Lack of association between SLCO1B1 polymorphisms and clinical myalgia following rosuvastatin therapy

Genetics

Lack of association between SLCO1B1 polymorphisms and clinical myalgia following rosuvastatin therapy Jacqueline S. Danik, MD, DPH, a Daniel I. Chasman, PhD, a Jean G. MacFadyen, BA, a Fredrik Nyberg, MPH, MD, PhD, b,c Bryan J. Barratt, PhD, d and Paul M. Ridker, MD, MPH a Boston, MA; Mölndal, and Gothenburg, Sweden; and Alderley Park, United Kingdom

Background Carriers of the rs4363657C and rs4149056C alleles in SLCO1B1 have increased myopathic complaints when taking simvastatin. Whether rosuvastatin has a similar effect is uncertain. This study assesses whether SLCO1B1 polymorphisms relate to clinical myalgia after rosuvastatin therapy. Methods In the JUPITER trial, participants without prior cardiovascular disease or diabetes who had low-density lipoprotein cholesterol b130 mg/dL and C-reactive protein ≥2 mg/L were randomly allocated to rosuvastatin 20 mg or placebo and followed for the first cardiovascular disease events and adverse effects. We evaluated the effect of rs4363657 and rs4149056 in SLCO1B1, which encodes organic anion–transporting polypeptide OATP1B1, a regulator of hepatic statin uptake, on clinically reported myalgia. Results

Among 4,404 participants allocated to rosuvastatin, clinical myalgia occurred with a rate of 4.1 events per 100 person-years as compared with 3.7 events per 100 person-years among 4,378 participants allocated to placebo (hazard ratio [HR] 1.13, 95% CI 0.98-1.30). Among those on rosuvastatin, there were no differences in the rate of myalgia among those with the rs4363657C (HR 0.95, 95% CI 0.79-1.14 per allele) or the rs4149056C allele (HR 0.95, 95% CI 0.79-1.15 per allele) compared with those without the C allele. Similar null data were observed when the myalgia definition was broadened to include muscle weakness, stiffness, or pain. None of the 3 participants on rosuvastatin or the 3 participants on placebo with frank myopathy had the minor allele at either polymorphism.

Conclusion

There appears to be no increased risk of myalgia among users of rosuvastatin who carry the rs4363657C or the rs4149056C allele in SLCO1B1. (Am Heart J 2013;165:1008-14.)

Statin-induced myopathy is an important adverse effect of hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors that may have a genetic basis. In particular, among those taking simvastatin in the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) and in the Heart Protection Study (HPS), 1 those with rs4363657 C and rs4149056 C alleles in SLCO1B1 had markedly elevated risks of myopathy that were allele dependent on at least an additive scale. This observation has since been confirmed From the aCenter for Cardiovascular Disease Prevention, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, bGlobal Epidemiology, AstraZeneca Research and Development, Mölndal, Sweden, cUnit of Occupational and Environmental Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden, and dPersonalised Healthcare and Biomarkers, AstraZeneca Research and Development, Alderley Park, United Kingdom. Submitted September 26, 2012; accepted January 17, 2013. Reprint requests: Jacqueline S. Danik, MD, DPH, Brigham and Women's Hospital, 900 Commonwealth Avenue East, Boston, MA 02215. E-mail: [email protected] 0002-8703/$ - see front matter © 2013, Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.ahj.2013.01.025

for simvastatin in the Statin Response Examined by Genetic HAP Markers (STRENGTH) trial. 2 SLCO1B1 encodes an organic anion–transporting polypeptide OATP1B1 that regulates the hepatic uptake of statins. It has been hypothesized based on pharmacokinetic data that this effect might be relevant for other statin agents, as well. 3–7 However, other than trials of simvastatin, largescale clinical trial data addressing this issue for other agents have not been available. We therefore evaluated the role of the rs4363657 and rs4149056 polymorphisms in SLCO1B1 as potential effect modifiers for clinical myalgia in the recently completed Justification for Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial, which randomly allocated apparently healthy men and women to rosuvastatin 20 mg daily or to placebo.

