J Rheum Dis.  2020 Apr;27(2):78-87. 10.4078/jrd.2020.27.2.78.

What is the Best Choice for Urate-lowering Therapy for Korean?

Affiliations
  • 1Division of Rheumatology, Department of Internal Medicine, Gyeongsang National University School of Medicine, Jinju, Korea.
  • 2Division of Rheumatology, Department of Internal Medicine, Chung-Ang University School of Medicine, Seoul, Korea. drsong@cau.ac.kr

Abstract

Gout is one of the most common forms of acute inflammatory arthritis caused by long-standing hyperuricemia. Various clinical and epidemiological studies have demonstrated that uric acid, which is strongly associated with the pathogenesis of gout, is closely related with increased cardiovascular (CV) risk. Thus, properly controlling uric acid levels within its physiological level using urate-lowering therapy has been hypothesized to improve CV outcomes. Recently, however, on the basis of the results of the largest prospective, the double-blind, randomized controlled trial, entitled "the Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout (CARES)," has aroused the possibility of increased CV-related and all-cause mortality in patients receiving febuxostat. Largely on the basis of this unpredicted result, the US and Korea Food and Drug Administration issued a public safety alert concerning the high risk of CV death with the use of febuxostat in February 2019. This unexpected announcement left many rheumatologists confused when they decide the first-line urate-lowering drug in Korea. In this review, we searched for previous studies on uric acid and increased risk of CV disease. In addition, we will introduce various interpretations of the results of the CARES trial and discuss the best choice of urate-lowering therapy for Korean.

Keyword

Cardiovascular disease; Allopurinol; Febuxostat; Hyperuricemia; Gout

MeSH Terms

Allopurinol
Arthritis
Cardiovascular Diseases
Epidemiologic Studies
Febuxostat
Gout
Humans
Hyperuricemia
Korea
Mortality
Prospective Studies
United States Food and Drug Administration
Uric Acid
Allopurinol
Febuxostat
Uric Acid

