- Email: [email protected]
Risk of Colchicine-Associated Myopathy in Gout: Influence of Concomitant Use of Statin
Accepted Manuscript Risk of Colchicine-Associated Myopathy in Gout: Influence of Concomitant Use of Statin Oh Chan Kwon, M.D., Seokchan Hong, M.D., Ph.D., Byeongzu Ghang, M.D., YongGil Kim, M.D., Ph.D., Chang-Keun Lee, M.D., Ph.D., Bin Yoo, M.D., Ph.D. PII:
S0002-9343(16)31306-7
DOI:
10.1016/j.amjmed.2016.12.006
Reference:
AJM 13844
To appear in:
The American Journal of Medicine
Received Date: 12 September 2016 Revised Date:
26 November 2016
Accepted Date: 9 December 2016
Please cite this article as: Kwon OC, Hong S, Ghang B, Kim YG, Lee CK, Yoo B, Risk of ColchicineAssociated Myopathy in Gout: Influence of Concomitant Use of Statin, The American Journal of Medicine (2017), doi: 10.1016/j.amjmed.2016.12.006. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Clinical Research Study
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Running head: Colchicine and statin in gout
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Risk of Colchicine-Associated Myopathy in Gout:
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Influence of Concomitant Use of Statin
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Oh Chan Kwon, M.D., Seokchan Hong, M.D., Ph.D., Byeongzu Ghang, M.D.,
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Yong-Gil Kim, M.D., Ph.D., Chang-Keun Lee, M.D., Ph.D., and Bin Yoo, M.D., Ph.D.
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Division of Rheumatology, Department of Medicine, University of Ulsan, College of
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Medicine, Asan Medical Center, Seoul, Korea
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Authorship: All authors had access to the data and contributed sufficiently to writing the
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manuscript to be included as authors.
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Please address correspondence to: Seokchan Hong, M.D., Ph.D.
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Division of Rheumatology, University of Ulsan, College of Medicine, Asan Medical Center
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88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea
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Tel.: +82-2-3010-1410; Fax: +82-2-3010-6969; E-mail: [email protected]
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Abstract
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Objective. To investigate the risk of myopathy when statins are coadministered with
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colchicine in patients with gout.
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Methods. In gout patients who received colchicine with or without statin, clinical data
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collected included medications and history of hypertension, chronic kidney disease, and liver
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cirrhosis. Myopathy was defined as the presence of muscle symptoms with elevated
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creatinine phosphokinase and/or myoglobin. Multivariate analysis was performed to identify
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risk factors for myopathy. Inverse probability of treatment weighting (IPTW)-adjusted
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analysis was used to evaluate the influence of concomitant colchicine and statin use on
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myopathy.
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Results. Of 674 patients, 486 received colchicine alone and 188 also received statin. The
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incidence of myopathy was not significantly higher in those on both drugs than in those on
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colchicine alone (2.7% vs 1.4%, p = 0.330). On multivariate analysis, chronic kidney disease
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(hazard ratio [HR] 29.056, 95% confidence interval [CI] 4.387–192.450, p < 0.001), liver
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cirrhosis (HR 10.676, 95% CI 1.279–89.126, p = 0.029), higher colchicine dose (HR 20.960,
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95% CI 1.835–239.481, p = 0.014), and concomitant CYP 3A4 inhibitor (HR 12.027, 95% CI
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2.743–52.725, p = 0.001) were associated with increased risk of myopathy. Concomitant use
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of statins, however, was not, even after adjusting for confounders (HR 1.123, 95% CI 0.262–
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4.814, p = 0.875; IPTW-adjusted HR 0.321, 95% CI 0.077–1.345, p = 0.120).
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Conclusion. Concomitant use statin and colchicine was not associated with increased risk of
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myopathy. Thus, concomitant use of statin with colchicine seems to be safe from myotoxicity
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in gout patients.
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Key words: colchicine, statin, gout, myopathy 2
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Introduction
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Colchicine has been widely used for the treatment of various inflammatory diseases such
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as gouty arthritis. Previous studies have shown the efficacy of colchicine in the control of
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acute gout attacks as well as prophylaxis of gout flares.1,2 Therefore, colchicine is
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recommended as a first-line drug for prophylaxis in gout.3 Other entities for which it is used
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include oral aphthosis, genital aphthosis, and joint manifestations of Behcet disease.4
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Statins, hydroxymethylglutaryl coenzyme A inhibitors, are considered to be the first
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choice of drugs for lowering LDL cholesterol levels in patients with dyslipidemia. The
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efficacy of statins on the prevention of cardiovascular events and mortality has been well
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established through several, large, well-controlled clinical trials.5-9
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Despite the benefits, colchicine and statin are both known to have a risk of myopathy.
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The incidence of colchicine-associated myopathy is unclear, while statin-associated
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myopathy occurs in approximately 1.5%–5% of patients taking a statin.10,11 There have been
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several case reports of myopathy after concomitant use of colchicine and a statin.12-15 These
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reports suggested that the risk of myopathy might be increased when colchicine is used in
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combination with a statin. An explanation posited for the presumed increased risk of
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myopathy is that both colchicine and statin are metabolized by the cytochrome P450 system.