Methods Details of JUPITER, a randomized, double-blind, placebo controlled trial evaluating rosuvastatin 20 mg in the prevention of first-ever cardiovascular events among men and women free

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Table I. Musculoskeletal adverse events in JUPITER during the follow-up period among 8782 individuals No. of events (%)⁎, IR †

Event Myalgia Muscle weakness, stiffness, or pain Rhabdomyolysis, myopathy, or myositis

Overall (n = 8782)

Rosuvastatin group (n = 4404)

Placebo group (n = 4378)

HR ‡ (95% CI) ‡

P‡

786 (9.0), 3.9 1692 (19.3), 9.10 6 (0.07), 0.03

417 (9.5), 4.1 862 (19.6), 9.30 3 (0.07), 0.03

369 (8.4), 3.7 830 (19.0), 8.89 3 (0.07), 0.03

1.13 (0.98-1.30) 1.04 (0.95-1.15) 1.00 (0.20-4.93)

.09 .39 1.00

In sensitivity analyses, there was little difference in the rosuvastatin or placebo group in Cox proportional models that defined an adverse musculoskeletal event as muscle stiffness or pain only (without weakness), muscle weakness, musculoskeletal pain, or musculoskeletal discomfort. All participants with myalgia reported the broader definition of muscle weakness, stiffness, or pain. ⁎ Proportion refers to the number of events/number at risk in each column. † Incident events per 100 person-years. ‡ Cox proportional hazard models were run regressing event on treatment term (rosuvastatin vs placebo coded 1,0). Hazard ratios compare rosuvastatin to placebo.

of diabetes or prior cardiovascular disease (NCT00239681) that was conducted between 2003 and 2008 in 26 countries, have been presented elsewhere. 8 The primary eligibility criteria for JUPITER were a low level of low-density lipoprotein cholesterol (LDL-C) (b130 mg/dL) and an elevated level of high sensitivity Creactive protein (≥2 mg/L). All participants were followed prospectively for the trial's primary end point (nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina, arterial revascularization, or cardiovascular death) and for all-cause mortality. As previously reported, after a median follow-up of 1.9 years (maximum 5 years), rosuvastatin use was associated with a 44% reduction in the trial's primary end point, a 54% reduction in myocardial infarction, a 48% reduction in stroke, a 46% reduction in revascularization, a 43% reduction in venous thromboembolism, and a 20% reduction in total mortality. 8,9

Collection of adverse events As formalized in the study protocol and outlined in the report of the main trial, 8,10 participants were assessed at each follow-up visit (at 3 and 6 months after randomization and then at 6-month intervals). At this time, study staff assessed study end points or adverse events as well as compliance with pill taking, use of concomitant medications, and development of major illnesses, and they performed laboratory evaluations. Adverse events included self-reported symptoms that were categorized using the Medical Dictionary for Regulatory Activities classifications, 11 such as myalgia, or the broader categories of muscle weakness, stiffness, or pain. In the event that any adverse event was considered serious (including, among others, important medical event, inpatient hospitalization, persistent or significant disability or incapacity, life-threatening event, and death), investigators were asked to complete a detailed serious adverse event form.

Genotyping Of randomized JUPITER participants, 12,648 provided consent for genetic analyses, had DNA available for genotyping, and had successful evaluation of SLCO1B1 polymorphisms, rs4363657 and rs4149056, using the 1M Omni Quad platform (Illumina, San Diego, CA). 12 Because the SLCO1B1 alleles encode nonsynonymous polymorphisms and the minor allele frequencies (MAFs) vary according to ancestry, 13 we restricted our evaluation on an a priori basis to the effects of SLCO1B1 among study participants of European ancestry. Verification of

European ancestry was done by identity-by-state clustering, using multidimensional scaling procedures in PLINK 14 applied to 1,067 ancestry informative single nucleotide polymorphisms (SNPs) selected from HapMap3. Estimation of subpopulation stratification measures was performed by EIGENSTRAT analysis. 15 Thus, the project focuses on the 8,781 JUPITER participants whose self-reported European ancestry could be confirmed.