Reference

1. Dalbeth N, Merriman TR, Stamp LK. Gout. Lancet. 2016; 388:2039–2052.
Article
2. Richette P, Doherty M, Pascual E, Barskova V, Becce F, Castaneda J, et al. 2018 updated European League Against Rheumatism evidence-based recommendations for the diagnosis of gout. Ann Rheum Dis. 2020; 79:31–38.
Article
3. Elfishawi MM, Zleik N, Kvrgic Z, Michet CJ Jr, Crowson CS, Matteson EL, et al. The rising incidence of gout and the increasing burden of comorbidities: a population-based study over 20 years. J Rheumatol. 2018; 45:574–579.
Article
4. Kim JW, Kwak SG, Lee H, Kim SK, Choe JY, Park SH. Prevalence and incidence of gout in Korea: data from the National Health Claims Database 2007–2015. Rheumatol Int. 2017; 37:1499–1506.
Article
5. Kuo CF, Grainge MJ, Mallen C, Zhang W, Doherty M. Rising burden of gout in the UK but continuing suboptimal management: a nationwide population study. Ann Rheum Dis. 2015; 74:661–667.
Article
6. McGill NW. Gout and other crystal-associated arthropathies. Baillieres Best Pract Res Clin Rheumatol. 2000; 14:445–460.
Article
7. Shiozawa A, Szabo SM, Bolzani A, Cheung A, Choi HK. Serum uric acid and the risk of incident and recurrent gout: a systematic review. J Rheumatol. 2017; 44:388–396.
Article
8. Choi HK, Ford ES, Li C, Curhan G. Prevalence of the metabolic syndrome in patients with gout: the Third National Health and Nutrition Examination Survey. Arthritis Rheum. 2007; 57:109–115.
Article
9. Jung JH, Song GG, Ji JD, Lee YH, Kim JH, Seo YH, et al. Metabolic syndrome: prevalence and risk factors in Korean gout patients. Korean J Intern Med. 2018; 33:815–822.
Article
10. Kuo CF, Grainge MJ, Mallen C, Zhang W, Doherty M. Comorbidities in patients with gout prior to and following diagnosis: case-control study. Ann Rheum Dis. 2016; 75:210–217.
Article
11. Choi HJ, Lee CH, Lee JH, Yoon BY, Kim HA, Suh CH, et al. Current gout treatment and flare in South Korea: prophylactic duration associated with fewer gout flares. Int J Rheum Dis. 2017; 20:497–503.
Article
12. Abeles AM, Pillinger MH. Febuxostat and the black box blues. ACR Open Rheumatol. 2019; 1:343–344.
Article
13. Choi H, Neogi T, Stamp L, Dalbeth N, Terkeltaub R. New perspectives in rheumatology: implications of the cardiovascular safety of febuxostat and allopurinol in patients with gout and cardiovascular morbidities trial and the associated Food and Drug Administration public safety alert. Arthritis Rheumatol. 2018; 70:1702–1709.
Article
14. Liu SC, Xia L, Zhang J, Lu XH, Hu DK, Zhang HT, et al. Gout and risk of myocardial infarction: a systematic review and meta-analysis of cohort studies. PLoS One. 2015; 10:e0134088.
Article
15. Kim SK. Interrelationship of uric acid, gout, and metabolic syndrome: focus on hypertension, cardiovascular disease, and insulin resistance. J Rheum Dis. 2018; 25:19–27.
Article
16. Kang EH, Kim SC. Cardiovascular safety of urate lowering therapies. Curr Rheumatol Rep. 2019; 21:48.
Article
17. Huang KH, Tai CJ, Tsai YF, Kuan YH, Lee CY. Correlation between gout and coronary heart disease in Taiwan: a nationwide population-based cohort study. Acta Cardiol Sin. 2019; 35:634–640.
18. Sautin YY, Nakagawa T, Zharikov S, Johnson RJ. Adverse effects of the classic antioxidant uric acid in adipocytes: NADPH oxidase-mediated oxidative/nitrosative stress. Am J Physiol Cell Physiol. 2007; 293:C584–C596.
Article
19. Braga TT, Forni MF, Correa-Costa M, Ramos RN, Barbuto JA, Branco P, et al. Soluble uric acid activates the NLRP3 inflammasome. Sci Rep. 2017; 7:39884.
Article
20. Tseng WC, Chen YT, Ou SM, Shih CJ, Tarng DC. Taiwan Geriatric Kidney Disease (TGKD) Research Group. U-shaped association between serum uric acid levels with cardiovascular and all-cause mortality in the elderly: the role of malnourishment. J Am Heart Assoc. 2018; 7:e007523.
Article
21. Kuo CF, See LC, Yu KH, Chou IJ, Chiou MJ, Luo SF. Significance of serum uric acid levels on the risk of all-cause and cardiovascular mortality. Rheumatology (Oxford). 2013; 52:127–134.
Article
22. Cho SK, Chang Y, Kim I, Ryu S. U-shaped association between serum uric acid level and risk of mortality: a cohort study. Arthritis Rheumatol. 2018; 70:1122–1132.
23. Kang E, Hwang SS, Kim DK, Oh KH, Joo KW, Kim YS, et al. Sex-specific relationship of serum uric acid with all-cause mortality in adults with normal kidney function: an observational study. J Rheumatol. 2017; 44:380–387.
Article
24. Lee SY, Park W, Suh YJ, Lim MJ, Kwon SR, Lee JH, et al. Association of serum uric acid with cardiovascular disease risk scores in Koreans. Int J Environ Res Public Health. 2019; 16:E4632.
Article
25. Ames BN, Cathcart R, Schwiers E, Hochstein P. Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis. Proc Natl Acad Sci U S A. 1981; 78:6858–6862.