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However, there is no sound clinical evidence supporting this interaction. Indeed, it is not clear
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whether the concomitant use of statin and colchicine is truly associated with an increased risk
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of myopathy compared with colchicine alone. Despite lack of evidence either way, there are
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many clinical situations in which coadministration of colchicine and a statin is needed, such
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as in patients with both gout and dyslipidemia.
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Therefore, in this study we aimed to assess whether the coadministration of statin and
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colchicine increases the risk of myopathy and to evaluate other factors that might be 3
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associated with the development of myopathy in patients with gout who are taking colchicine.
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Methods
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Study population
The electronic medical records of patients who were diagnosed with gout at a tertiary
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referral hospital in Seoul, South Korea between January 01, 2000 and March 31, 2016 were
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retrospectively reviewed. A diagnosis of gout was made based on the preliminary criteria for
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the classification of gout.16 Patients were excluded from the analysis if they had not received
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colchicine during the study period. From the medical records, the following data were
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collected: age; sex; diagnosis of hypertension, diabetes mellitus, chronic kidney disease
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(defined as an estimated glomerular filtration rate [GFR] <60 ml/min/1.73 m2), coronary
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artery disease, heart failure, cerebrovascular accident, cancer, fatty liver, liver cirrhosis, or
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nephrotic syndrome; concomitant use of a CYP3A4 inducer and/or CYP3A4 inhibitor at the
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same time as colchicine; duration of colchicine and/or statin administration; and daily
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colchicine dose.
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All patients with muscle symptoms such as myalgia or muscle weakness had laboratory
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tests to detect muscle damage. We defined myopathy as appropriate symptoms accompanied
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by elevation above the upper limit of normal of muscle enzymes, including creatinine
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phosphokinase and/or myoglobin, according to the proposal of the American College of
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Cardiology/American Heart Association/National Heart, Lung and Blood Institute.17
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This study was approved by the Institutional Review Board of the Asan Medical Center,
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Seoul, South Korea (IRB No.: 2016-0613). The requirement for informed consent was
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waived because of the retrospective nature of the study.
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Statistical analysis Student’s t-tests and chi-square tests were used for continuous and categorical variables,
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respectively. Cox regression analysis with a stepwise backward elimination procedure was
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performed to identify risk factors for myopathy. Factors which had a p value less than 0.3 on
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univariate analysis were selected for multivariate analysis. In analyzing the influence of
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concomitant statin and colchicine on the development of myopathy, inverse probability of
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treatment weighting (IPTW) was used to exclude the influence of confounders.
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Results
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Comparison of colchicine alone group and colchicine with statin group Of the 674 patients with gout, 486 were treated with colchicine alone and 188 took both
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colchicine and statin. Atorvastatin was the most commonly used statin (109/188, 58.0%),
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followed by simvastatin (34/188, 18.1%) and rosuvastatin (28/188, 14.9%). Demographic and
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clinical characteristics are shown in Table 1. The two groups were similar in terms of gender
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distribution (p = 0.770). However, the patients taking both colchicine and statins were
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significantly older than those taking colchicine only (55.71 [±12.57] years vs 52.51 [±12.76]
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years, p = 0.003), had higher levels of creatinine (1.12 [±0.24] mg/dl vs 1.06 [±0.19] mg/dl, p
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= 0.002), had a greater incidence of hypertension (37.8% vs 25.3%, p = 0.001), diabetes
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mellitus (18.1% vs 2.7%, p < 0.001), chronic kidney disease (19.1% vs 8.4%, p < 0.001),
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coronary artery disease (20.2% vs 0.8%, p < 0.001), heart failure (9.0% vs 3.1%, p = 0.001),
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cerebrovascular events (7.4% vs 0.4%, p < 0.001), and CYP 3A4 inhibitor use (13.3% vs
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0.6%, p < 0.001). Patients taking both colchicine and a statin had less cancer (4.3% vs 9.5%,
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p = 0.025) and were on a lower dose of colchicine (0.88 [±0.29] mg/day vs 0.96 [±0.27]
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mg/day, p = 0.001). However, the two groups had no significant differences in the proportions
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ACCEPTED MANUSCRIPT of patients with fatty liver, liver cirrhosis, nephrotic syndrome, use of CYP 3A4 inducer, and
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duration of medication use. Furthermore, the incidence of myopathy did not differ
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significantly between those taking colchicine with statin and those taking colchicine alone
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(5/188, 2.7% vs 7/486, 1.4%, p = 0.330) (Table 1).
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Characteristics of patients with gout who developed myopathy while taking colchicine Among the 674 patients with gout included in our study, 12 developed myopathy (Table
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2). The length of time from beginning colchicine or colchicine with statin to development of
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myopathy was a median of 48 days (31.75–56.00). All but one patient was male. Five patients
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were receiving both colchicine and a statin, and three patients were on a CYP 3A4 inhibitor.
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Most had comorbid conditions such as chronic kidney disease. Patients 2 and 8 had the most
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severe myopathy, developing rhabdomyolysis. EMG was performed in patient 8 and showed
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active myopathy. All patients who developed myopathy completely resolved after cessation
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of the offending drug.
