the United States, for screening and diagnosis as well as lifestyle modification for prevention or delay of diabetes mellitus in thosewith prediabetes or other risk factors. Ó 2014 National Lipid Association. All rights reserved.

Disclosures: Dr Kevin Maki discloses that in the past 12 months he Pfizer Inc., LipoScience Inc., Lilly, Merck and Co., Catabasis, GlaxoS- received consulting fees and/or research grants from Abbott Laboratories, mithKline, and Medtelligence, and has been a speaker for Merck and Vin- Amarin, Omthera (now a subsidiary of AstraZeneca), Trygg Pharmaceuti- dico. Dr Scott Grundy discloses that he has received an honorarium as a cals and that he was an employee of Biofortis Inc. Dr Ridker discloses that consultant to Sanofi. Dr Naveed Sattar discloses that he has received he has received research grants from Novartis, Amgen, Pfizer, and Astra- consulting fees as a member of the Advisory Boards of AstraZeneca, Bris- Zeneca, is a consultant for ISIS, Vascular Biogenics, Boston Heart, Gen- tol Meyers Squibb, Amgen, and Sanofi, and he received an honorarium as a zyme, and Jannsen, and receives patent royalties from patents held by speaker for MSD–UK Subsidiary of Merck. the Brigham and Women’s Hospital that relate to the use of inflammatory * Corresponding author. biomarkers in cardiovascular disease and diabetes that have been licensed E-mail address: [email protected] to AstraZeneca and Siemens. Dr Brown is editor of the Journal of Clinical Submitted February 27, 2014. Accepted for publication February 28, Lipidology and further discloses that he has received consulting fees or 2014. honoraria from Amgen, Bristol-Myers Squibb, Genzyme, Sanofi, ISIS,

Evidence grading: Quality of evidence Type of evidence Quality rating* Well-designed, well-executed RCTs that adequately represent populations to which the results are applied High and directly assess effects on health outcomes Well-conducted meta-analyses of such studies Highly certain about the estimate of effect; further research is unlikely to change our confidence in the estimate of effect RCTs with minor limitations affecting confidence in, or applicability of, the results Moderate Well-designed, well-executed nonrandomized controlled studies and well-designed, well-executed observational studies Well-conducted meta-analyses of such studies Moderately certain about the estimate of effect; further research may have an impact on our confidence in the estimate of effect and may change the estimate RCTs with major limitations Low Nonrandomized controlled studies and observational studies with major limitations affecting confidence in, or applicability of, the results Uncontrolled clinical observations without an appropriate comparison group (eg, case series, case reports) Physiological studies in humans Meta-analyses of such studies Low certainty about the estimate of effect; further research is likely to have an impact on our confidence in the estimate of effect and is likely to change the estimate. RCT, randomized controlled trial. This was the system used in the new American Heart Association/American College of Cardiology cholesterol guidelines1 that were published in the 2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults Report from the Panel members appointed to the Eighth Joint National Committee.3 Permission to reuse table granted from the American Medical Association.3 *The evidence quality rating system used in this guideline was developed by the National Heart, Lung, and Blood Institute’s (NHLBI’s) Evidence-Based Methodology Lead (with input from NHLBI staff, external methodology team, and guideline panels and work groups) for use by all the NHLBI cardiovascular disease guideline panels and work groups during this project. As a result, it includes the evidence quality rating for many types of studies, including studies that were not used in this guideline. Additional details regarding the evidence quality rating system are available in the online Supplement. Maki et al Statin safety: Diabetes Task Force S19

Treatment with statins is a cornerstone of therapy for STRENGTH OF RECOMMENDATION: B for the primary and secondary prevention of cardiovascular disease relationship between statin use and a modest increase in (CVD) events in patients with elevated levels of low- risk for new-onset diabetes mellitus/A for the net benefit of density lipoprotein (LDL) and non-high-density lipoprotein statin therapy for CVD event risk reduction associated with (non-HDL) cholesterol (-C).1,4–6 A large body of evidence statin therapy or intensification of statin therapy. has demonstrated the efficacy of statin therapy for this pur- QUALITY OF EVIDENCE: Moderate for the relation- pose.7–9 In 2008, investigators in the Justification for the ship between statin use and a modest increase in risk for Use of Statins in Prevention: an Intervention Trial Evalu- new-onset diabetes mellitus/High for the net benefit of ating Rosuvastatin (JUPITER) trial reported a small, but statin therapy for CVD event risk reduction associated with statistically significant, increase in the rate of physician- statin therapy or intensification of statin therapy. reported type 2 diabetes mellitus among those allocated EXPLANATION: The question of the influence of statin to rosuvastatin as compared with placebo.10,11 This report therapy on the odds or risk for developing new-onset motivated examinations of data from other randomized tri- diabetes has been addressed in several meta-analyses of als of statin therapy to assess the potential impact of statin data from randomized, controlled clinical trials.13,14,18 Re- medications on risk for new-onset diabetes.12–15 The results sults from the various analyses are generally consistent, and of these analyses prompted the US Food and Drug Admin- those from selected analyses are summarized in the istration in 2012 to add a statement to the labels of statin following section. The panel members felt that results medications indicating that increases in glycated hemoglo- from randomized, controlled trials were the most informa- bin (HbA1C) and fasting glucose levels have been reported tive and least subject to potential bias and confounding. with statin use.16,17 The Diabetes Subpanel of the National Accordingly, the evidence from observational studies is Lipid Association Expert Panel on Statin Safety reviewed not summarized in detail. Also, it should be noted that the published evidence relating statin use to the hazard the term diabetes will be used to indicate diabetes mellitus, for diabetes mellitus or worsening glycemia, with the the vast majority of which is likely to represent type 2 dia- aims of summarizing the results and providing practical betes mellitus. guidance on how to manage this issue in clinical practice. Sattar et al. presented a meta-analysis of 13 trials of statin therapy compared with placebo or usual care in 13 Update on 2006 Statin Safety Task Force 91,140 participants without diabetes at baseline (Fig. 1). They reported an excess of 174 cases of new-onset diabetes report questions (2226 vs 2052) in participants receiving statins during an The 2006 Statin Safety Expert Panel did not address the average follow-up period of approximately 4 years. The issue of statin use and diabetes risk. weighted odds ratio for new-onset diabetes was 1.09 (95% confidence interval [CI] 1.02 to 1.17) without substantial heterogeneity between trials (I2 5 11.2%). No clear 2014 Questions evidence was present to suggest differences between the statins studied (atorvastatin, simvastatin, rosuvastatin, pra- 1. How robust is the evidence linking statin use to vastatin, and lovastatin) regarding their associations with increased risk for diabetes mellitus, and what appears new-onset diabetes, although power was limited to infer to be the magnitude of risk? How does the increase in differences. The number needed to treat over a 4-year diabetes risk compare with the benefit of statin therapy period to produce 1 excess case of diabetes was 255. Using on CVD event risk? data from a meta-analysis by the Cholesterol Treatment ANSWER: Meta-analyses of statin trials indicate that Trialists,19 the authors estimated that treating 255 patients statin use is associated with a modest, but statistically with statin therapy resulting in a 1 mmol/L (38.7 mg/dL) significant, increase in risk for the development of type 2 reduction in LDL-C would prevent 5.4 coronary heart dis- diabetes mellitus of approximately 10% to 12%, and that ease (CHD) events (CHD death or nonfatal myocardial risks are somewhat higher for more intensive statin infarction) during 4 years, which understates the potential regimens. Meta-analyses, as well as results from multiple benefit because it does not account for the effect of statin individual trials, indicate with high certainty that statin treatment on stroke and revascularization, or the potential therapy reduces the risk of myocardial infarction, stroke, for a greater benefit with higher dose statin treatment. coronary revascularization, and cardiovascular death by Preiss et al. investigated the association between 25% to 30%, with larger effects for more intensive statin intensive-dose statin therapy (80 mg atorvastatin or simva- regimens. In both primary and secondary prevention, statin) and new-onset diabetes risk, compared with available data indicate that several fewer major CVD moderate-dose statin therapy (10 or 20 mg atorvastatin, events occur for each excess case of new-onset diabetes 40 mg pravastatin, 20 or 40 mg simvastatin).14 Data were associated with statin therapy, or intensification of statin included from 5 trials with 32,752 participants who were therapy. The risk of developing diabetes while on statin free of diabetes at baseline. Among participants assigned therapy may be limited to those with diabetes risk factors. to receive intensive-dose statin therapy, 1449 (8.8%) S20 Journal of Clinical Lipidology, Vol 8, No 3S, June 2014

Figure 1 Association between statin therapy and incident diabetes in 13 major cardiovascular trials. AFCAPS/TEXCAPS, Air Force/ Texas Coronary Atherosclerosis Prevention Study; ALLHAT, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial; ASCOT-LLA, Anglo-Scandinavian Cardiac Outcomes Trial–Lipid-Lowering Arm; CI, confidence interval; CORONA, Controlled Rosuvastatin Multinational Trial in Heart Failure; GISSI HF, Gruppo Italiano per lo Studio della Sopravvivenza nell’Insufficienza Cardiaca; GISSI PREV, Gruppo Italiano per lo Studio della Sopravvivenza nell Insufficienza Prevenzione; HPS, Heart Protection Study; JUPITER, Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin; LIPID, Long-term Intervention with Pravastatin in Ischemic Disease; MEGA, Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese; OR, odds ratio; PROSPER, Prospective Study of Pravastatin in the Elderly at Risk; 4S, Scandinavian Simvastatin Survival Study; WOSCOPS, West of Scotland Coronary Prevention Study. Permission to reuse this figure was granted by Elsevier.13 developed new-onset diabetes compared with 1300 (8.0%) intensive-dose statin therapy, compared with 3.4% of those assigned to moderate-dose statin therapy. The weighted on moderate-dose statin therapy, resulting in a hazard ratio odds ratio was 1.12 (95% CI 1.04–1.22), with no substantial of 0.97 (95% CI 0.77–1.22) for intensive-dose statin ther- heterogeneity between trials (I2 5 0%). The number needed apy. Among those with 2 to 4 risk factors, diabetes devel- to treat with intensive-dose statin therapy per year to pro- oped in 14.3% of those on intensive-dose statin therapy, duce 1 excess case of diabetes compared with moderate- compared with 11.9% of those on moderate-dose statin dose statin therapy was 498 (this equates to 125 needed therapy, resulting in a hazard ratio of 1.24 (95% CI 1.08– to treat during 4 years for comparison with the results 1.42). The corresponding hazard ratios for at least 1 CVD mentioned previously). The number needed to treat to pre- endpoint with intensive- vs moderate-dose statin therapy vent 1 CVD event per year was 155. Thus, if 498 patients were 0.87 (95% CI 0.76–1.00) for participants at low dia- were treated for 1 year with intensive-dose statin therapy betes risk at baseline, and 0.82 (95% CI 0.71–0.96) for instead of moderate-dose statin therapy, the projected num- those at high diabetes risk at baseline. ber of CVD events prevented would be 3.2, in comparison The findings from Treating to New Targets and Incre- with 1 excess case of diabetes. mental Decrease in End Points Through Aggressive Lipid Waters et al. assessed the incidence of new-onset Lowering in secondary prevention are similar to those from diabetes according to baseline diabetes risk factors in a an analysis from the JUPITER primary prevention trial that combined analysis from the Treating to New Targets and compared rosuvastatin 20 mg to placebo.20 Among subjects Incremental Decrease in End Points Through Aggressive with no major diabetes risk factors, the hazard ratio for Lipid Lowering secondary prevention trials that compared new-onset diabetes with rosuvastatin therapy was 0.99 intensive statin therapy (80 mg atorvastatin) vs moderate- (95% CI 0.45–2.21), whereas the hazard ratio for the pri- dose statin therapy (10 mg atorvastatin or 20–40 mg mary CVD endpoint was 0.48 (95% CI 0.33–0.68). Among simvastatin) (Fig. 2).18 Baseline risk for diabetes was esti- those with at least 1 major diabetes risk factor, the hazard mated based on the presence or absence of 4 risk factors: ratio for new-onset diabetes with rosuvastatin therapy was fasting glucose .100 mg/dL, fasting triglycerides 1.28 (95% CI 1.07–1.54), whereas the hazard ratio for the .150 mg/dL, body mass index .30 kg/m2, and history primary CVD endpoint was 0.61 (95% CI 0.47–0.79). of hypertension. Among those with 0 or 1 of these risk fac- The evidence reviewed here indicates that statin use is tors at baseline, diabetes developed in 3.2% of those on associated with a modest, but statistically significant, Maki et al Statin safety: Diabetes Task Force S21

Figure 2 Risk of developing new-onset diabetes and CV events according to the number of diabetes risk factors at baseline in the Treating to New Targets and Incremental Decrease in Endpoints Through Aggressive Lipid Lowering statin trials. Atorva, atorvastatin; CI, confidence interval; CV, cardiovascular; HR, hazard ratio; simva, simvastatin. Permission to reuse this figure was granted by Elsevier.18 overall increase in the odds for new-onset diabetes, with mellitus. The available data suggest that, if there is an pooled results from clinical trials suggesting that the degree adverse effect of statin treatment on glycemia, it is small of increase is approximately 10% to 12% compared with (mean increase of w0.3% or less), and has the potential to placebo or usual care. Results between different studies are be attenuated by adjustment of the treatment regimen for reasonably consistent, and a dose-response effect is indi- glycemic control. cated by the observation that intensive-dose statin therapy STRENGTH OF RECOMMENDATION: E. is associated with odds for new-onset diabetes 12% higher QUALITY OF EVIDENCE: Low. than that for moderate-dose statin therapy. The available EXPLANATION: Despite numerous clinical outcomes evidence does not indicate any clear differences between trials having included subjects with diabetes mellitus, few statins studied in clinical outcomes trials regarding their of the published articles from these studies report the associations with diabetes risk, although the analyses effects of statin therapy on indicators of glycemic control. conducted to date lack sufficient power to demonstrate The Collaborative Atorvastatin Diabetes Study (CARDS) such differences, if present. The hazard for new-onset evaluated the effects of 10 mg/d of atorvastatin (n 5 1410) diabetes with statin therapy may vary according to baseline vs placebo (n 5 1428) on CVD events in participants with diabetes risk, although more data are needed to investigate type 2 diabetes mellitus, but without evidence of clinical this possibility because the CIs in those at low risk for CVD at baseline.21 Mean (standard deviation [SD]) base- diabetes are large and do not rule out the possibility of line HbA1C levels were 7.8% (1.4) and 7.9% (1.4) in the some increase in risk. Statin therapy is effective for placebo and atorvastatin groups, respectively. After 4 years, reducing major CVD event rates in both primary and mean HbA1C was 8.1% (1.5) in the placebo group and 8.3% secondary prevention.7 Moreover, the available data show (1.5) in the atorvastatin group. These results are suggestive that several CVD events are prevented for each excess of a modestly larger increase in HbA1C level in the atorvas- case of diabetes associated with statin therapy, or intensifi- tatin group, although this must be interpreted with caution cation of statin therapy. because the values at year 4 were for completers and could have been biased or confounded by differential dropout or 2. What is the impact of statin treatment on glycemic con- changes in medications for glycemic control during the trol in patients with diabetes mellitus? trial. ANSWER: Because of a variety of methodological The Heart Protection Study investigators examined the concerns, the panel members do not feel that sufficient effects of simvastatin 40 mg/d (n 5 10,269) vs placebo evidence is available from randomized clinical trial data to (n 5 10,267) in high-risk patients,22 5963 of whom had 23 draw firm conclusions regarding the impact of statin been diagnosed with diabetes. Plasma HbA1C was treatment on glycemic control in patients with diabetes measured in a random sample of 1087 patients with S22 Journal of Clinical Lipidology, Vol 8, No 3S, June 2014 diabetes at study entry. Mean (standard error of the mean) with diabetes mellitus. Because of methodological con- HbA1C at baseline was 6.99% (0.11) for subjects assigned cerns, the panel members do not feel that sufficient to receive simvastatin and 7.06% (0.10) for subjects who evidence is available from randomized clinical trial data received placebo, and follow-up values 4 to 6 years later to draw firm conclusions regarding the impact of statin were 7.14% (0.06) and 7.17% (0.06), respectively. There treatment on glycemic control in patients with diabetes was no statistically significant difference between groups mellitus. In the JUPITER primary prevention trial conduct- for the increase in HbA1C (0.15% [0.09] vs 0.12% [0.09]). ed in subjects without diabetes mellitus, a slight increase in The Atorvastatin in Factorial with Omega-3 EE90 Risk HbA1C (w0.08%) was observed in the rosuvastatin group Reduction in Diabetes trial evaluated the effects of compared with the placebo group. These results, along atorvastatin 20 mg/d and omega-3-acid ethyl esters 2 g/d with those from the available studies of participants with on CVD risk, using a 2-by-2 factorial study design in diabetes mellitus treated with statin therapy, particularly persons with type 2 diabetes, but without known CVD and the CARDS, Heart Protection Study, and Atorvastatin in not taking lipid-lowering therapy.24 At baseline, mean Factorial with Omega-3 EE90 Risk Reduction in Diabetes HbA1C was 7.0% in both groups (atorvastatin [n 5 371] trials, suggest that if there is an adverse effect of statin or placebo [n 5 361]), and at 4 months, HbA1C had treatment on glycemia, it is small (mean increase of increased by 0.3% among subjects taking atorvastatin rela- w0.3% or less), and has the potential to be attenuated by tive to placebo (P , .0001). adjustment of the treatment regimen for glycemic control. Zhou et al. published a meta-analysis of randomized 3. Are there any subsets of patients in whom it would be trials that assessed the influence of statin therapy compared prudent to consider alternatives to statin treatment with placebo or standard care on indicators of glycemic because of concerns about increasing risk for new- control.25 The lengths of the treatment periods in the 26 onset diabetes? studies ranged from 4 weeks to 4 years and included 3232 participants. No significant effects overall were ANSWER: No change is recommended to current observed for statin therapy on HbA1C or fasting plasma practice on the basis of evidence for a modest increase in glucose concentrations. Atorvastatin therapy was associ- risk for diabetes associated with statin therapy because the ated with a modestly significant increase in HbA1C with a benefits of statin therapy for CVD event reduction in weighted mean difference of 0.20% (95% CI 0.08–0.31), patients at risk for diabetes (and with diabetes) have been whereas simvastatin therapy was associated with a modest amply demonstrated in randomized controlled clinical reduction in HbA1C with a weighted mean difference of trials. Although diabetes mellitus is associated with a 20.26% (95% CI 20.48 to 20.04). No significant effects number of adverse outcomes, the changes observed in were observed for cerivastatin, lovastatin, or rosuvastatin. measures of glucose homeostasis with statin use have been No data were available for fluvastatin, pravastatin, or small and are of uncertain clinical importance. pitavastatin. STRENGTH OF RECOMMENDATION: E. The most comprehensive data available regarding QUALITY OF EVIDENCE: Moderate. changes in glycemia and HbA1C associated with statin ther- EXPLANATION: Based on the evidence reviewed here, apy come from the JUPITER trial, although this was for sub- the panel members were of the opinion that decisions jects without diabetes mellitus.10,11 In JUPITER, there was regarding the use of statin therapy should be made in no significant overall change in fasting serum glucose be- accordance with guidelines for the management of high tween the treatment groups (mean [SD] change was 3 blood cholesterol.1,6,26 Clinicians should discuss the bene- [18.3] mg/dL for the rosuvastatin group vs 3 [17.3] mg/dL fits and risks, including that for new-onset diabetes, with in the placebo group). However, the change in HbA1C from patients. Other than the measurement of fasting glucose baseline to the final assessment was slightly but significantly or HbA1C before (ideally) and after treatment commence- (P ,.001) larger in subjects assigned to rosuvastatin (0.30% ment (within 1 year) for those deemed at elevated diabetes [0.35]) compared with placebo (0.22% [0.40]) and this differ- risk, no change is recommended to current practice on the ential was present during each year of follow-up. There was a basis of evidence for a modest increase in risk for diabetes slightly larger increase in body weight among subjects as- associated with statin therapy because the benefits of statin signed to rosuvastatin compared with placebo (0.44 vs therapy for CVD event reduction in patients at risk for dia- 0.15 kg), although subjects who developed diabetes gained betes (and with diabetes) have been amply demonstrated in less weight (0.10 vs 20.96 kg for rosuvastatin and placebo, randomized, controlled clinical trials. Although diabetes respectively) than subjects who did not (0.45 vs 0.18 kg, mellitus is associated with a number of adverse outcomes, for rosuvastatin and placebo, respectively). Because these the changes observed in measures of glucose homeostasis findings were from post-hoc analyses that may have been have been small and are of uncertain clinical importance. subject to various types of bias and confounding, additional Those with diabetes risk factors (Table 1) should be investigation will be needed to assess the clinical signifi- counseled regarding lifestyle modification, particularly cance, if any, of these observations. weight loss if overweight or obese, and engaging in In summary, a surprising paucity of data exists regarding adequate physical activity. Clinical trials of lifestyle modi- the effects of statin therapy on glycemic control in patients fication have shown that these strategies are efficacious for Maki et al Statin safety: Diabetes Task Force S23 preventing or delaying the onset of type 2 diabetes mellitus and excessive renal reabsorption and production (via gluco- in those with prediabetes (mainly impaired glucose toler- neogenesis) of glucose.30,31 The net result of these various ance).27,28 The Statin Safety Diabetes Subpanel endorses metabolic defects is an imbalance between the rate at which the American Diabetes Association’s Standards of Medical glucose enters the circulation from the liver, intestine, and Care in Diabetes recommendation that, where practical, pa- kidney, and the rate at which glucose is removed from cir- tients with prediabetes receive a referral to an effective culation by tissues, producing hyperglycemia. ongoing support program targeting weight loss of 7% of Little clinical investigation using reference methods has body weight (if overweight or obese) and at least 150 mi- been completed to assess the influence of statin therapy on nutes per week of moderate intensity physical activity, the determinants of glucose homeostasis. Baker et al. such as walking.29 performed a meta-analysis to assess the effects of statin treatment on insulin sensitivity.32 No significant effect was 4. What is known about the mechanisms that mediate the observed overall, but subset analyses suggested that pravas- relationship between statin use and risk of new-onset tatin use was associated with a modest increase in insulin type 2 diabetes mellitus? sensitivity (0.342 standard deviations, 95% CI 0.032- ANSWER: No firm conclusions can be drawn at present 0.651), simvastatin with a modest decline in insulin sensi- regarding the potential mechanistic link between statin tivity (20.321 standard deviations, 95% CI 20.526 to therapy and increased risk for diabetes mellitus. Research is 20.177), and atorvastatin and rosuvastatin with no differ- needed to further define the effects of statin therapy on the ences from the comparison conditions. Notably, only 3 of determinants of glucose homeostasis, particularly in those the 16 studies included in the meta-analysis included refer- at high risk for diabetes development. ence methods for assessing insulin sensitivity (euglycemic STRENGTH OF RECOMMENDATION: E. clamp or minimal model), whereas most used models that QUALITY OF EVIDENCE: Low. relied on fasting measures of glucose and insulin (homeo- EXPLANATION: Type 2 diabetes mellitus typically stasis model assessment of insulin resistance and quantita- results from a combination of insulin resistance (peripheral tive insulin sensitivity check index), which are relatively and hepatic) and a defect in the ability of the pancreatic insensitive indicators. One randomized, active-control beta cells to produce sufficient insulin to maintain normo- study,33 which was not considered in the Baker meta- glycemia.30 Pancreatic beta-cell dysfunction is progressive, analysis, used a reference method to assess insulin sensi- and those early in the disease process tend to have relative tivity (modified insulin suppression test). In this trial, 39 hypoinsulinemia (ie, insufficient compensatory hyperinsuli- patients with insulin resistance and mixed dyslipidemia nemia to overcome insulin resistance), whereas advanced were assessed before and after 3 months of treatment diabetes may be associated with absolute hypoinsulinemia. with gemfibrozil (1200 mg/d) or rosuvastatin (40 mg/d), In addition to defects in glucose disposal and pancreatic with measurement of the steady-state plasma glucose con- beta-cell function, diabetes is characterized by other meta- centration at the end of a 180-minute infusion of octreo- bolic disturbances, including pancreatic alpha-cell dysfunc- tide, insulin, and glucose. Rosuvastatin did not alter tion resulting in excessive glucagon production, deficiency steady-state plasma glucose compared with baseline (least and resistance to intestinal incretin hormones, disordered squares mean change 1.61% [95% CI 22.44 to central nervous system modulation of insulin secretion, 25.67%]) or compared with the change in the gemfibrozil

Table 1 Criteria for screening for prediabetes and diabetes before (or concurrent with) initiation of statin therapy29 1. Consider testing all overweight adults (body mass index $25 kg/m2)* with additional risk factors: Physical inactivity Diabetes in first-degree relative High-risk race/ethnicity (eg, African American, Latino, Native American, Asian American, Pacific Islander) Woman who delivered a baby weighing .9 lb, or was diagnosed with gestational diabetes mellitus Hypertension (defined as systolic/diastolic blood pressure $140/90 mm Hg, or on antihypertensive therapy) HDL-C , 35 mg/dL (0.90 mmol/L) and/or triglyceride level .250 mg/dL (2.82 mmol/L) Women with polycystic ovary syndrome HbA1C $ 5.7%, impaired glucose tolerance, or impaired fasting glucose on previous testing Other clinical conditions associated with insulin resistance (eg, severe obesity, acanthosis nigricans) History of cardiovascular disease 2. For all other persons not meeting these criteria, diabetes testing should begin at 45 y of age 3. If results are normal, testing should be repeated at a minimum of 3-y intervals; may consider more frequent testing depending on the initial results and risk status