Article
26. So A, Thorens B. Uric acid transport and disease. J Clin Invest. 2010; 120:1791–1799.
Article
27. Johnson RJ, Kang DH, Feig D, Kivlighn S, Kanellis J, Watanabe S, et al. Is there a pathogenetic role for uric acid in hypertension and cardiovascular and renal disease? Hypertension. 2003; 41:1183–1190.
Article
28. Kawamoto R, Ninomiya D, Kasai Y, Kusunoki T, Ohtsuka N, Kumagi T, et al. Serum uric acid is positively associated with handgrip strength among Japanese community-dwelling elderly women. PLoS One. 2016; 11:e0151044.
Article
29. Beavers KM, Beavers DP, Serra MC, Bowden RG, Wilson RL. Low relative skeletal muscle mass indicative of sarcopenia is associated with elevations in serum uric acid levels: findings from NHANES III. J Nutr Health Aging. 2009; 13:177–182.
Article
30. Can B, Kara O, Kizilarslanoglu MC, Arik G, Aycicek GS, Sumer F, et al. Serum markers of inflammation and oxidative stress in sarcopenia. Aging Clin Exp Res. 2017; 29:745–752.
Article
31. Lee J, Hong YS, Park SH, Kang KY. High serum uric acid level is associated with greater handgrip strength in the aged population. Arthritis Res Ther. 2019; 21:73.
Article
32. Richette P, Doherty M, Pascual E, Barskova V, Becce F, Castañeda-Sanabria J, et al. 2016 updated EULAR evidence-based recommendations for the management of gout. Ann Rheum Dis. 2017; 76:29–42.
Article
33. Hui M, Carr A, Cameron S, Davenport G, Doherty M, Forrester H, et al. British Society for Rheumatology Standards, Audit and Guidelines Working Group. The British Society for Rheumatology Guideline for the management of gout. Rheumatology (Oxford). 2017; 56:1246.
Article
34. Khanna D, Khanna PP, Fitzgerald JD, Singh MK, Bae S, Neogi T, et al. American College of Rheumatology. 2012 American College of Rheumatology Guidelines for management of gout. Part 2: therapy and antiinflammatory prophylaxis of acute gouty arthritis. Arthritis Care Res (Hoboken). 2012; 64:1447–1461.
Article
35. Azevedo VF, Kos IA, Vargas-Santos AB, da Rocha Castelar Pinheiro G, Dos Santos Paiva E. Benzbromarone in the treatment of gout. Adv Rheumatol. 2019; 59:37.
Article
36. Ye X, Wu J, Tang K, Li W, Xiong C, Zhuo L. Benzbromarone as a possible cause of acute kidney injury in patients with urolithiasis: two case reports. Medicine (Baltimore). 2019; 98:e15214.
37. Zhang MY, Niu JQ, Wen XY, Jin QL. Liver failure associated with benzbromarone: a case report and review of the literature. World J Clin Cases. 2019; 7:1717–1725.
Article
38. Sim DW, Yu JE, Jeong J, Jung JW, Kang HR, Kang DY, et al. Korean Severe Cutaneous Adverse Reactions Consortium. Variation of clinical manifestations according to culprit drugs in DRESS syndrome. Pharmacoepidemiol Drug Saf. 2019; 28:840–848.
Article
39. Grewal HK, Martinez JR, Espinoza LR. Febuxostat: drug review and update. Expert Opin Drug Metab Toxicol. 2014; 10:747–758.
Article
40. Becker MA, Schumacher HR Jr, Wortmann RL, MacDonald PA, Palo WA, Eustace D, et al. Febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase: a twenty-eight-day, multicenter, phase II, randomized, double-blind, placebo-controlled, dose-response clinical trial examining safety and efficacy in patients with gout. Arthritis Rheum. 2005; 52:916–923.
Article
41. Schumacher HR Jr, Becker MA, Wortmann RL, Macdonald PA, Hunt B, Streit J, et al. Effects of febuxostat versus allopurinol and placebo in reducing serum urate in subjects with hyperuricemia and gout: a 28-week, phase III, randomized, double-blind, parallel-group trial. Arthritis Rheum. 2008; 59:1540–1548.
Article
42. Becker MA, Schumacher HR Jr, Wortmann RL, MacDonald PA, Eustace D, Palo WA, et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med. 2005; 353:2450–2461.
Article
43. Becker MA, Schumacher HR, MacDonald PA, Lloyd E, Lademacher C. Clinical efficacy and safety of successful longterm urate lowering with febuxostat or allopurinol in subjects with gout. J Rheumatol. 2009; 36:1273–1282.
Article
44. Schumacher HR Jr, Becker MA, Lloyd E, MacDonald PA, Lademacher C. Febuxostat in the treatment of gout: 5-yr findings of the FOCUS efficacy and safety study. Rheumatology (Oxford). 2009; 48:188–194.
Article
45. White WB, Saag KG, Becker MA, Borer JS, Gorelick PB, Whelton A, et al. CARES Investigators. Cardiovascular safety of febuxostat or allopurinol in patients with gout. N Engl J Med. 2018; 378:1200–1210.
Article
46. White WB, Chohan S, Dabholkar A, Hunt B, Jackson R. Cardiovascular safety of febuxostat and allopurinol in patients with gout and cardiovascular comorbidities. Am Heart J. 2012; 164:14–20.
Article
47. Becker MA, Schumacher HR, Espinoza LR, Wells AF, MacDonald P, Lloyd E, et al. The urate-lowering efficacy and safety of febuxostat in the treatment of the hyperuricemia of gout: the CONFIRMS trial. Arthritis Res Ther. 2010; 12:R63.