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Clinical factors associated with myopathy
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Cox regression analysis was performed to evaluate the clinical factors associated with
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the development of myopathy (Table 3). On univariate analysis, hypertension, diabetes
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mellitus, chronic kidney disease, coronary artery disease, and concomitant use of CYP3A4
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inhibitor were significantly associated with myopathy. However, the use of statins was not
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(HR 2.006 [95% CI 0.636–6.322], p = 0.235). On multivariate analysis using Cox regression
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models, the following factors were significantly associated with an increased risk of
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myopathy: chronic kidney disease (adjusted HR 29.056, 95% CI 4.387–192.450. p < 0.001),
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liver cirrhosis (adjusted HR 10.676, 95% CI 1.279–89.126, p = 0.029), higher colchicine dose
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(adjusted HR 20.960, 95% CI 1.835–239.481, p = 0.014), and concomitant use of a CYP 3A4
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however, was not increased in concomitant statin use with colchicine (multivariate-adjusted
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HR 1.123, 95% CI 0.262–4.814, p = 0.875) (Table 3). Finally, adjustment with the propensity
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score using IPTW confirmed the finding that the risk of myopathy was not increased for
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patients who received both colchicine and a statin (IPTW adjusted HR 0.321, 95% CI 0.077–
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1.345, p = 0.120).
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Discussion
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Our results showed that concomitant use of statin and colchicine is not associated with
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increased risk of myopathy in patients with gout. To the best of our knowledge, this is the
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first study to evaluate the influence of concomitant use of a statin with colchicine on
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myopathy risk.
Although both colchicine and statin are known to cause myotoxicity, the mechanisms
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proposed for each drug are different. Colchicine-associated myopathy is thought to relate to
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destabilization of the microtubule system, leading to impaired autophagosome-lysosome
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fusion and accumulation of autophagic vacuoles.18,19 In contrast, myopathy caused by statins
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is related to various pathophysiologic mechanisms including reduction of essential co-
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enzyme production, myocyte membrane changes, and increased oxidation.20 Although the
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exact mechanism of myopathy after use of colchicine and statin is unknown, the differences
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in these pathways might explain why there is no synergistic effect of coadministered
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colchicine and statins to increase the incidence of myopathy.
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According to previous studies, the incidence of statin-associated myopathy is 1.5%–
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5%.10,11 Thus, in our present study, the incidence of myopathy in colchicine and statin group
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was 2.7% which was similar to the reported incidence of statin-associated myopathy. To date, 7
ACCEPTED MANUSCRIPT there has been no report on the incidence of colchicine-associated myopathy. However,
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considering that most reports are of sporadic cases mostly in patients with risk factors
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including renal function impairment, our reported incidence of 1.4% in colchicine-
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associated myopathy might seem somewhat higher than expected. A possible explanation for
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this can be that patients in our study had relatively more comorbidities including chronic
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kidney disease (Table 1).
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Chronic kidney disease was independently and significantly associated with an increased
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risk of myopathy (Table 3). Interestingly, in previous case reports of myopathy in patients on
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both colchicine and statin,12-15 all had some degree of renal insufficiency. Although not all
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patients who developed myopathy in our study had chronic kidney disease, it was the most
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important risk factor of myopathy having the highest HR. Thus, in terms of myotoxicity, it
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seems reasonable to avoid colchicine in patients with gout if the GFR is less than 60
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ml/min/1.73 m2.
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Our study showed that liver cirrhosis was also associated with increased risk of
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myopathy (Table 3). This can be explained by the fact that colchicine is primarily
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metabolized and excreted by the liver.15 Thus, when liver function deteriorates, colchicine
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levels in the blood will be increased, thereby possibly resulting in a higher risk of toxicity.
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A higher colchicine dose used was associated with increased risk of myopathy. Based on
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the adjusted HR, we estimated that with a colchicine dose of 1.2 mg daily, the risk of
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myopathy was 6.2 times higher than with a 0.6 mg dose. CYP 3A4 inhibitor use was also
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associated with an increased risk of myopathy. The most commonly used CYP 3A4 inhibitor
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in our study population was diltiazem (n = 22), followed by cyclosporine (n = 3), verapamil
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(n = 2), and amiodarone (n = 1). Given that patients with gout are likely to take a number of
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other drugs, clinicians should consider the possibility of drug interactions when colchicine
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use is essential.
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were checked only in patients who had muscle symptoms. Thus, we cannot exclude the
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possibility that myopathy was not detected when patients did not have evident symptoms. In
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addition, since specific tests such as EMG or muscle biopsy were not performed to diagnose
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the myopathy, the possibility of misdiagnosis may be considered. Furthermore, determining
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what medications were administered was based on medical records. Therefore, we cannot
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evaluate whether the patients actually took their drugs as prescribed or not, and it may be
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hard to clarify the offending drug responsible for myopathy.
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In conclusion, in the present study, we have shown that the coadministration of a statin
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with colchicine was not associated with an increased risk of myopathy compared with use of
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colchicine alone in patients with gout. Rather, the risk of myopathy was significantly
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increased with comorbidities (such as chronic kidney disease and liver cirrhosis), a higher
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colchicine dose, and CYP 3A4 inhibitor use. Thus, the concomitant use of a statin with
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colchicine seems to be safe in patients with gout who do not have comorbidities.
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Funding: This work was supported by the Research fund of Rheumatology Research
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Foundation (RRF-2015-04) and by the grant (2015-658) from the Asan Institute for Life
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Sciences, Asan Medical Center, Korea.
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Conflict of interest statement: The authors declare that there are no conflicts of interest in
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relation to this article.
