Фебуксостат: эффективность и безопасность препарата, перспективы применения (обзор литературы)


DOI: https://dx.doi.org/10.18565/therapy.2024.5.162-171

Е.В. Щемелева, Е.А. Скородумова

ГБУ «Санкт-Петербургский научно-исследовательский институт им. И.И. Джанелидзе»
Аннотация. Распространенность гиперурикемии и подагры растет во всем мире, что приводит в том числе к увеличению затрат системы здравоохранения. Клиническая значимость подагры еще более существенна по причине ее тесной ассоциации с сердечно-сосудистыми и метаболическими заболеваниями. В связи с этим актуален поиск рациональных средств фармакотерапии подагры. В представленном обзоре литературы освещены основные клинические исследования ингибитора ксантиноксидазы фебуксостата с акцентом на вопросах кардиоваскулярной безопасности и нефропротекции. Сделан вывод об эффективности и безопасности препарата при лечении подагры, наличии у него наряду с уратснижающим действием других потенциально ценных фармакотерапевтических свойств. Фебуксостат является препаратом выбора у пациентов со сниженной функцией почек, при неэффективности или плохой переносимости аллопуринола. Выявленные у фебуксостата плейотропные эффекты открывают перспективы для его использования в различных областях медицины, что требует дальнейших исследований.
Ключевые слова: гипер­урикемия, уратснижающие препараты, кардиоваскулярная безопасность, фебуксостат, сердечно-сосудистые заболевания, подагра, аллопуринол, хроническая болезнь почек
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Литература

1. Dehlin M., Jacobsson L., Roddy E. Global epidemiology of gout: Prevalence, incidence, treatment patterns and risk factors. Nat Rev Rheumatol. 2020; 16(7): 380–90.


https://doi.org/10.1038/s41584-020-0441-1. PMID: 32541923.


2. Jin Z., Wang D., Zhang H. et al. Incidence trend of five common musculoskeletal disorders from 1990 to 2017 at the global, regional and national level: results from the global burden of disease study 2017. Ann Rheum Dis. 2020; 79(8): 1014–22.


https://doi.org/10.1136/annrheumdis-2020-217050. PMID: 32414807.


3. Rai S.K., Avina-Zubieta J.A., McCormick N. et al. Trends in gout and rheumatoid arthritis hospitalizations in Canada from 2000 to 2011. Arthritis Care Res (Hoboken). 2017; 69(5): 758–62.


https://doi.org/10.1002/acr.23012. PMID: 27565008. PMCID: PMC5326689.


4. Robinson P.C., Merriman T.R., Herbison P. et al. Hospital admissions associated with gout and their comorbidities in New Zealand and England 1999–2009. Rheumatology (Oxford). 2013; 52(1): 118–26.


https://doi.org/10.1093/rheumatology/kes253. PMID: 22989425.


5. Benavent D., Peiteado D., Martinez-Huedo M.A. et al. Healthcare-related impact of gout in hospitalized patients in Spain. Sci Rep. 2021; 11(1): 13287.


https://doi.org/10.1038/s41598-021-92673-3. PMID: 34168227. PMCID: PMC8225766.


6. Burnier M. Gout and hyperuricaemia: modifiable cardiovascular risk factors? Front Cardiovasc Med. 2023; 10: 1190069.


https://doi.org/10.3389/fcvm.2023.1190069. PMID: 37304945. PMCID: PMC10248051.


7. Chung W.H., Wang C.W., Dao R.L. Severe cutaneous adverse drug reactions. J Dermatol. 2016; 43(7): 758–66.


https://doi.org/10.1111/1346-8138.13430. PMID: 27154258.


8. Stamp L.K., Merriman T.R., Barclay M.L. et al. Impaired response or insufficient dosage? Examining the potential causes of “inadequate response” to allopurinol in the treatment of gout. Semin Arthritis Rheum. 2014; 44(2): 170–74.


https://doi.org/10.1016/j.semarthrit.2014.05.007. PMID: 24925693. PMCID: PMC4225179.