Statistical analysis Incidence rates (IRs) of myalgia, muscle weakness, stiffness or pain, and clinically severe myopathy were calculated in the full JUPITER cohort, as well as among those allocated to rosuvastatin or placebo. To address whether there were differences in the incidence of clinical myalgia according to genotypes, we evaluated the significance of an additive relationship on the log scale between inheritance of the risk alleles at either rs4363657 and rs4149056 and incident rates of myopathy using Cox proportional hazards models. We also addressed whether these genotypes affected change in LDL-C using linear regression, again assuming an additive relationship between allele dose and LDL-C response. All P values reported are 2 sided, and all CIs were computed at the 95% level. The JUPITER trial protocol was approved by the local institutional review board at each participating center. The JUPITER trial and its genotyping were financially supported by Astra-Zeneca. The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the manuscript, and its final contents.

Results As anticipated and consistent with prior data (dbSNP Build 135), 13 the MAFs for both SLCO1B1 variants were lower among self-reported black participants (MAF 0.05 for rs4363657, MAF 0.01 for rs4149056) than among white participants (MAF 0.18 for rs4363657, MAF 0.17 for rs4149056). Thus, as specified on an a priori basis to avoid issues of population stratification, we conducted our analysis among white participants only. Among those allocated to rosuvastatin, there were 417 participants who had myalgia (IR 4.1 per 100 personyears) compared with 369 participants among those who

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Table II. Incidence of muscular complaints according to SLCO1B1 genotypes in the rosuvastatin group in the JUPITER trial (n = 4404) Allelic risk model

†

Event rs4363657 Myalgia Muscle weakness, stiffness, or pain Rhabdomyolysis, myopathy, or myositis rs4149056 Myalgia Muscle weakness, stiffness, or pain Rhabdomyolysis, myopathy, or myositis

No. of events (%)⁎, Incident events/100 person-years TT 286 (9.8), 4.24 598 (20.4), 9.67 3 (0.1), 0.04

TC 109 (9.0), 3.88 223 (18.4), 8.56 0

CC 13 (9.6), 4.39 24 (17.8), 8.51 0

TT 300 (9.7), 4.25 628 (20.3), 9.70 3 (0.1), 0.04

TC 104 (8.8), 3.81 211 (17.8), 8.32 0

CC 13 (10.7), 4.90 23 (19.0), 9.16 0

Genotype risk model HR ‡ (95% CI) for event for heterozygotes (TC) compared with common homozygotes (TT)

HR ‡ (95% CI) for event for rare homozygotes (CC) compared with common homozygotes (TT)

HR (95% CI) for event with increasing carriage of rare variant

P

0.95 (0.79-1.14)

.55

0.92 (0.73-1.14)

.43

1.01 (0.58-1.75)

.98

0.90 (0.79-1.03)

.12

0.89 (0.76-1.04)

.13

0.87 (0.58-1.30)

.49

0.95 (0.79-1.15)

.59

0.90 (0.72-1.12)

.33

1.13 (0.65-1.97)

.67

0.89 (0.78-1.02)

.09

0.86 (0.74-1.01)

.06

0.94 (0.62-1.42)

.75

P

P

⁎ Proportion refers to the number of events/number at risk in each column (genotype). † Refers to HR of an event with increasing carriage of the rare allele. The polymorphism is coded as a single independent variable denoting carriage of 0, 1, or 2 rare variant. The corresponding P value is a test with 1 degree of freedom. ‡ Refers to HR of an event comparing heterozygotes (TC) or rare homozygotes (CC) to the referent common homozygote (TT) in a Cox proportional hazard model. The corresponding P value is a test with 2 degrees of freedom.