HbA1C, glycated hemoglobin; HDL-C, high-density lipoprotein cholesterol. *The body mass index cutpoint for increased risk in some ethnic groups is lower. S24 Journal of Clinical Lipidology, Vol 8, No 3S, June 2014 treatment group (least squares mean change 3.61% [95% In summary, the available clinical evidence for changes CI 20.44 to 7.66%]).11 in insulin sensitivity induced by statin therapy is mixed, Since the publication of the Baker meta-analysis,32 re- with no clear evidence of worsening or improvement with sults from several additional studies have been published, statin therapy. However, few studies are available in which with mixed results.34 Theonlynewstudyinwhicha precise and reliable methods were used, and those that used reference method was used (euglycemic clamp) was a such methods were small and thus many are likely to have nonrandomized investigation of intraoperative insulin been underpowered. To our knowledge, no clinical data are sensitivity in users and nonusers of lipophilic statins available using reference methods regarding the effects of (atorvastatin and rosuvastatin) during coronary artery statin therapy on pancreatic beta-cell function, hepatic bypass grafting (n 5 60 per group).35 Baseline mean glucose production, and other parameters such as incretin (SD) insulin sensitivity did not differ significantly be- responses and renal tubular absorption of glucose. Accord- tween the groups: 4.9 (1.8) and 5.2 (1.8) mg/kg/min in ingly, no firm conclusions can be drawn at present the statin and control groups, respectively. In both groups, regarding the potential mechanistic link between statin insulin sensitivity declined during surgery and values therapy and increased risk for diabetes mellitus. were w20% lower in the statin group, with final means 5. What research efforts should be undertaken to further (SD) of 2.9 (1.3) and 3.7 (1.5) mg/kg/min in the statin define the changes in glucose homeostasis that occur and control groups, respectively (P , .05). To our knowl- with statin treatment and their clinical implications? edge, no results have been published from trials using reference methods to assess the impact of statin therapy ANSWER: At present, many gaps exist in the available on pancreatic beta-cell function (hyperglycemic clamp, evidence that have important clinical implications as out- intravenous glucose tolerance test, or glucose/meal toler- lined here. ance tests with mathematical modeling of insulin sensi- STRENGTH OF RECOMMENDATION: E. tivity and beta-cell function)36 or hepatic glucose QUALITY OF EVIDENCE: Not applicable. production (use of tracers to quantify hepatic glucose pro- EXPLANATION: It is notable that the identification of duction during glycemic clamping, or before and after a the association between statin use and elevated risk for glucose or meal load).37 new-onset diabetes mellitus is relatively recent, despite the As reviewed elsewhere,38–40 a number of cellular mech- completion of numerous clinical trials with statins anisms have been proposed as potential explanations for the involving many thousands of patients during more than observed effects of statin therapy on risk for new-onset dia- 25 years. This reflects, in part, the modest degree of betes based on results from studies in animal models and increase in risk, particularly relative to the benefits of statin cell cultures. Although none of these mechanisms has therapy for preventing CVD events. At present, many gaps been proven, the following summary of postulated mecha- exist in the available evidence that have important clinical nisms is adapted with permission from a review by Gold- implications. stein and Mascitelli:40 Clinical research and genetic investigations are needed to better define the mechanistic links between statin use and Dysregulation of cellular cholesterol leading to impaired diabetes risk. It would also be of interest to determine insulin secretion caused by disrupted voltage-gated cal- whether the changes in glucose homeostasis are reversible cium channel function in pancreatic beta cells resulting with discontinuation of statin therapy. Studies with contin- in attenuated fusion of insulin granules with the cell uous glucose monitoring would be helpful to better define membrane the nature of the changes in circulating glucose levels (eg, Disruption of mitochondrial function in the myocyte, changes in values overnight, early morning, postprandially) adipocyte, and pancreatic beta cell resulting in dimin- associated with statin therapy. It would also be of value to ished insulin secretion and increased peripheral insulin know whether the effect of statin treatment on new-onset resistance diabetes risk is exacerbated or attenuated by other cardio- Decreased expression of adipocyte insulin-responsive vascular drugs, including those that tend to worsen glucose glucose transporter (GLUT4) leading to increased pe- tolerance (eg, thiazides, some beta-adrenergic blockers) ripheral insulin resistance and those that have been associated with lower risk for Induction of muscle fatigue and reduced energy culmi- new-onset diabetes (eg, angiotensin-converting enzyme nating in diminished exercise potential and decreased ac- inhibitors, angiotensin II receptor antagonists).41,42 tivity, and thus diminished energy expenditure Ongoing and planned clinical trials of statin therapy Perpetuation of the sarcopenia (skeletal muscle wasting) should ideally include structured assessments of indicators of aging leading to increased insulin resistance of glucose homeostasis, including fasting glucose and Given the limited data available from clinical investiga- HbA1C. The relationship between weight gain and risk for tions with precise and reliable methods of assessing type 2 diabetes is strong and could explain the small but changes in the determinants of glucose tolerance in statistically significant differences observed between those response to statin therapy, the clinical importance of these on statin therapy and controls. If, for example, participants proposed cellular mechanisms remains uncertain. have lipoproteins measured outside the trial, this could Maki et al Statin safety: Diabetes Task Force S25 result in relaxation of dietary and weight control in those Recommendations to clinicians with significant lipoprotein reductions from the statin therapy. Therefore, assessment of glucose and insulin responses Preventing diabetes in statin-treated patients to an oral glucose or meal load as well as changes in body fat mass and distribution would be of value, at least in a In the large clinical trials of statins with cardiovascular subset of participants. endpoints, type 2 diabetes mellitus has often been diag- Because clinical trials generally last only a few years, nosed in patients without using formal criteria for this longer duration evaluations using other data sources, such designation. Diabetes was registered as confirmed when as those from managed care databases, would be helpful to investigators: (1) added the diagnosis to case report forms assess the influence of longer term exposure to statin without necessarily specifying the nature of the observa- treatment on risk for diabetes and associated micro- and tions, (2) began the use of hypoglycemic medications, or macrovascular complications. In addition, ongoing trials of (3) discovered an elevated blood glucose at a routine proprotein convertase subtilisin kexin type 9 inhibitors monitoring visit.15,20 Criteria set by the International Dia- should also evaluate for changes in diabetes, glucose, and betes Federation or the American Diabetes Association HbA1C to examine if effects are related to LDL-C reduction were not consistently documented at the time. Criteria for per se. diagnosis of type 2 diabetes mellitus recommended by the American Diabetes Association are shown in Table 2. 6. Should doctors measure glycemia parameters before Furthermore, the reason for the increased incidence of starting a statin prescription and/or during statin type 2 diabetes in these clinical trials is poorly understood therapy? at a mechanistic level. ANSWER: The panel endorses application of the current However, there are several lessons to be derived from Standards of Medical Care in Diabetes recommendations these studies. The first is that there are markers in most from the American Diabetes Association before and during patients that forewarn of the risk for developing diabetes statin therapy. Ideally, screening should occur before initi- mellitus (Table 1).15,20,29 Overweight or obesity, elevated ation of statin therapy, although clinicians should not gener- triglycerides, low plasma HDL-C, and high blood pressure ally delay the initiation of statin therapy to await results are all warning signs that the patient has an elevated risk for from screening tests in a patient for whom statin therapy type 2 diabetes. A family history in 1 or more first-degree is indicated. relatives is a powerful predictor as well, especially if STRENGTH OF RECOMMENDATION: E. apparent for both parents or in siblings.44 QUALITY OF EVIDENCE: Moderate. In all patients with risk factors for diabetes, diabetes EXPLANATION: The panel recommends following the prevention should be a major concern whether taking a guidance issued by the American Diabetes Association statin or not. The risk factor that appears to be most regarding screening for prediabetes and diabetes.29 Ideally, fundamental in the etiology of insulin resistance is obesity, screening should occur before initiation of statin therapy, and any patient with a body mass index $30 kg/m2 should although clinicians should not generally delay the initiation be made aware of this fact. Emphasis on weight loss and of statin therapy to await results from screening tests in a engaging in regular physical activity are the major behav- patient for whom statin therapy is indicated. ioral changes that underlie clinical efforts in prevention The current Standards of Medical Care in Diabetes of diabetes.29 Among those at high risk for the development recommendations are summarized in Table 1 for those indi- of diabetes, particularly those with prediabetes, referral to a viduals in whom screening for diabetes should be consid- support program that includes consultation with allied ered. Criteria for diagnosis of prediabetes and type 2 health professionals such as dietitians and exercise physiol- diabetes mellitus are summarized in Table 2. Fasting ogists to assist with attaining recommended targets for plasma glucose, HbA1C, or the 2-hour oral glucose toler- weight loss (7% of body weight for those overweight or ance test are considered appropriate for screening/testing, obese) and physical activity (at least 150 min/week) is rec- although these tests do not necessarily detect diabetes in ommended.29 Dietary advice regarding saturated fat and the same individuals.29 The rationale for the 3-year interval cholesterol is important for lipid management, but these between screenings in those with normal results is that false changes are often interpreted (incorrectly) as a recommen- negatives will be repeated before substantial time elapses, dation to increase dietary carbohydrate, and this should be and there is little likelihood that an individual will develop part of the discussion about dietary changes.45 significant complications of diabetes within 3 years of a In the long-term effort to reduce risk of CVD, it is negative test result.29 For those with diabetes risk factors, important to monitor weight in patients on statins or other especially prediabetes, before starting statin therapy, the therapy for lipid disorders. In some, the increased comfort panel members feel that consideration should be given to level produced by an effective reduction in LDL-C may screening or rescreening within 1 year of initiating statin cause a relaxation in dietary control and a trend toward therapy. This latter recommendation is consistent with the weight gain. This hypothetical concern seems sufficiently recent National Institute for Health and Care Excellence probable that it should lead to further interrogation and guidance in the United Kingdom.43 analysis of current data from clinical trials to evaluate S26 Journal of Clinical Lipidology, Vol 8, No 3S, June 2014

possible relationships between changes in body weight and/ or fat mass and blood glucose. Furthermore, future clinical trials with lipid-lowering drugs should include the careful monitoring of body weight, particularly in those with risk 200 mg/dL

$ factors for diabetes at baseline.

Responding to the diagnosis of diabetes in the statin-treated patient

If diabetes appears in any patient, there are also other causes, some admittedly rare, that should be considered, particularly when the risk factors noted here are not evident. These include: (1) the concomitant use of other drugs such as glucocorticoids, beta-adrenergic agonists, and

7.0 mmol/L) 11.1 mmol/L) excessive thyroid hormone replacement; (2) endocrinopa- $ $ thies such as neoplasms producing growth hormone, adrenocorticoids, catecholamines, or glucagon; (3) infec- † tion or inﬁltrative disease of the pancreas, including 11.1 mmol/L)

$ hemachromatosis, amyloidosis, tuberculosis, and viral in- ( hyperglycemic crisis, a random plasma glucose 126 mg/dL ( 200 mg/dL ( 6.5% 46,47

Diabetes $ $ $ fections; and (4) recurrent pancreatitis. If criteria for the diagnosis of diabetes are met during statin treatment, the question immediately arises as to what should be done to properly continue CVD risk reduction therapy. Diabetes increases risk of major vascular events, with or without other CVD risk factors. More aggressive control of lipid abnormalities and blood pressure in patients with diabetes has traditionally been emphasized.29 A re- newed emphasis on medical nutrition therapy and physical activity is in order. Patients should be informed that diabetes is a progressive disease and that clinical studies have shown that it is possible to slow the progression, or even to produce a reversion to nondiabetes status.48–50 Sig- niﬁcant weight loss has been repeatedly shown to lower * blood glucose, plasma triglycerides, and blood pressure and to raise HDL-C.51,52 That claim can be made for no other single therapeutic maneuver. Prediabetes 100 to 125 mg/dL (5.6 to 6.9 mmol/L) 140 mg/dL to 199 mg/dL (7.8 to 11.05.7% mmol/L) to 6.4% __ In a patient with classic symptoms of hyperglycemia or 29 With concern expressed in the press and in the medical literature regarding statins being associated with increased

x risk for onset of type 2 diabetes, some patients are likely to be concerned about the safety of continuing this treatment. Diabetes has a very bad reputation among laymen and may generate greater concern (eg, worry about amputation or blindness) than the possibility of heart disease, which has a much higher probability. Statins are the most effective drug class for lowering LDL-C and other atherogenic lipoproteins, and the best documented treatment in prevention of myocardial infarction, coronary death, and strokes in patients with diabetes. Statin therapy reduces the incidence of the very events that cause most deaths in diabetes. ‡

k Fortunately, we have data from excellent clinical event trials of statin therapy involving thousands of patients with diabetes.53 Table 3 presents a summary of these data. These provide reassuring information about the efficacy of statin Criteria for the diagnosis of prediabetes and diabetes therapy for CVD risk reduction in patients with diabetes, and we need to share this with our patients. There are The test should be performed in a laboratory using a method that is National Glycohemoglobin Standardization Program certified and standardized to the Diabetes Control and Complications Trial assay. The oral glucose tolerance test should be performed as described by the World Health Organization using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water. *For all these tests,†In risk the is absence continuous, of extending‡Fasting unequivocal below is hyperglycemia, the defined results lower as should limitx no be of caloric confirmed the intake by range for repeat andk at testing. becoming least disproportionately 8 greater hours. at higher ends of the range. also other studies with subgroup analyses that support these Fasting plasma glucose OR 2-h plasma glucose fromOR 75 g oral glucoseGlycated tolerance hemoglobin test OR Table 2 findings, confirming that statin treatment is effective for aie lSai aey ibtsTs Force Task Diabetes safety: Statin al et Maki

Table 3 Summary of clinical trial evidence for CVD event reduction in patients with diabetes Study Subjects Entry criteria Treatments Duration Outcomes (statin vs placebo) 4S56 4444 total Prior MI or angina pectoris Simvastatin 20-40 mg 5.4 y Total mortality 202 with Total-C 213-309 mg/dL Placebo With diabetes Y43% (95% CI 270 to 18, P 5 .087) diabetes TG # 221 mg/dL Without diabetes Y29% (95% CI 242 to 213, P 5 .001) Major CHD event With diabetes Y55% (95% CI 273 to 226, P 5 .002) Without diabetes Y32% (95% CI 240 to 223, P , .001) HPS22,23 20,536 total Coronary disease, other occlusive Simvastatin 40 mg 5 y Rate of first occurrence of major vascular event 5963 with arterial disease, or diabetes Placebo With diabetes Y22% diabetes 40–80 y of age (95% CI 230 to 213, P , .001) Total-C .135 mg/dL With diabetes, but without occlusive arterial disease (n 5 2912) Y33% (95% CI 246 to 217, P , .001) With diabetes and baseline LDL-C , 116 mg/dL (n 5 2426) Y27% (95% CI 240 to 213, P , .001) CARDS21 2838 subjects Type 2 diabetes Atorvastatin 10 mg 3.9 y Major CV event rate with diabetes 40–75 y of age Placebo Y37% (95% CI 252 to 217, P 5 .001) No prior history of CVD LDL-C , 160 mg/dL TG , 600 mg/dL at least 1 of the following: retinopathy, albuminuria, current smoking, hypertension 4S, Scandinavian Simvastatin Survival Study; CARDS, Collaborative Atorvastatin Diabetes Study; CHD, coronary heart disease; CI, confidence interval; CVD, cardiovascular disease; HPS, Heart Protection Study; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction; RR, relative risk; TG, triglycerides; total-C, total cholesterol. S27 S28 Journal of Clinical Lipidology, Vol 8, No 3S, June 2014 preventing atherosclerosis-related events in patients with References diabetes. None of these has suggested that the common complications related to microvascular disease are increased 1. Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA Guide- with statin therapy.54,55 Thus, the current clinical trial evi- line on the Treatment of Blood Cholesterol to Reduce Atherosclerotic dence documents the arteriovascular benefit of using statins Cardiovascular Risk in Adults: A Report of the American College of in type 2 diabetes. Furthermore, there is no current evidence Cardiology/American Heart Association Task Force on Practice Guidelines [e-pub ahead of print]. J Am Coll Cardiol. 2013. that there is clinical harm related to the common complica- http://dx.doi.org/10.1016/j.jacc.2013.11.002. Accessed March 14, 2014. tions of hyperglycemia, in patients with diabetes. 2. Guyatt GH, Oxman AD, Vist GE, et al. GRADE: an emerging The current recommendations from the American Dia- consensus on rating quality of evidence and strength of recommenda- betes Association regarding lipid management are summa- tions. BMJ. 2008;336:924–926. rized here (excerpted with permission).29 3. James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from Statin therapy should be added to lifestyle therapy, the panel members appointed to the Eighth Joint National Committee regardless of baseline lipid levels, for diabetic patients: (JNC 8). JAMA. 2014;311:507–520. 4. Expert Panel on Detection, Evaluation, and Treatment of High with overt CVD Blood Cholesterol in Adults. Executive summary of the Third without CVD who are over the age of 40 years and Report of the National Cholesterol Education Program (NCEP) have one or more other CVD risk factors (family history Expert Panel on Detection, Evaluation, and Treatment of High of CVD, hypertension, smoking, dyslipidemia, or Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. albuminuria). 2001;285:2486–2497. 5. Grundy SM, Cleeman JI, Merz CN, et al, Coordinating Committee of For lower-risk patients than the above (eg, without overt the National Cholesterol Education Program. Implications of recent CVD and under the age of 40 years), statin therapy should clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. J Am Coll Cardiol. 2004;44:720–732. be considered in addition to lifestyle therapy if LDL-C 6. Expert Dyslipidemia Panel, Grundy SM. An International Atheroscle- remains above 100 mg/dL or in those with multiple CVD rosis Society Position Paper: global recommendations for the manage- risk factors. ment of dyslipidemia. J Clin Lipidol. 2013;7:561–565. In individuals without overt CVD, the goal is LDL-C 7. Cholesterol Treatment Trialists (CTT) Collaborators, Baigent C, ,100 mg/dL (2.6 mmol/L). In individuals with overt CVD, Blackwell L, Emberson J, et al. Efficacy and safety of more intensive , lowering of LDL cholesterol: a meta-analysis of data from 170,000 a lower LDL-C goal of 70 mg/dL (1.8 mmol/L), with a participants in 26 randomised trials. Lancet. 2010;376:1670–1681. high dose of a statin, is an option. If drug-treated patients 8. Cholesterol Treatment Trialists (CTT) Collaborators, Mihaylova B, do not reach the above targets on maximum tolerated statin Emberson J, Blackwell L, et al. The effects of lowering LDL choles- therapy, a reduction in LDL-C w30-40% from baseline is terol with statin therapy in people at low risk of vascular disease: . Lancet an alternative therapeutic goal. Triglyceride levels meta-analysis of individual data from 27 randomised trials . , . 2012;380:581–590. 150 mg/dL (1.7 mmol/L) and HDL-C 40 mg/dL 9. Taylor F, Huffman MD, Macedo AF, et al. Statins for the primary pre- (1.0 mmol/L) in men and .50 mg/dL (1.3 mmol/L) in vention of cardiovascular disease. Cochrane Database Syst Rev. women are desirable. However, LDL-C–targeted statin 2013;(1):CD004816. therapy remains the preferred strategy. 10. Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359:2195–2207. Recommendations when beginning statin 11. Astra Zeneca. Clinical briefing document - Endocrine and Metabolic therapy in patients without known diabetes Drugs Advisory Committee meeting for rosuvastatin (Crestor). Avail- able at: http://www.fda.gov/downloads/advisorycommittees/committe mellitus esmeetingmaterials/drugs/endocrinologicandmetabolicdrugsadvisory committee/ucm193831.pdf. Accessed November 5, 2013. 1. Assess risk factors for diabetes (Table 1) as well as 12. Rajpathak SN, Kumbhani DJ, Crandall J, Barzilai N, Alderman M, CVD, and in those considered at elevated diabetes Ridker PM. Statin therapy and risk of developing type 2 diabetes: a . Diabetes Care risk, consider measurement of fasting glucose or meta-analysis . 2009;32:1924–1929. 13. Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident dia- HbA1C before statin commencement. betes: a collaborative meta-analysis of randomised statin trials. Lancet. 2. Emphasize the importance of weight maintenance with 2010;375:735–742. diet and physical activity before and during statin use 14. Preiss D, Seshasai SR, Welsh P, et al. Risk of incident diabetes with to attenuate diabetes risk as well as supporting CVD intensive-dose compared with moderate-dose statin therapy: a meta- . JAMA risk reduction. Assess body weight under standard con- analysis . 2011;305:2556–2564. 15. Waters DD, Ho JE, DeMicco DA, et al. Predictors of new-onset dia- ditions (fasting, no coat, no shoes) at every office visit. betes in patients treated with atorvastatin: results from 3 large random- Consider waist circumference measurement at intervals. ized clinical trials. J Am Coll Cardiol. 2011;57:1535–1545. 3. Use statins to lower CVD risk in accordance with cur- 16. Food and Drug Administration. FDA drug safety communication: rent guidelines unless there is a contraindication.1,6,26,29 important safety label changes to cholesterol lowering statin drugs. 4. If diabetes does present during statin therapy, emphasize Available at: http://www.fda.gov/drugs/drugsafety/ucm293101.htm. Accessed November 6, 2013. weight loss and hypoglycemic agents, if indicated, to 17. The National Lipid Association. FDA changes label on statin drugs. control plasma glucose and HbA1C. Provide dietetic Available at: https://www.lipid.org/communications/news/other/fda_ and behavioral counseling as appropriate. changes_label_on_statin_drugs. Accessed November 5, 2013. Maki et al Statin safety: Diabetes Task Force S29

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Original Contribution A clinician’s guide to statin drug-drug interactions

Kenneth A. Kellick, PharmD, FNLA*, Michael Bottorff, PharmD, FNLA, Peter P. Toth, MD, PhD, FNLA

Veterans Administration Western New York Healthcare System, State University of New York at Buffalo, Buffalo, NY 14215, USA (Dr Kellick); Department of Pharmacy, State University of New York at Buffalo, Buffalo, NY, USA (Dr Kellick); Department of Medicine, State University of New York at Buffalo, Buffalo, NY, USA (Dr Kellick); Department of Pharmacy Practice, South College School of Pharmacy, Knoxville, TN, USA (Dr Bottorff); Medical Center, Sterling, IL, USA (Dr Toth); and University of Illinois School of Medicine–Peoria, Peoria, IL, USA (Dr Toth)

KEYWORDS: Abstract: The statins are widely used worldwide to reduce risk for cardiovascular events in both the Cytochrome; primary and secondary prevention settings. Although generally quite safe, the statins can be associated Drug-drug interactions; with a variety of serious side adverse effects, including myalgia, myopathy, and changes in plasma Glucuronidation; enzymes of hepatic origin. Although rare, the most serious of these is rhabdomyolysis. Several drugs Pharmacogenetics; can interfere with the metabolism and disposal of the statins, thereby increasing risk for adverse events. Pharmacokinetics; It is important that clinicians treating patients with statins be aware of the potential for drug-drug Statins interactions between each statin and speciﬁc other drugs and take measures to prevent them. The prediction of potential drug-drug interactions derives from basic pharmacokinetic principles. Certain drug interactions are predicted by measuring the effect of interacting drugs on blood plasma concentrations of the statin. Individual patient variations resulting in part from polymorphisms in the metabolizing enzymes confound some of these predictions. Based on these known effects, a new classiﬁcation for predicting statin drug interactions is proposed. This report discusses likely prescription and nonpre- scription interactions as well as potential alternatives for special populations. Published by Elsevier Inc. on behalf of National Lipid Association.

The metabolism of statins is described by basic phar- excretion for these molecules. With the exception of macokinetic principles. Pharmacokinetic measures involve lovastatin and simvastatin, which are given as prodrugs, the rate of absorption, distribution, metabolism, and all statins are administered in the active hydroxyl acid form (Fig. 1). Once ingested, various other factors affect their absorption, distribution, metabolism, and excretion. Statins Disclosures: Dr Bottorff and Dr Toth disclose that they have relationships are moderately to well absorbed, with the time to reach with industry that might pose a potential conflict of interest. Dr Bottorff has peak plasma concentration averaging about 4 hours. received honoraria for serving as a speaker and/or consultant to AstraZeneca, Bristol-Myers Squibb, Sanofi, Boehringer Ingelheim, and Pfizer. Dr Toth is When consumed with food, lovastatin is more efficiently on the speaker bureaus for AbbVie, Amarin, AstraZeneca, Genzyme, Kowa, absorbed. Rosuvastatin, pitavastatin, and simvastatin are and Merck, and has served as a consultant to Amgen, Atherotech, Genzyme, not affected by food, whereas fluvastatin, pravastatin, and Kowa, LipoScience, and Merck. Dr Kellick has no financial relationships atorvastatin have a reduced absorption with food. Once with commercial entities producing health care goods or services. absorbed into the portal venous system, while all statins * Corresponding author. E-mail address: [email protected] undergo extensive first-pass metabolism, the rate of Submitted February 27, 2014. Accepted for publication February 28, this first-pass hepatic uptake inversely relates to the 2014. systemic bioavailability. Therefore, the lower systemic

1933-2874/$ - see front matter Published by Elsevier Inc. on behalf of National Lipid Association. http://dx.doi.org/10.1016/j.jacl.2014.02.010 Kellick et al Statins and drug interactions S31

Figure 1 Chemical structures of statins. Type I naphthalene statins (lovastatin, pravastatin, simvastatin); type II non-naphthalene (atorvastatin, pitavastatin, rosuvastatin, fluvastatin). Lovastatin and simvastatin are prodrugs. bioavailability of fluvastatin (19%–29%) may suggest a eventual absorption into the portal circulation. Hepatic more efficient first-pass metabolism. Pravastatin is the uptake is mediated by several transporters, including only statin not protein bound, which imparts a low systemic organic anion transporting polypeptide 1B1 (OATP1B1), exposure to the medication.1 which facilitates metabolism by additional CYP enzymes Statins undergo a complex metabolic fate, beginning (phase I metabolism) and glucuronidation (phase II meta- with absorption, followed by hepatic uptake, metabolism, bolism). Additional efflux transporters on the canalicular and eventually elimination from the liver into either the membranes of hepatocytes facilitate biliary excretion. systemic circulation or the biliary tract (Fig. 2).2 During the Some interacting drugs, such as cyclosporine, inhibit absorption process, most statins are substrates for the multiple sites of statin disposition (Table 1),3 resulting in P-glycoprotein (P-gp) efflux transporter, which reduces larger increases in serum concentrations and subsequent absorption into the portal circulation. Enterocyte cyto- risk for myopathy. Cyclosporine is an inhibitor of chrome P450 (CYP) may metabolize some statins before OATP1B1, OATP1B3, P-gp, and adenosine triphosphate

Figure 2 Metabolic fate of statins. BCRP, breast cancer–resistant protein, encoded by gene ABCG2; MDR1, multidrug-resistant protein 1; MRP2, multidrug-resistant–associated protein 2, encoded by gene ABCC2; OATP1B1, organic anion transporter protein 1B1, formerly known as OATP2, encoded by SLCO1B1 gene; OATP1B3, organic anion transporter protein 1B3, encoded by the SLCO1B3 gene; P-glycoprotein, P-gp, encoded by the ABCB1 gene. Adapted from Niemi et al.2 S32 Journal of Clinical Lipidology, Vol 8, No 3S, June 2014

theories involve classification of potential pathways as Table 1 Transporters and enzymes involved in statin metabolism follows: Transporters and enzymes affecting a lipophilic lactone prodrugs such as simvastatin are pre- Statin metabolism dominantly CYP metabolized; b polar statins such as rosuvastatin and pravastatin are Simvastatin CYP3A4 (intestinal and hepatic) substrates of transporters including the hepatic OATPs, Lovastatin OAT1B1 sodium/taurocholate cotransporting peptides (NTCP), P-gp MDR1 and the renal OATPs; and BCRP c statins such as fluvastatin that are metabolized by CYP Atorvastatin BCRP (intestinal) and access the hepatocyte by active transport. CYP3A4 (intestinal and hepatic) In addition, all statins have affinity to the multi-drug- OAT1B1 and OAT2B1 resistance protein (MRP2), P-gp, the bile salt export pump, P-gp Rosuvastatin BCRP (intestinal) and the BCRP. The latter transporters may have a minor CYP2C9 (minor) role in statin drug interactions. Finally, there appears to be a OAT1B1 and OAT1B3 delicate balance between these transporter proteins and 2,5–7 NTCP CYP metabolism. OAT2B1 P-gp is a member of the ATP binding cassette-subfamily Pravastatin BCRP (intestinal) B. P-gp is the 170-kD protein product of the multidrug OAT1B1 and OAT1B3 resistance gene ABCB1 (MDR1). Many compounds can OAT2B1 alter the function and/or expression of P-gp, providing Fluvastatin BCRP (intestinal) mechanisms for several clinically important drug-drug OATP1B1 interactions (DDIs), which were unexplained or attributed OAT1B3 solely to inhibition of CYP. Verapamil, cyclosporine, eryth- OAT2B1 CYP2C9 romycin, ketoconazole, and tamoxifen are examples of CYP3A4 agents that have demonstrated either in vitro or in vivo Pitavastatin BCRP (intestinal) inhibition of P-gp function. An interesting feature of P-gp MDR1 is the interaction with drug-metabolizing enzymes, specif- OAT1B1 andOAT1B3 ically the 3A4 isozyme of CYP (CYP3A4). P-gp and OATP2B1 CYP3A4 share many substrates and inhibitors and have a CYP2C9 (minor) common tissue distribution. After entering the enterocyte, BCRP, breast cancer–resistant protein; CYP, cytochrome P450; a compound with affinity for P-gp or as a substrate for MDR1, multidrug-resistant protein; OAT, organic anion transporters; CYP3A4 may be absorbed directly into the systemic circu- OATP, organic anion transporting polypeptides; P-gp, p-glycoprotein. 3 lation, metabolized by CYP3A4 in the enterocyte, or Adapted from Harper et al. secreted back into the intestinal lumen by P-gp. Drugs pumped back into the lumen may be reabsorbed at a distal site and exposed again to any of the 3 fates previously cassette transporter subfamily G, member 2 (ABCG2 or described. This may create a cycling effect (enteroenteric breast cancer–resistant protein [BCRP]). Transporters are recycling) and increase the mean residence time in the in- membrane proteins that move drugs (and other chemicals) testinal lumen and interaction, in the case of statins, with in and out of cells (Table 2).4 As such, transporters are an 3-hyroxy-3-methyglutaryl coenzyme A reductase. Fluvasta- important determinant of statin disposition and a source tin and pravastatin consistently demonstrate no significant of drug interactions when transporter inhibitors are coadmi- inhibition of P-gp transport. Rosuvastatin acid or its lactone nistered with a statin. All statins are substrates for do not appear to be substrates for P-gp, leaving the effect of 9 OATP1B1, which provides statin access into the hepatocyte P-gp largely with lovastatin, simvastatin, and atorvastatin. both for pharmacologic activity and subsequent metabolism What appears to be the conundrum in understanding and elimination. In addition, genetic polymorphisms in the variations in statin tolerance are single-nucleotide poly- solute carrier organic anion transporter family member 1B1 morphisms in individuals and specific patient populations. gene (SLCO1B1) have been associated with a higher statin The OATP1B1 (SLBO1B1) and BCRP (ABC2) genes have 8,10 exposure and increased risk for myopathy.2,5–8 been studied most extensively. In diploid carriers of the OAT1B1 521T . single-nucleotide polymorphism (174Val . Ala variant rs4149056), therapeutic doses of 5 Individual variation in enzyme induction, statins showed altered pharmacokinetics (Tables 3A, B).8 inhibition, and patient response Fluvastatin has no apparent association with variations in implied OATP1B1 function from studies in different ge- Although traditional models attribute statin metabolism netic groups. The results in Table 3, however, only partially to the cytochrome hepatic systems, more contemporary translate into day-to-day clinical scenarios with regard to Kellick et al Statins and drug interactions S33

