Severity of statin-induced adverse effects on muscle and associated conditions: data from the DAMA study

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1 Expert Opinion on Drug Safety ISSN: (Print) X (Online) Journal homepage: Severity of statin-induced adverse effects on muscle and associated conditions: data from the DAMA study Juan Pedro-Botet, Jesús Millán Núñez-Cortés, Juan J. Chillarón, Juana A. Flores-Le Roux & Joan Rius To cite this article: Juan Pedro-Botet, Jesús Millán Núñez-Cortés, Juan J. Chillarón, Juana A. Flores-Le Roux & Joan Rius (2016): Severity of statin-induced adverse effects on muscle and associated conditions: data from the DAMA study, Expert Opinion on Drug Safety, DOI: / To link to this article: Accepted author version posted online: 20 Sep Submit your article to this journal Article views: 16 View related articles View Crossmark data Full Terms & Conditions of access and use can be found at Download by: [Biblioteca, Universitat Pompeu Fabra] Date: 29 September 2016, At: 05:39

2 Publisher: Taylor & Francis Journal: Expert Opinion on Drug Safety DOI: / Severity of statin-induced adverse effects on muscle and associated conditions: data from the DAMA study Juan Pedro-Botet 1, Jesús Millán Núñez-Cortés 2, Juan J. Chillarón 1, Juana A. Flores-Le Roux 1, Joan Rius 3 1 Unidad de Lípidos y Riesgo Vascular. Endocrinology and Nutrition Department. Hospital del Mar, Universidad Autónoma de Barcelona, Barcelona, Spain. 2 Unidad de Lípidos. Hospital Universitario Gregorio Marañón, Universidad Complutense, Madrid, Spain. 3 Cardiovascular Medical Advisor. Medicina Familiar y Comunitaria, Barcelona, Spain Address for correspondence: Dr. J. Pedro-Botet Endocrinology Department Hospital del Mar, Barcelona. Spain. Telf: FAX: @parcdesalutmar.cat Abstract 1

3 Objective: To describe the severity of muscle injury (myalgia, myositis and rhabdomyolysis) and associated conditions related to statin therapy that may be clinically significant. Research design and methods: A cross-sectional one-visit, non-interventional, national multicenter study including patients of both sexes over 18 years of age referred for past or present muscle symptoms associated with statin therapy was conducted. Clinical, biochemical and drug therapy characteristics were obtained at the initial evaluation. Results: 3,845 patients were recruited from a one-day record from 2,001 physicians. Myalgia was present in 78.2% of patients, myositis in 19.3% and rhabdomyolysis in 2.5%. The prevalence of different comorbidities such as diabetes, hypertension, atrial fibrillation, and coronary heart disease increased as the severity of myopathy rose. High-intensity statin therapy was used in 33.4% of patients. Concomitant drugs metabolized by the CYP450 3A4 pathway were taken by 9.3% of patients, and statins with this metabolic route by 75%. Independent variables associated with myositis or rhabdomyolysis compared with myalgia alone in the multivariate model were excessive alcohol consumption and pravastatin therapy. Conclusions: Myalgia was the most common muscle adverse effect associated with statin therapy. Excessive alcohol consumption and pravastatin were independently associated with myositis or rhabdomyolysis. 1. Introduction 2

4 Since the introduction of lovastatin in 1987 as the first 3-hydroxy-3-methyl-glutaryl- CoA reductase inhibitor approved for human therapy [1], statins have become the most widely used lipid-lowering drugs and have been proven to be effective in cardiovascular disease prevention [2-4], primarily by reducing plasma low-density lipoprotein (LDL) cholesterol concentrations and possibly through other pleiotropic effects. Although statins are generally well tolerated, muscular adverse effects appear to be the most common obstacle limiting their use. The clinical spectrum of statin-induced myotoxicity includes a heterogeneous group of clinical symptoms, signs and laboratory findings, which range from asymptomatic elevations in serum creatine kinase (CK) levels or myalgia to more severe painful myositis and, rarely, fatal rhabdomyolysis [5]. On the other hand, some evidence suggests that structural muscle injury can be present even in the absence of high CK concentrations [6,7]. Understanding statin-induced myotoxicty is significant [8], given the large and expanding number of patients eligible for statin therapy as stated in the 2013 American College of Cardiology/American Heart Association (ACC/AHA) guidelines on blood cholesterol treatment [9]. Furthermore, myalgia, one of the most frequent statin-related side effects, may result in poor patient compliance or even drug discontinuation [10] and thus represents a major barrier to maximizing cardiovascular risk reduction. The aim of the present study was to describe the severity of muscle injury (myalgia, myositis and rhabdomyolysis) related to statin therapy and associated clinical conditions. 2. Research design and methods 2.1. Study population and setting A cross-sectional, one-visit, non-interventional, national multicenter study, including the first 1-3 patients of both sexes over 18 years of age referred for any reason who had 3