9. Ильиных Е.В., Владимиров С.А., Елисеев М.С. Фебуксостат в терапии подагры: от теории к практике. Современная ревматология. 2017; 11(4): 83–88. (Ilyinykh E.V., Vladimirov S.A., Eliseev M.S. Febuxostat in gout therapy: from theory to practice. Sovremennaya revmatologiya = Modern Rheumatology Journal. 2017; 11(4): 83–88 (In Russ.)).


https://doi.org/10.14412/1996-7012-2017-4-83-88. EDN: ZXYAHF.


10. Love B.L., Barrons R., Veverka A., Snider K.M. Urate-lowering therapy for gout: Focus on febuxostat. Pharmacotherapy. 2010; 30(6): 594–608.


https://doi.org/10.1592/phco.30.6.594. PMID: 20500048.


11. European Medicines Agency. Adenuric: EPAR – Product Information. URL: https://www.ema.europa.eu/en/documents/product-information/adenuric-epar-product-information_en.pdf (date of access – 20.06.2024).


12. Li S., Yang H., Guo Y. et al. Comparative efficacy and safety of urate-lowering therapy for the treatment of hyperuricemia: A systematic review and network meta-analysis. Sci Rep. 2016; 6: 33082.


https://doi.org/10.1038/srep33082. PMID: 27605442. PMCID: PMC5015109.


13. Xie H., Hu N., Pan T. et al. Effectiveness and safety of different doses of febuxostat compared with allopurinol in the treatment of hyperuricemia: A meta-analysis of randomized controlled trials. BMC Pharmacol Toxicol. 2023; 24(1): 79.


https://doi.org/10.1186/s40360-023-00723-5. PMID: 38098046. PMCID: PMC10722766.


14. Liu C.W., Chang W.C., Lee C.C. 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(10): 1011–22.


https://doi.org/10.1016/j.numecd.2019.06.016. PMID: 31378626.


15. Чикина М.Н., Желябина О.В., Елисеев М.С. Влияние уратснижающей терапии на показатели качества жизни у пациентов с подагрой. Современная ревматология. 2021; 15(3): 62–68. (Chikina M.N., Zhelyabina O.V., Eliseev M.S. The effect of urate-reducing therapy on quality of life in patients with gout. Sovremennaya revmatologiya = Modern Rheumatology Journal. 2021; 15(3): 62–68 (In Russ)).


https://doi.org/10.14412/1996-7012-2021-3-62-68. EDN: MJPIEB.


16. Shibagaki Y., Ohno I., Hosoya T. et al. Efficacy and renal effect of febuxostat in patients with moderate-to-severe kidney dysfunction. Hypertens Res. 2014; 37(10): 919–25.


https://doi.org/10.1038/hr.2014.107. PMID: 24942770.


17. Hira D., Chisaki Y., Noda S. et al. Population pharmacokinetics and therapeutic efficacy of febuxostat in patients with severe renal impairment. Pharmacology. 2015; 96(1–2): 90–98.


https://doi.org/10.1159/000434633. PMID: 26183164.


18. Елисеев М.С., Желябина О.В., Чикина М.Н., Тхакоков М.М. Эффективность фебуксостата у пациентов с подагрой в зависимости от функции почек. РМЖ. Медицинское обозрение. 2022; 6(3): 140–147. (Eliseev M.S., Zhelyabina O.V., Chikina M.N., Tkhakokov M.M. Effectiveness of febuxostat in patients with gout depending on renal function. breast cancer. Russkiy meditsinskiy zhurnal. Meditsinskoye obozreniye = Russian Medical Journal. Medical Review. 2022; 6(3):140–147 (In Russ.)).


https://doi.org/10.32364/2587-6821-2022-6-3-140-147. EDN: CMIOLK.


19. Choi H.K., Curhan G. Independent impact of gout on mortality and risk for coronary heart disease. Circulation. 2007; 116(8): 894–900.


https://doi.org/10.1161/circulationaha.107.703389. PMID: 17698728.