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ACCEPTED MANUSCRIPT Table 1. Baseline characteristics of patients with gout who received colchicine with or without a statin Colchicine with statin
Colchicine without statin
(N = 188)
(N = 486)
183 (97.3)
471 (96.9)
0.770
55.71 ± 12.57
52.51 ± 12.76
0.003
1.12 ± 0.24
1.06 ± 0.19
0.002
Age (years)
Hypertension
71 (37.8)
0.001
Diabetes mellitus
34 (18.1)
13 (2.7)
<0.001
Chronic kidney disease
36 (19.1)
41 (8.4)
<0.001
Coronary artery disease
38 (20.2)
4 (0.8)
<0.001
Heart failure
17 (9.0)
15 (3.1)
0.001
14 (7.4)
2 (0.4)
<0.001
8 (4.3)
46 (9.5)
0.025
17 (9.0)
34 (7.0)
0.368
1 (0.5)
8 (1.6)
0.457
Nephrotic syndrome
1 (0.5)
4 (0.8)
>0.999
CYP 3A4 inducer
1 (0.5)
5 (1.0)
>0.999
25 (13.3)
3 (0.6)
<0.001
0.88 ± 0.29
0.96 ± 0.27
0.001
203.96 ± 162.50
223.47 ± 127.91
0.140
5 (2.7)
7 (1.4)
0.330
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Baseline creatinine (mg/dl)
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Male
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p value
Cerebrovascular event Cancer Fatty liver
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Liver cirrhosis
CYP 3A4 inhibitor
Colchicine dose (mg/day)
Duration of medication (days) Myopathy
Except where indicated otherwise, values are the number (%).
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Table 2. Characteristics of patients with gout treated with colchicine who developed myopathy Sex/
Baseline Cr
Colchicine dose
Duration
Comorbidities
Age
(mg/dl)
(mg/day)
(Days)
1
M/64
0.92
0.6
166
HTN
2
M/52
1.50
1.2
19
DM, CKD, CAD
3
M/71
1.06
1.2
29
HTN, CAD, CVA
4
M/68
1.40
1.2
56
5
M/65
1.00
1.2
6
M/52
1.10
7
M/62
8
Statin
CYP 3A4 inhibitor
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No.
CK
Myoglobin
(IU/L)
(ng/mL)
Cyclosporine
550
692
Atorvastatin
No
8547
9477
Rosuvastatin
No
641
N/A
HTN, CKD, CAD
Atorvastatin
Diltiazem
495
N/A
18
HTN, DM, CKD, CAD
Rosuvastatin
No
981
453
0.6
314
HTN, DM
No
Diltiazem
N/A
133
0.70
1.2
45
HF
No
No
N/A
111
M/64
1.80
1.8
46
CKD, HF
No
No
2180
2788
9
M/53
0.87
1.2
40
HTN, fatty liver
No
No
666
N/A
10
F/69
1.53
0.6
54
HTN, CKD
No
No
293
N/A
11
M/61
0.90
1.2
50
Cancer, LC
No
No
291
275
12
M/31
0.87
0.8
56
No
No
No
2517
N/A
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Atorvastatin
Cr = creatinine; HTN = hypertension; DM = diabetes mellitus; CKD = chronic kidney disease; CAD = coronary artery disease; CVA =
cerebrovascular accident; HF = heart failure; LC = liver cirrhosis 2
ACCEPTED MANUSCRIPT Table 3. Analysis of clinical factors associated with myopathy in patients with gout treated with colchicine Univariate analysis 95% CI
p value
Female
3.822
0.488–29.927
0.202
Age
1.043
0.995–1.094
Baseline creatinine
4.083
0.369–45.232
Colchicine dose
7.068
0.622–80.343
Hypertension
3.431
1.088–10.820
0.035
Diabetes mellitus
5.033
1.361–18.612
0.015
Chronic kidney disease
6.286
1.991–19.844
0.002
Coronary artery disease
8.816
2.641–29.435
<0.001
Heart failure
4.475
0.979–20.461
0.053
Cerebrovascular event
4.057
0.522–31.522
0.181
Cancer
1.181
0.152–9.184
0.874
Fatty liver
1.009
0.130–7.855
0.993
7.015
0.905–54.379
0.062
0.049
N/A
0.838
0.049
N/A
0.813
7.922
2.144–29.270
0.002
2.006
0.636–6.322
0.235
Adjusted hazard ratio
95% CI
p value
Chronic kidney disease
29.056
4.387–192.450
<0.001
Liver cirrhosis
10.676
1.279–89.126
0.029
Colchicine dose
20.960
1.835–239.481
0.014
CYP 3A4 inhibitor
12.027
2.743–52.725
0.001
Statin
1.123
0.262–4.814
0.875
CYP 3A4 inducer CYP 3A4 inhibitor Statin
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Nephrotic syndrome
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Liver cirrhosis
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Unadjusted hazard ratio
0.078
0.252 0.115
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Multivariate analysis
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ACCEPTED MANUSCRIPT Clinical Significance Statin can be added safely to colchicine in gout patients, in respect to myopathy. Chronic kidney disease and liver cirrhosis seem to increase risk of colchicine-
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avoided if possible.