received placebo (IR 3.7 per 100 person-years; hazard ratio [HR] 1.13 [0.98-1.30]) (Table I). Muscular weakness, stiffness, or pain was also slightly more common among those allocated to rosuvastatin (IR 9.30 per 100 personyears) compared with placebo (IR 8.89 per 100 personyears; HR 1.04 [0.95-1.15]). There were only 6 cases of frank myopathy that occurred in the whole cohort, 3 in the rosuvastatin and 3 in the placebo group. There were no differences across rs4363657 and rs4149056 genotypes in the distribution of clinical covariates that have been shown to affect incidence of myopathy with statin use, such as age, gender, body mass index or renal function as measured by creatinine. Neither the rs4363657 C allele nor the rs4149056 C allele was associated with the rate of clinical myalgia (HRs 0.95 [95% CI 0.79-1.14] for rs4363657 and HR 0.95 [95% CI 0.79-1.15] for rs4149056), among those allocated to rosuvastatin (Table II). Similar null data were observed when the definition of myalgia was broadened to include any complaint of muscle weakness, stiffness, or pain. Additional models that addressed other muscular events such as pain or discomfort also showed no differences in incidence of muscular events by genotypes. Of the 3 severe myopathy cases that occurred among those on rosuvastatin or the 3 on placebo, none was a carrier of the rare variant of either polymorphism. Creatine kinase (CK) was measured at baseline, at a single time point at the close of study, and if clinically indicated by site study

investigators, resulting in CKs acquired at different follow-up periods; nonetheless, when assessing for differences of CK values among those on rosuvastatin, no differences in CK values were seen across either rs4363657 or rs4149056 genotypes. Figure 1 illustrates graphically the risk of clinical myalgia by treatment assignment and by SLCO1B1 genotypes. No differences in rates of clinical myalgia are seen either by treatment groups or by genotypes, and as noted, similar null results are seen for broader definitions of adverse events. With regard to possible pharmacodynamic effects, there was attenuation of rosuvastatin-induced reductions in LDL-C with carriage of either the rs4363657 C or the rs4149056 C allele (52.1%, 50.4%, and 47.4% LDL reduction at 1 year for rs4363657 TT, TC, and CC, respectively; 52.1%, 50.4%, and 47.2% reduction for rs4149056 TT, TC, and CC) (Table III).

Discussion Prior data indicate that myalgia and rhabdomyolysis occur with greater frequency among participants receiving simvastatin who carry specific genetic polymorphisms in the SLCO1B1 gene. 1,2 Among those allocated to 80 mg of simvastatin in the SEARCH Study, those with the rs4363657 C and rs4149056 C alleles had 4-fold higher risk of severe myopathy with increasing carriage of the

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Figure 1 rs4363657 Myalgia (Allelic risk model)* Overall Rosuvastatin Placebo

rs4149056 P-interaction† 0.57

P-interaction 0.36

P-interaction 0.30

P-interaction 0.22

Rosuvastatin Arm (Genotype risk CC model)** TC TT (referent) Muscle Weakness/ (Allelic risk model)* Stiffness/Pain Overall Rosuvastatin Placebo Rosuvastatin Arm (Genotype risk CC model)** TC TT (referent) 0.5

1.0 Lessevents Fewer associated with “C” allele

2.0 More More events associated with “C” allele

0.5

1.0 Less Fewer events associated with “C” allele

2.0 More More events More associated events with “C” allele

Risk of muscular complaints by treatment groups and by SLCO1B1 genotypes. *Hazard ratio of event in an allelic risk model (with increasing number of minor alleles) in Cox proportional hazard models among all participants of European ancestry, and then among those assigned to rosuvastatin or placebo. **Hazard ratio of event in a genotype risk model in a Cox proportional hazard model, comparing heterozygotes (TC) or rare homozygotes (CC) to the referent common homozygote (TT) in the rosuvastatin group. †Interaction was assessed between genotype and treatment in Cox proportional hazard models that regressed event on genotype (coded in a single variable as 0,1,2), treatment (rosuvastatin vs placebo), and an interaction term of genotype multiplied by treatment status. Likelihood P interaction values were calculated by comparing models with and without the interaction term.