20. Krishnan E., Baker J.F., Furst D.E. et al. Gout and the risk of acute myocardial infarction. Arthritis Rheum. 2006; 54(8): 2688–96.


https://doi.org/10.1002/art.22014. PMID: 16871533.


21. Seminog O.O., Goldacre M.J. Gout as a risk factor for myocardial infarction and stroke in England: Evidence from record linkage studies. Rheumatology (Oxford). 2013; 52(12): 2251–59.


https://doi.org/10.1093/rheumatology/ket293. PMID: 24046469.


22. Clarson L.E., Hider S.L., Belcher J. et al. Increased risk of vascular disease associated with gout: a retrospective, matched cohort study in the UK clinical practice research datalink. Ann Rheum Dis. 2015; 74(4): 642–47.


https://doi.org/10.1136/annrheumdis-2014-205252. PMID: 25165032. PMCID: PMC4392302.


23. White W.B., Saag K.G., Becker M.A. et al. Cardiovascular safety of febuxostat or allopurinol in patients with gout. N Engl J Med. 2018; 378(13): 1200−10.


https://doi.org/10.1056/nejmoa1710895. PMID: 29527974.


24. Food and Drug Administration. FDA adds Boxed Warning for increased risk of death with gout medicine Uloric (febuxostat). URL: https://www.fda.gov/drugs/drug-safety-and-availability/fda-adds-boxed-warning-increased-risk-death-gout-medicine-uloric-febuxostat (date of access – 20.05.2024).


25. Mackenzie I.S., Ford I., Nuki G. et al. Long-term cardiovascular safety of febuxostat compared with allopurinol in patients with gout (FAST): A multicentre, prospective, randomised, open-label, non-inferiority trial. Lancet. 2020; 396(10264): 1745–57.


https://doi.org/10.1016/S0140-6736(20)32234-0. PMID: 33181081.


26. Bai Y., Wu B., Gou L. et al. Cardiovascular safety evaluation of febuxostat and allopurinol: Findings from the FDA Adverse Event Reporting System. J Clin Med. 2023; 12(18): 6089.


https://doi.org/10.3390/jcm12186089. PMID: 37763029. PMCID: PMC10531992.


27. Xie H., Hu N., Pan T. et al. Effectiveness and safety of different doses of febuxostat compared with allopurinol in the treatment of hyperuricemia: A meta-analysis of randomized controlled trials. BMC Pharmacol Toxicol. 2023; 24(1): 79.


https://doi.org/10.1186/s40360-023-00723-5. PMID: 38098046. PMCID: PMC10722766.


28. Desideri G., Rajzer M., Gerritsen M. et al. Effects of intensive urate lowering therapy with febuxostat in comparison with allopurinol on pulse wave velocity in patients with gout and increased cardiovascular risk: The FORWARD study. Eur Heart J Cardiovasc Pharmacother. 2022; 8(3): 236–42.


https://doi.org/10.1093/ehjcvp/pvaa144. PMID: 33410912.


29. Deng J.H., Zhong G.W., Zhang J.X. Is febuxostat associated with higher risk of cardiovascular death than allopurinol in treating gout or asymptomatic hyperuricemia? Ann Palliat Med. 2022; 11(8): 2789–91.


https://doi.org/10.21037/apm-22-618. PMID: 35948476.


30. Ju C., Lai R.W.C., Li K.H.C. et al. Comparative cardiovascular risk in users versus non-users of xanthine oxidase inhibitors and febuxostat versus allopurinol users. Rheumatology. 2020; 59(9): 2340–49.


https://doi.org/10.1093/rheumatology/kez576. PMID: 31873735.


31. Chen C.H., Chen C.B., Chang C.J. 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(2): 391–401.


https://doi.org/10.1002/cpt.1377. PMID: 30690722.


32. Pawar A., Desai R.J., Liu J. et al. Updated assessment of cardiovascular risk in older patients with gout initiating febuxostat versus allopurinol. J Am Heart Assoc. 2021; 10(7): e020045.


https://doi.org/10.1161/JAHA.120.020045. PMID: 33764153. PMCID: PMC8174329.