Table 2 Membrane transporters Transporter/alias (gene) Organ or cells Comment P-gp/MDR1 (ABCB1) Intestinal enterocyte Drug absorption, distribution, and excretion Hepatocyte (canalicular) Source of drug interaction Kidney proximal tubule BCRP (ABCB2) Intestinal enterocyte Drug absorption, distribution, and excretion Hepatocyte (canalicular) Genetic polymorphisms Kidney proximal tubule Source of drug interaction OATP1B1/OATP2 (SLCO1B1) Hepatocyte (sinusoidal) Drug distribution, excretion Genetic polymorphisms Source of drug interaction OATP1A2/OATP-A (SLCO1A2) Cholangiocyte Drug distribution, excretion Distal nephron OATP2B1/OATP-B (SLCO2B1) Hepatocytes (sinusoidal) Drug distribution, excretion Source of drug interaction ABCRP, breast cancer–resistant protein; CYP, cytochrome P450; MDR1, multidrug-resistant protein; OAT, organic anion transporters; OATP, organic anion transporting polypeptides; P-gp, p-glycoprotein; SLCO2B1, gene for solute carrier organic anion transporter family member 2B1. Adapted from Giacomini et al.4

muscle side effects. It may apply most often to simvastatin have been most commonly described. Focusing on simva- and atorvastatin. statin, the potential for DDIs involves complete inhibition Differences in the ABC2 gene may explain some ethnic of intestinal CYP3A4-mediated metabolism in addition to differences. It has been suggested that 1% to 4% of African OATP1B1-mediated uptake of the statin acid. Based on this Americans, 5% to 10% Caucasians, and 35% to 45% of mechanism, cyclosporine, telithromycin, and posaconazole Asians carry variations in the ABCG2 (BCRP) gene. These are also likely to produce similar multiple-fold increases in changes suggest differences in the absorption of rosuvasta- areas under the curve (AUCs). Although a critical interac- tin, simvastatin-lactone, fluvastatin, and atorvastatin, but tion, the combination of gemfibrozil and simvastatin not simvastatin acid (active moiety) or pravastatin perhaps is less daunting because gemfibrozil only inhibits (Table 4).8–16 OATP1B1 in turn because neither gemfibrozil, nor its glucuronide, are CYP3A4 inhibitors. Focus on drugs that have the highest potential Atorvastatin may be more complex because of the to interact with statins passive absorption of atorvastatin acid. Cyclosporine enterocyte concentrations and BCRP intestinal inhibition would Although multiple pathways have been shown to play a result in full inhibition of CYP3A4, causing the interaction. role in statin DDIs, the CYP3A4 and CYP2C9 pathways Yet for the other atorvastatin interactions, there is less involvement of BCRP and a greater involvement of

Table 3A Comparison of peripheral blood plasma concentrations of different statins in individuals with homozygous (OATP1B1) 521CC (dysfunctional) compared with Table 3B Comparison of postdosing plasma concentrations those with fully functional homozygous (OATP1B1) 521 TT of different statins in homozygous BCRP 421AA individuals (fold AUC changes are based on group mean AUC 0–N)* compared with homozygous BCRP 421CC individuals (fold AUC changes are based on group mean AUC 0–N)* Statin AUC change Drug AUC change Simvastatin acid 3.21-fold [ (1221%) Pitavastatin 3.08-fold [ (1208%) Rosuvastatin 2.44-fold [ (1144%) Atorvastatin 2.45-fold [ (1145%) Simvastatin acid 1.22-fold [ (122%) Pravastatin 1.91-fold [ (191%) Simvastatin lactone 2.11-fold [ (1111%) Rosuvastatin 1.62-fold [ (161%) Atorvastatin lactone 1.94-fold [ (194%) Fluvastatin 1.19-fold [ (119%, ns) Atorvastatin acid 1.72-fold [ (172%) Fluvastatin 1.72-fold [ (172%) AUC, area under the curve; ns, not signiﬁcant; OATP, organic anion Y transporting polypeptide. Pravastatin 1.13-fold (ns) [ 1 *Heterozygous individuals with the c.521 TC genotype generally Pitavastatin 1.05-fold ( 5%, ns) show smaller AUC value increases than individuals with the c.521CC ge- AUC, area under the curve; BCRP, breast cancer–resistant protein; notype. ns, not signiﬁcant. 8 Adapted with permission from Elsby et al. Adapted with permission from Elsby et al.8 S34

Table 4 Predicted vs observed fold increases in various statins and enzyme systems*

Predicted fold increase in AUC from inhibition of composite pathways Clinically predicted fold Statin Perpetrator drug BCRP (intestine) CYP3A4 (intestine) OAT1B1 CYP3A4 hepatic increase in AUC Simvastatin Cyclosporine 1.67 4.5 (56) 1.0 (0.09) 7.5 Telithromycin 1.67 1.2 (0.2) 2.0 (1.6) 4.0 Posaconazole 1.67 NI 1.7 (0.9) 4.0 Atorvastatin Cyclosporine 1.72 (174) 1.45 3.2 (103) NA 8.0 Lopinavir/ritonavir NA, low solubility 1.45 1.9 (2.3) 1.1 (0.14) 1.0 (0.16) 2.9 Clarithromycin NI 1.45 2.0 (2.7) 1.1 (0.4) 3.2 Itraconazole NI 1.45 NI 1.0 (0.4) 1.45 BCRP (intestine) OAT1B3 CYP2C9 Fluvastatin Cyclosporine 1.72 (100) 1.8 (19) NI 3.2 Fluconazole NI NI 1.7 (9.9) 1.7 Statin Precipitating drug BCRP (intestine) Active uptake (OATP1B1:NTCP:OATP1B3) OAT3 Overall predicted fold Clinically observed fold (fe 5 0.38:0.21:0.11 5 0.7) increase in AUC increase in AUC Rosuvastatin Cyclosporine 2.0 (100) 3.2 (56) NI 6.4 7.1 Gemﬁbrozil NI 1.5 (OATP1B) (2.0) 1.2 (2.1) 1.8 1.9

Lopinavir/ritonavir No effect-low solubility 1.5 (OATP1B) NA 1.5 (1.9) 2.1 2014 June 3S, No 8, Vol Lipidology, Clinical of Journal (1.9 if all inhibited) (2.3) Atazanavir/ritonavir 2.0 (25) 1.6 (OATP1B) (3.5) NA 3.2 3.1 Efflux (intestine) OATP1B1 OAT3 Pravastatin Cyclosporine 2.9 2.0 (103) NI 5.8 3.82 Clarithromycin NI 1.6 (2.7) NI 1.6 2.1 Gemfibrozil NI 1.3 (0.9) 1.4 (2.6) 2.1 2.0 OAT Pitavastatin Cyclosporine 4.2 (39) 4.2 4.55 Erythromycin 1.5 (0.7) 1.5 2.8 Gemfibrozil 1.5 (0.8) 1.5 1.45 AUC, area under the curve; BCRP, breast cancer–resistant protein; CYP3A4, cytochrome P450 isozyme 3A4; DDI, drug-drug interaction; IC50, half maximal inhibitory concentration; Ki, reversible inhibition constant; NA, not applicable; NI, not an inhibitor; OAT, organic anion transporter; OATP, organic anion transporting polypeptide. *(number), ratio of inlet max, unbound /IC50 or Ki (.0.1 indicates potential for interaction); [number], ratio of [I2]/IC50 or Ki (.10 indicates potential for interaction). Adapted with permission from Elsby et al.8 Kellick et al Statins and drug interactions S35 combined OATP1/CYP3A4 interaction. Fluvastatin inter- relative risk to an exposed patient.17 An interaction result- actions are predominately related to complete inhibition of ing in less than a 2-fold increase in statin AUC, a marker CYP2C9. The AUC changes for fluvastatin involve for systemic exposure, would be classified as ‘‘mild’’ risk. OAT1B3 and BCRP. There is a strong likelihood that Interactions producing more than a 2- but less than 5-fold pharmacogenetic differences in intestinal BCRP are the increase in systemic exposure would be classified as ‘‘mod- cause of the fluvastatin/cyclosporine interaction. Pitavasta- erate.’’ A strong interaction would result in a 5-fold or tin is largely eliminated through OATP1B1. Although this higher increase in statin exposure. This system should is a common pathway for erythromycin and gemfibrozil, only be used as a guide, because an individual patient’s the AUC changes in these drug combinations with pitavas- response may be dictated by other clinical features, such tatin are less than predicted. The cause may be only partial as inherent susceptibility to statin-related myopathy, un- inhibition of OATP1B1. identified genetic predisposition, and history or presence Multiple mechanisms including complete inhibition of of other predictors of statin muscle side effects (eg, hypo- various OATPs (1B1 and OAT3 enzyme systems, inhibition thyroidism, vitamin D deficiency, electrolyte disturbances, of intestinal efflux, and intestinal BCRP and possibly other low baseline muscle mass).11 proteins) may be responsible for increased blood levels of statins (Table 4).8 These cannot always be accurately pre- Understanding package labeling dicted by pharmacokinetic modeling. Pravastatin and gemfibrozil theoretically would produce a DDI by completely The US Food and Drug Administration (FDA) label inhibiting OAT1B1; however, gemfibrozil is also able to repository maintains copies of all statin labeling.18 The re- inhibit the renal transporter OAT3. This suggests the possi- pository first used the portable document format and then bility that the drug interaction involves mediation of both transitioned to the new technology called the ‘‘structured the hepatic and renal pathways. Similarly, the interaction product label’’ for use in the National Library of Medicine. of cyclosporine and pravastatin cannot be attributed solely Changes up until 2008 were minor, adding only new indica- to OAT1B1 inhibition. Therefore, other potential mecha- tions, drug interactions, or adverse reactions. With the nisms of intestinal efflux may be responsible. possible exception of the 2001 cerivastatin (Baycol) recall, The cyclosporine induced changes in rosuvastatin AUC warning information was sparse. Starting with its review of are likely related to inhibition of all active uptake ezetimibe/simvastatin (Vytorin) in the Ezetimibe and Sim- (OATP1B1, NTCP, and OATP1B3) in addition to intestinal vastatin in Hypercholesterolemia Enhances Atherosclerosis BCRP. The gemfibrozil/rosuvastatin DDI could be related Regression study, the FDA began issuing study review com- to inhibition of both OATP1B1/3 and OAT3. There may be munications and commenced major labeling changes for the issues with this theory in day-to-day clinical practice, various statins. In 2011, dosing limits on simvastatin were where many patients may not present with the DDI. established and the labeling for both lovastatin and simva- Following the previous discussion, it is important to statin was revised. Subsequent labeling changes included know how the statins and their potential interactants affect obviating the need for routine liver transaminase monitoring, intestinal, hepatic, and possibly renal efflux pumps. There suggested dosing limits on concomitant statin prescription are likely pharmacogenetic differences among various with either niacin, amiodarone, or calcium channel blockers, cohorts involving differing hepatic uptake (via OATP1B1/ and warnings regarding statin-induced cognitive impairment 3 and NTCP), first-pass metabolism via CYP3A4, absorp- and diabetes mellitus. The FDA is assuming a greater role in tion via BCRP, and renal elimination by OAT3. Under- postmarketing surveillance and keeping package labeling standing more definitively how these drugs affect or are current with contemporary literature.19–21 affected by these enzyme and transport systems can be Using the concepts presented here, the 2012 simvastatin useful in DDI prediction. Although not fully recognized (Zocor) package insert can be examined as an example.22 until studying cerivastatin interactions, glucuronidation is The values of the geometric mean ratio, AUC, and now identified as a common metabolic pathway for the maximum concentration are determined separately. Each conversion of active open acid forms of several statins dose is compared with the reference dose on a pairwise ba- (including atorvastatin and rosuvastatin) to their lactone sis. The geometric mean ratios for each dose level are form. Catabolism of lactone forms of statins is common to CYP3A4 enzyme activity.

Suggested nomenclature for classifying statin drug interaction

There appears to be a concentration-dependent relationship between the risk of myopathy/myonecrosis (clinical Figure 3 A proposed ranking of signiﬁcance with respect to rhabdomyolysis) and the serum concentration of a statin. area under the curve (AUC) changes and drug-drug interaction As such, we propose adopting the system shown in Figure 3 possibilities. AUC, area under the curve; CYP, cytochrome for the clinician to apply drug interaction studies with the P450. Adapted from Rodrigues et al.17 S36 Journal of Clinical Lipidology, Vol 8, No 3S, June 2014

Table 5 Simvastatin drug interactions22 Geometric mean ratio (ratio* with/without coadministered drug) Coadministered drug and dosing regimen Simvastatin (mg) Simvastatin form No effect 5 1.00 AUC Contraindicated with simvastatin Telithromycin† 200 mg QD for 4 d 80 mg Simvastatin acid‡ 12 Simvastatin 8.9 Nelﬁnavir† 1250 mg BID for 14 d 20 mg QD for 28 d Simvastatin acid‡ 6.2 Simvastatin † ‡ Itraconazole 200 mg QD for 4 d 80 mg Simvastatin acid AUC not reported Cmax Simvastatin 13.1 Posaconazole 100 mg (oral suspension) QD for 13 d 40 mg Simvastatin acid 7.3 Simvastatin 10.3 200 mg (oral suspension) QD for 13 d 40 mg Simvastatin acid 8.5 Simvastatin 10.6 Avoid .1 quart of grapefruit juice with simvastatin Grapefruit juicex (high dose) 60 mg single dose Simvastatin acid 7 Simvastatin 16 200 mL of double-strength TIDjj Grapefruit juicex (low dose) 20 mg single dose Simvastatin acid 1.3 Simvastatin 1.9 8 oz (about 237 mL) of single-strength{ Avoid taking with .10 mg simvastatin, based on clinical and/or postmarketing experience Verapamil SR 240 mg QD days 1-7 then 80 mg on day 10 Simvastatin acid 2.3 240 mg BID on days 8-10 Simvastatin 2.5 Diltiazem 120 mg BID for 10 d 80 mg on day 10 Simvastatin acid 2.69 Simvastatin 3.10 Diltiazem 120 mg BID for 14 d 20 mg on day 14 Simvastatin 4.6 Avoid taking with .20 mg simvastatin, based on clinical and/or post-marketing experience Amiodarone 400 mg QD for 3 d 40 mg on day 3 Simvastatin acid 1.75 Simvastatin 1.76 Amlodipine 10 mg QD x 10 d 80 mg on day 10 Simvastatin acid 1.58 Simvastatin 1.77 Ranolazine SR 1000 mg BID for 7 d 80 mg on day 1 and Simvastatin acid 2.26 days 6-9 Simvastatin 1.86 No dosing adjustments required for the following Fenoﬁbrate 160 mg QD ! 14 d 80 mg QD on days 8-14 Simvastatin acid 0.64 Simvastatin 0.89 Niacin extended-release** 2 g single 20 mg single dose Simvastatin acid 1.6 dose Simvastatin 1.4 Propranolol 80 mg single dose 80 mg single dose Total inhibitor 0.79 Active inhibitor 0.79

AUC, area under the curve; BID, twice a day; Cmax, maximum concentration; TID, 3 times a day; QD, every day; SR, slow release. *Results based on a chemical assay except results with propranolol as indicated. †Results could be representative of the following cytochrome P450 3A4 isozyme inhibitors: ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors, and nefazodone. ‡Simvastatin acid refers to the b-hydroxyacid of simvastatin. xThe effect of amounts of grapefruit juice between those used in these 2 studies on simvastatin pharmacokinetics has not been studied. jjDouble strength: 1 can of frozen concentrate diluted with 1 can of water. Grapefruit juice was administered TID for 2 d, and 200 mL together with single-dose simvastatin and 30 and 90 min after single-dose simvastatin on day 3. {Single strength: 1 can of frozen concentrate diluted with 3 cans of water. Grapefruit juice was administered with breakfast for 3 d; simvastatin was administered in the evening on day 3. **Chinese patients have an increased risk for myopathy with simvastatin coadministered with lipid-modifying doses ($1 g/day niacin) of niacin- containing products. Because the risk is dose-related, it is recommended that Chinese patients not receive simvastatin 80 mg coadministered with lipid-modifying doses of niacin-containing products. Kellick et al Statins and drug interactions S37 compared with the reference dose. If the confidence inter- elimination, is not as susceptible to drug interactions by the vals include unity, it is implied that the relationship CYP3A4 pathway. For example, the same CYP3A4 inhib- between the test dose and the reference dose is propor- itor will produce a much larger increase in simvastatin tional. If the lower confidence interval lies just less than AUC compared with the increase in atorvastatin AUC.30,31 1.0, this may be an indication that the true response at Atorvastatin, although less likely to cause CYP3A4 interac- this level is slightly more than dose-proportional compared tions, has potentially similar drug interactions. If poten- with the reference dose level. This concept may be tially interacting medications must be used, it is wise to confusing to the understanding of the true potential for clin- choose a statin metabolized through a different enzyme sys- ically significant DDIs. tem. Rosuvastatin, pravastatin, pitavastatin, and fluvastatin More recent package inserts for statins (Lipitor, Crestor, are associated with fewer potentially severe interactions Livalo) provide greater clarity.23–25 The statin AUC, when than those noted previously. Although there are fewer coadministered with the reference drug, is expressed as an interacting medications involving severe and major drug x-fold change and represents a simple ratio between coad- interactions for the non-CYP3A4 metabolized statins ministration and statin alone (ie, 1-fold 5 no change). (Table 13), commonalities still exist. This concept appears simpler and provides information Fibrate: Recently, the American College of Cardiology/ similar to that in package inserts of other drug classes as American Heart Association guidance on cholesterol well as many clinical prediction models. The modified pack- management made a strong statement against using gem- age inserts for drug coadministered interactions are shown in fibrozil with ANY statin.32 Gemfibrozil is known to Tables 5–11.22–28 These tables are by no means complete, reduce the glucuronidation and elimination of statins. If hence current reference sources, such as Table 1229 and a fibrate is to be used in combination with a statin, other contemporary drug interaction references should be then fenofibrate is generally the fibrate of choice. Each consulted before prescribing interacting drugs. statin has its own limitations with respect to gemfibrozil, Table 13 suggests dose limits for various drugs based on and some formularies still allow open gemfibrozil utili- FDA package labeling. As new drugs are approved, the zation. Understanding the potential for pharmacokinetic FDA does not always update the statin package inserts, interactions between fibrates and statins may be a good even if a suspected dose limit may occur. It is often best guide for practitioners if gemfibrozil is still to be consid- to consult proprietary drug databases that reference these ered (Table 14). limits for the most up to date information. Over-the-counter supplements, medications, and foods: The Natural Medicines Comprehensive Database Common interacting drugs and over-the-counter is the most frequently used resource to investigate medications, supplements, and foods over-the-counter supplements/medicines and their effects on statin medications. For ease, the most common When the potential for simvastatin/lovastatin interac- interactions can be divided into major (do not use) and tions is examined, many common drugs can cause clinical moderate (clinical outcome not severe). Concomitant issues. Atorvastatin, being less dependent on CYP3A4 for ingestion of alcohol and statins, and other medications

Table 6 Lovastatin drug interactions26

Geometric mean ratio (ratio* with/without coadministered drug) No effect 5 1.00 AUC Coadministered drug and dosing regimen Lovastatin (mg) Lovastatin Lovastatin acid Gemﬁbrozil 600 mg BID for 3 d 40 mg 0.96 2.80 Itraconazole 200 mg QD for 4 d 40 mg on day 4 .36† 22 Itraconazole 100 mg QD for 4 d 40 mg on day 4 .14.8† 15.4 Grapefruit juice (high dose) 200 mL of double 80 mg single dose 15.3 5.0 strength Grapefruit juice (low dose) about 250 mL of single 40 mg single dose 1.94 1.57 strength for 4 d Cyclosporine (dose NA) 10 mg daily for 10 d 5- to 8-fold ND Total lovastatin acid Diltiazem 120 mg BID for 14 d 20 mg 3.57 AUC, area under the curve; BID, twice a day; NA, not applicable; ND, not determined; QD, every day. *Results based on a chemical assay. †Estimated minimum change. S38 Journal of Clinical Lipidology, Vol 8, No 3S, June 2014

Table 7 Atorvastatin drug interactions23 Coadministered drug and dosing regimen Atorvastatin dose (mg) Atorvastatin change in AUC* Cyclosporine 5.2 mg/kg/d, stable dose 10 mg QD for 28 d [ 8-fold‡ Tipranavir 500 mg BID/ritonavir 200 mg BID for 7 d 10 mg SD [ 9.4-fold‡ Telaprevir 750 mg every 8 h for 10 d 20 mg SD [ 7.88-fold‡ Saquinavir 400 mg BID/ritonavir 400 mg BID for 15 d† 40 mg QD for 4 d [ 3.9-fold‡ Clarithromycin 500 mg BID for 9 days 80 mg QD for 8 d [ 4.4-fold‡ Darunavir 300 mg BID/ritonavir 100 mg BID for 9 d 10 mg QD for 4 d [ 3.9-fold‡ Itraconazole 200 mg QD for 4 d 40 mg SD [ 3.3-fold‡ Fosamprenavir 700 mg BID/ritonavir 100 mg BID for 14 d 10 mg QD for 4 d [ 2.53-fold‡ Fosamprenavir 1400 mg BID for 14 d 10 mg QD for 4 d [ 2.3-fold‡ Nelfinavir 1250 mg BID for 14 d 10 mg QD for 28 d [ 74%‡ Grapefruit juice 240 mL QD 40 mg SD [ 37% Diltiazem 240 mg QD for 28 d 40 mg SD [ 51% Erythromycin 500 mg QID for 7 d 10 mg SD [ 51% Amlodipine 10 mg, single dose 80 mg [ 15% Cimetidine 300 mg QD for 4 wk 10 mg QD for 2 wk Y Less than 1% Colestipol 10 mg BID for 28 wk 40 mg QD for 28 wk Not determined Maalox TC 30 mL QD for 17 d 10 mg QD for 5 d Y 33% Efavirenz 600 mg QD for 14 d 10 mg QD for 3 d Y 41% Rifampin 600 mg QD, 7 d (coadministered)† 40 mg SD [ 30%‡ Rifampin 600 mg QD, 5 d (doses separated)† 40 mg SD Y 80% Gemfibrozil 600 mg BID 7 d 40 mg SD [ 35% Fenofibrate 160 mg QD 7 d 40 mg SD [ 3% AUC, area under the curve; BID, twice a day; QD, every day; QID, 4 times a day; SD, single dose. *Results based on a chemical assay. †Because of the dual interaction mechanism of rifampin, simultaneous coadministration of atorvastatin with rifampin is recommended, because delayed administration of atorvastatin after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations. ‡Clinically significant.

metabolized through the liver, can result in DDIs. Special populations with potentially increased Although no speciﬁc quantity recommendations are risk for DDIs available, moderate amounts of alcohol (2 standard drinks in a 24-hour period) offer less concern for phar- Elderly: More elderly patients are being treated with macokinetic and pharmacodynamic effects than larger statins. As muscle mass decreases with aging, there amounts. Grapefruit juice contains bergamottin, a natural may be an increased risk of myopathy in elderly patients. furanocoumarin, which can inhibit CYP3A4 and OAT. In addition, polypharmacy is pervasive in the elderly and This inhibitory effect can last for up to 24 hours. Either increases the chance of a DDI. As age increases, metab- grapefruit juice should be avoided with statins or the olizing enzymes may be less functional as well, quantity consumed should be kept to less than 60 mL. increasing the likelihood of increased AUC and more Separating administration of grapefruit juice and statins DDIs. It is critical that elderly patients on polypharmacy by 4 hours may limit the interaction. be regularly reevaluated for the risk of DDIs and drug Like grapefruit, sweet orange (citrus sinensis) juice may lists be rigorously kept up to date.33–36 Atorvastatin inhibit OATP. Tangerines are related to the sweet orange and rosuvastatin may mildly increase serum concentra- and may also have an interaction. Separation of the fruit or tions of ethinyl estradiol and norgestrel, which may be juice from statin administration by 4 hours may be advis- used as part of postmenopausal therapies. able. St John’s wort induces CYP3A4. There are noted Chinese/Japanese: Pharmacokinetic data have shown major interactions between statins and St. John’s wort, and that Asians taking statins have higher serum levels of these this combination should be avoided. St. John’s wort drugs than Caucasians. The FDA has issued caution when mediates P-gp. It will decrease metabolism of simvastatin treating Chinese patients with simvastatin doses and possibly atorvastatin, but not likely pravastatin, ﬂuvas- exceeding 20 mg/day administered with niacin.37 This fol- tatin, or rosuvastatin. Red yeast rice is a popular nonpre- lowed the observation in the Heart Protection Study 2 of scription treatment for hyperlipidemia. Red yeast rice has increased risk of myopathy in those taking simvastatin varying amounts of monacolin K (similar to lovastatin). 40 mg administered with niacin-containing products Products are not standardized and no red yeast rice product (.1 g/day). Rosuvastatin labeling notes higher blood should be given to a patient taking a prescription statin. levels in patients of Asian heritage (Filipino, Chinese, Kellick et al Statins and drug interactions S39

Table 8 Rosuvastatin drug interactions24 Coadministered drug and dosing regimen Rosuvastatin dose (mg)* Rosuvastatin change in AUC Cyclosporine (stable dose required 75-200 mg BID) 10 mg/d for 10 d [ 10-fold‡ Gemfibrozil 600 mg BID ! 7 d 80 mg [ 1.9-fold‡ Lopinavir/ritonavir combination 400 mg/100 mg BID for 10 d 20 mg/day for 7 d [ 2-fold‡ Atazanavir/ritonavir combination 300 mg/100 mg QD for 7 d 10 mg [ 3.1-fold‡ Eltrombopag 75 mg QD for 5 d 10 mg [ 3.1-fold Tipranavir/ritonavir combination 500 mg/200 mg BID for 11 d 10 mg [ 26% Dronedarone 400 mg BID 10 mg [ 1.4-fold Itraconazole 200 mg QD for 5 d 10 mg or 80 mg [ 39% [ 28% Ezetimibe 10 mg daily for 14 d 10 mg daily for 14 d [ 1.2-fold Fosamprenavir/ritonavir 700 mg/100 mg BID for 7 d 10 mg [ 8% Fenofibrate 67 mg TID for 7 d 10 mg [ 7% Aluminum and magnesium hydroxide combination 40 mg Y 54%‡ antacid administered simultaneously; 40 mg Y 22% administered 2 h apart Erythromycin 500 mg QID for 7 d 80 mg Y 20% Ketoconazole 200 mg BID for 7 d 80 mg [ 2% Itraconazole 200 mg QD for 5 d 10 mg [ 39% 80 mg [ 28% Fluconazole 200 mg QD for 11 d 80 mg [ 14% AUC, area under the curve; BID, twice a day; QD, every day; QID, 4 times a day, TID, 3 times a day. †Mean ratio (with/without coadministered drug and no change 5 1-fold) or % change (with/without coadministered drug and no change 5 0%); symbols of [ and Y indicate the exposure increase and decrease, respectively. *Single dose unless otherwise noted. ‡Clinically significant.

Japanese, Korean, Vietnamese, or Asian-Indian). A 5-mg in the pitavastatin labeling. Atorvastatin and ﬂuvastatin rosuvastatin initiation dose may be appropriate for this offer no current special population warning for Asian group. Pitavastatin was recently approved based on groups. Labeling in Asian countries differs from the research in Japanese patients. Differences in Japanese higher doses used in the United States. Initiation of ther- and Caucasian pharmacokinetics with pitavastatin are still apy with low doses of all statins in Asian and Asian- under investigation. No speciﬁc recommendations appear American patients remains the most prudent approach.37

Table 9 Fluvastatin drug interactions27 Coadministered drug and dosing regimen Fluvastatin dose (mg)* Fluvastatin change in AUC† Cyclosporine – stable dose BID‡ 20 mg QD for 14 wk [ 90% Fluconazole 400 mg QD d 1200 mg BID d 2-4‡ 40 mg QD [ 84% Cholestyramine 8 g QD 20 mg QD administered 4 h after Y 51% a meal plus cholestyramine Rifampicin 600 mg QD for 6 d 20 mg QD Y 53% Cimetidine 400 mg BID for 5 d, QD on day 6 20 mg QD [ 30% Ranitidine 150 mg BID for 5 d, QD on day 6 20 mg QD [ 10% Omeprazole 40 mg QD for 6 d 20 mg QD [ 20% Phenytoin 300 mg QD 40 mg BID for 5 d [ 40% Propranolol 40 mg BID for 3.5 d 40 mg QD Y 5% Digoxin 0.1-0.5 mg QD for 3 wk 40 mg QD No change Diclofenac 25 mg QD 40 mg QD for 8 days [ 50% Glyburide 5-20 mg QD for 22 d 40 mg BID for 14 d [ 51% Warfarin 30 mg QD 40 mg QD for 8 d [ 30% Clopidogrel 300 mg loading dose on 80 mg XL QD for 19 d Y 2% day 10, 75 mg dose on days 11-19 AUC, area under the curve; BID, twice a day; QD, every day. *Single dose, unless otherwise noted. †Mean ratio (with/without coadministered drug and no change 5 1-fold) or % change (with/without coadministered drug and no change 5 0%); symbols of [ and Y indicate the exposure increase and decrease, respectively. ‡Considered clinically signiﬁcant. S40 Journal of Clinical Lipidology, Vol 8, No 3S, June 2014

Table 10 Pravastatin drug interactions28 Coadministered drug and dosing regimen Pravastatin dose (mg) Pravastatin change in AUC Cyclosporine 5 mg/kg single dose 40 mg single dose [ 282% Clarithromycin 500 mg BID for 9 d 40 mg QD ! 8d [ 110% Boceprevir 800 mg TID for 6 d 40 mg single dose [ 63% Darunavir 600 mg BID/Ritonavir 100 mg BID for 7 d 40 mg single dose [ 81% Colestipol 10 g single dose 20 mg single dose Y 47% Cholestyramine 4 g single dose 20 mg single dose Administered simultaneously Y 47% Administered 1 h before cholestyramine [ 12% Administered 4 h after cholestyramine Y 12% Cholestyramine 24 g daily for 4 wk 20 mg BID for 8 wk Y 51% 5 mg BID for 8 wk Y 38% 10 mg BID for 8 wk Y 18% Fluconazole 200 mg IV for 6 d 20 mg PO 1 10 mg IV Y 34% 200 mg PO for 6 d 20 mg PO 1 10 mg IV Y 16% Kaletra 400 mg/100 mg BID for 14 d 20 mg daily for 4 d [ 33% Verapamil IR 120 mg for 1 d and verapamil ER 480 mg for 3 d 40 mg single dose [ 31% Cimetidine 300 mg QID for 3 d 20 mg single dose [ 30% Antacids 15 mL QID for 3 d 20 mg single dose Y 28% Digoxin 0.2 mg daily for 9 d 20 mg daily for 9 d [ 23% Probucol 500 mg single dose 20 mg single dose [ 14% Warfarin 5 mg daily for 6 d 20 mg BID for 6 d Y 13% Itraconazole 200 mg daily for 30 d 40 mg daily for 30 d [ 11% (compared with day 1) Gemﬁbrozil 600 mg single dose 20 mg single dose Y 7.0% Aspirin 324 mg single dose 20 mg single dose [ 4.7% Niacin 1 g single dose 20 mg single dose Y 3.6% Diltiazem 20 mg single dose [ 2.7% Grapefruit juice 40 mg single dose Y 1.8% AUC, area under the curve; BID, twice a day; ER, extended release; IR, immediate release; IV, intravenous; PO, orally; QD, every day; QID, 4 times a day; TID, 3 times a day.