5 been treated with statins over the last two years and had past or present muscle symptoms attributed to statin therapy, was conducted. The recruitment date of patients was the same for all investigators. These were chosen by a snowball sampling strategy [11]. After this process, we invited 2,135 professionals of whom 2,001 agreed to participate and represent all Spanish regions. Seventy-three percent were physicians with healthcare activity in primary care and 27% in specialized care. The study was approved by the Ethics Committee of the Institut Hospital del Mar d Investigacions Mèdiques. Data on age, sex, smoking habit, alcohol consumption, anthropometric parameters, presence of established cardiovascular disease, atrial fibrillation, hypothyroidism or other medical conditions and cardiovascular risk factors such as diabetes mellitus, hypertension, dyslipidemia and the metabolic syndrome were obtained at the initial evaluation. Current pharmacologic treatment including dosage and administration route was also recorded. Regarding laboratory parameters, lipid profile, serum creatinine, estimated glomerular filtration rate (egfr) and CK levels were collected. In accordance with the American College of Cardiology (ACC)/American Heart Association (AHA)/National Heart, Lung and Blood Institute (NHLBI) [12], the presence of myopathy was defined as any muscle-related sign or symptom (clinical and/or biochemical) after initiation of statin therapy, and ranges from mild myalgia without CK elevation to rhabdomyolysis with kidney failure. The term myalgia refers to heaviness, weakness or pain without elevation of CK, myositis for muscular symptoms with CK elevation, and rhabdomyolysis when CK levels exceed 10,000 U/L, usually associated with myoglobinuria and renal impairment. In agreement with the 2012 European guidelines on cardiovascular disease prevention in clinical practice [13], cardiovascular risk was classified as follows: a) very high: 4

6 established cardiovascular disease; type 2 or 1 diabetes mellitus with 1 cardiovascular risk factor or target organ damage; severe kidney failure (egfr < 30 ml/min/1.73 m 2 ) or a SCORE risk > 10%; b) high: markedly-elevated single risk factor (such as familial dyslipidemias and severe hypertension), type 2 or 1 diabetes mellitus without cardiovascular risk factors or target organ damage, moderate chronic kidney disease (egfr ml/min/1.73 m 2 ) or a SCORE risk between 5% and 10%; and c) moderate: SCORE risk between 1% and 5%. Statin therapy was classified according to the 2013 ACC/AHA blood cholesterol guidelines [9] as: high-intensity ( 50% LDL cholesterol reduction): atorvastatin mg, rosuvastatin mg; moderate-intensity (30 to < 50% LDL cholesterol reduction): atorvastatin mg, rosuvastatin 5-10 mg, simvastatin mg, pravastatin mg, lovastatin 40 mg, fluvastatin XL 80 mg, fluvastatin 40 mg bid, pitavastatin 2-4 mg; and low-intensity (< 30% LDL cholesterol reduction): simvastatin 10 mg, pravastatin mg, lovastatin 20 mg, fluvastatin mg, pitavastatin 1 mg Statistical analysis Data were expressed as mean ± standard deviation for continuous variables and as percentages and frequencies for categorical variables. Student s t-test was performed to assess differences between two means. When the comparison among continuous variables was between three or more groups, ANOVA test was performed. Chi-square or Fisher s exact tests were used to evaluate the degree of association of categorical variables. Logistic regression analysis including variables with a p value < 0.1 in univariate analysis or considered clinically relevant was applied to evaluate factors independently associated with the presence of myositis or rhabdomyolysis compared with myalgia alone. A p value < 0.05 was considered statistically significant. The statistical analysis was calculated with SAS (version Service Pack 4). 5