33. Guan X., Zhang S., Liu J. et al. Cardiovascular safety of febuxostat and allopurinol in patients with gout: A meta-analysis. Front Pharmacol. 2022; 13: 998441.


https://doi.org/10.3389/fphar.2022.998441. PMID: 36249825. PMCID: PMC9563376.


34. Jeong H., Choi E., Suh A. et al. Risk of cardiovascular disease associated with febuxostat versus allopurinol use in patients with gout: A retrospective cohort study in Korea. Rheumatol Int. 2023; 43(2): 265–81.


https://doi.org/10.1007/s00296-022-05222-0. PMID: 36346443. PMCID: PMC9898368.


35. Shin A., Choi S.R., Han M. et al. Cardiovascular safety associated with febuxostat versus allopurinol among patients with gout: Update with accumulated use of febuxostat. Semin Arthritis Rheum. 2022; 56: 152080.


https://doi.org/10.1016/j.semarthrit.2022.152080. PMID: 35973263.


36. Sawada S., Kajiyama K., Shida H. et al. Cardiovascular risk of urate-lowering drugs: A study using the National Database of Health Insurance Claims and Specific Health Checkups of Japan. Clin Transl Sci. 2023; 16(2): 206–15.


https://doi.org/10.1111/cts.13439. PMID: 36317407. PMCID: PMC9926079.


37. Gao L., Wang B., Pan Y. et al. Cardiovascular safety of febuxostat compared to allopurinol for the treatment of gout: A systematic and meta-analysis. Clin Cardiol. 2021; 44(7): 907–16.


https://doi.org/10.1002/clc.23643. PMID: 34013998. PMCID: PMC8259158.


38. Konishi M., Kojima S., Uchiyama K. et al. Febuxostat for Cerebral and Cardiorenovascular Events Prevention Study (FREED) investigators. Effect of febuxostat on clinical outcomes in patients with hyperuricemia and cardiovascular disease. Int J Cardiol. 2022; 349: 127–33.


https://doi.org/10.1016/j.ijcard.2021.11.076. PMID: 34864084.


39. Sánchez-Lozada L.G., Soto V., Tapia E. et al. Role of oxidative stress in the renal abnormalities induced by experimental hyperuricemia. Am J Physiol Renal Physiol. 2008; 295(4): F1134–41.


https://doi.org/10.1152/ajprenal.00104.2008. PMID: 18701632. PMCID: PMC2576157.


40. Choi Y.J., Yoon Y., Lee K.Y. et al. Uric acid induces endothelial dysfunction by vascular insulin resistance associated with the impairment of nitric oxide synthesis. FASEB J. 2014; 28(7): 3197–204.


https://doi.org/10.1096/fj.13-247148. PMID: 24652948.


41. Мазуров В.И., Сайганов С.А., Мартынов А.И. с соавт. Влияние уратснижающей терапии на течение хронической болезни почек у пациентов с бессимптомной гиперурикемией: метаанализ рандомизированных контролируемых исследований. Вестник Северо-Западного государственного медицинского университета им. И.И. Мечникова. 2024; 15(4): 5–18. (Mazurov V.I., Sayganov S.A., Martynov A.I. et al. Impact of urate-lowering therapy on the course of chronic kidney disease in patients with asymptomatic hyperuricemia: a meta-analysis of randomized controlled trials. Vestnik Severo-Zapadnogo gosudarstvennogo medicinskogo universiteta im. I.I. Mechnikova = Herald of North-Western State Medical University named after I.I. Mechnikov. 2024; 15(4): 5–18 (In Russ.)).


https://doi.org/10.17816/mechnikov604850. EDN: ESRPKU.


42. Chewcharat A., Chen Y., Thongprayoon C. et al. Febuxostat as a renoprotective agent for treatment of hyperuricaemia: A meta-analysis of randomised controlled trials. Intern Med J. 2021; 51(5): 752–62.


https://doi.org/10.1111/imj.14814. PMID: 32149437.