HIV: Recently, the FDA issued warnings about protease statins. These are usually speciﬁc to the drugs metabo- inhibitors and non-nucleoside reverse transcriptase inhib- lized by CYP3A4. Current National Institutes of Health itors used in highly active antiretroviral therapy and guidelines recommend ﬂuvastatin, pitavastatin, and

Table 11 Pitavastatin drug interactions25 Pitavastatin change Coadministered drug and dosing regimen Dose regimen in AUC* Cyclosporine 2 mg/kg/d on day 6 Pitavastatin 2 mg QD [ 4.6-fold† Erythromycin 500 mg 4 times daily for 5 d Pitavastatin 4 mg single dose on day 4 [ 2.8-fold† Rifampin 600 mg QD for 5 d Pitavastatin 4 mg QD [ 29% Atazanavir 300 mg daily for 5 d Pitavastatin 4 mg QD [ 31% Darunavir/ritonavir 800 mg/100 mg QD on days 6-16 Pitavastatin 4 mg QD on days 1-5 and 12-16 Y 26% Lopinavir/ritonavir 400 mg/100 mg BID on days 9-24 Pitavastatin 4 mg QD on days 1-5 and 20-24 Y 20% Gemfibrozil 600 mg BID for 7 d Pitavastatin 4 mg QD [ 45% Fenofibrate 160 mg daily for 7 d Pitavastatin 4 mg QD [ 18% Ezetimibe 10 mg daily for 7 d Pitavastatin 2 mg QD Y 2% Enalapril 20 mg daily for 5 d Pitavastatin 4 mg QD [ 6% Digoxin 0.25 mg daily for 7 d Pitavastatin 4 mg QD [ 4% Diltiazem LA 240 mg on days 6-15 Pitavastatin 4 mg QD on days 1-5 and 11-15 [ 10% Grapefruit juice for 4 d (quantity not specified) Pitavastatin 2 mg single dose on day 3 [ 15% Itraconazole 200 mg daily for 5 d Pitavastatin 4 mg single dose on day 4 Y 23% BID, twice daily; QD, once daily; LA, long acting. *Data presented as x-fold change represent the ratio between coadministration and pitavastatin alone (ie, 1-fold 5 no change). Data presented as % change represent % difference relative to pitavastatin alone (ie, 0% 5 no change). †Considered clinically significant. Kellick et al Statins and drug interactions S41

Table 12 Comparison of drug-drug interactions across all statins Level 3 (moderate) Level 4 (mild) Level 1 (severe) Level 2 (major) *Less likely to cause *Unlikely to cause *Do not use* *Use with caution* severe drug interaction* drug interaction* Simvastatin/lovastatin Protease inhibitors Amiodarone Afatinib Barbiturates Boceprevir Amlodipine Aprepitant Carbamazepine Clarithromycin Conivaptan Fosaprepitant Clopidogrel Cobicistat Diltiazem Bosentan Nevirapine Elvitegravir Dronedarone Colchicine Emtricitabine Efavirenz Dalfopristin/quinupristin Tenofovir Other fibrates Daptomycin Cyclosporine Fluconazole Digoxin Oxcarbazepine Danazol Grapefruit juice Esomeprazole Rifabutin Delavirdine Imatinib Fluvoxamine Rifapentine Erythromycin Lomitapide Fosphenytoin Gemfibrozil Ranolazine Lansoprazole Itraconazole Simeprivir Niacin, niacinamide Ketoconazole Ticagrelor Omeprazole Nefazodone Troleandomycin Pantoprazole Posaconazole Verapamil Phenytoin Red yeast Rice Quinine Telaprevir Repaglinide Telithromycin Rifampin Voriconazole St. John’s wort Warfarin Atorvastatin Posaconazole Boceprevir Amiodarone Barbiturates Red yeast rice Clarithromycin Antacids Carbamazepine Telithromycin Conivaptan Aprepitant Cimetidine Voriconazole Cyclosporine Fosaprepitant Clopidogrel Darunavir Atazanavir Miconazole Delavirdine Bosentan Nevirapine Digoxin Colchicine Oral contraceptives Diltiazem Colestipol Oxcarbazepine Erythromycin Dalfopristin/quinupristin Pioglitazone Fluconazole Danazol Rifabutin Fosamprenavir Daptomycin Rifapentine Gemfibrozil Efavirenz Spironolactone Grapefruit juice Imatinib Esomeprazole Itraconazole Fosphenytoin Ketoconazole Indinavir Lopinavir/ritonavir Lansoprazole Nefazodone Mifepristone Nelfinavir Niacin, niacinamide Other fibrates Nilotinib Saquinavir Omeprazole Simeprivir Telaprevir Pantoprazole Tipranavir Phenytoin Troleandomycin Quinine Verapamil Ranolazine Rifampin St. John’s wort Warfarin Rosuvastatin Red yeast rice Antacids Colchicine Erythromycin Atazanavir Daptomycin Oral contraceptives Clarithromycin Darunavir Cyclosporine Indinavir (continued on next page) S42 Journal of Clinical Lipidology, Vol 8, No 3S, June 2014

Table 12 (continued)

Level 3 (moderate) Level 4 (mild) Level 1 (severe) Level 2 (major) *Less likely to cause *Unlikely to cause *Do not use* *Use with caution* severe drug interaction* drug interaction* Fosamprenavir Itraconazole Gemfibrozil and other fibrates Niacin, niacinamide Lopinavir/Ritonavir Warfarin Nelfinavir Ritonavir Saquinavir Simeprivir Telithromycin Pravastatin Red yeast rice Bile acid resins Boceprevir Clarithromycin Colchicine Cyclosporine Daptomycin Darunavir Itraconazole Erythromycin Niacin, niacinamide Gemfibrozil and other fibrates Orlistat Simeprivir Telithromycin Warfarin Fluvastatin Red yeast rice Cyclosporine Amiodarone Clopidogrel Erythromycin Antiretroviral protease inhibitors Irbesartan Gemfibrozil and other fibrates Cholestyramine Rifabutin Telithromycin Cimetidine Rifapentine Colchicine Zafirlukast Daptomycin Delavirdine Diclofenac Digoxin Efavirenz Ethanol Fluconazole Fluoxetine Fluvoxamine Glyburide Imatinib Niacin, niacinamide Nilotinib Omeprazole Phenytoin Ranitidine Rifampin Sulfinpyrazone Sulfonamides Voriconazole Warfarin Pitavastatin Cyclosporine Atazanavir Colchicine Warfarin Red yeast rice Darunavir Niacin, niacinamide Erythromycin Raltegravir Fosamprenavir Gemfibrozil and other fibrates Lopinavir; Ritonavir Rifampin Ritonavir Saquinavir Simeprivir Telithromycin Tipranavir

Adapted with permission from Clinical Pharmacology [database online]. Tampa, FL: Elsevier/Gold Standard, Inc.; 2013.29 Kellick et al Statins and drug interactions S43

Table 13 Dose limits of various statins with respect to various interacting medications21–29,47 Statin/interactant Simva Lova Atorva Rosuva Prava Fluva Pitava Ketoconazole Avoid Avoid Posaconazole Avoid Avoid Boceprevir Avoid Avoid No mention Simeprevir Caution Caution Caution Caution Caution Caution Nefazodone Avoid Avoid Cyclosporine Avoid Avoid Avoid 5 mg/d 20 mg/d 20 mg/d Gemfibrozil Avoid Avoid Avoid 10 mg/d Avoid Caution Avoid Danazol Avoid Avoid Tipranavir Avoid Telaprevir Avoid HIV protease inhibitor Avoid Avoid 20 mg* 10 mg* Verapamil diltiazem 10-mg limit Clarithromycin 20-mg limit 40-mg limit Itraconazole 20-mg limit Fosamprenavir 6 ritonavir 20-mg limit Nelfinavir 40-mg limit Fluconazole 20 mg/d Amiodarone 20-mg limit Amlodipine Ranolazine Grapefruit juice Avoid large Avoid large quantity quantity Niacin Limit to 1 g/d Limit to 1 g/d Limit to 1 g/d Limit to 1 g/d Limit to 1 g/d Erythromycin 1 mg/d Rifampin 2 mg/d atorva, atorvastatin; fluva, fluvastatin; lova, lovastatin; pitava, pitavastatin; prava, pravastatin; rosuva, rosuvastatin; simva, simvastatin.

pravastatin (except for pravastatin with darunavir/ritona- fluvastatin have a moderate antiviral effect, and pravasta- vir) over lovastatin and simvastatin. Atorvastatin and ro- tin has no antiviral activity. With respect to worrisome suvastatin may be used with caution. In combination DDIs with antiviral drugs as part of new therapy for hep- with non-nucleoside reverse transcriptase inhibitors, atitis C, boceprevir, classified as a nonstructural protein some statins may have increased efficacy, whereas others 3/4A protease inhibitor should not be given with simva- may have decreased efficacy (Table 15).38,39 statin or lovastatin. Boceprevir is a potent inhibitor of Hepatitis C and nonalcoholic fatty liver disease CYP3A4. An atorvastatin/boceprevir interaction has not (NAFLD): Hepatitis C is a leading cause of liver failure been noted. Conversely, telaprevir, also an NS3/4A pro- and transplantation. Data have already demonstrated the tease inhibitor, is contraindicated with simvastatin, lova- increased cardiovascular risk of patients with hepatitis C. statin, and atorvastatin. Non-CYP3A4 statins should be In this condition, statins may not only help prevent car- used when patients are subjected to treatment with these diovascular disease but may also block the protein syn- newer agents. Statins do not appear to affect the concen- thesis necessary for hepatitis C replication. One study trations of sofosbuvir. suggested that simvastatin administered as monotherapy Simeprevir on the other hand inhibits OATP1B1. has the strongest antiviral activity, lovastatin and Rosuvastatin dose should be initiated at 5 mg once daily and not exceed 10 mg daily. Atorvastatin should be started Table 14 Statin/fibrate combination therapy: at the lowest dose and not exceed 40 mg daily. Simvastatin pharmacokinetic interactions22–28,46,47 doses should be kept lowest as needed and no data is noted with pitavastatin, lovastatin, or lovastatin and doses should Statin Gemfibrozil Fenofibrate also be kept as low as possible.28 [ Atorvastatin in Cmax (expected) No change Using statins in patients with NAFLD has long been a [ Simvastatin in Cmax by 2-fold No change subject of controversy. NAFLD includes disorders ranging [ Pravastatin in Cmax by 2-fold No change from simple hepatic steatosis to nonalcoholic steatohepati- [ Rosuvastatin in Cmax by 2-fold No change tis and cirrhosis. Covered in another article in this publi- Fluvastatin No change No change cation, it should be noted that changes in alanine Lovastatin [ in C by 2.8-fold No change max aminotransferase often occur independently of statin ther- Pitavastatin [ in Cmax by 41% Unknown apy. Most recently, the FDA has obviated the need for Cmax, maximum concentration. routine liver function testing because minor elevations have S44 Table 15 Drug interactions between highly active antiretroviral therapy regimens and other drugs39 Drug PI Effect on PI or concomitant drug concentrations Recommendation Atorvastatin ATV/r [ atorvastatin possible Titrate atorvastatin dose carefully and use lowest dose necessary ATV DRV/r DRV/r 1 atorvastatin 10 mg similar to atorvastatin Titrate atorvastatin dose carefully and use the lowest necessary dose. Do not exceed 20 mg FPV/r 40 mg administered alone; atorvastatin daily FPV FPV 6 RTV [ atorvastatin AUC 130% to 153%; SQV/r SQV/r [ atorvastatin AUC 79% LPV/r LPV/r [ atorvastatin AUC 488% Use with caution and use the lowest atorvastatin dose necessary TPV/r [ atorvastatin AUC 836% DO NOT COADMINISTER Lovastatin All PIs Significant [ lovastatin expected Contraindicated. Do not coadminister Pitavastatin All PIs ATV [ pitavastatin AUC 31% and Cmax [ 60% No dose adjustment necessary ATV: no significant effect LPV/r Y pitavastatin AUC 20% LPV: no significant effect Pravastatin DRV/r Pravastatin AUC [ 81% Use lowest possible starting dose of pravastatin with careful monitoring LPV/r Pravastatin AUC [ 33% No dose adjustment necessary SQV/r pravastatin AUC Y 47% to 50% No dose adjustment necessary Rosuvastatin ATV/r ATV/r [ rosuvastatin AUC 3-fold and Titrate rosuvastatin dose carefully and use the lowest necessary dose. Do not exceed 10 mg LPV/r Cmax [ 7-fold rosuvastatin daily LPV/r [ rosuvastatin AUC 108% and Cmax [ 366% DRV/r rosuvastatin AUC [ 48% and Cmax [ 139% Titrate rosuvastatin dose carefully and use the lowest necessary dose while monitoring for toxicities FPV 6 RTV No significant effect on rosuvastatin No dosage adjustment necessary SQV/r No data available Titrate rosuvastatin dose carefully and use the lowest necessary dose while monitoring for toxicities

TPV/r rosuvastatin AUC [ 26% and Cmax [ 123% No dose adjustment necessary 2014 June 3S, No 8, Vol Lipidology, Clinical of Journal Simvastatin All PIs Signiﬁcant [ simvastatin level; CONTRAINDICATED, do not coadminister SQV/r 400 mg/400 mg BID [ simvastatin AUC 3059%

Concomitant drug class/name NNRTI Effect on NNRTI or concomitant drug concentrations Recommendations Fluvastatin ETR [ fluvastatin possible [ fluvastatin possible Lovastatin EFV Simvastatin AUC Y 68% Adjust simvastatin dose according to lipid responses, not to exceed the maximum recommended Simvastatin dose. If EFV used with RTV-boosted PI, simvastatin and lovastatin should be avoided ETR Y Lovastatin possible Adjust lovastatin or simvastatin dose according to lipid responses, not to exceed the maximum NVP Y Simvastatin possible recommended dose. If ETR or NVP used with RTV-boosted PI, simvastatin and lovastatin should be avoided Pitavastatin EFV, No data No recommendation ETR NVP RPV Pravastatin, rosuvastatin EFV Pravastatin AUC Y 44% rosuvastatin: no data Adjust statin dose according to lipid responses, not to exceed the maximum recommended dose. ETR No significant effect expected No dosage adjustment necessary

ABC, abacavir; APV, amprenavir; ATV/r, ritonavir-boosted atazanavir; AUC, area under the curve; DRV/r, ritonavir- boosted darunavir; ETR, etravirine; EFV, efavirenz; FPV/r, ritonavir-boosted fosamprenavir; LPV/r, ritonavir-boosted lopinavir; NFV, nelﬁnavir; NNRTI, non-nucleoside reverse transcriptase inhibitor; NVP, nevirapine; PI, protease inhibitor; RAL, raltegravir; RPV, rilpivirine; RTV, ritonavir; SQV/r, ritonavir-boosted saquinavir; T20, enfuvirtide; TDF, tenofovir disoproxil fumarate; TPV/r, ritonavir-boosted tipranavir. Kellick et al Statins and drug interactions S45

Table 16 Safety of statins in chronic kidney disease Atorvastatin and fluvastatin are minimally excreted by the kidneys Dosing modifications for other statins (NKF recommendations):46 ➢ Simvastatin and lovastatin: 50% dose reduction if GFR , 30 mg/mL ➢ Pravastatin: no dose adjustment (package insert: start with 10 mg once daily in renal impairment) ➢ Rosuvastatin: not discussed in NKF guidelines (prescribing information: start at 5 mg and do not exceed 10 mg in severe chronic renal insufficiency [creatinine clearance ,30 mL/min] in patients not on dialysis ➢ Pitavastatin: not discussed in NKF guidelines (package insert: patients with moderate and severe renal impairment [GFR 30-59 mL/min/1.73 m2 and 15-29 mL/min/1.73 m2 not receiving hemodialysis, respectively] as well as end- stage renal disease receiving hemodialysis: initial, 1 mg orally daily and maximum 2 mg daily) GFR, glomerular filtration rate; NKF, National Kidney Foundation.

led to physicians inappropriately discontinuing statin that a system to express the likelihood for a statin DDI be therapy, putting patients at increased risk of cardiovascular created as an adjunctive tool for practitioners. disease. The currently labeled recommendations for statins should be used with caution in patients with liver disease who consume substantial amounts of alcohol.40–43 Conclusions Pediatrics: Young adults are rarely on interacting medi- Statin absorption, distribution, metabolism, and excre- cations that would create a clinical dilemma. Some epi- tion are complex and vary from statin to statin. The leptics may be prone to DDIs. As noted previously, transporters and enzymes involved in these processes are some statins may mildly increase serum concentrations now better understood and serve to explain the mechanisms of ethinyl estradiol and norgestrel (found in oral contra- of statin interactions with a variety of drugs that alter what ceptives). The clinical significance is unknown. There is is otherwise an excellent safety profile. As new drugs enter little information with regard to safety issues in children the US market, understanding these mechanisms allows the who are on statins for familial hypercholesterolemia clinician to predict the impact new drugs may have on (FH). Little is known about safety issues in this popula- statin disposition, given the effect of a new drug on known tion and more data and endpoints are needed. The 4 sta- transporters and metabolizing enzyme systems. tins currently approved for use in children with FH by We propose that clinicians become familiar with the the FDA, all with labeling consistent with the recent statins they prefer and refer to an individual statin table to American Heart Association pediatric statement in terms identify drugs they often coprescribe that may interact with of age and when treatment should be started, are lova- a particular statin. Once identified, the potential interacting statin, simvastatin, pravastatin, and atorvastatin.44,45 agent can be classified as having mild, moderate, or severe FH: FH patients present similar challenges with respect interacting potential. One option would be to avoid the to DDIs as other patients on multiple drug regimens. The interaction by changing to a different statin or to a potential for statin and ezetimibe interactions is minor at therapeutic equivalent to the interacting agent. This is the best. Statins and bile acid resins have few interactions preferred option for severe interactions. If a combination other than those attributed to the resin class. The poten- cannot be avoided, the effected statin should be dosed tial for myopathic side effects with the higher doses of according to its identified dosing limit. This is the preferred statins exists, but is similar to the general population. option for interactions with moderate intensity. Patients Chronic kidney disease (CKD)/end-stage renal dis- who receive drug combinations with mild potential for ease: Statins have been shown to reduce cardiovascular interaction may be carefully monitored for symptoms of events in those with CKD (stages I-IV), but not for those statin toxicity because of a low potential for serious side with end-stage renal disease and receiving hemodialysis. effects. Recommendations for statin dosing in CKD patients is shown in Table 16.46 References

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Original Contribution An assessment by the Statin Liver Safety Task Force: 2014 update

Harold Bays, MD, FNLA*, David E. Cohen, MD, PhD, Naga Chalasani, MBBS, Stephen A. Harrison, MD, COL, MC

Louisville Metabolic and Atherosclerosis Research Center, 3288 Illinois Avenue, Louisville, KY 40213, USA (Dr Bays); Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA (Dr Cohen); Indiana University School of Medicine, Indianapolis, IN, USA (Dr Chalasani); and Brooke Army Medical Center, University of Texas Health Center San Antonio, Uniformed Services University of the Health Sciences, San Antonio, TX, USA (Dr Harrison)

KEYWORDS: Abstract: In the 2006 Report of the National Lipid Association’s Statin Safety Task Force, a panel of Cholesterol; experts in hepatology published their ﬁndings on speciﬁc questions related to the liver blood testing National Lipid during statin therapy. Among their recommendations was that regulatory agencies reconsider the Association; statin-labeling recommendation at that time, which required post-statin liver enzyme testing. Since Lipid; then, the Food and Drug Administration altered statin labeling such that unless clinically indicated Liver; for other reasons, after a pre-statin therapy baseline evaluation, follow-up liver enzyme testing was Statin not uniformly required after statin initiation. This 2014 report provides an update on interim issues relevant to statins and liver safety. Some of the points discussed include the value of baseline liver enzymes before initiating statin therapy, safety of statin use in patients with nonalcoholic fatty liver disease, potential drug interactions between statins and drugs used to treat hepatitis, the use of statins in liver transplant recipients, and the use of statins in patients with autoimmune liver disease. Finally, this panel provides diagnostic and algorithmic approaches when evaluating statin-treated patients who experience elevations in liver enzymes. Ó 2014 National Lipid Association. All rights reserved.

Disclosures: In the past 12 months, Dr. Harold Bays has served as a Safety Monitoring Boards of AbbVie and Merck; and his institution has consultant and/or speaker to Amarin, Amgen, Astra Zeneca, Bristol received research grants from Gilead, Intercept, Cumberland, and Enter- Meyers Squibb, Catabasis, Daiichi Sankyo, Eisai, Isis, Merck, Novartis, ome. Dr. Stephen Harrison discloses he has received consulting fees/hon- VIVUS, WPU, and his research site has received research grants from oraria from Merck, Vertex, and the Chronic Liver Disease Foundation; Alere, Amarin, Amgen, Ardea, Astra Zeneca, Boehringer Ingelheim, consulting fees from Nimbus and Genentech; and honoraria from the Bristol-Myers Squibb, California Raisin Board, Catabasis, Eisai, Elcelyx, American Association for Study of Liver Diseases. Eli Lilly, Esperion, Essentialis, Forest, Gilead, Given, GlaxoSmithKline, Disclaimer: The view(s) expressed herein are those of the author(s) and High Point Pharmaceuticals LLC, Hoffman LaRoche, Home Access, Jans- do not reflect the official policy or position of San Antonio Military Med- sen, Merck, Metabolex, Micropharma Limited, Necktar, Novartis, Novo ical Center, the U.S. Army Medical Department, the U.S. Army Office of Nordisk, Omthera, Orexigen, Pfizer, Pronova, Regeneron, Stratum Nutri- the Surgeon General, the Department of the Army, Department of Defense tion, Takeda, TIMI, Transtech Pharma, Trygg, VIVUS, WPU, and or the U.S. Government. Xoma. Dr. David Cohen reports having received consulting fees from * Corresponding author. Merck, Aegerion, Dignity Sciences, Genzyme, and Novartis, and has addi- E-mail address: [email protected] tionally received honoraria from Merck. Dr. Naga Chalasani reports Submitted February 27, 2014. Accepted for publication February 28, serving as a consultant to Aegerion, Salix, and Lilly; is on the Data and 2014.

Evidence grading: Strength of recommendation* Grade Strength of recommendation A Strong recommendation There is high certainty based on the evidence that the net benefit** is substantial B Moderate recommendation There is moderate certainty based on the evidence that the net benefit is moderate to substantial, or there is high certainty that the net benefit is moderate C Weak recommendation There is at least moderate certainty based on the evidence that there is a small net benefit D Recommend against There is at least moderate certainty based on the evidence that it has no net benefit or that the risks/harms outweigh benefits E Expert opinion There is insufficient evidence or evidence is unclear or conflicting, but this is what the expert panel recommends N No recommendation for or against There is insufficient evidence or evidence is unclear or conflicting *The system was adapted as a hybrid of the National Heart Lung and Blood Institutes (NHLBI) rating system (NHLBI cardiovascular-based methodology) used in the new American Heart Association/American College of Cardiology cholesterol guidelines1 and adapted from the original Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system of evidence rating.2 **Net benefit is defined as benefits minus risks/harms of the service/intervention.

Evidence grading: Quality of evidence Type of evidence Quality rating* Well-designed, well-executed RCTs that adequately represent populations to which the results are applied and High directly assess effects on health outcomes Well-conducted meta-analyses of such studies Highly certain about the estimate of effect; further research is unlikely to change our confidence in the estimate of effect RCTs with minor limitations affecting confidence in, or applicability of, the results Moderate Well-designed, well-executed nonrandomized controlled studies and well-designed, well-executed observational studies Well-conducted meta-analyses of such studies Moderately certain about the estimate of effect; further research may have an impact on our confidence in the estimate of effect and may change the estimate RCTs with major limitations Low Nonrandomized controlled studies and observational studies with major limitations affecting confidence in, or applicability of, the results Uncontrolled clinical observations without an appropriate comparison group (eg, case series, case reports) Physiological studies in humans Meta-analyses of such studies Low certainty about the estimate of effect; further research is likely to have an impact on our confidence in the estimate of effect and is likely to change the estimate. RCT, randomized controlled trial. This was the system used in the new American Heart Association/American College of Cardiology cholesterol guidelines1 that were published in the 2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults Report from the Panel members appointed to the Eighth Joint Na- tional Committee.3 Taken from James PA, Oparil S, Carter BL, et al. 2014 Evidence-based guideline for the management of high blood pressure in adults: Report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2013 Dec 18. http://dx.doi.org/10.1001/jama.2013.284427 [Epub ahead of print]. Permission to reuse table granted from the American Medical Association. *The evidence quality rating system used in this guideline was developed by the National Heart, Lung, and Blood Institute’s (NHLBI’s) Evidence-Based Methodology Lead (with input from NHLBI staff, external methodology team, and guideline panels and work groups) for use by all the NHLBI cardiovascular disease guideline panels and work groups during this project. As a result, it includes the evidence quality rating for many types of studies, including studies that were not used in this guideline. Additional details regarding the evidence quality rating system are available in the online Supplement. Bays et al Statin safety: Liver Task Force S49

Because of the frequency of routine blood testing of a ‘‘liver function tests.’’ Elevations in hepatic transaminases ‘‘panel’’ of various laboratory parameters, elevated liver represent a release of enzymes from hepatocytes and are enzymes are commonplace in the day-to-day management not a specific finding related to liver function. More of patients. The challenge to clinicians is to have a accurate assessments of ‘‘liver function’’ would include reasonable and effective approach toward diagnosing albumin, prothrombin time, and perhaps direct bilirubin. various etiologies of elevated liver enzymes, and then to This distinction is important because elevations in ALT determine their clinical meaning in making treatment and/or aspartate aminotransferase (AST) alone may not be decisions. Although many clinicians recognize that mild- of clinical significance. Conversely, elevations in ALT to-moderate elevations in liver enzymes may not always and/or AST associated with elevated bilirubin levels may represent hepatotoxicity, other clinicians may have con- suggest clinically significant acute liver injury (with the cerns that any elevation in liver enzymes might represent caveat that elevated blirubin levels can sometimes be due to harm to patients. benign causes of hyperbilirubinemia, such as Gilbert’s In the clinical development and use of pharmaceuticals, syndrome). relatively common early safety signals that prevent further Mild-to-moderate elevations in liver transaminases, with development or withdrawal of a drug after approval include no increase in bilirubin levels may reflect liver inflammation prolongation of the QT interval on electrocardiogram. (eg, hepatitis). It is also possible these findings are reflective Hepatotoxicity is also among the most common causes of of a noninflammatory hepatic steatosis (as opposed to an discontinuation of drug development or drug withdrawal inflammatory steatohepatitis). These are histiological di- from the market (both early and late).4 Although mainly agnoses. An increase in liver enzymes with statin therapy has used in drug development, an illustrative metric that may no specific hepatic histiopathologic findings, as is true with be conceptually useful for clinicians is Hy’s Law other potential etiologies such as celiac disease. Hence, (Table 1).5 Hy’s law is a term often used by regulatory whether it is an increase in liver enzymes before statin agencies to assign high risk for significant liver injury in therapy or an increase in liver enzymes while being treated patients with persistent and substantial alanine aminotrans- with statin therapy, patients benefit when clinicians have a ferase (ALT) elevations (greater or equal to 3 times the up- logical diagnostic plan in place to determine the cause and per limits of normal [ULN] in the presence of clinical implications of elevated liver enzymes. hyperbilirubinemia [more than 2 times the ULN]) without elevated alkaline phosphatase and without other causes of liver injury. In the 1970s, Hyman Zimmerman described Update on 2006 Statin Safety Task Force how drug-induced liver injury (DILI) was associated with report questions a high rate (10% to 50%) of mortality caused by acute liver failure in the pretransplantation era. For every 10 patients Statins are the most common drugs used in treatment of meeting the Hy’s law, it was estimated that 1 patient would hypercholesterolemia and among the most commonly used progress to acute liver failure, and for every 10 patients pharmaceuticals in clinical practice. As acknowledged by who experience ALT .5to.10 times the ULN, it was the hepatologist experts in the 2006 National Lipid Asso- estimated that 1 patient would meet Hy’s law. Because ciation Statin Safety Task Force Report, statins can increase 6 Hy’s law cases are thought to represent hepatocellular liver-associated enzymes. Table 2 lists the questions and injury sufficient to impair bilirubin excretion, only a few answers addressed by these hepatology experts in 2006 as cases are needed to suggest to regulatory agencies (eg, well as the list of questions and answers from this 2014 the US Food and Drug Administration [FDA]) that the Task Force. The following are six follow-up questions ad- drug is likely to cause severe, if not fatal, DILI. The occur- dressed by the current 2014 expert panel. rence of Hy’s law cases in a drug development program almost invariably results in cessation of drug development.4 But although the profile defining Hy’s law is potentially 2014 Questions concerning for DILI, mild to moderate elevations in liver enzymes alone (ie, without an increase in bilirubin) may 1. Have any unexpected safety concerns arisen since the not always reflect a true ‘‘toxicity’’ because increases in regulatory recommendation that liver enzymes need hepatic aminotransferases are not technically abnormal not be measured after initiating statin therapy?