S0002-9343(16)31306-7
DOI:
10.1016/j.amjmed.2016.12.006
Reference:
AJM 13844
To appear in:
The American Journal of Medicine
Received Date: 12 September 2016 Revised Date:
26 November 2016
Accepted Date: 9 December 2016
Please cite this article as: Kwon OC, Hong S, Ghang B, Kim YG, Lee CK, Yoo B, Risk of ColchicineAssociated Myopathy in Gout: Influence of Concomitant Use of Statin, The American Journal of Medicine (2017), doi: 10.1016/j.amjmed.2016.12.006. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1
Clinical Research Study
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Running head: Colchicine and statin in gout
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Risk of Colchicine-Associated Myopathy in Gout:
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Influence of Concomitant Use of Statin
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Oh Chan Kwon, M.D., Seokchan Hong, M.D., Ph.D., Byeongzu Ghang, M.D.,
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Yong-Gil Kim, M.D., Ph.D., Chang-Keun Lee, M.D., Ph.D., and Bin Yoo, M.D., Ph.D.
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Division of Rheumatology, Department of Medicine, University of Ulsan, College of
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Medicine, Asan Medical Center, Seoul, Korea
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Authorship: All authors had access to the data and contributed sufficiently to writing the
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manuscript to be included as authors.
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Please address correspondence to: Seokchan Hong, M.D., Ph.D.
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Division of Rheumatology, University of Ulsan, College of Medicine, Asan Medical Center
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88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea
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Tel.: +82-2-3010-1410; Fax: +82-2-3010-6969; E-mail: [email protected]
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Abstract
2
Objective. To investigate the risk of myopathy when statins are coadministered with
4
colchicine in patients with gout.
5
Methods. In gout patients who received colchicine with or without statin, clinical data
6
collected included medications and history of hypertension, chronic kidney disease, and liver
7
cirrhosis. Myopathy was defined as the presence of muscle symptoms with elevated
8
creatinine phosphokinase and/or myoglobin. Multivariate analysis was performed to identify
9
risk factors for myopathy. Inverse probability of treatment weighting (IPTW)-adjusted
10
analysis was used to evaluate the influence of concomitant colchicine and statin use on
11
myopathy.
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Results. Of 674 patients, 486 received colchicine alone and 188 also received statin. The
13
incidence of myopathy was not significantly higher in those on both drugs than in those on
14
colchicine alone (2.7% vs 1.4%, p = 0.330). On multivariate analysis, chronic kidney disease
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(hazard ratio [HR] 29.056, 95% confidence interval [CI] 4.387–192.450, p < 0.001), liver
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cirrhosis (HR 10.676, 95% CI 1.279–89.126, p = 0.029), higher colchicine dose (HR 20.960,
17
95% CI 1.835–239.481, p = 0.014), and concomitant CYP 3A4 inhibitor (HR 12.027, 95% CI
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2.743–52.725, p = 0.001) were associated with increased risk of myopathy. Concomitant use
19
of statins, however, was not, even after adjusting for confounders (HR 1.123, 95% CI 0.262–
20
4.814, p = 0.875; IPTW-adjusted HR 0.321, 95% CI 0.077–1.345, p = 0.120).
21
Conclusion. Concomitant use statin and colchicine was not associated with increased risk of
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myopathy. Thus, concomitant use of statin with colchicine seems to be safe from myotoxicity
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in gout patients.
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Key words: colchicine, statin, gout, myopathy 2
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Introduction
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Colchicine has been widely used for the treatment of various inflammatory diseases such
4
as gouty arthritis. Previous studies have shown the efficacy of colchicine in the control of
5
acute gout attacks as well as prophylaxis of gout flares.1,2 Therefore, colchicine is
6
recommended as a first-line drug for prophylaxis in gout.3 Other entities for which it is used
7
include oral aphthosis, genital aphthosis, and joint manifestations of Behcet disease.4
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Statins, hydroxymethylglutaryl coenzyme A inhibitors, are considered to be the first
9
choice of drugs for lowering LDL cholesterol levels in patients with dyslipidemia. The
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efficacy of statins on the prevention of cardiovascular events and mortality has been well
11
established through several, large, well-controlled clinical trials.5-9
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Despite the benefits, colchicine and statin are both known to have a risk of myopathy.
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The incidence of colchicine-associated myopathy is unclear, while statin-associated
14
myopathy occurs in approximately 1.5%–5% of patients taking a statin.10,11 There have been
15
several case reports of myopathy after concomitant use of colchicine and a statin.12-15 These
16
reports suggested that the risk of myopathy might be increased when colchicine is used in
17
combination with a statin. An explanation posited for the presumed increased risk of
18
myopathy is that both colchicine and statin are metabolized by the cytochrome P450 system.
19
However, there is no sound clinical evidence supporting this interaction. Indeed, it is not clear
20
whether the concomitant use of statin and colchicine is truly associated with an increased risk
21
of myopathy compared with colchicine alone. Despite lack of evidence either way, there are
22
many clinical situations in which coadministration of colchicine and a statin is needed, such
23
as in patients with both gout and dyslipidemia.
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Therefore, in this study we aimed to assess whether the coadministration of statin and
25
colchicine increases the risk of myopathy and to evaluate other factors that might be 3
ACCEPTED MANUSCRIPT 1
associated with the development of myopathy in patients with gout who are taking colchicine.