rare allele and a 17-fold higher risk when comparing the rarer CC to the more common TT homozygotes. 1 Similarly, in HPS, a 3-fold higher risk of myopathy was observed among those taking 40 mg of simvastatin as compared with those allocated to placebo. 1 In marked contrast, in this randomized evaluation of 20 mg of rosuvastatin, we found no evidence of a comparable pharmacogenetic effect; among those allocated to rosuvastatin 20 mg daily in the JUPITER trial, there were no differences in clinical myalgia among carriers and noncarriers of the rs4363657 C allele or the rs4149056 C allele in SLCO1B1. Furthermore, of the 6 JUPITER participants who developed frank myopathy during the trial (3 on rosuvastatin, 3 on placebo), none had either minor allele. Thus, these data suggest that there may be clinically relevant differences between rosuvastatin and simvastatin in genetically mediated risks for myopathy or dose effects of the different statins. SLCO1B1 encodes an organic anion–transporting polypeptide OATP1B1, which regulates the hepatic uptake of statins. 3,16–21 The rs4149056 polymorphism in SLCO1B1 encodes a valine-to-alanine substitution that results in a less active form of the transporter. 18,22–24 As such,

carriers of this polymorphism would be anticipated to have reduced hepatic uptake of statin and hence a somewhat diminished inhibition of cholesterol synthesis, perhaps particularly hydrophilic statins such as rosuvastatin and pravastatin, 3,25 which depend on active hepatic uptake, and a concomitant increase in circulating statin concentration and hence an increased risk for systemic myopathy. 26 As shown in Table III, inheritance of increasing numbers of either of the minor alleles of the SLCO1B1 polymorphisms was associated with a smaller magnitude of LDL-C reduction, a statistically significant effect previously described for simvastatin, atorvastatin, and pravastatin. 1,27–32 However, in contrast to simvastatin, this genetically mediated effect on efficacy of LDL-C reduction did not translate into higher risks of myalgia or myopathy for rosuvastatin at the 20-mg/d dose in this study. Although the underlying etiology of statin-induced myopathy remains uncertain, there are several possible explanations for the differences observed here for rosuvastatin as compared with simvastatin. Regardless of genotype, myopathy rates for rosuvastatin are lower than those for simvastatin, despite greater potency of

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Table III. Baseline and 12-month LDL-C among participants of European ancestry in the JUPITER trial on rosuvastatin according to SLCO1B1 genotypes⁎ rs4363657

Characteristic Baseline LDL-C (mg/dL), median (IQR) On-treatment LDL-C (mg/dL) % Change in LDL-C

rs4149056

TT TC CC TC or CC (n = 2346) (n = 997) (n = 100) (n = 1097) P † 109 (96-120) 51 (41-63) −52.1

109 (96-120) 53 (43-66) −50.4

110.5 (94-119) 55 (45-67.5) −47.4

110.0 (96-120) 53 (43-66) −50.4

.92 .0014 .0002

TT TC CC TC or CC (n = 2485) (n = 978) (n = 89) (n = 1067) P † 109 (96-120) 51 (41-63) −52.1

110 (96-120) 53 (43-67) −50.4

109 (93-119) 55 (45-67) −47.2

110 (96-120) 53 (44-67) −50

.82 .0014 .0002

IQR, interquartile range. ⁎ Among those compliant at 12 months. † P values are derived from the Wilcoxon rank sum test comparing all 3 groups. Similar values were obtained in comparisons of TC or CC with TT (referent).