Table 1 Hy’s law criteria must meet each of the following

Elevations in alanine or aspartate aminotransferase $3 times the upper limit of normal Increases in total bilirubin .2 times the upper limit of normal No other demonstrable cause, such as cholestasis (as might be suggested by an increase in alkaline phosphatase); viral hepatitis A, B, or C; preexisting or acute hepatobiliary disease; or another drug capable of causing the observed injury (see Table 3) S50 Journal of Clinical Lipidology, Vol 8, No 3S, June 2014

Table 2 Questions addressed by liver experts in the 2006 and 2014 National Lipid Association Statin Safety Task Force Report6 2006 National Lipid Association Statin Safety Task Force Questions Answer Are elevations in serum aminotransferase levels associated with 3-hydroxy-3-methylglutaryl coenzyme A reductase Yes inhibitor, or statin, therapy? Are statin-associated elevations in aminotransferase levels indicative of liver damage or dysfunction? No Are statin-associated elevations in aminotransferases a class effect? Yes Does statin therapy increase the incidence of liver failure, liver transplants, or death associated with liver failure in Yes the general population? Should liver enzymes and liver function tests be monitored in patients receiving long-term statin therapy? No Are any of the following conditions a contraindication for statin therapy? Chronic liver disease No Compensated cirrhosis No Decompensated cirrhosis or acute liver failure Yes Can statins be used in patients with nonalcoholic fatty liver disease or nonalcoholic steatohepatitis? Yes 2014 National Lipid Association Statin Safety Task Force Questions Have any unexpected safety concerns arisen since the regulatory recommendation that liver enzymes need not be No measured after initiating statin therapy? Should baseline liver enzymes be obtained before initiating statin therapy? Yes Are statins safe to use in patients with nonalcoholic fatty liver disease? Yes Do statins have drug interactions with medications used to treat infections (eg, hepatitis B, C) that require change Yes in statin, change in statin dosing, or change in antiviral regimen dosing? Can statins safely be used in liver transplant recipients? Yes Can statins safely be used in patients with autoimmune hepatitis? Yes

ANSWER: No. no data exist to show that routine periodic monitoring STRENGTH OF RECOMMENDATION: A (strong). of liver biochemistries is effective in identifying the very QUALITY OF EVIDENCE: Low. rare individual who may develop significant liver injury EXPLANATION: The initial 2006 National Lipid As- from ongoing statin therapy. The Panel believed that sociation Statin Safety Task Force Expert Liver Panel routine periodic monitoring will instead identify patients with isolated increased aminotransferase levels, which recommended that routine liver enzyme testing not be 6 could motivate physicians to alter or discontinue statin required. Subsequently, in 2012, the FDA issued a commu- therapy, thereby placing patients at increased risk for nication regarding ‘‘Important safety label changes to cardiovascular events.1 The National Lipid Associa- 7 cholesterol-lowering statin drugs,’’ wherein they stated : tion’s Statin Task Force also stated that routine moni- ‘‘Labels have been revised to remove the need for toring of liver function tests is not supported by the routine periodic monitoring of liver enzymes in patients available evidence.’’ taking statins. The labels now recommend that liver enzyme tests should be performed before starting statin ‘‘FDA reviewed post-marketing data to evaluate the risk therapy and as clinically indicated thereafter. FDA has of clinically serious hepatotoxicity associated with concluded that serious liver injury with statins is rare statins. FDA had conducted several post-marketing and unpredictable in individual patients, and that reviews of statins and hepatotoxicity between years routine periodic monitoring of liver enzymes does not 2000 and 2009 by searching the Agency’s Adverse Event appear to be effective in detecting or preventing serious Reporting System (AERS) database. Those reviews liver injury.’’7 consistently noted that reporting of statin-associated serious liver injury to the AERS database was extremely This decision was based on the FDA’s comprehensive low (reporting rate of #2 per one million patient-years). review of the statin class of drugs. In its description of the FDA’s updated review focused on cases of severe liver Data Summary, the FDA stated:7 injury, defined as a 4 (severe liver injury) or a 5 (death or liver transplant) using the Drug Induced Liver Injury ‘‘FDA reviewed current monitoring guidelines, including Network (DILIN) liver injury severity scale, which were the National Lipid Association’s Liver Expert Panel and reported to AERS from marketing of each statin Statin Safety Task Force recommendations. The Liver through 2009. Cases meeting those criteria were further Expert Panel stated that the available scientific evidence assessed for causality. Seventy-five cases (27 cases with a does not support the routine monitoring of liver bio- severity score of 4, and 48 cases with a severity score of 5 chemistries in asymptomatic patients receiving statins. (37 deaths and 11 liver transplants) were assessed for The Panel made this recommendation because (1) causality. Thirty of the 75 cases (14 deaths, 7 liver irreversible liver damage resulting from statins is excep- transplantations, and 9 severe liver injury) were assessed tionally rare and is likely idiosyncratic in nature, and (2) as possibly or probably associated with statin therapy. Bays et al Statin safety: Liver Task Force S51

No cases were assessed as highly likely or definitely damage (especially when recommended in direct-to- associated with statin therapy. FDA concluded that, consumer advertisements), which may adversely affect despite a rising use of statins as a class since the late statin compliance. 1990s, there has not been a detectable increase in the Nonetheless, it is the consensus of this liver expert panel annual rates of fatal or severe liver injury cases possibly that obtaining baseline liver enzymes is optimal in the care or probably causally associated with statin use.’’ of statin-treated patients. First, in many locations of clinical ‘‘FDA also reviewed cases from the DILIN and Acute practice, liver enzymes are included in a battery of Liver Failure Study Group (ALFSG), organizations that generalized blood testing when evaluating patients (which have been submitting reports to FDA of drug-associated may also include glucose, electrolytes, and kidney blood liver injury in their liver injury outcome studies. As of testing) with no or minimal additional cost. Second, should January 1, 2011, DILIN had submitted 25 reports of future liver enzymes (or glucose levels) be found to be statin-associated liver injury to FDA, 12 of which gave abnormal in a statin-treated patient, it may be useful to have hospitalization as an outcome. A 2010 article from a baseline value to compare. Finally, patients in need of ALFSG included 133 prospectively identified cases of statin therapy are typically those at risk for atherosclerotic idiopathic drug-induced liver injury resulting in acute liver failure.3 Of these 133 patients, 15 were taking statins, and coronary heart disease (CHD). Often such risks are in the in six of these 15 individuals a statin was identified as the form of increased body fat (adiposity), especially with only potential drug to cause drug-induced liver injury.’’ dysfunctional fat (adiposopathy), diabetes mellitus, and metabolic syndrome—each that may contribute to or be ‘‘Based on all available data, FDA has determined that associated with fatty liver (Table 3). all currently marketed statins appear to be associated with a very low risk of serious liver injury and that routine periodic monitoring of serum alanine amino- 3. Are statins safe to use in patients with nonalcoholic fatty transferase (ALT) does not appear to detect or prevent liver disease? serious liver injury in association with statins.’’7 ANSWER: Yes. STRENGTH OF RECOMMENDATION: B (moderate). Data since the this FDA position continue to support a QUALITY OF EVIDENCE: Moderate. favorable benefit:risk ratio with a strategy of obtaining liver EXPLANATION: The 2006 National Lipid Association enzymes at baseline and then as clinically indicated after- Statin Safety Task Force indicated that although decom- wards. Data published since 2006 continue to demonstrate pensated cirrhosis or acute liver failure was a contraindi- 8 that the risk of statin-promoted liver failure is very rare. cation for statin use, other chronic liver diseases (presumably including uncomplicated chronic hepatitis B 2. Should baseline liver enzymes be obtained before initi- and C) and compensated cirrhosis were not contraindica- ating statin therapy? tions for statin use. The current question expands upon this ANSWER: Yes. topic by specifically addressing nonalcoholic fatty liver STRENGTH OF RECOMMENDATION: E (expert disease (NAFLD), which is the most common cause of opinion). chronic liver disease in Western nations, especially among QUALITY OF EVIDENCE: Low. patients with adiposopathy (dysfunctional adipose tissue) EXPLANATION: The current prescribing information and dyslipidemia.10–12 The challenge is that it is difficult to of statins generally state: ‘‘Persistent elevations in hepatic clinically distinguish between the subset of NAFLD pa- transaminases can occur. Check liver enzyme tests before tients with the more benign nonalcoholic fatty liver (hepatic initiating therapy and as clinically indicated thereafter.’’9 steatosis), and the more serious nonalcoholic steatohepatitis As noted previously, no clinical trial data support a favor- (NASH), which may progress to cirrhosis, liver failure, and able benefit:risk ratio for liver enzyme testing performed liver cancer.11 In other words, the distinction between he- after baseline values in statin-treated patients, unless clini- patic steatosis and NASH is a histopathologic one. cally indicated. With regard to obtaining liver enzyme Although some published data support that statins may testing before initiating statin therapy, no randomized clin- improve hepatic steatosis,13-16 little data exist to support ical trial evidence is available to support or refute obtaining statins as an effective treatment for steatohepatitis. The to- liver enzyme testing at baseline. Therefore, a natural ques- tality of evidence suggests that, at a minimum, statin ther- tion may be: Why get them? Routine liver enzyme apy can be used safely in dyslipidemic individuals with screening in the general population is not generally recom- NAFLD and that weight loss in overweight or obese pa- mended. Obtaining liver enzyme testing requires the proce- tients is often an effective treatment modality in NAFLD. dure of phlebotomy (which is a procedure not without risk). 4. Do statins have drug interactions with medications used Obtaining liver enzyme testing in asymptomatic patients to treat infections (hepatitis B, C, etc.) that require may also increase cost and, if abnormalities are found, change in statin, change in statin dosing, or change in may (sometimes) result in unnecessary liver testing and antiviral regimen dosing? even potential liver biopsies. Finally, obtaining baseline liver enzyme testing may enhance the patient’s fear of liver ANSWER: Yes. S52 Journal of Clinical Lipidology, Vol 8, No 3S, June 2014

Table 3 Illustrative causes of elevated liver enzymes in Table 3 (continued) adolescents and adults* Primary biliary cirrhosis Celiac disease Primary sclerosing cholangitis Congestive cardiomyopathy Thrombotic occlusion of the hepatic veins (Budd-Chiari Endocrine diseases syndrome) Adiposity resulting in adiposopathy Selected medications Diabetes mellitus and insulin resistance syndromes Antibiotics Hyperthyroidism and hypothyroidism B Amoxicillin Metabolic syndrome B Amphotericin Excessive ethanol intake (with or without alcoholic hepatitis) B Azole antifungal agents (eg, fluconazole, In patients without underlying liver disease, ethanol ketoconazole) intake that is more likely to cause increases in liver B Ciprofloxacin enzymes include .2 units a day for men and 1 unit per B Erythromycin day for women (unit 5 generally defined as 12 oz of B Isoniazid beer, 5 oz of wine, 1.5 oz for 80 proof mixed drinks) B Nitrofurantoin Fatty liver B Protease inhibitors Nonalcoholic fatty liver disease B Rifampin Nonalcoholic steatohepatitis B Sulfonamide antibiotics (eg, sulfamethoxazole) Gallbladder disease (eg, cholelithiasis with obstruction) B Tetracycline Genetic diseases B Trimethoprim Alpha 1 antitrypsin deficiency Cardiovascular disease medications Cystic fibrosis B Amiodarone Hemochromatosis (excessive iron storage) B Ezetimibe when combined statins Hepatic porphyrias B Fibrates (gemfibrozil, fenofibrate) Wilson’s disease (excessive copper storage) B Hydralazine Infections B Labetalol Viral infection B Methyldopa B Adenovirus B Niacin (especially over-the-counter slow-release B Cytomegalovirus preparations at doses greater than 1500 mg/d) B Coxsackievirus B Quinidine B Echovirus B Statins B Epstein-Barr (eg, mononucleosis) Herbal supplements B Hepatitis A, B, C, and E B Chaparral B Herpes simplex virus B Ephedra B Human immunodeficiency virus B Gentian B Rubella B Germander Bacterial infection, especially with sepsis B Jin Bu Huan B Chlamydia B Kavakava B Rickettsia B Ma-huang B Spirochetes B Scutellaria B Tuberculosis and other mycobacteria B Senecio/crotalaria (bush teas) Fungal infection B Senna B Candidiasis B Shark cartilage B Histoplasmosis Hormones Parasitic infections (protozoa and helminthes) B Anabolic steroids (eg, testosterone) B Schistosomiasis B Estrogens B Leptospirosis B Excessive thyroid hormone B Toxoplasmosis B Systemic corticosteroids B Visceral larva migrans B Tamoxifen Malignancies Illicit drugs Primary liver cancer B Anabolic steroids Metastatic cancer B Cocaine Leukemia and lymphoma B Methylenedioxymethamphetamine (MDMA or Other liver diseases ecstasy) Autoimmune hepatitis (eg, idiopathic, inflammatory B Phencyclidine (PCP) bowel disease, ulcerative colitis, rheumatoid arthritis, Neurologic and psychiatric medications systemic lupus erythematosus) B Carbamazepine HELLP syndrome in pregnancy (Hemolysis, ELevated liver B Chlorpromazine enzymes, Low Platelet count) B Phenobarbital (continued) (continued) Bays et al Statin safety: Liver Task Force S53

protease inhibitors (eg, boceprevir, telaprevir, and simepre- Table 3 (continued) vir), and nucleotide analogue inhibitors (eg, sofosbuvir). B Phenytoin This is an evolving therapeutic area, with the potential that B Trazodone agents such as boceprevir and telaprevir will be less B Valproic acid prescribed (at least in the United States) in the near future. Pain medications With regard to hepatitis B, examples of therapeutic agents B Acetaminophen include interferon-alpha, pegylated interferon-alpha, ente- B Aspirin cavir, tenofovir, and sometimes adefovir, lamivudine and B Nonsteroidal anti-inflammatory drugs Other medications telbivudine. Even without specific mention in drug labeling, B Dantrolene clinicians should be aware of potential drug interactions B Disulfiram with statins, as might be applicable via similar cytochrome B Etretinate P450 metabolism of these agents and statins. If a drug B Halothane interaction is possible, then consideration should be given B Heparin to change the statin to one without a potential drug B Orlistat interaction or to limit the statin to lower doses. B Propylthiouracil B Sulfonylureas 5. Can statins safely be used in liver transplant recipients? B Vitamin A and derivatives ANSWER: Yes. B Zafirlukast STRENGTH OF RECOMMENDATION: C (weak). Toxins 2-Nitropropane QUALITY OF EVIDENCE: Low. Carbon tetrachloride EXPLANATION: Cardiovascular complications are Chloroform common among patients undergoing liver transplantation, Dimethylformamide with an increase in NASH being an additional cardiovas- Hydrazine cular risk factor beyond other more traditional cardiovas- Hydrocarbons cular risk factors.17 No cardiovascular outcome study exists Hydrochlorofluorocarbons to support reduction in cardiovascular events with statin Hypervitaminosis A therapy in this patient population. Nonetheless, it seems Insecticides appropriate to consider the use of statin therapy in clini- Mushrooms cally appropriate liver transplant recipients having a Organophosphates reasonable mid- to long-term prognosis. Toluene Trichloroethylene 6. Can statins safely be used in patients with autoimmune † ‘‘Weight loss’’ or ‘‘workout’’ or ‘‘body building’’ supplements hepatitis? Liver injury from the supplement itself Liver injury from other toxic ingredients ANSWER: Yes. Liver injury from a bad batch of the supplement STRENGTH OF RECOMMENDATION: E (expert *Increases in aspartate aminotransferase (AST) and to a lesser opinion). extent, alanine aminotransferase (ALT) may be derived from other QUALITY OF EVIDENCE: Low. body tissues, such as muscle and red blood cells that, although not EXPLANATION: The published data report rare cases liver related, should also be evaluated when AST and ALT blood levels of statin-induced autoimmune hepatotoxicity.18–20 are increased. Also, the list in this table is not all-inclusive because Although these few case reports of suspected statin- many other possible causes of elevated liver enzymes exist. †Specific supplements are not listed in the table because dietary induced autoimmune hepatitis exist, no conclusive findings supplements are not regulated by the Food and Drug Administration have yet suggested an ‘‘at-risk’’ patient population or pro- before being marketed. Thus, evidence of the potential to definitively vided a potential mechanism of action. Given the sporadic cause liver injury is mainly via case and media reports, and not through nature of this association, the very rare cases of autoim- the rigors of controlled clinical trials. This makes it challenging to mune hepatotoxicity occurring in statin treated patients definitively confirm a specific supplement causes any safety adverse outcomes. Also, as noted in the table, liver injury due to supplements are likely to be idiosyncratic associations. However, a may not only be the result of the supplement itself, but may also be more common clinical challenge is the patient having due to an added ingredient to the supplement, or an unintended toxin both a systemic autoimmune disease (eg, rheumatoid introduced into a batch of the supplement during processing. arthritis, multiple sclerosis, antiphospholipid syndrome, systemic lupus erythematosus) along with hypercholesterolemia, but with or without autoimmune liver disease. Lit- STRENGTH OF RECOMMENDATION: A (strong) tle to no evidence exists that statins are unsafe when (depending on the medication used). administered to patients with (non-statin) autoimmune liver QUALITY OF EVIDENCE: High. disease, as long as the autoimmune liver disease is not asso- EXPLANATION: Examples of drugs used to treat ciated with substantial liver dysfunction or damage. If auto- infectious hepatitis C include interferons (eg, pegylated immune diseases are to be treated with pharmacotherapy, interferon), nucleoside/nucleotide analogues (eg, ribavirin), then drugs potentially used to treat such disorders should S54 Journal of Clinical Lipidology, Vol 8, No 3S, June 2014

Figure 1 Comprehensive approach to patients with elevated liver blood testing (transaminases ,3 times the upper limits of normal).23,24 Bays et al Statin safety: Liver Task Force S55

Figure 2 Comprehensive approach to patients with elevated liver blood testing (transaminases .3 times the upper limits of normal). S56 Journal of Clinical Lipidology, Vol 8, No 3S, June 2014 be investigated for potential interactions regarding the prolonged discontinuance of medical therapies, such as catabolism and excretion of statins. statins.

Provider recommendations to patients Recommendations from the 2014 Statin Liver Safety Task Force It is not uncommon to find media, Internet, and book- promoting sources that warn against the use of statins because of concerns of liver toxicity (among other reported Recommendations to clinicians reasons). It is true that statins may potentially cause very rare hepatic adverse experiences. However, these extremely Table 1 provides clinicians a summary of Hy’s law, rare occurrences should not detract from the potential which represents the constellation of liver blood abnormal- benefit of proven reduction in CHD risk, which has far ities with the highest potential for liver toxicity (eg, DILI). greater health implications than the possibility of serious Table 2 provides a summary of recommendations made by liver injury. The objective evidence strongly suggests that the 2006 and 2014 Liver Safety Panels. Table 3 provides for patients at risk for CHD, the risks of not taking the clinicians an ‘‘at-a-glance’’ summary of illustrative diagno- statin outweigh the risks of taking the statin. Patients should ses for the patient with elevated liver enzymes, with or appreciate that based on data from objective, large-scale without statin use. The intended utility of Table 3 is to clinical trials, statins are not only remarkably safe, but, emphasize that when a statin-treated patient experiences most of all, statins reduce the chances of CHD events, elevated liver enzymes, the first inclination should not be including myocardial infarction (heart attack), stroke, and to assume the elevated liver enzymes are due to the statin. revascularization procedures among patients with and Rather, onset of increased liver enzymes should prompt the without manifest vascular disease. Statins have been shown clinician to engage in a careful and systematic evaluation to reduce deaths from these diseases.21,22 (history and physical examination), with a consideration of all potential etiologies. Figures 1 and 2 represent algorithmic approaches to References statin considerations in the patient with elevated liver enzyme blood testing. Mild-to-modest elevations in liver 1. Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA Guide- enzymes (,3 times the ULN), are very common in clinical line on the Treatment of Blood Cholesterol to Reduce Atherosclerotic practice. As such, perhaps the 2 most important diagnostic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice approaches include repeating the values for confirmation Guidelines [e-pub ahead of print]. J Am Coll Cardiol. 2013. and the use of sound clinical judgment. As noted in http://dx.doi.org/10.1016/j.jacc.2013.11.002 accessed March 14, 2014. Figure 1, if the clinical presentation is most likely NAFLD, 2. Guyatt GH, Oxman AD, Vist GE, et al. GRADE: an emerging then the next step is usually lifestyle interventions (eg, consensus on rating quality of evidence and strength of recommenda- . BMJ appropriate nutrition and physical activity, management tions . 2008;336:924–926. 3. James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline of potential secondary causes). Clearly, for the majority for the management of high blood pressure in adults: report from of patients with mild elevations in liver enzymes, invest- the panel members Appointed to the Eighth Joint National Committee ments in a large battery of diagnostic procedures (special- (JNC 8). JAMA. 2014;311:507–520. ized blood testing, imaging studies, biopsies) are best 4. Stein EA, Bays H, O’Brien D, Pedicano J, Piper E, Spezzi A. Lapaqui- reserved for situations wherein other causes are suspected stat acetate: development of a squalene synthase inhibitor for the treatment of hypercholesterolemia. Circulation. 2011;123:1974–1985. (Table 3), the presentation is atypical, or if the patient 5. US Department of Health and Human Services Food and Drug Admin- does not respond as anticipated. Especially for the nonspe- istration Center for Drug Evaluation and Research (CDER) Center for cialist in hepatology, these algorithms may provide a Biologics Evaluation and Research (CBER). Guidance for Industry, reasonably cost-effective approach. If these algorithms Drug-Induced Liver Injury: Premarketing Clinical Evaluation 2009. were followed before referral to a liver specialist, then Available at: http://www.fda.gov/downloads/Drugs/GuidanceComplia nceRegulatoryInformation/Guidances/UCM174090.pdf. Accessed this panel believes it is less likely that the patient with March 14, 2014. elevated liver enzymes would require additional testing 6. Cohen DE, Anania FA, Chalasani N, National Lipid Association Statin by the liver specialist before diagnostic decisions, imple- Safety Task Force Liver Expert Panel. An assessment of statin safety mentation of therapy, or recommendation for more unique by hepatologists. Am J Cardiol. 2006;97:77C–81C. or invasive procedures (such as specialized imaging proce- 7. US Food and Drug Administration. FDA Drug Safety Communication: important safety label changes to cholesterol-lowering statin drugs. dures or liver biopsy). Conversely, a lack of such a diag- Available at: http://www.fda.gov/drugs/drugsafety/ucm293101.htm. nostic workup may result in the liver specialist spending Accessed January 29, 2014. the first patient encounter ordering these same tests, with 8. Reuben A, Koch DG, Lee WM, Acute Liver Failure Study Group. a request that the patient return at a later date for an addi- Drug-induced acute liver failure: results of a U.S. multicenter, pro- . Hepatology tional medical evaluation. Streamlining the diagnostic prospective study . 2010;52:2065–2076. 9. Pfizer. LIPITORÒ (atorvastatin calcium) prescribing information. cess may allow for earlier diagnosis and treatment of Available at: http://labeling.pfizer.com/ShowLabeling.aspx?id5587. patients with elevated liver enzymes and may perhaps avoid Revised February 2013. Bays et al Statin safety: Liver Task Force S57

10. Torres DM, Williams CD, Harrison SA. Features, diagnosis, and treat- steatohepatitis: a randomized placebo-controlled trial. J Clin Gastro- ment of nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. enterol. 2009;43:990–994. 2012;10:837–858. 17. Vanwagner LB, Bhave M, Te HS, Feinglass J, Alvarez L, Rinella ME. Pa- 11. Chatrath H, Vuppalanchi R, Chalasani N. Dyslipidemia in tients transplanted for nonalcoholic steatohepatitis are at increased risk for patients with nonalcoholic fatty liver disease. Semin Liver Dis. postoperative cardiovascular events. Hepatology. 2012;56:1741–1750. 2012;32:22–29. 18. Alla V, Abraham J, Siddiqui J, et al. Autoimmune hepatitis triggered 12. Bays HE, Toth PP, Kris-Etherton PM, et al. Obesity, adiposity, and by statins. J Clin Gastroenterol. 2006;40:757–761. dyslipidemia: a consensus statement from the National Lipid Associ- 19. Russo MW, Scobey M, Bonkovsky HL. Drug-induced liver injury ation. J Clin Lipidol. 2013;7:304–383. associated with statins. Semin Liver Dis. 2009;29:412–422. 13. Foster T, Budoff MJ, Saab S, Ahmadi N, Gordon C, Guerci AD. Ator- 20. John SG, Thorn J, Sobonya R. Statins as a Potential risk factor for vastatin and antioxidants for the treatment of nonalcoholic fatty liver autoimmune diseases: a case report and review [e-pub ahead of print]. disease: the St Francis Heart Study randomized clinical trial.AmJ Am J Ther. 2013 Accessed March 14, 2014. Gastroenterol. 2011;106:71–77. 21. Taylor F, Huffman MD, Macedo AF, et al. Statins for the primary pre- 14. Athyros VG, Tziomalos K, Gossios TD, et al. Safety and efﬁcacy of vention of cardiovascular disease. Cochrane Database Syst Rev. long-term statin treatment for cardiovascular events in patients with 2013;(1):CD004816. coronary heart disease and abnormal liver tests in the Greek Atorvas- 22. Lardizabal JA, Deedwania PC. Beneﬁts of statin therapy and compli- tatin and Coronary Heart Disease Evaluation (GREACE) Study: a ance in high risk cardiovascular patients. Vasc Health Risk Manag. post-hoc analysis. Lancet. 2010;376:1916–1922. 2010;6:843–853. 15. Ekstedt M, Franzen LE, Mathiesen UL, Holmqvist M, Bodemar G, 23. Davern TJ, Chalasani N, Fontana RJ, et al, Drug-Induced Liver Injury Kechagias S. Statins in non-alcoholic fatty liver disease and chroni- Network (DILIN). Acute hepatitis E infection accounts for some cases cally elevated liver enzymes: a histopathological follow-up study.J of suspected drug-induced liver injury. Gastroenterology. 2011;141: Hepatol. 2007;47:135–141. 1665–1672 e1661–1669. 16. Nelson A, Torres DM, Morgan AE, Fincke C, Harrison SA. A pilot 24. D’Agata ID, Balistreri WF. Evaluation of liver disease in the pediatric study using simvastatin in the treatment of nonalcoholic patient. Pediatr Rev. 1999;20:376–390 quiz 389–390. Journal of Clinical Lipidology (2014) 8, S58–S71

Original Contribution An assessment by the Statin Muscle Safety Task Force: 2014 update

Robert S. Rosenson, MD, FNLA*, Steven K. Baker, MSc, MD, FRCP(C), Terry A. Jacobson, MD, FNLA, Stephen L. Kopecky, MD, Beth A. Parker, PhD

Mount Sinai Heart, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA (Dr Rosenson); McMaster University, Hamilton, ON, Canada (Dr Baker); Emory University, Atlanta, GA, USA (Dr Jacobson); Mayo Clinic, Rochester, MN, USA (Dr Kopecky); and Department of Cardiology, Henry Low Heart Center, Hartford Hospital, Hartford, CT, USA (Dr Parker)

KEYWORDS: Abstract: The National Lipid Association’s Muscle Safety Expert Panel was charged with the duty of Muscle adverse events; examining the deﬁnitions for statin-associated muscle adverse events, development of a clinical index Myalgia; to assess myalgia, and the use of diagnostic neuromuscular studies to investigate muscle adverse Myopathy; events. We provide guidance as to when a patient should be considered for referral to neuromuscular Neuromuscular testing; specialists and indications for the performance of a skeletal muscle biopsy. Based on this review of Rhabdomyolysis; evidence, we developed an algorithm for the evaluation and treatment of patients who may be intol- Statin intolerance; erant to statins as the result of adverse muscle events. The panel was composed of clinical cardiolo- Statins gists, clinical lipidologists, an exercise physiologist, and a neuromuscular specialist. Ó 2014 National Lipid Association. All rights reserved.