43. Kohagura K., Kojima S., Uchiyama K. et al. Febuxostat and renal outcomes: Post-hoc analysis of a randomized trial. Hypertens Res. 2023; 46(6): 1417–22.


https://doi.org/10.1038/s41440-023-01198-x. PMID: 36750608.


44. Kimura K., Hosoya T., Uchida S. et al. Febuxostat therapy for patients with stage 3 CKD and asymptomatic hyperuricemia: A randomized trial. Am J Kidney Dis. 2018; 72(6): 798–810.


https://doi.org/10.1053/j.ajkd.2018.06.028. PMID: 30177485.


45. Nagaraju S.P., Shenoy S.V., Rao I. et al. Effect of febuxostat versus allopurinol on the glomerular filtration rate and hyperuricemia in patients with chronic kidney disease. Saudi J Kidney Dis Transpl. 2023; 34(4): 279–87.


https://doi.org/10.4103/1319-2442.395443. PMID: 38345582.


46. Yang H., Li R., Li Q. et al. Effects of febuxostat on delaying chronic kidney disease progression: A randomized trial in China. Int Urol Nephrol. 2023; 55(5): 1343–52.


https://doi.org/10.1007/s11255-022-03437-5. PMID: 36534221.


47. Tsukamoto S., Okami N., Yamada T. et al. Prevention of kidney function decline using uric acid-lowering therapy in chronic kidney disease patients: A systematic review and network meta-analysis. Clin Rheumatol. 2022; 41(3): 911–19.


https://doi.org/10.1007/s10067-021-05956-5. PMID: 34642880.


48. Lin T.C., Hung L.Y., Chen Y.C. et al. Effects of febuxostat on renal function in patients with chronic kidney disease: A systematic review and meta-analysis. Medicine (Baltimore). 2019; 98(29): e16311.


https://doi.org/10.1097/md.0000000000016311. PMID: 31335677. PMCID: PMC6709169.


49. Chung T.T., Yu K.H., Kuo C.F. et al. Impact of urate-lowering drugs on the progression and recovery from chronic kidney disease among gout patients. Arthritis Res Ther. 2019; 21(1): 210.


https://doi.org/10.1186/s13075-019-1993-9. PMID: 31533805. PMCID: PMC6751683.


50. Jeong H.J., Park W.Y., Kim S.H. et al. Urate-lowering efficacy and renal safety of febuxostat in patients with hyperuricemia and stage 4–5 chronic kidney disease not yet on dialysis: A meta-analysis of observational studies. Semin Arthritis Rheum. 2022; 56: 152073.


https://doi.org/10.1016/j.semarthrit.2022.152073. PMID: 35914389.


51. Hsu Y.O., Wu I.W., Chang S.H. et al. Comparative renoprotective effect of febuxostat and allopurinol in predialysis stage 5 chronic kidney disease patients: A nationwide database analysis. Clin Pharmacol Ther. 2020; 107(5): 1159–69.


https://doi.org/10.1002/cpt.1697. PMID: 31628864. PMCID: PMC7232862.


52. Choi S.Y., Choi S.W., Lee S. et al. Efficacy and tolerability of febuxostat in gout patients on dialysis. Intern Med J. 2021; 51(3): 348–54.


https://doi.org/10.1111/imj.14776. PMID: 32043690.


53. Kang S.H., Kim B.Y., Son E.J. et al. Comparison between the effects of allopurinol and febuxostat on the survival of patients on maintenance hemodialysis. Am J Nephrol. 2023; 54(3–4): 117–25.


https://doi.org/10.1159/000530972. PMID: 37231773. PMCID: PMC10308552.


54. Sarhan I.I., Abdellatif Y.A., Saad R.E., Teama N.M. Renoprotective effect of febuxostat on contrast-induced acute kidney injury in chronic kidney disease patients stage 3: Randomized controlled trial. BMC Nephrol. 2023; 24(1): 65.


https://doi.org/10.1186/s12882-023-03114-4. PMID: 36949408. PMCID: PMC10035112.


55. Kakimoto M., Fujii M., Sato I. et al. Antioxidant action of xanthine oxidase inhibitor febuxostat protects the liver and blood vasculature in SHRSP5/Dmcr rats. J Appl Biomed. 2023; 21(2): 80–90.


https://doi.org/10.32725/jab.2023.009. PMID: 37376883.