2 3
Methods
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Study population
The electronic medical records of patients who were diagnosed with gout at a tertiary
7
referral hospital in Seoul, South Korea between January 01, 2000 and March 31, 2016 were
8
retrospectively reviewed. A diagnosis of gout was made based on the preliminary criteria for
9
the classification of gout.16 Patients were excluded from the analysis if they had not received
10
colchicine during the study period. From the medical records, the following data were
11
collected: age; sex; diagnosis of hypertension, diabetes mellitus, chronic kidney disease
12
(defined as an estimated glomerular filtration rate [GFR] <60 ml/min/1.73 m2), coronary
13
artery disease, heart failure, cerebrovascular accident, cancer, fatty liver, liver cirrhosis, or
14
nephrotic syndrome; concomitant use of a CYP3A4 inducer and/or CYP3A4 inhibitor at the
15
same time as colchicine; duration of colchicine and/or statin administration; and daily
16
colchicine dose.
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All patients with muscle symptoms such as myalgia or muscle weakness had laboratory
18
tests to detect muscle damage. We defined myopathy as appropriate symptoms accompanied
19
by elevation above the upper limit of normal of muscle enzymes, including creatinine
20
phosphokinase and/or myoglobin, according to the proposal of the American College of
21
Cardiology/American Heart Association/National Heart, Lung and Blood Institute.17
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This study was approved by the Institutional Review Board of the Asan Medical Center,
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Seoul, South Korea (IRB No.: 2016-0613). The requirement for informed consent was
24
waived because of the retrospective nature of the study.
25 4
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Statistical analysis Student’s t-tests and chi-square tests were used for continuous and categorical variables,
3
respectively. Cox regression analysis with a stepwise backward elimination procedure was
4
performed to identify risk factors for myopathy. Factors which had a p value less than 0.3 on
5
univariate analysis were selected for multivariate analysis. In analyzing the influence of
6
concomitant statin and colchicine on the development of myopathy, inverse probability of
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treatment weighting (IPTW) was used to exclude the influence of confounders.
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Results
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Comparison of colchicine alone group and colchicine with statin group Of the 674 patients with gout, 486 were treated with colchicine alone and 188 took both
13
colchicine and statin. Atorvastatin was the most commonly used statin (109/188, 58.0%),
14
followed by simvastatin (34/188, 18.1%) and rosuvastatin (28/188, 14.9%). Demographic and
15
clinical characteristics are shown in Table 1. The two groups were similar in terms of gender
16
distribution (p = 0.770). However, the patients taking both colchicine and statins were
17
significantly older than those taking colchicine only (55.71 [±12.57] years vs 52.51 [±12.76]
18
years, p = 0.003), had higher levels of creatinine (1.12 [±0.24] mg/dl vs 1.06 [±0.19] mg/dl, p
19
= 0.002), had a greater incidence of hypertension (37.8% vs 25.3%, p = 0.001), diabetes
20
mellitus (18.1% vs 2.7%, p < 0.001), chronic kidney disease (19.1% vs 8.4%, p < 0.001),
21
coronary artery disease (20.2% vs 0.8%, p < 0.001), heart failure (9.0% vs 3.1%, p = 0.001),
22
cerebrovascular events (7.4% vs 0.4%, p < 0.001), and CYP 3A4 inhibitor use (13.3% vs
23
0.6%, p < 0.001). Patients taking both colchicine and a statin had less cancer (4.3% vs 9.5%,
24
p = 0.025) and were on a lower dose of colchicine (0.88 [±0.29] mg/day vs 0.96 [±0.27]
25
mg/day, p = 0.001). However, the two groups had no significant differences in the proportions
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ACCEPTED MANUSCRIPT of patients with fatty liver, liver cirrhosis, nephrotic syndrome, use of CYP 3A4 inducer, and
2
duration of medication use. Furthermore, the incidence of myopathy did not differ
3
significantly between those taking colchicine with statin and those taking colchicine alone
4
(5/188, 2.7% vs 7/486, 1.4%, p = 0.330) (Table 1).
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5 6
Characteristics of patients with gout who developed myopathy while taking colchicine Among the 674 patients with gout included in our study, 12 developed myopathy (Table
8
2). The length of time from beginning colchicine or colchicine with statin to development of
9
myopathy was a median of 48 days (31.75–56.00). All but one patient was male. Five patients
10
were receiving both colchicine and a statin, and three patients were on a CYP 3A4 inhibitor.
11
Most had comorbid conditions such as chronic kidney disease. Patients 2 and 8 had the most
12
severe myopathy, developing rhabdomyolysis. EMG was performed in patient 8 and showed
13
active myopathy. All patients who developed myopathy completely resolved after cessation
14
of the offending drug.