Muscle complaints represent the most frequent adverse muscle event must be categorized with the use of standard reports among patients treated with statins. These com- definitions to minimize misinterpretation of the etiology plaints occur in a population that often has musculoskeletal and misclassification of muscle adverse reports in those us- pain and dysfunction in the absence of statins; therefore, ing statins for prevention of cardiovascular diseases. These the careful assessment of such adverse reports is essential associations are usually temporal, and causality is often to provide the most efficacious cardiovascular risk man- very hard to prove. It should also be noted that statins are agement. The spectrum of statin-associated muscle toxicity, not the only chemical entity that can induce myopathic often termed ‘‘statin-associated myopathy,’’ is considered to changes. Other common drugs include substances of include several distinct entities that may overlap in clinical abuse (alcohol, cocaine, opioids), neuroleptics and psycho- presentation (Table 1); however, there is no evidence that tropic agents (haloperidol, risperidone), immunosuppres- the constellation of muscle adverse reports is a continuum sants (cyclosporine A, azathioprine), antiviral agents that begins with myalgia and progress to more severe man- (zidovudine, ritonavir, didanosine), analgesics and anti- ifestations of myopathy. Thus, each statin-associated inflammatory drugs (salicylates, nonsteroidal anti- inflammatory drugs, glucocorticoids), fibrates (gemfibrozil, fenofibrate), anesthetics and neuromuscular blocking * Corresponding author. E-mail addresses: [email protected]; [email protected]; agents (propofol, ketamine, succinylcholine). Furthermore, [email protected] genetic, infectious, and immune disorders can present with Submitted March 3, 2014. Accepted for publication March 11, 2014. muscle signs and symptoms. Misdiagnosis may preclude

Evidence grading: strength of recommendation* Grade Strength of recommendation A Strong Recommendation There is high certainty based on the evidence that the net benefit† is substantial B Moderate Recommendation There is moderate certainty based on the evidence that the net benefit is moderate to substantial, or there is high certainty that the net benefit is moderate C Weak Recommendation There is at least moderate certainty based on the evidence that there is a small net benefit D Recommend Against There is at least moderate certainty based on the evidence that it has no net benefit or that the risks/harms outweigh benefits E Expert Opinion There is insufficient evidence or evidence is unclear or conflicting, but this is what the expert panel recommends N No Recommendation for or against There is insufficient evidence or evidence is unclear or conflicting *The system was adapted as a hybrid of the National Heart Lung and Blood Institutes (NHLBI) rating system (NHLBI cardiovascular-based methodology) used in the new American Heart Association/American College of Cardiology cholesterol guidelines1 and adapted from the original Grading of Recommendations Assessment, Development, and Evaluation system of evidence rating.2 †Net benefit is defined as benefit minus risks/harms of the service/intervention. unnecessarily the future use of this class of efficacious these drugs. They need to be evaluated by history, physical agents in a given patient and delay appropriate treatment examination and laboratory testing when appropriate. of other unrelated myopathic disorders. These findings may include muscle discomfort (myalgia), Statin-associated adverse muscle symptoms may present muscle weakness (myopathy), tenderness to palpation, with from the patient at any time after beginning therapy with or without muscle inflammation (myositis) and/or

Evidence grading—quality of evidence Type of evidence Quality rating* Well-designed, well-executed RCTs is that adequately represent populations to which the results are applied and High directly assess effects on health outcomes Well-conducted meta-analyses of such studies Highly certain about the estimate of effect; more research is unlikely to change our confidence in the estimate of effect RCTs with minor limitations affecting confidence in, or applicability of, the results Moderate Well-designed, well-executed nonrandomized controlled studies and well-designed. Well-executed observational studies Well-conducted -meta-analysis of such studies Moderately certain about the estimate of effect; additional research may have an impact on our confidence n the estimate of effect and may change the estimate RCTs with major limitations Low Nonrandomized controlled studies and observational studies with major limitations affecting confidence in, or applicability of, the results Uncontrolled clinical observations without an appropriate comparison group (eg, case series, case reports) Physiological studies in humans Meta-analyses of such studies Low certainty about the estimate of effect; further research is likely to have an impact on our confidence in the estimate of effect and is likely to change the estimate. RCT, randomized controlled trial. This was the system used in the new American Heart Association/American College of Cardiology cholesterol guidelines1 that were published in the 2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults Report from the Panel members appointed to the Eighth Joint Na- tional Committee (JNC 8).3 From James PA, Oparil S, Carter BL, et al.3 *The evidence quality rating system used in this guideline was developed by the Nations Heart, Lung, and Blood Institute’s (NHLBI’s) Evidence-Based Methodology Lead (with input from NHLBI staff, external methodology team, and guideline panels and work groups) for use by all the NHLBI cardiovascular disease guideline panels and work groups during this project. As a result, it includes the evidence quality rating for many types of studies, including studies that were not used in this guideline. Additional details regarding the evidence quality rating system are available in the online Supplement. S60 Journal of Clinical Lipidology, Vol 8, No 3S, June 2014

Table 1 Spectrum of statin-associated muscle adverse events Myalgia—unexplained muscle discomfort often described as ‘‘ﬂu-like’’ symptoms with normal CK level. The spectrum of myalgia complaints includes: - Muscle aches; - Muscle soreness; - Muscle stiffness; - Muscle tenderness; and - Muscle cramps with or shortly after exercise (not nocturnal cramping). Myopathy—muscle weakness (not attributed to pain and not necessarily associated with elevated CK). Myositis—muscle inﬂammation Myonecrosis—muscle enzyme elevations or hyperCKemia - Mild .3-fold greater than baseline untreated CK levels or normative upper limit that are adjusted for age, race, and sex. - Moderate $10-fold greater than untreated baseline CK levels or normative upper limit that are adjusted for age, race, and sex. - Severe $50-fold above baseline CK levels or normative upper limit that are adjusted for age, race, and sex. Myonecrosis with myoglobinuria or acute renal failure (increase in serum creatinine $0.5 mg/dL (clinical rhabdomyolysis). CK, creatine kinase.

myonecrosis. Inflammation is usually accompanied by pain tenderness. We maintain the grading of muscle injury or and tenderness and white cell infiltration in the muscle ‘‘myonecrosis’’ based on the magnitude of serum CK eleva- tissue. Myonecrosis may occur in a subacute form with tion, which is also termed hyperCKemia. This grading elevations of creatine phosphokinase (CK) with or without maintains the categories of mild, moderate, and severe pain. The most severe form of myonecrosis is referred to as CK elevations but uses the patient’s own prestatin CK level rhabdomyolysis (rhabdo: rod-like structures, myo: muscle, vs an arbitrary normative range when baseline CK levels and lys: dissolution). This is the acute and massive lysis are available (Table 1). Other consensus documents of skeletal muscle cells with significant shifts in electro- proposed by the National Lipid Association in 2006 and lytes in the extracellular fluid and release of large amounts adopted by the Canadian Working Group Consensus Con- of CK and myoglobin into the blood plasma. The latter ference6 used normative CK thresholds that do not can result in acute renal failure due to myoglobin precipita- adequately account for differences in age, sex, muscle tion in the kidney tubules. Rhabdomyolysis can occur mass, and other important clinical features that may predis- without muscle pain or weakness, but muscle pain pose an individual to a statin adverse muscle event. Thus, commonly precedes or accompanies this condition. we advocate the use of the individual’s own CK levels Myositis may follow acute myonecrosis. Myalgia, myop- when available. Severe CK elevations continue to be athy, myositis, and myonecrosis can be different processes defined as .50 times the baseline concentration or upper in their etiology, onset, and outcome. Given this confusion, normal range when baseline values are unavailable, which we propose a new nosology for statin-associated muscle is consistent with the absolute CK concentration of adverse events (Table 1). 10,000 IU/L that was proposed by the Food and Drug The terminology in this report differs from other expert Administration.7 The term ‘‘clinical rhabdomyolysis’’ thus panels, particularly in the use of less ambiguous terminol- represents a severe form of ‘‘myonecrosis with myoglobi- ogy, a myalgia clinical index score, and the use of nuria and/or acute renal failure’’ to more precisely describe neuromuscular diagnostic studies. In the first National the clinical implications of severe statin toxicity. There is Lipid Association Statin Task Force Report by Muscle the cellular evidence that chemical toxicity or acute electro- Experts,4 the nonspecific term ‘‘myopathy,’’ initially pro- lyte changes can cause muscle cell dissolution without posed by the American College of Cardiology/American inflammatory infiltrate so that inflammation is not neces- Heart Association/National Heart, Lung, and Blood Insti- sarily part of rhabdomyolysis. Muscle damage from auto- tute Clinical Advisory Panel5 to account for the entire spec- immune damage (inflammatory damage) or chemical trum of muscle-related disorders in statin-treated patients, toxicity can increase CK levels because both release muscle has been replaced by ‘‘statin-associated muscle adverse cell contents. Treating chronic muscle symptoms and se- events.’’ Myopathy is no longer categorized into asymptom- vere myonecrosis with associated myoglobinuria and acute atic and symptomatic myopathy.4 Instead, we use the more renal failure (clinical rhabdomyolysis) as different entities precise neuromuscular terminology of ‘‘myalgia’’ to is more consistent with the clinical and pathologic picture. describe muscle pain and ‘‘myopathy’’ to describe muscle The relationship to statin therapy of these adverse muscle weakness. Myositis is the term that describes muscle events requires different approaches for management. inflammation that is determined by skeletal muscle biopsy Of these manifestations of statin-associated muscle and/or magnetic resonance imaging. Inflammation of the adverse reports, myalgia complaints are most common, muscles is commonly associated with muscle pain and ranging from 1% to 5% in controlled clinical trials to 11% Rosenson et al Statin-associated muscle events S61 to 29% in observational cohorts.8–13 In the Justification for More consistent rates of muscle adverse events result the Use of Statins in Prevention: An Intervention Trial from strict definitions with an objective laboratory measure. Evaluating Rosuvastatin (JUPITER), the largest and most Rates of severe muscle injury with myoglobinuria are far recent clinical trial with a statin, 18,902 subjects were ran- less common, and reporting rates are dependent on the domized (double blind) to rosuvastatin 20 mg daily or pla- numbers of exposed individuals and duration of exposure. cebo.14 During an average follow-up of 17 months, muscle Thus, major challenges in the assessment of statin- symptoms (pain, stiffness, or weakness) was noted in 1421 associated muscle toxicity derives from the absence of (16.0%) vs 1375 (15.4%), P 5 .34. In the rosuvastatin- uniform and validated definitions of myalgia, and the lack treated group, myopathy was diagnosed in 10 patients vs of conducting routine muscular examinations and accepted 9 on placebo, and rhabdomyolysis occurred in one patient tests of muscle performance (strength and endurance) to taking rosuvastatin. However, lower rates of myalgia and confirm myopathy. The use of CK, a naturally elaborated myopathy in clinical trials have been attributed to the muscle enzyme for the diagnosis of muscle injury, is near absence of formal assessment of muscle complaints complicated by different racial normative levels with prospective questionnaires15 as well as the exclusion (Fig. 1),16 differences in individuals who exercise intermit- of patients with statin-associated muscle symptoms by his- tently vs regularly, and by the type of exercise (resistance tory or prerandomization run-in phase. As a result, clinical vs endurance training) and the duration and intensity of trials may result in the underreporting of myalgia. Howev- the exercise. er, clinical trials as well as observational studies may attri- In 2 retrospective analyses, most patients tolerated bute muscle symptoms to statins that have other etiologies statins on repeat challenge. A recent retrospective cohort and therefore overestimate the strength of this relationship. study that included electronic medical records and elec- In addition, many people with risk factors for myalgia are tronic chart reviews from medical practices affiliated with excluded from clinical trials, so the incidence in clinical the Brigham and Women’s Hospital and Massachusetts trial participants is likely an underestimation of the inci- General Hospital, 2721 outpatients were rechallenged with dence in clinical practice. a statin after discontinuation because of statin intolerance.

Figure 1 Median creatine kinase levels according to age, race, and sex. Reprinted with permission from Neal et al.16 S62 Journal of Clinical Lipidology, Vol 8, No 3S, June 2014

Of these patients rechallenged with a statin, 92.2% STRENGTH OF RECOMMENDATION: B (Moderate). remained on this treatment 12 months after the initial QUALITY OF EVIDENCE: Moderate. statin-related discontinuation.17 The authors suggested that EXPLANATION: Myalgia refers to unexplained muscle most patients with statin-related clinical events are able to discomfort often described as muscle aches, soreness, tolerate statins long term and that many of these events stiffness, or tenderness with or without a normal CK level. may have other causes. A retrospective electronic medical As previously noted, there are many causes of myalgia, and chart review of 1605 patients referred to the Cleveland it is difficult to distinguish symptoms from any single cause Clinic Preventive Cardiology Service with documented without a significant investigation in each patient. There statin intolerance to at least 2 statins were rechallenged has been little scientific study of this question with regard with statin therapy. Of the statin-intolerant patients, intoler- to statins. A recent double-blind clinical trial, The Effect of ance that resulted primarily from myalgia, 72.5% were able STatins On Muscle Performance (STOMP; National Heart, to tolerate long-term (.6-month follow-up) therapy with a Lung, and Blood Institute 5R01HL081893, NCT00609063) stable dosage of statin.18 Although these analyses suggest sought to determine the incidence of statin-associated mus- the need for rechallenge before a diagnosis of statin intol- cle complaints in statin-na€ıve subjects by using a carefully erance is assigned, the use of a standardized questionnaire, defined study protocol and definition of statin myalgia.23 In repeat analysis of abnormal laboratory values (serum CK, brief, 202 subjects were randomly assigned to dosing with transaminases), and exclusion of other conditions or disor- 80 mg of atorvastatin vs placebo for 6 months and were ders unrelated to the statin were not ascertained. contacted by phone twice monthly during the study to In this report, we provide a paradigm to enhance inquire about muscle complaints via the Short-Form accurate diagnosis of statin-associated muscle adverse McGill Pain Questionnaire24 and Short-Form Brief Pain In- events. There is a need for validated tools to accurately ventory.25 These surveys measured the location and inten- diagnose statin vs nonstatin muscle injury and to assess sity of participants’ muscle pain and the extent to which treatment approaches for the high-risk patient who is the muscle pain interfered with daily functioning. Study ‘‘intolerant’’ to statin therapy. Incident reports of statin- participants were considered to have developed statin- associated muscle injury may increase with the recent 2013 associated myalgia if ALL of the following occurred: American College of Cardiology/American Heart Associ- new-onset or increased symptoms of myalgia (muscle ation Cholesterol Guidelines that recommend high- aches, stiffness, cramping, soreness, and tenderness) intensity and high-dose statins as initial therapy for the that were unassociated with recent exercise; prevention of atherosclerotic cardiovascular events in high- symptoms that persisted for at least 2 weeks; risk individuals.1 This may be accompanied by greater rates symptoms that resolved within 2 weeks of stopping the of myonecrosis, particularly with simvastatin since in the study drug; and Aggrastat to Zocor [A to Z] and the Study of the Effective- symptoms that reoccurred within 4 weeks of restarting ness of Additional Reductions in Cholesterol and Homo- the medication. cysteine [SEARCH], where a dose of 80 mg/day was used as the top dose.17,18 Muscle-related symptoms with Using this standardized definition of study myalgia, we the greater dose of study drug was associated with discon- found that 24 (9.4%) of atorvastatin and 12 (4.6%) of tinuation in 1.8% of simvastatin 40 mg/80 mg groups vs placebo patients (P 5 .05) were classified with myalgia 1.5% of in those taking placebo followed by simvastatin when symptoms were assessed every 2 weeks. The observa- 20 mg in the A to Z study. However, greater rates of tion that some placebo patients satisfied the myalgia adverse muscle events, including myonecrosis, were not definition demonstrates the challenges with the use of different with high-dose vs low dose atorvastatin in the self-reported symptoms to estimate the incidence of statin Treating to New Targets, or in the Incremental Decrease myalgia. Investigators from the STOMP study found no in Endpoints through Aggressive Lipid Lowering that evidence of measured weakness in those patients with compared atorvastatin 80 mg vs simvastatin 40 mg.19–22 myalgia despite a doubling in CK levels (discussed under Dechallenge and Rechallenge section). It should also be noted that this small study did not reach the common defi- 2014 Questions nition of statistical significance that is P , .05. 2. Are there currently validated scales that can accurately The panel was asked to answer several specific questions diagnosis statin-associated myalgia in clinical practice? for this report. The following questions were addressed by the current panel with their answers. Each answer is ANSWER: No. provided with an explanation and statements regarding STRENGTH OF RECOMMENDATION: Strong. both the strength and the quality of the evidence. QUALITY OF EVIDENCE: Moderate. EXPLANATION: To date, there have been no validated 1. Can statin-associated myalgia be reliably differentiated scales to diagnose statin-associated myalgia. A statin- from myalgia associated with a placebo? associated myalgia index is proposed based on symptoms ANSWER: Yes. and signs reported by participants in the aforementioned Rosenson et al Statin-associated muscle events S63

STOMP study23 and the Prediction of Muscular Risk in fatigue (n 5 3), worsening of pain in previous injuries Observational conditions study (PRIMO).10 In this (n 5 3), groin pain (n 5 3), and foot cramping (n 5 1). consensus of clinicians participating in this working group, Similarly, in the PRIMO study, statin-associated muscle we propose a quantitative myalgia score that is largely pain ‘‘generally affected the lower limbs.’’10 based on the findings from STOMP. This score provides various weighted values based on the distribution of the Temporal pattern muscle complaints, temporal pattern of onset and improvement after statin withdrawal, and reoccurrence on rechal- Studies to date indicate that symptoms of myalgia are lenge (Table 2). The statin myalgia clinical index score more likely to occur within the first month of treatment. For rates these symptoms as probable, possible, or unlikely example, in STOMP, time to symptom onset was shorter in related to the statin. We recognize that the statin myalgia atorvastatin-treated participants with myalgia than in clinical index requires validation in a prospective study placebo-treated participants with myalgia (35 6 31 vs that includes an independent cohort. 61 6 33 days; P 5 .045). Furthermore, in PRIMO, the median time of pain onset was 1 month. Therefore, the ranking Clinical symptoms was assigned based on the available data, suggesting that time to onset of muscle symptoms may better define true A scoring system for each category of the statin statin myalgia as opposed to myalgia associated with other myopathy clinical index is derived from data that suggest diseases, deconditioning, or deficiencies. that skeletal muscle symptoms attributable to statin therapy are typically manifested as large muscle symmetric (eg, Dechallenge and rechallenge bilateral) aches (Table 2). Consequently, this symptom receives the greatest score (3 points), with bilateral aches of In STOMP, 23 atorvastatin and 14 placebo subjects the smaller distal or proximal musculature receiving 2 reported new, unexplained muscle pain. Nineteen atorvas- points, and asymmetric, nonuniform symptoms receiving tatin and 10 placebo subjects ultimately met the study 1 point. For example, in the STOMP study, subjects who re- definition for myalgia. Consequently, taking subjects off ported myalgia while taking atorvastatin therapy reported and on medication can be critical for further distinguishing predominantly leg symptoms: hip flexor, quadriceps, the causality of muscle pain to the statin drug, and it is hamstring, and/or calf aches (n 5 10), quadriceps or calf estimated that symptoms will be reproduced 73%–100% of cramps (n 5 5), and/or quadriceps, hamstring, and/or calf the time.26 Cham et al.26 also noted that in approximately fatigue (n 5 6), whereas myalgic participants on placebo 75% of patients with statin-associated muscle side effects, reported more diverse symptoms such as whole-body discontinuation of the statin improved the symptoms, with a median time of improvement with drug discontinuation of 2 weeks and a median time of re-emergence of symptoms Table 2 Proposed statin myalgia clinical index score on rechallenge also 2 weeks. Given these data, we awarded Clinical symptoms (new or increased unexplained muscle a larger number of points based on a quicker time course of symptoms) symptom abatement and return with drug dechallenge and Regional distribution/pattern rechallenge. Symmetric hip flexors/thigh aches 3 This myalgia clinical index score requires validation in a Symmetric calf aches 2 prospective trial in which patients with previous myalgia Symmetric upper proximal aches 2 are randomized to placebo or statin and then crossed over to Non-specific asymmetric, intermittent 1 either statin or placebo to determine the reproducibility of Temporal pattern Symptoms onset ,4 weeks 3 symptoms. The proposed statin myalgia clinical index score Symptoms onset ,4 weeks 3 represents a direction for future research initiatives. Symptoms onset 4–12 weeks 2 3. Are statin-associated muscle complaints altered by acute . Symptoms onset 12 weeks 1 and chronic physical activity? Dechallenge Improves upon withdrawal (,2 weeks) 2 ANSWER: Yes. Improves upon withdrawal (2–4 weeks) 1 STRENGTH OF RECOMMENDATION: A (Strong). Does not improve upon withdrawal (.4 weeks) 0 QUALITY OF EVIDENCE: Moderate. Challenge EXPLANATION: Statins are less tolerated in physically , Same symptoms reoccur upon rechallenge 4 weeks 3 active individuals. For example, only 20% of 22 profes- Same symptoms reoccur upon rechallenge 1 sional athletes with familial hypercholesterolemia were 4–12 weeks shown to ultimately tolerate statin therapy despite multiple Statin myalgia clinical index score 27 Probable 9–11 trials with multiple medications. In the PRIMO study, Possible 7–8 incidence of muscle pain with statin therapy increased Unlikely ,7 with the level of physical activity from 10.8% in those engaging in leisure-type physical activity to 14.7% in those S64 Journal of Clinical Lipidology, Vol 8, No 3S, June 2014

Table 3 Tests that might support or conﬁrm the diagnosis of statin-associated muscle adverse events A validated muscle adverse event clinical score; elevated muscle enzymes (CK); (serum aldolase and myoglobin not recommended); if CK levels .50 times the upper limit of normal and/or dark brown urine, then obtain urinary myoglobin; general pain questionnaires (brief pain inventory [preferred because most widely used], McGill, adaptation of quality of life); strength and aerobic testing; metabolic tests (magnetic resonance spectroscopy, O2 uptake intake); pharmacogenetic testing; and muscle biopsy. CK, creatine kinase.

regularly engaging in vigorous activity, suggesting that ANSWER: Yes. statin-associated muscle side effects are provoked by phys- STRENGTH OF RECOMMENDATION: Strong. ical activity.10 Moreover, several studies indicate that acute QUALITY OF EVIDENCE: Moderate. physical activity increases the CK response to exercise in EXPLANATION: In these considerations, the term participants on statins. For example, CK levels obtained myopathy can be expressed by muscle weakness; however, 24 and 48 hours after a treadmill exercise test were 62% this term is generally used to describe the entire spectrum and 77% greater, respectively, in men treated with 4 weeks of statin-associated muscular adverse reports. To improve of lovastatin 40 mg daily than in age-matched, placebo- the accuracy of specific skeletal muscle adverse reports, we treated subjects.28 After intense and prolonged exercise in will discuss this form of myopathy in terms of muscle the 2011 Boston Marathon, exercise-related increase in weakness (not attributed to pain) and not necessarily CK levels at 24 hours were greater in statin users than con- associated with elevated CK levels (Table 3). trols after adjustment for changes in plasma volume.29 The diagnosis of myopathy is made by physical exam- Several other studies, however, have failed to find an effect ination in which the individual has proximal weakness in of statin therapy on exercise-associated muscle damage,30 upper and lower extremities #4 by Medical Research possibly because of differences in study design and meth- Council definition (Table 4).32 Weakness alone can be odology. Cumulatively, data suggest that statin therapy, neuropathic or myopathic or both occurring simultaneously, although well-tolerated by the majority of patients, may so one must rule out neurologic compromise. This can orig- evoke a greater incidence of muscle-related side effects in inate in the central nervous system (eg, amyotrophic lateral chronically physically active individuals and may also sclerosis or cerebrovascular disease), in the peripheral exacerbate CK release and presumably the skeletal muscle nerves (eg, nerve root compression by spinal stenosis or damage associated with acute exercise. diabetic neuropathy), in the neuromuscular junction (eg, Other potential mediators of the relationship between myasthenia gravis), or in the vasculature (eg, polarteritis acute/chronic exercise and statin myalgia include vitamin D and polymyalgia rheumatic). Weakness can also result status, genetics, and aerobic fitness.31 Therefore, a relevant from a variety of drugs and chemicals that are listed in question is whether clinicians should prescribe discontinu- Table 4 as well as direct immune injury as in polymyositis ation of statin use for several days prior to endurance or dermatomyositis. A detailed history and physical exam- events, especially if heat stress or other potential causes ination must be undertaken before one should simply of rhabdomyolysis are anticipated. The latter could have consider statins as the causative element. We advise that in- been particularly important for older runners in the Boston dividuals who experience muscle symptoms have a brief Marathon study, who were more susceptible to experience assessment of muscle strength and before initiation of treat- muscle injury.29 ment. Serial assessment of muscle strength is unnecessary in asymptomatic individuals and ought to occur once yearly 4. Are there tests available to support or confirm the diag- in oligosymptomatic patients who elect to remain on statin nosis of statin-associated myopathy? therapy and whose CK is not .3 times the upper limit of