Article
48. Katsiki N, Borghi C. The future of febuxostat after the Cardiovascular Safety of Febuxostat and Allopurinol in Patients with Gout and Cardiovascular Morbidities (CARES) trial: who cares? Expert Opin Pharmacother. 2018; 19:1853–1856.
Article
49. Johnson TA, Kamatani N, Kuwabara M. Xanthine oxidase inhibitor withdrawal syndrome? Comment on the article by Choi et al. Arthritis Rheumatol. 2019; 71:1966–1967.
Article
50. Ghang B, Ahn SM, Kim J, Kim YG, Lee CK, Yoo B. Discontinuing febuxostat might cause more deaths than continuing febuxostat: the untold story from the CARES trial. Rheumatology (Oxford). 2019; 11. 21. [Epub]. DOI: 10.1093/rheumatology/kez552.
Article
51. Su CY, Shen LJ, Hsieh SC, Lin LY, Lin FJ. Comparing cardiovascular safety of febuxostat and allopurinol in the real world: a population-based cohort study. Mayo Clin Proc. 2019; 94:1147–1157.
Article
52. Cuenca JA, Balda J, Palacio A, Young L, Pillinger MH, Tamariz L. Febuxostat and cardiovascular events: a systematic review and meta-analysis. Int J Rheumatol. 2019; 2019:1076189.
Article
53. Zhang M, Solomon DH, Desai RJ, Kang EH, Liu J, Neogi T, et al. Assessment of cardiovascular risk in older patients with gout initiating febuxostat versus allopurinol: population-based cohort study. Circulation. 2018; 138:1116–1126.
54. Ju C, Lai RWC, Li KHC, Hung JKF, Lai JCL, Ho J, et al. Comparative cardiovascular risk in users versus non-users of xanthine oxidase inhibitors and febuxostat versus allopurinol users. Rheumatology (Oxford). 2019; 12. 24. [Epub]. DOI: 10.1093/rheumatology/kez576.
Article
55. Kang EH, Choi HK, Shin A, Lee YJ, Lee EB, Song YW, et al. Comparative cardiovascular risk of allopurinol versus febuxostat in patients with gout: a nation-wide cohort study. Rheumatology (Oxford). 2019; 58:2122–2129.
Article
56. Kimura K, Hosoya T, Uchida S, Inaba M, Makino H, Maruyama S, et al. FEATHER Study Investigators. Febuxostat therapy for patients with stage 3 CKD and asymptomatic hyperuricemia: a randomized trial. Am J Kidney Dis. 2018; 72:798–810.
Article
57. Chen CH, Chen CB, Chang CJ, Lin YJ, Wang CW, Chi CC, et al. Hypersensitivity and cardiovascular risks related to allopurinol and febuxostat therapy in Asians: a population-based cohort study and meta-analysis. Clin Pharmacol Ther. 2019; 106:391–401.
Article
58. Foody J, Turpin RS, Tidwell BA, Lawrence D, Schulman KL. Major cardiovascular events in patients with gout and associated cardiovascular disease or heart failure and chronic kidney disease initiating a xanthine oxidase inhibitor. Am Health Drug Benefits. 2017; 10:393–401.
59. Kojima S, Matsui K, Hiramitsu S, Hisatome I, Waki M, Uchiyama K, et al. Febuxostat for cerebral and CaRdiorenovascular events PrEvEntion StuDy. Eur Heart J. 2019; 40:1778–1786.
Article
60. U.S. Food and Drug Administration. FDA adds boxed warning for increased risk of death with gout medicine uloric (febuxostat) [Internet]. Silver Spring (MD): U.S. Food and Drug Administration;c2017. cited 2020 Feb 18. Available from: https://www.fda.gov/DRugs/DrugSafety/ucm631182.htm.
61. Ministry of Food and Drug Safety. Safety information of febuxostat [Internet]. Cheongju: Ministry of Food and Drug Safety;c2019. cited 2020 Feb 18. Available from: https://nedrug.mfds.go.kr/pbp/CCBAC01/getItem?safeLetterNo=289.
62. American College of Rheumatology. 6W025 Gout management: new ACR Clinical Guideline [Internet]. Atlanta (GA): American College of Rheumatology;c2020. cited 2020 Feb 18. Available from: https://plan.core-apps.com/tristar_acr19/event/dd3623777338a651afd0e05cf7ba0b1b.
63. Hung SI, Chung WH, Liou LB, Chu CC, Lin M, Huang HP, et al. HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol. Proc Natl Acad Sci U S A. 2005; 102:4134–4139.
64. Kang HR, Jee YK, Kim YS, Lee CH, Jung JW, Kim SH, et al. Adverse Drug Reaction Research Group in Korea. Positive and negative associations of HLA class I alleles with allopurinol-induced SCARs in Koreans. Pharmacogenet Genomics. 2011; 21:303–307.
Article
65. Jung JW, Song WJ, Kim YS, Joo KW, Lee KW, Kim SH, et al. HLA-B58 can help the clinical decision on starting allopurinol in patients with chronic renal insufficiency. Nephrol Dial Transplant. 2011; 26:3567–3572.
Article
66. Liu CW, Chang WC, Lee CC, Shau WY, Hsu FS, Wang ML, et al. The net clinical benefits of febuxostat versus allopurinol in patients with gout or asymptomatic hyperuricemia - a systematic review and meta-analysis. Nutr Metab Cardiovasc Dis. 2019; 29:1011–1022.
Article
Full Text Links
  • JRD
Actions
Cited
CITED
export Copy
Close
Share
  • Twitter
  • Facebook
Similar articles
Copyright © 2024 by Korean Association of Medical Journal Editors. All rights reserved.     E-mail: koreamed@kamje.or.kr