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Clinical factors associated with myopathy
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Cox regression analysis was performed to evaluate the clinical factors associated with
18
the development of myopathy (Table 3). On univariate analysis, hypertension, diabetes
19
mellitus, chronic kidney disease, coronary artery disease, and concomitant use of CYP3A4
20
inhibitor were significantly associated with myopathy. However, the use of statins was not
21
(HR 2.006 [95% CI 0.636–6.322], p = 0.235). On multivariate analysis using Cox regression
22
models, the following factors were significantly associated with an increased risk of
23
myopathy: chronic kidney disease (adjusted HR 29.056, 95% CI 4.387–192.450. p < 0.001),
24
liver cirrhosis (adjusted HR 10.676, 95% CI 1.279–89.126, p = 0.029), higher colchicine dose
25
(adjusted HR 20.960, 95% CI 1.835–239.481, p = 0.014), and concomitant use of a CYP 3A4
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ACCEPTED MANUSCRIPT inhibitor (adjusted HR 12.027, 95% CI 2.743–52.725, p = 0.001). The risk of myopathy,
2
however, was not increased in concomitant statin use with colchicine (multivariate-adjusted
3
HR 1.123, 95% CI 0.262–4.814, p = 0.875) (Table 3). Finally, adjustment with the propensity
4
score using IPTW confirmed the finding that the risk of myopathy was not increased for
5
patients who received both colchicine and a statin (IPTW adjusted HR 0.321, 95% CI 0.077–
6
1.345, p = 0.120).
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Discussion
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Our results showed that concomitant use of statin and colchicine is not associated with
11
increased risk of myopathy in patients with gout. To the best of our knowledge, this is the
12
first study to evaluate the influence of concomitant use of a statin with colchicine on
13
myopathy risk.
Although both colchicine and statin are known to cause myotoxicity, the mechanisms
15
proposed for each drug are different. Colchicine-associated myopathy is thought to relate to
16
destabilization of the microtubule system, leading to impaired autophagosome-lysosome
17
fusion and accumulation of autophagic vacuoles.18,19 In contrast, myopathy caused by statins
18
is related to various pathophysiologic mechanisms including reduction of essential co-
19
enzyme production, myocyte membrane changes, and increased oxidation.20 Although the
20
exact mechanism of myopathy after use of colchicine and statin is unknown, the differences
21
in these pathways might explain why there is no synergistic effect of coadministered
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colchicine and statins to increase the incidence of myopathy.
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According to previous studies, the incidence of statin-associated myopathy is 1.5%–
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5%.10,11 Thus, in our present study, the incidence of myopathy in colchicine and statin group
25
was 2.7% which was similar to the reported incidence of statin-associated myopathy. To date, 7
ACCEPTED MANUSCRIPT there has been no report on the incidence of colchicine-associated myopathy. However,
2
considering that most reports are of sporadic cases mostly in patients with risk factors
3
including renal function impairment, our reported incidence of 1.4% in colchicine-
4
associated myopathy might seem somewhat higher than expected. A possible explanation for
5
this can be that patients in our study had relatively more comorbidities including chronic
6
kidney disease (Table 1).
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Chronic kidney disease was independently and significantly associated with an increased
8
risk of myopathy (Table 3). Interestingly, in previous case reports of myopathy in patients on
9
both colchicine and statin,12-15 all had some degree of renal insufficiency. Although not all
10
patients who developed myopathy in our study had chronic kidney disease, it was the most
11
important risk factor of myopathy having the highest HR. Thus, in terms of myotoxicity, it
12
seems reasonable to avoid colchicine in patients with gout if the GFR is less than 60
13
ml/min/1.73 m2.
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Our study showed that liver cirrhosis was also associated with increased risk of
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myopathy (Table 3). This can be explained by the fact that colchicine is primarily
16
metabolized and excreted by the liver.15 Thus, when liver function deteriorates, colchicine
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levels in the blood will be increased, thereby possibly resulting in a higher risk of toxicity.
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A higher colchicine dose used was associated with increased risk of myopathy. Based on
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the adjusted HR, we estimated that with a colchicine dose of 1.2 mg daily, the risk of
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myopathy was 6.2 times higher than with a 0.6 mg dose. CYP 3A4 inhibitor use was also
21
associated with an increased risk of myopathy. The most commonly used CYP 3A4 inhibitor
22
in our study population was diltiazem (n = 22), followed by cyclosporine (n = 3), verapamil
23
(n = 2), and amiodarone (n = 1). Given that patients with gout are likely to take a number of
24
other drugs, clinicians should consider the possibility of drug interactions when colchicine
25
use is essential.
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2
were checked only in patients who had muscle symptoms. Thus, we cannot exclude the
3
possibility that myopathy was not detected when patients did not have evident symptoms. In
4
addition, since specific tests such as EMG or muscle biopsy were not performed to diagnose
5
the myopathy, the possibility of misdiagnosis may be considered. Furthermore, determining
6
what medications were administered was based on medical records. Therefore, we cannot
7
evaluate whether the patients actually took their drugs as prescribed or not, and it may be
8
hard to clarify the offending drug responsible for myopathy.
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In conclusion, in the present study, we have shown that the coadministration of a statin
10
with colchicine was not associated with an increased risk of myopathy compared with use of
11
colchicine alone in patients with gout. Rather, the risk of myopathy was significantly
12
increased with comorbidities (such as chronic kidney disease and liver cirrhosis), a higher
13
colchicine dose, and CYP 3A4 inhibitor use. Thus, the concomitant use of a statin with
14
colchicine seems to be safe in patients with gout who do not have comorbidities.
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Funding: This work was supported by the Research fund of Rheumatology Research
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Foundation (RRF-2015-04) and by the grant (2015-658) from the Asan Institute for Life
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Sciences, Asan Medical Center, Korea.
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Conflict of interest statement: The authors declare that there are no conflicts of interest in
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relation to this article.