7 3. Results Demographic, anthropometric and clinical characteristics of 3,845 patients included in the study from 2,001 physicians are shown in Table 1. Myalgia was present in 3,008 (78.2%) patients, myositis in 742 (19.3%) and rhabdomyolysis in 95 (2.5%). Nonstatistically significant differences in smoking status were found among groups. By contrast, higher alcohol consumption was associated with increasing myopathy severity (Table 1). In general, the prevalence of different comorbidities such as diabetes, hypertension, atrial fibrillation and coronary heart disease rose as the severity of myopathy increased. Thus, patients with myalgia alone had less frequently associated comorbidities, except for the prevalence of abdominal obesity which was lower among patients with rhabdomyolysis. Furthermore, as the severity of myopathy increased, so did the incidence of patients with very high cardiovascular risk, and the incidence of patients with high and moderate risk decreased (Table 1). Each patient took a mean of 3 drugs daily, with a minimum of 1 (statin alone) and a maximum of 16. Atorvastatin was the most frequently prescribed statin and maximum statin doses were used in 29.8% of patients. Low-, moderate- and high-intensity statin therapy was used in 5.4, 61.2 and 33.4% of patients, respectively. Concomitant drugs metabolized by the CYP450 3A4 pathway were taken by 9.3% of patients, and statins by this metabolic route (lovastatin, simvastatin and atorvastatin) by 75%. Approximately 10% of patients on statin therapy revealed a potential interaction with other drugs metabolized by the same pathway. No significant differences were observed in the use of statins metabolized by CYP450 3A4 and myopathy severity. However, differences in the incidence of drug interactions via cytochrome P450 3A4 were observed depending on myopathy severity (Table 1). 6

8 Independent variables associated with myositis or rhabdomyolysis compared with myalgia alone in the multivariate model were alcohol consumption > 30 g/d in men or > 20 g/d in women and pravastatin therapy (Table 2). 4. Discussion The reported incidence of myalgia during statin therapy varies from 1% to 30% [3,4,12-16]. The DAMA study confirmed myalgia as the most frequent statin-associated muscle complaint. Patients with myalgia showed a lower prevalence of comorbidities. With increasing myopathy severity, the number of patients at very high cardiovascular risk rose. This could be explained by the fact that patients with myositis or rhabdomyolysis had a higher prevalence of associated cardiovascular risk factors such as smoking, hypertension, dyslipidemia, atrial fibrillation and established cardiovascular disease. Furthermore, patients with lesser myopathy severity (myalgia) were those with a lower consumption of drugs metabolized by cytochrome P450 3A4. Observational reports suggest that statin-associated muscle complaints are more frequent in older adults and/or women [5,17,18]. In the present study, no significant differences between the severity of muscle symptoms and the patient's age and gender were found. It is known that the higher the dose of statin used, the more likely it is to cause myotoxicity [19]. In the present study about 30% of patients with statin-induced muscle adverse effects were receiving maximum statin doses and 33% a high intensity statin therapy according to the ACC/AHA blood cholesterol guidelines [9]. Statin-induced myotoxicity appears to be independent of the degree of low-density lipoprotein cholesterol reduction [20,21]. In the DAMA study, it should be noted that patients with myositis or rhabdomyolysis presented a poorer lipid control. 7