rosuvastatin for LDL-C reduction. This, in part, reflects the fact that there are differences in mechanisms of metabolism of statins; myopathic complaints are more common for statins that are oxidized by cytochrome P450 3A4 [CYP3A4], such as lovastatin, simvastatin, and atorvastatin, than for statins not oxidized by CYP3A4, such as pravastatin and rosuvastatin. However, data describing interactions between these pathways and polymorphism in SCLO1B1 are scant, and at least one report has suggested increased myopathy with simvastatin as compared with atorvastatin among carriers of the rs4149056 C allele, 29 despite both being oxidized by CYP3A4. It is also possible that increased circulating statin levels as a result of polymorphism in SCLO1B1 are less toxic to muscle cells for hydrophilic agents such as rosuvastatin 33 and pravastatin 21,34 as compared with more hydrophobic agents such as simvastatin. 35 On the other hand, reduced transporter activity into hepatocytes may be particularly relevant for hydrophilic statins that depend on active transport for uptake into hepatocytes where inhibition of cholesterol synthesis occurs. Limitations of our study deserve consideration. First, because there was only 1 case of rhabdomyolysis and very few cases of frank myopathy, we relied on physician report of clinical myalgia for our primary analyses, a syndrome described by the American College of Cardiology/American Heart Association clinical advisory on the use and safety of statins as any muscle complaint related to the use of statin. 36 The rates of muscle weakness, stiffness, or pain and myalgia observed in our study are also concordant with those reported elsewhere. 30,31 Second, because the overall risk for severe myotoxicity may be higher with high-dose simvastatin than other statins, 37 studies of similar sample size would have greater power to find a true pharmacogenetic effect for simvastatin than for rosuvastatin. We believe, however, that the large size of our trial makes it unlikely that we have missed any clinically relevant effects. A recent pilot study noted differences in the relationship of SLCO1B1 polymorphisms and myalgia, noting no rela-

tionship of such polymorphisms among 30 individuals on rosuvastatin, but noting a relationship of the SNPs with myalgia among 46 individuals on atorvastatin. 38 Accordingly, we anticipate sufficient power among 417 cases of myalgia among those on rosuvastatin to detect a relationship of SLCO1B1 polymorphisms with myalgias. Third, the JUPITER trial evaluated a fixed dose of rosuvastatin, and thus, we are not able to address potential dose-dependent effects in our study. Nonetheless, the dose of rosuvastatin used in the JUPITER trial was 20 mg daily and the median on-treatment LDL-C was 55 mg/dL, a level below that of the simvastatin studies. Finally, we do not have direct comparison data for rosuvastatin and simvastatin in the same population, and differences across populations could account, in part, for differences observed. The SEARCH trial participants were a secondary prevention cohort. HPS studied individuals who were high risk because of existing coronary disease, other occlusive arterial disease, or diabetes. STRENGTH was a short study in patients with hypercholesteremia. JUPITER was a primary prevention study in individuals with low LDL-C but elevated C-reactive protein. As such, it is theoretically possible that some of the difference observed might be caused by a third as-yet unidentified factor that differentiates the secondary prevention populations evaluated in the SEARCH and HPS trials from the primary prevention population evaluated in JUPITER. In a similar manner, it is possible that participants in SEARCH and HPS received concomitant medications that inhibit CYP3A4 such as erythromycin, amlodipine, amiodarone, cyclosporine, and azole antifungal drugs more frequently than did the participants in JUPITER. None of these limitations alter our primary finding that there appears to be no clinical use to evaluating SLCO1B1 polymorphism among individuals being treated with rosuvastatin.

Acknowledgements This research was supported by research funds from AstraZeneca to P.M.R. and D.I.C. Dr Danik has received

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support from the National Heart, Lung, and Blood Institute (HL-076443) and the American Heart Association (D005113). Dr Ridker reports that he currently or in the past 5 years has received research funding support from not-for-profit entities including the National Heart, Lung, and Blood Institute; the National Cancer Institute; the American Heart Association; the Doris Duke Charitable Foundation; the Leducq Foundation; the Donald W Reynolds Foundation; and the James and Polly Annenberg La Vea Charitable Trusts. Dr Ridker also reports that currently or in the past 5 years, he has received investigator-initiated research support from forprofit entities including Astra-Zeneca, Bayer, BristolMyers Squibb, Dade-Behring, Novartis, Pharmacia, Roche, Sanofi-Aventis, and Variagenics. Dr Ridker reports being listed as a coinventor on patents held by the Brigham and Women's Hospital that relate to the use of inflammatory biomarkers in cardiovascular disease and has served as a consultant to Schering-Plough, Sanofi/ Aventis, AstraZeneca, Isis Pharmaceutical, Dade-Behring, and Interleukin genetics.

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