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ACCEPTED MANUSCRIPT Table 1. Baseline characteristics of patients with gout who received colchicine with or without a statin Colchicine with statin
Colchicine without statin
(N = 188)
(N = 486)
183 (97.3)
471 (96.9)
0.770
55.71 ± 12.57
52.51 ± 12.76
0.003
1.12 ± 0.24
1.06 ± 0.19
0.002
Age (years)
Hypertension
71 (37.8)
0.001
Diabetes mellitus
34 (18.1)
13 (2.7)
<0.001
Chronic kidney disease
36 (19.1)
41 (8.4)
<0.001
Coronary artery disease
38 (20.2)
4 (0.8)
<0.001
Heart failure
17 (9.0)
15 (3.1)
0.001
14 (7.4)
2 (0.4)
<0.001
8 (4.3)
46 (9.5)
0.025
17 (9.0)
34 (7.0)
0.368
1 (0.5)
8 (1.6)
0.457
Nephrotic syndrome
1 (0.5)
4 (0.8)
>0.999
CYP 3A4 inducer
1 (0.5)
5 (1.0)
>0.999
25 (13.3)
3 (0.6)
<0.001
0.88 ± 0.29
0.96 ± 0.27
0.001
203.96 ± 162.50
223.47 ± 127.91
0.140
5 (2.7)
7 (1.4)
0.330
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Baseline creatinine (mg/dl)
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Male
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p value
Cerebrovascular event Cancer Fatty liver
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Liver cirrhosis
CYP 3A4 inhibitor
Colchicine dose (mg/day)
Duration of medication (days) Myopathy
Except where indicated otherwise, values are the number (%).
1
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Table 2. Characteristics of patients with gout treated with colchicine who developed myopathy Sex/
Baseline Cr
Colchicine dose
Duration
Comorbidities
Age
(mg/dl)
(mg/day)
(Days)
1
M/64
0.92
0.6
166
HTN
2
M/52
1.50
1.2
19
DM, CKD, CAD
3
M/71
1.06
1.2
29
HTN, CAD, CVA
4
M/68
1.40
1.2
56
5
M/65
1.00
1.2
6
M/52
1.10
7
M/62
8
Statin
CYP 3A4 inhibitor
RI PT
No.
CK
Myoglobin
(IU/L)
(ng/mL)
Cyclosporine
550
692
Atorvastatin
No
8547
9477
Rosuvastatin
No
641
N/A
HTN, CKD, CAD
Atorvastatin
Diltiazem
495
N/A
18
HTN, DM, CKD, CAD
Rosuvastatin
No
981
453
0.6
314
HTN, DM
No
Diltiazem
N/A
133
0.70
1.2
45
HF
No
No
N/A
111
M/64
1.80
1.8
46
CKD, HF
No
No
2180
2788
9
M/53
0.87
1.2
40
HTN, fatty liver
No
No
666
N/A
10
F/69
1.53
0.6
54
HTN, CKD
No
No
293
N/A
11
M/61
0.90
1.2
50
Cancer, LC
No
No
291
275
12
M/31
0.87
0.8
56
No
No
No
2517
N/A
M AN U
TE D
EP
AC C
*
SC
Atorvastatin
Cr = creatinine; HTN = hypertension; DM = diabetes mellitus; CKD = chronic kidney disease; CAD = coronary artery disease; CVA =
cerebrovascular accident; HF = heart failure; LC = liver cirrhosis 2
ACCEPTED MANUSCRIPT Table 3. Analysis of clinical factors associated with myopathy in patients with gout treated with colchicine Univariate analysis 95% CI
p value
Female
3.822
0.488–29.927
0.202
Age
1.043
0.995–1.094
Baseline creatinine
4.083
0.369–45.232
Colchicine dose
7.068
0.622–80.343
Hypertension
3.431
1.088–10.820
0.035
Diabetes mellitus
5.033
1.361–18.612
0.015
Chronic kidney disease
6.286
1.991–19.844
0.002
Coronary artery disease
8.816
2.641–29.435
<0.001
Heart failure
4.475
0.979–20.461
0.053
Cerebrovascular event
4.057
0.522–31.522
0.181
Cancer
1.181
0.152–9.184
0.874
Fatty liver
1.009
0.130–7.855
0.993
7.015
0.905–54.379
0.062
0.049
N/A
0.838
0.049
N/A
0.813
7.922
2.144–29.270
0.002
2.006
0.636–6.322
0.235
Adjusted hazard ratio
95% CI
p value
Chronic kidney disease
29.056
4.387–192.450
<0.001
Liver cirrhosis
10.676
1.279–89.126
0.029
Colchicine dose
20.960
1.835–239.481
0.014
CYP 3A4 inhibitor
12.027
2.743–52.725
0.001
Statin
1.123
0.262–4.814
0.875
CYP 3A4 inducer CYP 3A4 inhibitor Statin
SC
M AN U
TE D
Nephrotic syndrome
EP
Liver cirrhosis
RI PT
Unadjusted hazard ratio
0.078
0.252 0.115
AC C
Multivariate analysis
3
ACCEPTED MANUSCRIPT Clinical Significance Statin can be added safely to colchicine in gout patients, in respect to myopathy. Chronic kidney disease and liver cirrhosis seem to increase risk of colchicine-
RI PT
associated myopathy. Colchicine dose increment and coadministration of CYP 3A4 inhibitors should be
AC C
EP
TE D
M AN U
SC
avoided if possible.