9 The use of statins metabolized by CYP3A4 (lovastatin, simvastatin and atorvastatin), together with cytochrome inhibitor drugs, produces significant rises in plasma statin concentrations, increasing their risk of toxicity 6-fold [22,23]. A study of >950,000 patient records from two US databases showed that 83% of patients with dyslipidemia used a CYP3A4-metabolyzed statins and that of these, 25 to 30% also received a CYP3A4 inhibitor [24].The results of the present study prove that 9.3% of patients treated with statins received a drug metabolized by CYP3A4. Since 75% of patients received a statin metabolized by CYP3A4, overall 10% of participants were taking concomitant drugs that could cause drug interactions. High alcohol consumption is described as a cause of the potentially-fatal adverse event, rhabdomyolysis [25,26]. In fact, multivariate analysis in the DAMA study revealed that patients with an alcohol intake > 30 g per day in men and 20 g in women showed a 53% increased risk of myositis or rhabdomyolysis compared to having myalgia alone. Although alcohol exerts toxic effects on muscle that can raise the risk of statinassociated muscle symptoms, no clearly apparent mechanism of interaction has been described for this association [27]. Additionally, the use of pravastatin was the other factor independently related to increased muscle involvement severity, posing a 4-fold higher risk. Although in a recent survey of the Food and Drug Administration Adverse Effect Reporting System database linking muscle-related adverse effects to statin use pravastatin appeared to have the lowest risk rates compared to other statins (28), the findings of the present study suggest that, when muscle toxicity occurs with pravastatin, this condition may be more severe. Since physicians almost reflexively switch to pravastatin when they perceive statinassociated muscle symptoms, the present findings are almost assuredly due to the rechallenge likelihood. This was also noted in a network meta-analysis analyzing all 8

10 statins [29]. Although the mechanism of statin myotoxicity remains unknown, experimental studies have demonstrated that Rab GTPase inactivation, which is involved in intracellular membrane transport, is a crucial factor in fluvastatin/pravastatin-induced-morphological abnormality in skeletal muscle fibers (30). Our study has several limitations. In this respect, it only detected associated risks, not real interactions. In general, clinically-significant interactions are rare compared with potential interactions. The study examined the possibility of cross-sectional interactions, which underestimates the risk of interactions over time, as demonstrated in longitudinal studies. Moreover, other common sites of interaction with statins, such as transportation systems to the inside or outside of the hepatocyte (OATP and P-glycoprotein), were not considered. Finally, the participating centers and physicians were not randomly selected, which prevented data being extrapolated to the total population, despite the sample size being significant. Furthermore, physicians were aware of the purpose of the study, and this could have act as bias in the recollection of data. 5. Conclusions The DAMA study provides new data on the severity of muscle injury (myalgia, myositis and rhabdomyolysis) induced by statin treatment. The most severe muscle adverse effects were independently related to excessive alcohol intake and pravastatin. Furthermore, two thirds of patients with statin-induced adverse effects on muscle were not on high-intensity statin therapy, and concomitant drugs metabolized by the CYP450 3A4 were taken by less than 10% of patients, suggesting that muscle complaints occur commonly in current clinical practice. These results will facilitate identification of patients at high risk for severe muscle injury. 9

11 Acknowledgements This study was presented at the 83rd European Atherosclerosis Society Congress, Glasgow march 22-25, We thank Miss Christine O Hara for review of the English version of the manuscript. Funding Esteve provided support for this study, without participating in the design, data analysis or writing of this article Declaration of Interest The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. References Papers of special note have been highlighted as: * of interest ** of considerable interest 1. Endo A. The origin of the statins Atheroscler Suppl 2004;5: Baigent C, Keech A, Kearney PM, et al; Cholesterol Treatment Trialists (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005;366:

12 3. Cholesterol Treatment Trialists (CTT) Collaboration, Baigent C, Blackwell L, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a metaanalysis of data from 170,000 participants in 26 randomised trials. Lancet 2010; 376: Cholesterol Treatment Trialists (CTT) Collaborators, Mihaylova B, Emberson J, et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 2012;380: **An individual patient data meta-analysis of 27 randomized trials of statin therapy with over 174,000 participants confirms that statin therapy significantly reduces vascular mortality and major morbidity among patients with a less than 1% annual risk of a major vascular event. 5. Sathasivam S. Statin induced myotoxicity. Eur J Intern Med 2012;23: Phillips PS, Haas RH, Bannykh S, et al. Statin-associated myopathy with normal creatine kinase levels. Ann Intern Med 2002;137: Mohaupt MG, Karas RH, Babiychuk EB, et al. Association between statinassociated myopathy and skeletal muscle damage. CMAJ 2009;181:E Tiwari A, Bansal V, Chugh A, Mookhtiar K. Statins and myotoxicity: a therapeutic limitation. Expert Opin Drug Saf 2006;5: Stone NJ, Robinson J, Lichtenstein AH, et al ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63:

13 10. Sung JC, Nichol MB, Venturini F, et al. Factors affecting patient compliance with antihyperlipidemic medications in an HMO population. Am J Manag Care 1998;4: Goodman LA. Snowball sampling. Ann Math Stat. 1961;32: Pasternak RC, Smith SC, Bairey-Merz CN, et al; American College of Cardiology; American Heart Association; National Heart, Lung and Blood Institute. ACC/AHA/NHLBI. Clinical Advisory on the use and safety of statins. Circulation 2002;106: Perk J, De Backer G, Gohlke H, et al; Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice; European Association for Cardiovascular Prevention and Rehabilitation. European Guidelines on cardiovascular disease prevention in clinical practice (version 2012): The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts). Atherosclerosis 2012;223: Bruckert E, Hayem G, Dejager S, et al. Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients-the PRIMO study. Cardiovasc Drugs Ther 2005;19: Cohen JD, Brinton EA, Ito MK, et al. Understanding statin use in America and gaps in patient education (USAGE): an internet-based survey of 10,138 current and former statin users. J Clin Lipidol 2012;6: Parker BA, Capizzi JA, Grimaldi AS, et al. Effect of statins on skeletal muscle function. Circulation 2013;127:

14 17. Rosenson RS. Current overview of statin-induced myopathy. Am J Med 2004;116: Davidson MH, Robinson JG. Safety of aggressive lipid management. J Am Coll Cardiol 2007;49: Silva M, Matthews ML, Jarvis C, et al. Metaanalysis of drug-induced adverse events associated with intensive-dose statin therapy. Clin Ther 2007;29: Abd TT, Jacobson TA. Statin-induced myopathy: a review and update. Expert Opin Drug Saf 2011;10: Rallidis LS, Fountoulaki K, Anastasiou-Nana M. Managing the underestimated risk of statin-associated myopathy. Int J Cardiol 2012;159: Neuvonen PJ. Drug interactions with HMG-CoA reductase inhibitors (statins): the importance of CYP enzymes, transporters and pharmacogenetics. Curr Opin Investig Drugs 2010;11: Rowan CG, Brunelli SM, Munson J, et al. Clinical importance of the drug interaction between statins and CYP3A4 inhibitors: a retrospective cohort study in The Health Improvement Network. Pharmacoepidemiol Drug Saf 2012;21: Ming EE, Davidson MH, Gandhi SK, et al. Concomitant use of statins and CYP3A4 inhibitors in administrative claims and electronic medical records databases. J Clin Lipidol 2008;2: Sauret JM, Marinides G, Wang GK. Rhabdomyolysis. Am Fam Physician 2002;65: Stroes ES, Thompson PD, Corsini A, et al. Statin-associated muscle symptoms: impact on statin therapy-european Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management. Eur Heart J 2015;36:

15 *Recent consensus of the European Atherosclerosis Society for diagnosis and treatment of statin-associated muscle symptons. 27. Thompson PD, Panza G, Zaleski A, Taylor B. Statin-associated side effects. J Am Coll Cardiol. 2016;67: *A comprehensive review of skeletal muscle, metabolic, neurological and other possible statin-associated side effects with specific practical recommendations for the clinician. 28. Hoffman KB, Kraus C, Dimbil M, Golomb BA. A survey of the FDA's AERS database regarding muscle and tendon adverse events linked to the statin drug class. PLoS One 2012;7:e Naci H, Brugts J, Ades T. Comparative tolerability and harms of individual statins: a study-level network meta-analysis of participants from 135 randomized, controlled trials. Circ Cardiovasc Qual Outcomes 2013;6:390-9 *This large meta-analysis describes the evidence from 135 randomized trials on the potential adverse effects of statins. 30. Sakamoto K, Honda T, Yokoya S, et al. Rab-small GTPases are involved in fluvastatin and pravastatin-induced vacuolation in rat skeletal myofibers. FASEB J 2007;21:

16 Table 1. Demographic and anthropometric data, clinical characteristics, associated clinical conditions and cardiovascular risk of the 3,845 patients included in the DAMA study. Characteristics All (n=3,845) Myalgia (n=3,008) Myositis (n=742) Rhabdomyolysis (n=95) Age (years) ± ± ± ± 11.7 Men/women (%) 2,527/1,248 (67.5/32.5) 2,040/968 (67.8/32.2) 487/255 (65.3/34.4) 70/25 (73.7/26.3) Smoking, n (%) 1,217 (31.6) 956 (31.8) 225 (30.3) 36 (37.9) Alcohol intake 30/20 g/day n (%) 242 (6.3) 165 (5.5) 70 (9.4) 7 (7.4) Intense exercise 381 (9.9) 285 (9.5) 77 (9.4) 7 (7.4) BMI (Kg/m 2 ) 28.4 ± ± ± Abdominal obesity n, (%) 1,750 (46.1) 1,339 (45.1) # 378 (51.4)* 33 (34.7)*# Systolic BP (mmhg) ± ± 14.3 # ± ± 18.1# Diastolic BP (mmhg) ± ± ± ± 12.6 CK (IU/L) ± ± ± ± Total cholesterol (mg/dl) ± ± 50.0 # ± ± 51.1# LDL cholesterol (mg/dl) ± ± ± ± 43.2 LDL cholesterol > 160 mg/dl n (%) (41.1) 329 (44.9) 46 (49.5) HDL cholesterol (mg/dl) ± ± 13.4 # 48.5 ± ± 12.7# HDL cholesterol < 40/50 mg/dl (%) (31.0) 263 (36.2) 34 (36.2) Triglycerides (mg/dl) ± ± 79.8# ± ± 70.7 # Diabetes (%) 1,090 (28.35) 826 (27.46) 238 (32.08) 26 (27.37) Hypertension (%) 2,014 (52.38) 1,524 (50.66) # 430 (57.95) 60 (63.16)# Hypothyroidism (%) 346 (9.0) 257 (8.54) 77 (10.38) 12 (12.63) Atrial fibrillation (%) 270 (7.0) 194 (6.45) 70 (9.43) 6 (6.32) CHD (%) 873 (22.70) 650 (21.61) 197 (26.55) 26 (27.37) CVD (%) 209 (5.44) 149 (4.95) 53 (7.14) 7 (7.37) 15

17 PAD (%) 245 (6.37) 176 (5.85) 59 (7.95) 10 (10.53) Cardiovascular risk (%) Very high High Moderate 1,354 (35.21) 987 (25.67) 1,504 (39,12) 1,023 (34.01)# 791 (26.30)# 1,194 (39.69)# 284 (38.27) 177 (23.85) 281 (37.87) 47 (49.47)# 19 (20)# 29 (30.53)# Other drugs via CYP3A4 n (%) 358 (9.3) 258 (8.6) 88 (11.9) 12 (12.6) Statin n (%) Simvastatin Lovastatin Atorvastatin Fluvastatin Pravastatin Rosuvastatin Pitavastatin 1,204 (31.3) 30 (0.8) 1,645 (42.8) 86 (2.2) 112 (2.9) 347 (9.0) 421 (11.0) 971 (32.3) 17 (0.6) 1,254 (41.7) # 59 (2.0) 75 (2.5) 272 (9.0) 360(12.0) 206 (27.8) 8 (1.1) 342 (46.09)* 24 (3.2) 36 (4.9) 69 (9.3) 57 (7.7) 27 (28.4) 5 (5.3) 49 (51.6)*# 3 (3.2) 1 (1.1) 6 (6.3) 4 (4.2) Maximun statin dose n (%) 1,090 (29.8) 825 (29.0)# 229 (31.81) 36 (39.1)# According to 2012 European guidelines in cardiovascular disease prevention in clinical practice [12]. CHD, coronary heart disease; CVD, cerebrovascular disease; PAD, peripheral arterial disease. * P < 0.05 rhabdomyolysis vs myositis. # P < 0.05 myalgia vs rhabdomyolysis. P < 0.05 myalgia vs myositis. 16

18 Table 2. Factors independently associated with the presence of myositis or rhabdomyolysis on the logistic regression analysis. OR Confidence interval P Abdominal obesity Alcohol intake 30/20 g/d Hypothyroidism Other drugs metabolized via CYP3A4 Simvastatin Lovastatin Atorvastatin Fluvastatin Pravastatin Rosuvastatin Pitavastatin