56. Tian J., Zhang S., Li L. et al. Febuxostat ameliorates APAP-induced acute liver injury by activating Keap1/Nrf2 and inhibiting TLR4/NF-κB p65 pathways. Exp Biol Med (Maywood). 2023; 248(20): 1864–76.


https://doi.org/10.1177/15353702231211862. PMID: 38031247. PMCID: PMC10792428.


57. Raeispour M., Talebpour Amiri F., Farzipour S. et al. Febuxostat, an inhibitor of xanthine oxidase, ameliorates ionizing radiation-induced lung injury by suppressing caspase-3, oxidative stress and NF-κB. Drug Chem Toxicol. 2022; 45(6): 2586–93. https://doi.org/10.1080/01480545.2021.1977315. PMID: 34538151.


58. Tsukamoto T., Tsujii M., Odake K. et al. Febuxostat reduces muscle wasting in tumor-bearing mice with LM8 osteosarcoma cells via inhibition of reactive oxygen species generation. Free Radic Res. 2021; 55(7): 810–20.


https://doi.org/10.1080/10715762.2021.1947502. PMID: 34278932.


59. Zhang C., Tang L., Zhang Y. et al. Febuxostat, a xanthine oxidase inhibitor, regulated long noncoding RNAs and protected the brain after intracerebral hemorrhage. Neuroreport. 2023; 34(14): 703–12.


https://doi.org/10.1097/WNR.0000000000001945. PMID: 37556585.


60. Higa Y., Hiasa M., Tenshin H. et al. The xanthine oxidase inhibitor febuxostat suppresses adipogenesis and activates Nrf2. Antioxidants (Basel). 2023; 12(1): 133.


https://doi.org/10.3390/antiox12010133. PMID: 36670994. PMCID: PMC9854541.


61. Johnson R.J., Andrews P., Benner S.A., Oliver W. Theodore E. Woodward award. The evolution of obesity: Insights from the mid-Miocene. Trans Am Clin Climatol Assoc. 2010; 121: 295–305. PMID: 20697570. PMCID: PMC2917125.


62. Johnson R.J., Stenvinkel P., Andrews P. et al. Fructose metabolism as a common evolutionary pathway of survival associated with climate change, food shortage and droughts. J Intern Med. 2020; 287(3): 252–62.


https://doi.org/10.1111/joim.12993. PMID: 31621967. PMCID: PMC10917390.


63. Елисеев М.С., Желябина О.В. Уратснижающая терапия и риск развития сахарного диабета 2-го типа у пациентов с подагрой (результаты перспективного исследования). Современная ревматология. 2023; 17(5): 73–78. (Eliseev M.S., Zhelyabina O.V. Urate-lowering therapy and the risk of developing type 2 diabetes mellitus in patients with gout (results of a prospective study). Sovremennaya revmatologiya = Modern Rheumatology Journal. 2023; 17(5): 73–78 (In Russ.)).


https://doi.org/10.14412/1996-7012-2023-5-73-78. EDN: DNZICE.


Об авторах / Для корреспонденции

Елена Владимировна Щемелева, к. м. н., научный сотрудник отдела неотложной кардиологии и ревматологии ГБУ «Санкт-Петербургский научно-исследовательский институт скорой помощи им. И.И. Джанелидзе». Адрес: 192242, г. Санкт-Петербург, ул. Будапештская, д. 3.
E-mail: schemeleva@yandex.ru
ORCID: https://orcid.org/0000-0003-3566-6761
Елена Андреевна Скородумова, д. м. н., ведущий научный сотрудник отдела неотложной кардиологии и ревматологии ГБУ «Санкт-Петербургский научно-исследовательский институт скорой помощи им. И.И. Джанелидзе». Адрес: 192242, г. Санкт-Петербург, ул. Будапештская, д. 3.
E-mail: elskor@mail.ru
ORCID: https://orcid.org/0000-0002-5017-0214


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