Table 4 Diagnostic criteria for myopathy Physical examination - Proximal weakness in upper and lower extremities #4 by Medical Research Council definition; Standardized muscle testing with isokinetic dynamometer, aerobic capacity, and respiratory exchange ratio with fasted patient and standardized procedure on metabolic cart (requires off drug/on drug comparison); and Confirmation by electromyography 6 muscle biopsy. Rosenson et al Statin-associated muscle events S65 normal. In individuals with clinically significant CK eleva- center study identified 52 patients with myalgia, weakness, tions and/or evidence of myopathy (Medical Research or both, and a CK level .200 U/L (mean 1000 U/L) Council #4/5), interval muscle strength assessments associated with statin therapy.42 Five patients (10%) throughout a dechallenge/rechallenge paradigm will enable demonstrated abnormal biopsy findings with an underlying a more confident attribution of muscle symptoms to the neuromuscular disorder, whereas 47 had normal muscle bi- statin drug. Persistent myalgia and even moderate CK ele- opsies. However, these CK elevations persisted after with- vations are consistent with polymysitis. Patients with these drawal of statin therapy, and this brings into question the symptoms, particularly if muscle groups are tender, need a causal relationship. In such studies, there have been found muscle biopsy. no consistent histologic changes that can be linked with In endurance athletes, muscle weakness has been certainty to the statin, and so these may have other coinci- described as reduced exercise performance and/or pro- dent causes. Electromyographic changes were noted in all 5 longed recovery time after exercise. Many endurance patients with an underlying disorder but in none with athletes are hesitant to take statins because of the potential normal biopsies. Routine electromyography (EMG) ap- that this therapy will reduce their exercise performance. In pears to serve as a useful screening test to identify patients these individuals, the diagnosis of myopathy may require with skeletal muscle pathology. However, after 6 months of standardized muscle testing with an isokinetic dynamom- follow-up, 6 patients with normal EMG and biopsy findings eter, aerobic capacity, and respiratory exchange ratio in a continued to manifest mild CK elevations (,1000 U/L). fasted patient with the use of standardized procedures with Armour and Zhou43 reported on 69 patients with statin- a metabolic cart. A complete description of these pro- associated muscle adverse effects and noted only 11 of cedures has been referenced in the methods paper to the 52 patients (21%) with elevated serum CK levels. These pa- STOMP study.33 More research into symptoms that are tients were withdrawn from therapy, and had CK levels re- attributed to statins is needed. There are promising research turned to normal after a mean follow-up of 18 months. techniques that can define muscle metabolism and function- Symptoms persisted in approximately 20% up to 14 months ality that may shed new light on this issue. Although not and improved in 80% by the end of follow-up. Clinicians pragmatic for clinical practice these remain in the realm should be aware of this group of asymptomatic patients of highly specialized laboratories and research. These whose condition is generally referred to as idiopathic or include the use of 31P magnetic resonance spectroscopy benign CK elevations. Because this was not a controlled to assess phosphocreatine recovery kinetics,34 as well as study, it is not certain as to the relationship that statins the assessment of oxygen uptake kinetics during transi- may have had with the source of the disorders. Many a- tional exercise.35 Slowed kinetics represent an index of or oligo-symptomatic neuromuscular conditions have mitochondrial myopathies. In addition, although pharmaco- been identified as causes of elevated CK levels (for review, genetic testing has not yet become uniform and widespread, see Silvestri and Wolfe).44 It is the position of this there are many genetic variants identified that may predis- consensus panel that if an underlying neuromuscular disor- pose an individual to statin myalgia. For example, there are der is identified, then it is necessary to determine whether a several published case studies of patients for whom statin genuine statin-associated muscle adverse event has therapy has unmasked mutations in various muscle meta- occurred or whether it can be explained by other mecha- bolic genes related to myopathies such as McArdle nisms. The finding of incidental serum CK elevations in disease.36 Moreover, variants in the rs4363657 single- the absence of any clinically discernible change in the pa- nucleotide polymorphism located within SLCO1B1 on tient’s baseline symptoms does not constitute an adverse chromosome 12 (which is involved in regulating the hepatic event. Alternatively, potentiation of myalgias or weakness uptake of statins) are strongly associated with an increased or escalation of CK levels in a neuromuscular patient would risk of statin-induced myopathy.37 Therefore, genotyping be considered an adverse event. However, it may not neces- patients with a family history of statin intolerance or mus- sarily be caused by the statin. In these patients, if the symp- cle metabolic disorders may be efficacious for diagnosing toms are persistent and particularly if there is tenderness, and treating statin myopathy.38–41 we recommend a skeletal muscle biopsy to establish the diagnosis. It is unlikely that all statins have the same 5. Are there recommendations when to obtain a muscle bi- toxicity profiles for nerve and muscle in different neuro- opsy in patients with statin-associated muscle muscular diseases. For example, fluvastatin exhibited selec- symptoms? tive toxicity to cultured spinal motor neurons but not ANSWER: Yes. cortical neurons or Schwann cells.45 By contrast, STRENGTH OF RECOMMENDATION: Strong. atorvastatin-fed wobbler mice displayed 30% attenuation QUALITY OF EVIDENCE: Moderate. in motor neuron loss after 1 month.46 Skeletal muscle EXPLANATION: Certain individuals who develop also manifests differential sensitivities to various statins statin-associated myopathy may have an underlying histo- in mice, with type II glycolytic fibers being more suscepti- logic disorder of skeletal muscle or an inflammatory ble than type I oxidative fibers.47,48 cellular infiltrate that becomes clinically manifest after Recently, the European Federation of Neurological taking a statin. For example, a 5-year prospective single- Societies issued a critical review on the utility of muscle S66 Journal of Clinical Lipidology, Vol 8, No 3S, June 2014 biopsy in the work-up of myalgia.49 Despite the availability hyperCKemia can be followed conservatively with assis- of only class IV studies, the consensus best practice guide- tance from electrodiagnostic studies. Standard practice lines recommended a biopsy if 1 or more of the following recommends an EMG, and in those individuals with features are present: 1) myoglobinuria; 2) second-wind fibrillations and/or positive sharp waves in the affected phenomenon; 3) weakness; 4) muscle hypertrophy or atro- muscles, a skeletal muscle biopsy is recommended to assist phy; 5) CK elevations (.2–3 times baseline levels or in correctly diagnosing the type of muscle disorder that is normative ranges adjusted for age, sex, and race); and/or responsible for the CK elevation. Importantly, spontaneous 6) myopathic EMG. Statin-associated muscle events do activity, in the form of positive sharp waves and fibrilla- not typically cause myoglobinuria (except in rare cases of tions, can be observed in neuropathies and radiculopathies. severe myotoxicity), or number 2 or 4 above. Therefore, thorough neurologic examinations will ulti- The identification of anti-3-hydroxy-3-methylglutaryl mately decide the potential utility of a muscle biopsy. It coenzyme A reductase antibodies in the context of statin- is noteworthy that no specific sets of histologic criteria have induced necrotizing myopathy increases the need to been established to classify or grade the severity of statin- investigate persistent CK elevations after statin withdrawal related pathologic changes in human skeletal muscle. For because immunosuppressive treatment can be effective, and non-specific findings, the practitioner must still contextu- a delay in diagnosis may decrease the likelihood of a alize the biopsy findings with clinical data to define the favorable outcome.50 Persistent symptoms after statin with- most appropriate clinical diagnosis. drawal, particularly with elevations in serum CK levels in 6. Can patients who are initially intolerant to one statin combination with weakness, should be investigated with a generally tolerate a different statin? biopsy. Histopathologic diagnoses, by disclosing other treatable forms of myositis, such as polymyositis and der- ANSWER: Yes. matomyositis, may also lead to a more complete systemic STRENGTH OF RECOMMENDATION: B (Moderate). work-up for either extra-muscular involvement or underly- QUALITY OF EVIDENCE: Moderate. ing neoplasm. Giant cell arteritis with polymyagia rheu- EXPLANATION: Although clinicians attempt to find matic may require a temporal artery biopsy to establish the ‘‘right’’ statin for an individual, it is unlikely that the diagnosis. patients who are ‘‘truly’’ statin intolerant will tolerate a Muscle symptoms can linger beyond 14 months, and it is second agent at an equivalent potency dose unless there is a difficult to identify the patients who will have a prolonged clear pharmacogenomic, pharmacokinetic, or pharmacody- recovery. CK normalization often lags behind symptom namic difference. As an example, the SLCO1B1 polymor- improvement, and this should not be the only indication for phism was shown to increase the risk of myositis in muscle biopsy (Table 5). Myopathic electrodiagnostic find- simvastatin37 and cerivastatin-treated patients,51 but this ings should lead to additional evaluation in the form of a pharmacokinetic interaction has not been accompanied by muscle biopsy and referral to a neuromuscular specialist. greater rates of skeletal muscle adverse reactions in ator- Before considering muscle biopsies in patients with vastatin or rosuvastatin-treated individuals.52,53 moderately elevated CK levels, alternative causes for high Retrospective data derived from registries suggest that CK levels needs to be considered first. These include recent most patients who are intolerant to one statin because of unaccustomed or eccentric exercise, metabolic abnormal- myalgia can generally tolerate a different statin. The ities (ie, hypothyroidism, hypoparathyroidism, vitamin D experience from several general practices in the Partner’s deficiency, hypophosphatemia), seizure, acute alcohol HealthCare network suggest that 92% of patients can toxicity or other myotoxic drug exposure (ie, colchicine, tolerate a second statin after discontinuing their initial steroids, antiretrovirals, cocaine), or intramuscular injec- statin due to a variety of adverse events.15 The Cleveland tion. We advocate that the performance of skeletal muscle Clinic Preventive Cardiology Program found that of pa- biopsies be limited to individuals with severe myalgia and/ tients referred who were intolerant to two statins largely or weakness in association with CK values .3 times above because of myalgia that 72.5% could successfully tolerate their untreated levels or above sex and racial norms if a third statin.16 Because of the use of retrospective data, untreated CK levels are unavailable. Isolated asymptomatic nonstandard definitions of statin associated muscle adverse

Table 5 Indications for skeletal muscle biopsy after excluding increased physical activity, trauma, metabolic derangements, comorbid conditions associated with increased CK, and known drug interactions Threshold for biopsy—CK values should be adjusted $3 times the upper limit of normal above sex and racial norms in association with either severe myalgia or weakness. Isolated asymptomatic CK elevations between 3 and 10 times the ULN ought to be followed conservatively. Electromyography myopathic discharges with fibrillations and/or positive sharp waves in affected muscles (usually proximal). Proximal muscle weakness (#4 on Medical Research Council scale) in upper and/or lower extremities. CK, creatine kinase; ULN, upper limit of normal. Rosenson et al Statin-associated muscle events S67 events and verification of abnormal laboratory values specimens collected before and after 8-week treatment with (transaminases, CK elevations after exercise) through high-dose simvastatin (80 mg daily) and atorvastatin repeat testing, these numbers certainly underestimate the (40 mg daily) demonstrated that the simvastatin group clinical problem of statin intolerance but also leave the spe- alone had a greater than 50% reduction in mitochondrial cific etiology poorly defined in such patients. DNA.54 However, the evidence supporting such a concept from human studies is extremely weak and has not been 7. Does the evidence base for treating statin-associated developed in a trial of appropriate design. muscle symptoms or statin muscle intolerance generally consist of high-quality, randomized controlled trials Alternate dosing strategies with appropriate placebo or control groups? ANSWER: No. For patients intolerant to multiple statins dosed on a daily EXPLANATION: There are few large completed ran- basis, we suggest a less-than-daily dose of a different statin. domized studies using double-blind techniques to answer The patient who is highly resistive to any statin therapy, this question. Most large reports consist of observational either because of prior actual or perceived side effects, or cohorts in whom statins had been discontinued and then due to fear of developing side effects, presents a growing reintroduced at a later time. Most of the clinical trials with challenge to the clinician. In this situation, we have found a statins have not evaluated muscle symptoms prospec- once-weekly dose of a long-acting statin, such as rosuvas- tively15 or used standardized questionnaires to assess tatin, to be an attractive option. The key to this strategy is a statin-associated muscle adverse events. Most often, medi- frank discussion with the patient regarding potential side cal records have been reviewed using search terms that do effects, and if such side effects occur, advice to contact a not provide context for the muscle adverse event or report physician and obtain a CK measure (if possible) before whether these adverse events were reproducible on re- stopping the drug. Lipid levels should be checked between 4 challenge with the use of a statin agent of equipotency. and 12 weeks of therapy and the dose frequency increased as For specific pharmacologic management, several tolerated to achieve the desired lipid goals. The highest possible approaches to the patient with statin-associated tolerated dose is a reasonable end point, regardless of goal myalgia and myopathy exist including lowering the statin attainment, because it has been demonstrated that even dosage, switching to another statin, particularly to mini- modest LDL-C reductions improve long-term outcomes.55 mize drug-drug interactions that result in elevated statin Both rosuvastatin and atorvastatin have long half-lives, levels (see the report in this supplement from the Statin making them suitable for nondaily dosing. This has the Drug Interaction Safety Panel), reducing the dosing potential for lowering LDL-C levels while minimizing or frequency to less than daily, implementing combination preventing adverse side effects. In multiple studies of lipid-lowering therapy to achieve further reductions in low- patients predominantly experiencing statin-associated my- density lipoprotein cholesterol (LDL-C) levels in patients algias, less-than-daily dosing of rosuvastatin has been not at their LDL-C target who cannot tolerate greater- tolerated in approximately three-quarters of patients who intensity statin therapy, or using a nonstatin lipid-lowering have been able to achieve an LDL-C reduction of 40%– therapy or a nutraceutical approach (red yeast rice) in 45%.56–59 In a randomized, controlled design, rosuvastatin patients who cannot tolerate a statin at any dosage. The use once weekly in those with a previous statin adverse event of supplements, although a common practice, has not been was tolerated in 74% of the study group.60 The mean consistently demonstrated to be beneficial. Rechallenge dose was 10 mg weekly with a 23% reduction in LDL-C. studies suggest that simply stopping and restarting the In addition, rosuvastatin at 5 and 10 mg twice weekly statin after several weeks allows for 70%–80% of patients was well tolerated by 80% of patients and produced a sig- to take a statin that may be at a reduced dosage (low- nificant reduction of LDL-C by 26%.61 Although these moderate intensity) or intermittently.15,16 methods may prove beneficial, this regimen is not optimal For patients with statin-associated muscle events, we because it lowers LDL-C much less than a daily regimen, generally suggest a written inventory of symptoms using an which must be weighed particularly when treating high- instrument similar to the proposed Statin Myalgia Clinical risk patients. Furthermore, these dosing regimens have Index (Table 2) followed by a 2- to 4-week wash out and not been studied in terms of their effectiveness in reducing reassessment of symptoms. cardiovascular events. Although some may consider a statin that is independent of cytochrome P450 3A4 metabolism such as pravastatin, Addition of nonstatin lipid-lowering therapy rosuvastatin, fluvastatin, or pitavastatin, there have been no randomized studies that have compared muscle adverse The combination of statin plus nonstatin therapy may be events in the same trial. Some have suggested that used as another alternative and can even provide reductions lipophilic statins (simvastatin and lovastatin) are more of LDL-C similar to those seen with high-dose statin likely to produce muscular effects as opposed to the more regimens. Ezetimibe may be considered in those with statin hydrophilic statins (pravastatin, rosuvastatin, and fluvasta- intolerance who have not achieved the LDL-C goal.62 tin). Studies in animals, primarily in mice, with biopsy Alternatively, a bile acid binding resin such as colesevelam S68 Journal of Clinical Lipidology, Vol 8, No 3S, June 2014

Figure 2 Algorithm for the evaluation of stain-associated muscle injury. may result in a 15%–19% reduction of LDL-C.63 It should mechanism unrelated to statin therapy.65 To date, however, be noted that there are no outcome data that have demon- most of the evidence is anecdotal, without prospective ran- strated additional cardiovascular event reduction when non- domized controlled trials. statin LDL-C-lowering therapies are added to statin In randomized controlled trials, coenzyme Q10 (CoQ10) therapy. levels and supplementation have not been demonstrated to be helpful, although studies are ongoing.66–68 These trials Supplement use have been short in duration (4–12 weeks), used lower dos- ages of CoQ10 than are used for the treatment of other Low vitamin D levels have been reported in up to 64% neurologic disease such as Parkinson disease (100– of individuals with statin myalgia. One symptom of vitamin 400 mg/day dosage vs 1200 mg/day dosage), and involved D deficiency is myalgia,64 and treatment of a low vitamin D few study participants (40–60 patients). In addition, pa- level may alleviate symptoms due to myalgia even though tients who were enrolled in these trials had self-reported the improvement in symptoms may result from a statin myalgia. Thus, it is not clear whether their myalgic Rosenson et al Statin-associated muscle events S69 symptoms could be reliably reproduced in the context of following the algorithm presented in Figure 2 for the eval- the study design. In the ongoing Co-Enzyme Q10 in Statin uation of statin-associated muscle injury. Myopathy study,69 authors will examine the effect of CoQ10 supplementation on the extent and intensity of muscle pain during treatment with simvastatin by recruiting 135 Financial disclosures patients with a documented history of myalgia during statin treatment. The presence of statin-related myalgia will be The following authors disclose that they have modest tested in a crossover run-in trial design during, which the relationships with industry that might pose a potential presence and absence of symptoms will be documented conflict of interest(s): Dr. Rosenson (consulting fees: during statin and placebo treatment, respectively. Individ- Aegerion, Amgen, AstraZeneca, Genentech, GSK, Janssen, uals who experience myalgia while taking statins, but not LipoScience, Novartis, Regeneron, Sanofi, Sticares placebo, will be randomized to receive simvastatin 20 mg InterACT; Research grants: Amgen, Astra Zeneca, Genen- daily plus either 600 mg daily of CoQ10 or placebo. Treat- tech, Roche, Sanofi; Royalty: UpToDate, Inc.; Ownership ment will continue for 8 weeks or until muscle symptoms interest: LipoScience, Inc.; Honoraria: Kowa); Dr. Jacobson are reported continuously for 1 week or become intolerable, is a consultant for Amarin, Amgen, Astra Zeneca, Merck, and then subjects will crossover to the alternative treatment Sanofi, and Regeneron; Dr. Kopecky (Consulting fees: (CoQ10 or placebo). Applied Clinical Intelligence, Prime Therapeutics; Hono- Nutraceuticals, such as red yeast rice, contain monacolin raria: Atherosclerosis Advisory Board Merck; Research K, which produces a cholesterol-lowering effect and is a grants: Genzyme, Regeneron); Dr. Parker (Honoraria: form of lovastatin. However, the appreciable monacolin Pharmacovigilance Advisory Board Amgen, Inc.). Dr. content may be marginal and vary between brands, and the Baker has no financial relationships with commercial safety of commercially available products is not known interests. while still exposing the patient to potential statin-associated side effects.70 In a study of 43 patients with prior statin- associated myalgia, red yeast rice (2400 mg twice daily) References was not superior to pravastatin (20 mg twice daily) in the development of recurrent myalgias, muscle pain, or muscle 1. Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA Guide- strength after 12 weeks.70 Until the Food and Drug Admin- line on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of istration approves a formulation of red yeast rice that is Cardiology/American Heart Association Task Force on Practice suitable for the treatment of hypercholesterolemia, low- Guidelines. J Am Coll Cardiol, in press. dose statin therapy still is preferable because it offers a 2. Guyatt GH, Oxman AD, Vist GE, et al, Group Grade Working Group. more consistent LDL-C response at a lower cost. GRADE: an emerging consensus on rating quality of evidence and . BMJ In general, for patients with intolerance to their first strength of recommendations . 2008;336:924–926. 3. James PA, Oparil S, Carter BL, et al. 2014 Evidence-Based Guideline statin, we then suggest another statin at the initial starting for the Management of High Blood Pressure in Adults: Report From dose. For patients intolerant to multiple statins, we suggest the Panel Members Appointed to the Eighth Joint National Committee a less-than-daily dose of a different statin. The patient who (JNC 8). JAMA. 2014;311:507–520. is highly resistive to any statin therapy, either because of 4. 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Diagnosis, prevention, and along with prestatin initiation advice to arrange for an management of statin adverse effects and intolerance: proceedings examination during the symptoms if possible and if of a Canadian Working Group Consensus Conference. Can J Cardiol. intolerable to stop the drug. Lipid levels should be checked 2011;27:635–662. between 4 and 12 weeks of therapy, and the dose frequency 7. Graham DJ, Staffa JA, Shatin D, et al. Incidence of hospitalized rhab- . JAMA increased as tolerated. The greatest tolerated dose is a domyolysis in patients treated with lipid-lowering drugs . 2004; 292:2585–2590. reasonable end point, regardless of goal attainment, 8. Phillips PS, Haas RH, Bannykh S, et al, Scripps Mercy Clinical because it has been demonstrated that even modest Research Center. Statin-associated myopathy with normal creatine ki- LDL-C reductions improve long-term outcomes.55 nase levels. Ann Intern Med. 2002;137:581–585. 9. Phillips PS, Haas RH. Observations from a statin myopathy clinic. 8. What algorithm should be followed for the evaluation of Arch Intern Med. 2006;166:1232–1233 author reply 1233. statin-associated muscle injury? 10. Bruckert E, Hayem G, Dejager S, Yau C, Begaud B. Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic Several algorithms have been proposed for the manage- patients—the PRIMO study. Cardiovasc Drugs Ther. 2005;19: ment of statin-associated myalgia.71,72 We recommend 403–414. S70 Journal of Clinical Lipidology, Vol 8, No 3S, June 2014

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54. Schick BA, Laaksonen R, Frohlich JJ, et al. Decreased skeletal muscle 63. Davidson MH, Donovan JM, Misir S, Jones MR. A 50-week extension mitochondrial DNA in patients treated with high-dose simvastatin. study on the safety and efficacy of colesevelam in adults with primary Clin Pharmacol Ther. 2007;81:650–653. hypercholesterolemia. Am J Cardiovasc Drugs. 2010;10:305–314. 55. Cholesterol Treatment Trialists (CTT) Collaboration, Baigent C, 64. Ahmed W, Khan N, Glueck CJ, et al. Low serum 25 (OH) vitamin D Blackwell L, Emberson J, et al. Efficacy and safety of more intensive levels (,32 ng/mL) are associated with reversible myositis-myalgia in lowering of LDL cholesterol: a meta-analysis of data from 170,000 statin-treated patients. Transl Res. 2009;153:11–16. participants in 26 randomised trials. Lancet. 2010;376:1670–1681. 65. Gupta A, Thompson PD. The relationship of vitamin D deficiency to 56. Piamsomboon C, Laothavorn P, Saguanwong S, et al. Efficacy and statin myopathy. Atherosclerosis. 2011;215:23–29. safety of atorvastatin 10 mg every other day in hypercholesterolemia. 66. Marcoff L, Thompson PD. The role of coenzyme Q10 in statin- J Med Assoc Thai. 2002;85:297–300. associated myopathy: a systematic review. J Am Coll Cardiol. 2007; 57. Juszczyk MA, Seip RL, Thompson PD. Decreasing LDL cholesterol 49:2231–2237. and medication cost with every-other-day statin therapy. Prev Cardiol. 67. Fedacko J, Pella D, Fedackova P, et al. Coenzyme Q(10) and selenium 2005;8:197–199. in statin-associated myopathy treatment. Can J Physiol Pharmacol. 58. Backes JM, Venero CV, Gibson CA, et al. Effectiveness and tolera- 2013;91:165–170. bility of every-other-day rosuvastatin dosing in patients with prior 68. Bogsrud MP, Langslet G, Ose L, et al. No effect of combined coen- statin intolerance. Ann Pharmacother. 2008;42:341–346. zyme Q10 and selenium supplementation on atorvastatin-induced 59. Glueck CJ, Aregawi D, Agloria M, et al. Rosuvastatin 5 and 10 mg/d: myopathy. Scand Cardiovasc J. 2013;47:80–87. a pilot study of the effects in hypercholesterolemic adults unable to 69. Parker BA, Gregory SM, Lorson L, Polk D, White CM, tolerate other statins and reach LDL cholesterol goals with nonstatin Thompson PD. A randomized trial of coenzyme Q10 in patients lipid-lowering therapies. Clin Ther. 2006;28:933–942. with statin myopathy: rationale and study design. J Clin Lipidol. 60. Ruisinger JF, Backes JM, Gibson CA, Moriarty PM. Once-a-week ro- 2013;7:187–193. suvastatin (2.5 to 20 mg) in patients with a previous statin intolerance. 70. Halbert SC, French B, Gordon RY, et al. Tolerability of red yeast rice Am J Cardiol. 2009;103:393–394. (2,400 mg twice daily) versus pravastatin (20 mg twice daily) in pa- 61. Gadarla M, Kearns AK, Thompson PD. Efficacy of rosuvastatin (5 mg tients with previous statin intolerance. Am J Cardiol. 2010;105: and 10 mg) twice a week in patients intolerant to daily statins.AmJ 198–204. Cardiol. 2008;101:1747–1748. 71. Jacobson TA. Toward ‘‘pain-free’’ statin prescribing: clinical algo- 62. Ballantyne CM, Houri J, Notarbartolo A, et al. Effect of ezetimibe co- rithm for diagnosis and management of myalgia. Mayo Clin Proc. administered with atorvastatin in 628 patients with primary hypercho- 2008;83:687–700. lesterolemia: a prospective, randomized, double-blind trial. 72. Abd TT, Jacobson TA. Statin-induced myopathy: a review and update. Circulation. 2003;107:2409–2415. Expert Opin Drug Saf. 2011;10:373–387. Journal of Clinical Lipidology (2014) 8, S72–S81

Original Contribution An assessment by the Statin Intolerance Panel: 2014 update

John R. Guyton, MD, FNLA*, Harold E. Bays, MD, FNLA, Scott M. Grundy, MD, PhD, FNLA, Terry A. Jacobson, MD, FACP, FNLA

Division of Endocrinology, Diabetes, and Metabolism, Duke University Medical Center, 201 Trent Drive, Baker House 281, Durham, NC 27710, USA (Dr. Guyton); Louisville Metabolic and Atherosclerosis Research Center, Louisville KY, USA (Dr. Bays); Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX, USA (Dr. Grundy); and Ofﬁce of Health Promotion and Disease Prevention, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA (Dr. Jacobson)

KEYWORDS: Abstract: This article from the National Lipid Association Statin Intolerance Panel provides a frame- Drug intolerance; work for understanding statin intolerance and makes general recommendations for health professionals. Patient-centered For speciﬁc guidance on adverse events related to muscle, liver, cognition, and glucose metabolism, medicine; one should refer to the other reports of the Statin Safety Task Force for those topics. Although statin Statin adverse effects; adverse effects rarely lead to permanent sequelae, symptomatic intolerance frequently hinders cardio- Statins; vascular risk reduction by statins. We emphasize here the advisory role of the clinician helping each Statin safety patient to make personal decisions on statin tolerability. We identify a pressing need for further research on statin intolerance and make suggestions for research design. Ó 2014 National Lipid Association. All rights reserved.

In 2006, the National Lipid Association (NLA) pre- clinician in dealing with its manifestations. General recom- sented the analysis and recommendations of a Statin Safety mendations are provided, but this article does not attempt to Task Force, which clarified issues related to safety of statin summarize the conclusions or recommendations of the spe- drugs. Since then, statin intolerance (adverse effects related cific NLA Statin Safety Task Force Panels for muscle, liver, to quality of life, leading to decisions to decrease or stop cognition, and diabetes risk. We identify a pressing need for the use of an otherwise-beneficial drug) has come to the more research on statin intolerance and make suggestions forefront of clinical concern, whereas the safety of statins for research design. (assessment of potential to cause death or irreversible impairment) has come to be regarded as largely favorable. In this article, we seek to provide a framework for under- Update on 2006 Statin Safety Task Force standing statin intolerance and the roles of patient and report questions

Several articles in the 2006 Statin Safety Task Force * Corresponding author. report dealt with the overall safety of statins. Statin beneﬁt E-mail address: [email protected] in appropriately targeted patients appeared to be orders of Submitted March 3, 2014. Accepted for publication March 4, 2014. magnitude greater than risk with regard to irreversible

Evidence grading: Strength of recommendation* Grade Strength of recommendation A Strong Recommendation There is high certainty based on the evidence that the net benefit† is substantial B Moderate Recommendation There is moderate certainty based on the evidence that the net benefit is moderate to substantial, or there is high certainty that the net benefit is moderate C Weak Recommendation There is at least moderate certainty based on the evidence that there is a small net benefit D Recommend Against There is at least moderate certainty based on the evidence that it has no net benefit or that the risks/harms outweigh benefits E Expert Opinion There is insufficient evidence or evidence is unclear or conflicting, but this is what the expert panel recommends N No Recommendation for or against There is insufficient evidence or evidence is unclear or conflicting *The system was adapted as a hybrid of the National Heart, Lung, and Blood Institute (NHLBI) rating system (NHLBI cardiovascular-based methodology) used in the new American Heart Association/American College of Cardiology cholesterol guidelines.1 and adapted from the original Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system of evidence rating.2 †Net benefit is defined as benefits minus risks/harms of the service/intervention. organ damage and impairment. Benefit-to-risk estimates of statin safety have not changed in the interim since 2006. were even greater with regard to mortality averted from What is new since 2006 is a better understanding of how to atherosclerotic disease vs mortality (attributable to rhabdo- advise the individual patient with specific adverse effects, myolysis) associated with statin use.4–6 These assessments ie, statin intolerance.

2014 Questions they rise to the level of intolerance requiring cessation or dose reduction depends on a benefit-risk assessment. For 1. Does statin intolerance exist? most patients appropriately started on statins, mild-to- moderate abnormalities in liver and muscle enzymes, as ANSWER: Yes. well as diabetes risk, do not represent serious adverse STRENGTH OF RECOMMENDATION: A (Strong). effects, in that the benefits of proven coronary heart disease QUALITY OF EVIDENCE: Moderate. reduction with statins outweigh potential risks of laboratory EXPLANATION: The Panel strongly recommends that abnormalities. This is discussed in detail by other panels in the existence of statin-induced adverse reactions leading to this updated Statin Safety Task Force report. Cognitive intolerance be recognized. As discussed herein, additional abnormalities are acknowledged but appear to be rare and evidence is needed to define the frequency of statin reversible. This brings us back to the most commonly intolerance and to make recommendations for appropriate reported adverse effect associated with statins—myalgia. patient management. The strongest evidence at present for statin intolerance in In the individual case, we define statin intolerance to be the population is the consensus of experienced clinicians adverse symptoms, signs, or laboratory abnormalities that myalgia appears in some patients taking statins, remits attributed by the patient (or provider) to the statin and in with withdrawal, and reoccurs with rechallenge. Our own most cases perceived by the patient to interfere unaccept- clinical impressions agree with this consensus. The expert ably with activities of daily living (such as sleep, work/ panel strongly affirms that statin intolerance related to housework, or leisure-time activity), leading to a decision myalgia exists, but how frequently it occurs remains of to stop or reduce statin therapy. Although less likely, the moderate certainty. When faced with patients who complain provider might also decide to stop or reduce statin therapy of myalgia while taking statins, we suggest that the usual on the basis of clinical/laboratory assessment (abnormal burden of proof is reversed. Ordinarily, one must endeavor to liver function tests, creatine phosphokinase values) sug- prove that a drug exerts an effect, but this is strictly true only gesting undue risk. We also define statin intolerance for an for purported beneficial effects to support clinical use of the aggregate population in a stricter sense as clinical or drug. In the situation of a drug-associated adverse reaction, laboratory adverse experiences linked to statin treatment whether or not it might be overreported by patients, the by appropriate scientific evidence and presenting with pain, burden for the medical community is to prove that it does not impairment, or risk–justifying statin cessation or dose exist or that its real frequency lies below a certain small reduction. By either definition, our answer to the question level. ‘‘Does statin intolerance exist?’’ is yes. The incidence of reported statin intolerance is widely Drug tolerance is related to safety but can be distin- variable and dependent upon how the intolerance was guished from it in that intolerance refers to ‘‘unpleasant assessed and the setting. Some might argue that the greater drug-related adverse events without serious or permanent reported rates of statin intolerance are driven by the media. sequelae.’’7 The distinction often hinges on degree of However, within a few years after the introduction of statins distress or impairment. In the individual case, the patient’s for clinical use, one clinic reported that 5% of their patients subjective feelings, preferences, and judgment are determi- prescribed simvastatin stopped within 6 months because of native although best aided by evaluation and effective perceived adverse reactions, and overall 14%, most of communication from the clinician. Guidance for the indi- whom continued treatment, described myalgia.8 As early as vidual case depends on understanding statin intolerance in 1995, Shepherd suggested that lovastatin might induce the population sense. Therefore, we address the stricter some kind of myopathy ‘‘with or without elevation of mus- population-based definition of statin intolerance here and cle enzyme levels’’ in approximately 5% of patients.9 These return to the individual later when considering patient- early reports were unlikely to have been influenced by centered medicine. media or internet attention to muscle reactions. Most statin intolerance is related to myalgia. In rare In contrast to these clinically based reports, randomized instances, patients have clinically evident myopathy with clinical trials of statins with large numbers of subjects have weakness and/or markedly increased serum muscle en- not shown significant differences in the number of subjects zymes (myositis, see Muscle Safety Panel Report in this reporting muscle symptoms between statin- and placebo- issue for definitions of adverse muscle reactions). Some allocated groups.10 The challenge here is that some describe cognitive dysfunction, which usually lacks objec- randomized trials dropped patients with muscle or other tive documentation. Adverse effects of statins also include complaints during the lead-in before randomization. Also, abnormalities in liver enzymes, asymptomatic increase in common exclusion criteria for entry into a statin clinical muscle enzymes, and metabolic derangement associated trial have been a previous history of statin intolerance with risk for new onset of type 2 diabetes mellitus. There is and being on other medications known to increase statin little evidence that statins can induce severe acute liver blood levels. Thus, although it may seem paradoxical, clin- disease or chronic liver disease. The hepatic enzyme, ical trial results obtained thus far are unlikely to assess the muscle enzyme, and metabolic abnormalities unquestion- frequency of statin intolerance accurately. A definitive ably occur, but they are usually asymptomatic, and whether study would recruit patients who report myalgia associated Guyton et al Statin intolerance overview S75 with statin use and then randomize them to double-blind ANSWER: No. statin vs placebo. Surprisingly, after 26 years of clinical STRENGTH OF RECOMMENDATION: E, Expert availability of statins, definitive trials remain to be per- Opinion. formed, as we discuss later in this article. QUALITY OF EVIDENCE: Low. EXPLANATION: Well-designed clinical trials provide 2. Are statins generally well tolerated and safe? reliable results for their primary end points, which are ANSWER: Yes. generally efficacy end points and, to a much lesser degree, STRENGTH OF RECOMMENDATION: A (Strong). for their prespecified secondary end points, which often QUALITY OF EVIDENCE: High. include safety end points. Statin tolerability appears far EXPLANATION: The risk for mortality or permanent down the list of end points in most randomized clinical organ damage associated with statins is very small. Mor- trials. The sole exception is a trial of 420 subjects reported 16 tality risk is almost entirely related to rhabdomyolysis. very recently by Parker et al. with a primary end point of Between 1987 and 2001, the US Food and Drug Admin- statin-associated myalgia. Clinical trials often exclude pa- istration received 42 reports of deaths from rhabdomyolysis tients with co-morbid conditions that might affect tolera- associated with the use of statins excluding cerivastatin, bility. Patients who enroll in statin trials begin with a which is an average of 3 reported deaths per year.11 In a self-assessment of health sufficiently robust to take on the study of claims data from managed health care plans extra effort of trial visits and lifestyle and medication between 1998 and 2001, the rate of rhabdomyolysis in hos- adherence. Retention in clinical trials and maintenance of pitalized patients treated with simvastatin, pravastatin, or study medications is actively encouraged. Apart from the 16 atorvastatin was 4.4 per 100,000 person-years.12 Random- study by Parker et al., end points related to statin intoler- ized clinical trials reported a similar rate, but rhabdomyol- ance, such as myalgia or other muscle symptoms, usually ysis also occurred among those assigned to placebo.5 Some have been assessed only by spontaneous reporting as cases arose from drug interactions and were avoidable. The adverse events and not by targeted questions to monitor case fatality rate for hospitalized rhabdomyolysis was about these symptoms. 1 in 10.5 Therefore, mortality caused by statin treatment is Two large clinical trials included specific monitoring for rare. In contrast, the benefit of statin use is to avoid several statin adverse effects. The Prospective Study of Pravastatin hundred deaths and several hundred cases each of heart and in the Elderly at Risk (PROSPER) performed cognitive and brain infarction per 100,000 patients treated. disability assessments as tertiary end points. Pravastatin did No effect of statin treatment on cancer incidence or not change the rate of decrease of cognitive function and 17 mortality was evident in a meta-analysis of individual data did not affect disability scores. The Heart Protection from 175,000 patients in 27 randomized clinical trials of Study (HPS) specifically recorded ‘‘new unexplained mus- 18 statins. The negative results apply to 23 separate anatomic cle pain or weakness’’ at postrandomization visits. sites and also to the subset of participants with baseline Although muscle complaints were common at 6% for any low-density lipoprotein cholesterol (LDL-C) ,2 mmol/L given visit, the fraction of subjects ever reporting them (77 mg/dL).13 was exactly the same at 33% in both the simvastatin- and Increased incidence of type 2 diabetes mellitus is a placebo-assigned groups. During the prerandomization relatively newly identified statin adverse effect whose run-in phase of HPS that included 4 weeks of placebo fol- frequency is mainly increased in those with other elements lowed by 4 to 6 weeks of simvastatin 40 mg, 36% of poten- of the metabolic syndrome or prediabetes such as obesity, tial subjects were dropped before randomization. However, glucose intolerance, and hypertension. It is unclear whether less than 3% had adverse symptoms from simvastatin as the 19 this effect is reversible with statin discontinuation or after reason for stopping. These data suggest an upper limit for weight loss with diet and exercise. It is clear, however, that simvastatin-related muscle reactions well below the level of the benefits from statins as measured by the number needed 10.5% described in the Prediction of Muscular Risk in 20 to treat for a reduction in myocardial infarction and stroke Observational Studies (PRIMO), but the upper limit in is much more favorable than the number needed to harm HPS applies only to people similar to those who volunteer from incident diabetes. This is described in detail by the for a clinical trial. Interestingly, among individuals in HPS Diabetes Safety Panel. who attended the first randomization visit but were not Statins are among the safest drugs used in medical randomized, 15.4% reported new unexplained muscle 19 practice. No evidence to the contrary has arisen from symptoms in response to active inquiry. Thus, active in- observational data or clinical trials. Long-term follow-up quiry led to a greater percentage of patients being excluded studies of randomized clinical trials ranging from 10 to from the trial and thus may have led to an underestimation 15 years support the safety of statins.14,15 Individual of statin-related muscle symptoms during the trial. An patients have taken statins at relatively high doses over internet-based survey reported muscle-related adverse 21 periods of 251 years without discernible adverse effects. events in 29% of 10,138 current and former statin users. The respondents for this survey were drawn from 27,946 3. Do large randomized trials provide reliable estimates of hypercholesterolemic individuals in an online-registered statin intolerance? multinational consumer panel. Clearly, reports of muscle S76 Journal of Clinical Lipidology, Vol 8, No 3S, June 2014 side effects among statin users in practice are relatively EXPLANATION: A common perception among patients frequent compared with the 3% limit at the outset of HPS. is that a person should stop any medication to which an There is a continuing need for observational studies of ‘‘allergy’’ has developed. Although this is true in some statin intolerance. We also call attention to the need for cases—for example, a typical drug rash occurring after the randomized, double-blind trials that extend the work of administration of penicillin or allopurinol—the develop- Parker et al.,16 examining statin intolerance as a primary ment of a mild symptomatic muscle reaction or occasional end point with innovative approaches for subject enroll- difficulty recalling a name should not necessarily lead to ment and pre-randomization evaluation (see below). discontinuation of statin treatment. It may be necessary for One of the more challenging aspects of determining the the clinician to educate the patient, letting him or her know frequency of statin intolerance is the absence of a validated that the potential adverse reaction, even if caused by the clinical scale. Validated scales for assessment of the tolera- statin, is not a true allergic response but rather a manifes- bility of other lipid-altering drugs have been proposed and tation of individual sensitivity to the drug (ie, an idiosyn- tested. It is surprising that no similar tolerance instrument has cratic reaction, excepting, of course, urticarial or other yet been developed for statins, which is by far the most classic allergic reactions, which are rare with statins). widely used lipid-altering drug class. The Muscle Safety The decision for or against continuing to take a statin Panel report in this issue proposes a statin myalgia index, sometimes can be simplified by casting it as a question of which needs to be validated in a prospective clinical trial. tolerance (ie, how bothersome are the symptoms?) rather than a question of diagnosis (ie, are the symptoms really 4. Is statin intolerance best defined in the context of due to the statin?). The latter question is often very difficult patient-centered medicine? to answer in the individual case. ANSWER: Yes. This kind of patient-centered approach again supports STRENGTH OF RECOMMENDATION: E, (Expert the need for validated scales for statin intolerance, which Opinion). incorporate assessments of the degree to which the poten- QUALITY OF EVIDENCE: Not Applicable. tial bothersome aspects of statin therapy affect the daily EXPLANATION: In its recent formulation of standards lives of patients. These would be similar to those often for trustworthy clinical practice guidelines, the Institute of assessed in quality-of-life scales by recording and Medicine reaffirmed the fundamental role of scientific measuring the effect on work/housework and leisure time evidence for clinical practice, then added the following activity, and the degree to which perceived adverse effects qualifying statement: ‘‘At the same time, and particularly influenced the willingness of patients to persist with statin under conditions of uncertainty regarding optimal deci- treatment. sions, clinician experiential knowledge and skill (the ‘‘art of An example of tolerable symptoms that might not medicine’’) and patient values and preferences remain lead to statin discontinuation would be the development essential contributors to quality healthcare practice, in a of mild leg stiffness on rising in the morning, which lasts complex interplay with science.’’22 This is best exemplified for 30–60 minutes and does not interfere with daily by the recent concepts of ‘‘patient centered medicine’’23,24 activities. At the other extreme, statin-induced muscle and the importance of ‘‘shared decision making.’’25 weakness can lead to an inability to rise from a chair Levenstein et al.26 suggested that the health care pro- unaided by hands and arms or to difficulty walking up vider must manage 2 parallel agendas in pursuit of stairs. We cannot conceive of a benefit from statin use that patient-centered medicine. The clinician’s own agenda is would outweigh such weakness, especially if confirmed by to make a diagnosis via history and objective data. The dechallenge and rechallenge. Most patients with adverse clinician must also evaluate the patient’s agenda, which effects related to statins present with symptoms between includes expectations, feelings, and fears. The 2 agendas the extremes described above. Estimation of the relative merge in a joint process of deciding on further observation, harm vs benefit, and deference to patient values and evaluation, or treatment. In the context of statin-associated preferences, comprise the dual agenda for the clinician muscle reactions, the role of patient-centered medicine is who practices patient-centered medicine. In general, further emphasized by the subjective nature of the problem. continuation of the statin can often be advised when As reviewed in this supplement by the Muscle Safety Panel, symptoms are mild and last only a short portion of the the role of objective data in dealing with muscle reactions is day, and when daily activities, occupational endeavors, very limited. The agenda for the clinician is to advise and sleep, and recreational and exercise routines are not support the patient in his or her decision to continue, termi- compromised. nate, or change treatment for the lipid disorder. 6. Are recommendations for widespread use of statins to 5. Is it safe to advise a patient to continue statin therapy prevent atherosclerotic cardiovascular disease appro- even when some degree of statin intolerance is present? priate, given the emerging evidence with regard to statin intolerance? ANSWER: Yes. STRENGTH OF RECOMMENDATION: B, Moderate. ANSWER: Yes. QUALITY OF EVIDENCE: Low. STRENGTH OF RECOMMENDATION: A (Strong). Guyton et al Statin intolerance overview S77

QUALITY OF EVIDENCE: High. that reason. Alternatives to the parallel group comparison EXPLANATION: We reaffirm the conclusions of estab- are study designs in which every subject receives a statin lished guidelines that call for widespread use of statins to at some point in the trial. Fewer subjects are needed, but treat patients with increased risk for atherosclerotic cardio- the variability of the drug-placebo sequence introduces po- vascular disease.1,27–29 During the past 9 years, new large tential confounding. From the point of view of a prospec- randomized trials have added to the data confirming efficacy tive research study, these ‘‘crossover’’ designs offer to and safety of statin use (Stroke Prevention by Aggressive each individual a probable answer with regard to statin Reduction in Cholesterol Levels [SPARCL], Incremental intolerance. This could help recruitment and give the Decrease in End points through Aggressive Lipid lowering advantage of focusing the trial on the group of patients [IDEAL], and Justification for the Use of statins in Preven- who want to discover if their symptoms are truly related tion: an Intervention Trial Evaluating Rosuvastatin to statin treatment. The traditional crossover design [JUPITER]).30–32 Although a prospective observational (Fig. 1B) could heighten the attention of subjects to symp- study estimated the prevalence of statin intolerance as toms in the period immediately after commencement of high as 10%–15%,20,21 such high rates have not been seen study drug vs placebo, because these times are known to in randomized clinical trials. Even if the higher estimates the subject. A variation on the crossover trial design intro- apply, at least 85% of patients will still have the benefits duces the real statin drug at an unknown, randomly chosen of statin therapy. Overemphasis on statin intolerance can time within the overall study period (Fig. 1C). By providing hinder appropriate clinical use of a drug that greatly amelio- a placebo run-in period of variable and unknown length, rates the impact of atherosclerotic vascular disease. 7. Are there clinical trial designs that may reliably address questions of statin intolerance? ANSWER: Yes. STRENGTH OF RECOMMENDATION: E, Expert Opinion. QUALITY OF EVIDENCE: Not Applicable. EXPLANATION: Research questions needing attention relate (1) to the frequency, severity, and impact on daily activities of statin adverse effects; and (2) to alternative strategies for reaching lipid treatment goals in statin- intolerant patients. Observational studies of real-world clinical use of statins and randomized, placebo-controlled, double-blind clinical trials provide complementary information on the frequency and impact of statin intolerance. Both strategies should continue to be implemented. Randomized trials give definitive evaluation of the relationship between drug exposure and adverse effects, whereas observational studies test the applicability of results to actual clinical use. In both kinds of studies, the use of genetic testing for the common SLCO1B1*5 mutation (w15% of alleles, w28% of patients) and other genetic variants may provide the opportunity to test hypotheses via Mendelian randomization.33 Certain elements of design should be included in randomized trials, if clear answers on statin intolerance are to be obtained. First, statin tolerance/intolerance must be the primary end point. Second, the comparison should include blinded statin vs placebo medication. An active comparator is not mandatory in atherosclerosis prevention trials lasting 1 to 6 months, depending on clinical scenario.34 Third, investigators are encouraged to consider recruiting subjects with a personal history of statin intolerance to provide sufficient statistical power at reason- Figure 1 Three types of randomized trial designs for statin- able cost. intolerance studies: (A) Parallel group; (B) Crossover; and (C) The most straightforward study design is the parallel Crossover with variable time of treatment onset. In each panel, group comparison (Fig. 1A). This type of comparison offers patients are assumed to be randomly assigned. Open bars, placebo the least-complex interpretation and may be preferred for treatment. Solid bars, statin treatment. S78 Journal of Clinical Lipidology, Vol 8, No 3S, June 2014 this type of design might reduce the role of anxiety and At present, clinicians, regulatory agencies, and insurers focused attention on determining study results. (federal and private) may benefit from a provisional The other broad issue for new research is the testing of definition of statin intolerance that may allow for better alternative strategies for lipid treatment when statin intol- communication and research. For this purpose, the NLA erance is recognized. Examples of research questions in Expert Panel on Statin Intolerance proposes the following this category include the following: definition: a. Can low-dose statin combined with nonstatin drugs Statin intolerance is a clinical syndrome characterized achieve the goals of therapy with regard to either by the inability to tolerate at least 2 statins: one lipid-lowering or clinical outcomes? statin at the lowest starting daily dose AND another b. Can nonstatin drugs in combination achieve the goals of statin at any daily dose, due to either objectionable therapy? symptoms (real or perceived) or abnormal lab de- c. Can different statin regimens achieve the goals of ther- terminations, which are temporally related to statin apy in statin-intolerant patients? treatment and reversible upon statin discontinuation, but reproducible by re-challenge with other known In targeting these research questions toward goals of determinants being excluded (such as hypothyroid- therapy, some complexity of goals must be recognized. The ism, interacting drugs, concurrent illnesses, significant ideal of recruiting statin-intolerant subjects for large ran- changes in physical activity or exercise, and underly- domized clinical trials with clinical cardiovascular end ing muscle disease). Specifically, the lowest starting points is probably not feasible at this time. Surrogate end statin daily dose, is defined as rosuvastatin 5 mg, points will be necessary, of which the best may be LDL-C, atorvastatin 10 mg, simvastatin 10 mg, lovastatin non–high-density lipoprotein-cholesterol, or some measure 20 mg, pravastatin 40 mg, fluvastatin 40 mg, and of molar concentration of LDL particles (either apolipo- pitavastatin 2 mg. protein B or a physically derived measure such as nuclear magnetic resonance particle concentrations). A validated A further question is whether degrees of statin intolerance index of statin intolerance should also be included among should be proposed. One might consider ‘‘complete statin study end points. intolerance’’ to be the inability to tolerate the lowest daily 8. Is there a universally accepted definition of statin intol- recommended starting dose of at least 1 statin, plus the erance that can be used by clinicians, researchers, in- aforementioned conditions. Such a definition of complete surers, and regulatory authorities? statin intolerance, however, has some limitations. First, some statins dosed on a non-daily basis at their lowest recom- ANSWER: No. mended starting dose, eg, atorvastatin 10 mg or rosuvastatin STRENGTH OF RECOMMENDATION: E, Expert 5–10 mg taken 2 or 3 days a week—may achieve LDL-C Opinion. lowering comparable with or better than that of oral non- QUALITY OF EVIDENCE: Low. statin drugs.35 Second, nondaily statin doses have not been EXPLANATION: The lack of standard definition(s) for studied in randomized clinical trials, and, thus, the evidence statin intolerance has made it difficult for clinicians, base for their clinical benefit is lacking. researchers, and regulatory agencies to communicate effectively about such a widespread and important clinical and public health issue. A basic dilemma, which we Recommendations from the Statin addressed in the discussion following Question #1, is that Intolerance Expert Panel statin intolerance should be defined differently for the individual case (perspective of the patient and the treating Recommendations to clinicians clinician) and for a population of treated individuals (research perspective). For the individual case, the patient’s judgment to discontinue the drug is determinative, although 1. The clinician should acknowledge that statin intolerance best guided by counsel from the provider. From the is a real phenomenon, manifesting mostly as an array of population or research perspective, randomized, blinded, muscle-related symptoms that include aching, stiffness, placebo-controlled challenge trials are required, without proximal motor weakness, fatigue, and back pain. Esti- discounting the complementary value of continuing obser- mates of the frequency of muscle symptoms verifiably vational studies. related to statin use range from 1% to 10%. Severe There remains a need, however, for a pragmatic myopathy with objective weakness and/or markedly definition that will mediate between the research and the elevated muscle enzymes is rare. Reliable research individual perspectives described previously. A pragmatic designs are only beginning to address the actual fre- definition will help the clinician provide accurate and quency of statin muscle intolerance in populations. helpful advice to the patient. Ultimately a validated clinical 2. Cognitive difficulties while taking statins continue to be scale, which will be based on research results, will be part reported by a small number of patients, but objective of the definition. documentation of impaired cognition is generally Guyton et al Statin intolerance overview S79

lacking. No evidence points toward progressive or per- 8. The clinician may optionally pursue nonstatin treatment manent impairment of cognition induced by statins. of high LDL-C or non–high-density lipoprotein in The frequency of cognitive difficulties is unknown, but statin-intolerant patients, with or without concomitant is clearly much lower than that of muscle symptoms. statin therapy, based mainly on the probable inferences 3. Statin treatment results in substantial increases in serum that LDL is causally involved in atherosclerosis and hepatic transaminase levels (alanine aminotransferase that LDL-C–lowering is the major mechanism of cardio- and/or aspartate aminotransferase increases .3 times vascular event reduction by statins. Options to be the upper limit of normal) in 0.3%–3% of patients in a considered include bile acid sequestrants, niacin, ezeti- dose-dependent manner. However, evidence does not mibe, fibrates, plant sterol esters or stanol esters (formu- support the concerns that statins may seriously impair lated in margarines), viscous fiber (such as that found in the metabolic functions of the liver acutely, or that sta- oat bran, legumes, and psyllium), and substitution of tins may induce cumulative damage to liver cells leading mono- or polyunsaturated fats for trans unsaturated or to chronic liver disease. Baseline determination of liver saturated fats in the diet. Of the nonstatin therapies, function before statin initiation is recommended, but those agents that have proven cardiovascular outcome regular monitoring of hepatic transaminase levels in data should be considered first. statin-treated patients is no longer recommended. 9. Specific recommendations for many issues of statin 4. The use of statins is associated with increased risk for intolerance related to muscle, liver, cognition, and dia- new-onset diabetes mellitus, especially when greater betes risk can be found in the reports of the Statin Safety doses of statins are used. However, the magnitude of Task Force Panels addressing those topics. increased risk is small compared with other diabetes risk factors such as obesity. Moreover, the benefit of proven coronary heart disease reduction with statins out- Recommendations to patients weighs the risk of new-onset diabetes. 5. In every individual case, the decision on statin intoler- 1. Taking a statin is one of the most effective ways to lower ance is the patient’s decision, based on subjective feel- your risk of atherosclerosis, a disease of arteries in ings, preferences, and judgment, although it is best which cholesterol builds up in the arterial wall. Athero- aided by evaluation and effective communication from sclerosis is a silent disease that usually develops without the clinician. any symptoms until instability of the inner lining of 6. Statin intolerance usually does not involve substantial arteries leads to the sudden appearance of a blood clot, risk for mortality or permanent disability. Therefore, causing a heart attack or stroke. Almost every adult in the clinician should help the patient distinguish statin the United States has atherosclerosis to some extent. intolerance from ‘‘drug allergy,’’ which could imply sub- At least 1 in 3 people over their lifetime will experience stantial risk with any drug rechallenge. The question for a heart attack or stroke that kills the person or damages statin rechallenge, usually with modified dosing, may be heart or brain. This is the reason that statins are recom- best presented as a question of tolerance (How bother- mended for so many people. some are the symptoms?) rather than a question of diag- 2. About 1 in 10 people who try taking a statin will report nosis (Are the symptoms really due to the statin?). The some kind of intolerance, most commonly muscle aches latter question is often too difficult to answer for an in- in the legs, trunk, or shoulders and upper arms. Statins dividual patient. can cause weakness or muscle breakdown (which has 7. Based on the foregoing considerations, we recommend caused a few deaths), but these effects are rare compared that the clinician and patient attempt to maintain statin with muscle aches. The prevention of death and treatment in some form in almost every case of statin disability from improving atherosclerosis is far greater intolerance. In a large observational study of routine than the risk from taking a statin. clinical practice, the fraction of patients who reported 3. A few people have reported memory lapses or difficulty muscle symptoms with high doses of statins (as with their thinking while taking a statin. This is much currently recommended) was about 10%. In that less frequent than muscle problems. In older people, study, the muscle symptoms generally led to changes most problems with memory or thinking are caused by in lipid-lowering therapy. Most of such patients can be something else. Careful observation and clinical trials continued on statin treatment, commonly with doses suggest that statins do not contribute to the common and/or alternative statins that achieve a lower degree problem of dementia in older people. If you experience of LDL-C lowering than initially targeted. Because of memory or thinking problems, you and your health care the logarithmic dose response for LDL-C lowering, sta- provider will want to carefully consider whether stop- tins taken at 4-fold lower doses or even less can often ping your statin drug is worth the increased risk for heart achieve clinically meaningful LDL-C reductions. Ator- attack and stroke. vastatin or rosuvastatin at doses of 5–10 mg taken 4. Although abnormal blood tests for liver enzymes develop once or twice a week may reduce LDL-C by 16%–26%. in as many as 1 in 30 people taking high-dose statins, S80 Journal of Clinical Lipidology, Vol 8, No 3S, June 2014

there is little evidence that statins damage the liver or Benecol are known to lower LDL-C), and by increasing block essential functions of the liver. In the past, regula- consumption of soluble or viscous fiber such as that tory agencies such as the US Food and Drug Administra- found in beans, oat or rice bran, and psyllium powder tion recommended that blood tests for liver enzymes be (Metamucil and other brands). However, it is very diffi- checked while taking statins, but this recommendation cult to get as much LDL-C lowering as a statin provides, has been withdrawn, and no monitoring is needed. Your by diet and lifestyle changes alone. health care provider may still want to check liver tests before or at the time of starting statin treatment, or if you have symptoms suggesting a liver problem. Recommendations for research on statin 5. People taking statins have a small increase in their risk intolerance for developing diabetes mellitus with high blood sugar. However, the benefit of reducing risk for heart attack 1. The frequency of statin intolerance will be best deter- and stroke outweighs the small increase in risk for dia- mined from the combined results of observational betes. A few pounds of weight loss can fully counteract studies and prospective randomized clinical trials. the effect of a statin on diabetes risk. 2. Development of a validated index of statin muscle intol- 6. If you feel that you have experienced a side effect (usu- erance is an important early goal for research. ally muscle aches) while taking a statin, the decision of 3. The following design elements for clinical trials should whether to continue taking the statin is your decision to be strongly considered: (a) statin tolerance as the pri- make, guided by the best advice that your health care mary end point; (b) randomized, blinded comparison provider can give. Before stopping a statin due to of statin vs placebo medication; and (c) recruitment of possible side effects, it is generally recommended that patients with a personal history of statin intolerance. you speak to your health care provider first. Often it 4. Alternative strategies for achieving LDL-C–lowering can be difficult to decide whether the symptoms a person goals should be investigated using varying combinations experiences are truly caused by the statin. Because of of statin and nonstatin drugs. the good safety record of statins, it is reasonable to 5. In addition to the foregoing, research on the causes, ask how bothersome the symptoms are, and continue impact, and possible amelioration of statin intolerance with statin treatment if you feel that the symptoms are should receive increased attention. Properly designed minor, readily tolerated, and not so bothersome that randomized trials should assess whether supplementa- your ability to exercise is limited. tion with vitamin D, coenzyme Q10, and other potential 7. Experience has shown that most people who experience therapies may improve statin tolerability. intolerance to a statin will still be able to take a different statin or perhaps the same statin at a lower dose. Although higher doses of statins have the best record Financial disclosures for preventing heart attacks and strokes, lower doses (for example, one quarter as much) can often provide The following authors disclose that they have modest benefit by lowering LDL-C and possibly reducing your relationships with industry that might pose a potential chances of heart attacks and strokes. Given how benefi- conflict of interest(s). Dr. Guyton has received research cial statins are in the prevention of heart attack and grants from Merck, Abbott, Genzyme, Sanofi, Regeneron, stroke, a health care provider may often try different GSK, Amarin, and Amgen and consulting fees from Merck, statin drugs at different doses to help find one that you Regeneron, and ARMO Biosciences. Dr. Harold Bays has can tolerate. Most patients who have symptoms on 1 served as a consultant and/or speaker to Amarin, Amgen, statin can usually tolerate a different statin or the same Astra Zeneca, Bristol Meyers Squibb, Catabasis, Daiichi statin at a lower dose. Sankyo, Eisai, Isis, Merck, Novartis, VIVUS, WPU, and his 8. If you cannot take a statin at any dose, or if you do not research site has received research grants from Alere, get enough cholesterol lowering while taking a statin Amarin, Amgen, Ardea, Astra Zeneca, Boehringer Ingel- (perhaps because the dose has been reduced), your pro- heim, Bristol-Myers Squibb, California Raisin Board, Cata- vider may recommend or prescribe 1 of several alterna- basis, Eisai, Elcelyx, Eli Lilly, Esperion, Essentialis, Forest, tive drugs for lowering cholesterol. There is some Gilead, Given, GlaxoSmithKline, High Point Pharmaceuti- evidence that alternative cholesterol medications reduce cals LLC, Hoffman LaRoche, Home Access, Janssen, risk for heart attacks and strokes, although the evidence Merck, Metabolex, Micropharma Limited, Necktar, Novar- is not as conclusive as it is for statins. tis, Novo Nordisk, Omthera, Orexigen, Pfizer, Pronova, 9. Apart from cholesterol-lowering medication, diet and Regeneron, Stratum Nutrition, Takeda, TIMI, Transtech lifestyle changes can reduce heart attack and stroke Pharma, Trygg, VIVUS, WPU, and Xoma. Dr. Scott Grundy risk. A person can lower their LDL-C by reducing trans discloses that he has received an honorarium as a consultant and saturated fat in the diet, by adding plant sterol esters to Sanofi. Dr. Jacobson is a consultant for Amarin, Amgen, or stanol esters (the margarines Promise Activ and Astra Zeneca, Merck, Sanofi, and Regeneron. Guyton et al Statin intolerance overview S81

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