Skip to main content
Log in

The Effects of Pharmacological Urate-Lowering Therapy on Cardiovascular Disease in Older Adults with Gout

  • Review Article
  • Published:
Drugs & Aging Aims and scope Submit manuscript

Abstract

Cardiovascular disease is an important cause of mortality in older patients. In addition to the traditional risk factors for cardiovascular disease, hyperuricemia has been increasingly associated with an elevated risk of cardiovascular disease. Uric acid itself has several unfavorable effects on the cardiovascular system, and hyperuricemia can lead to the development of gout. Gout is the most prevalent inflammatory rheumatic disease. Older patients with gout have an increased risk of cardiovascular morbidity and mortality due to an increased prevalence of traditional risk factors, as well as the inflammatory burden of gout activity. As the prevalence of traditional risk factors and the prevalence of both hyperuricemia and gout are increasing in older adults, cardiovascular risk management in these patients is very important. This risk management consists of, on the one hand, treatment of individual traditional risk factors and, on the other hand, of urate lowering, thereby decreasing inflammatory burden of gout. However, there is insufficient evidence to conclude that urate-lowering therapy reduces the risk of cardiovascular events. Moreover, from a cardiovascular point of view, there is no preference for one urate lowering drug over another in patients with gout, nor is there enough evidence to support a preference in patients with gout with increased cardiovascular risk. Personalized treatment in older patients with gout should be aimed at optimizing serum uric acid levels, as well as targeting traditional cardiovascular risk factors. Further prospective randomized trials are needed to support the hypothesis that urate lowering reduces cardiovascular risk in older patients with gout.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Robinson JG, Bakris G, Torner J, Stone NJ, Wallace R. Is it time for a cardiovascular primary prevention trial in the elderly? Stroke. 2007;38:441–50.

    Article  PubMed  Google Scholar 

  2. Van Bussel EF, Hoevenaar-Blom MP, Poortvliet RKE, Gussekloo J, van Dalen JW, van Gool WA, et al. Predictive value of traditional risk factors for cardiovascular disease in older people: a systematic review. Prev Med. 2020;132: 105986. https://doi.org/10.1016/j.ypmed.2020.105986. (Epub 2020 Jan 17).

    Article  PubMed  Google Scholar 

  3. Saito Y, Tanaka A, Node K, Kobayashi YJ. Uric acid and cardiovascular disease: a clinical review. Cardiology. 2021;78(1):51–7. https://doi.org/10.1016/j.jjcc.2020.12.013. (Epub 2020 Dec 30).

    Article  Google Scholar 

  4. Ndrepepa G. Uric acid and cardiovascular disease. Clin Chim Acta. 2018;484:150–63.

    Article  CAS  PubMed  Google Scholar 

  5. Hansildaar R, Vedder D, Baniaamam M, Tausche AK, Gerritsen M, Nurmohamed MT. Cardiovascular risk in inflammatory arthritis and gout. Lancet Rheumatol. 2021;3(1):e58–70.

    Article  CAS  PubMed  Google Scholar 

  6. 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.

    Article  PubMed  Google Scholar 

  7. Li X, Meng X, He Y, Spiliopoulou A, Timofeeva M, Wei WQ, et al. Genetically determined serum urate levels and cardiovascular and other diseases in UK Biobank cohort: a phenome-wide mendelian randomization study. PLoS Med. 2019;16(10): e1002937. https://doi.org/10.1371/journal.pmed.1002937.eCollection2019Oct.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Drosos GC, Vedder D, Houben E, Boekel L, Atzeni F, Badreh S, et al. EULAR recommendations for cardiovascular risk management in rheumatic and musculoskeletal diseases, including systemic lupus erythematosus and antiphospholipid syndrome. Ann Rheum Dis. 2022;81(6):768–79.

    Article  CAS  PubMed  Google Scholar 

  9. Marotta T, Liccardo M, Schettini F, Verde F, Ferrara AL. Association of hyperuricemia with conventional cardiovascular risk factors in elderly patients. J Clin Hypertens (Greenwich). 2015;17(1):27–32.

    Article  CAS  PubMed  Google Scholar 

  10. Huang G, Xu JB, Zhang TJ, Nie XL, Li Q, Liu Y, et al. Hyperuricemia is associated with cardiovascular diseases clustering among very elderly women—a community based study in Chengdu, China. Sci Rep. 2017;7(1):996.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Wu X, Jian G, Tang Y, Cheng H, Wang N, Wu J. Asymptomatic hyperuricemia and incident congestive heart failure in elderly patients without comorbidities. Nutr Metab Cardiovasc Dis. 2020;30(4):666–73.

    Article  CAS  PubMed  Google Scholar 

  12. Wu J, Lei G, Wang X, Tang Y, Cheng H, Jian G, et al. Asymptomatic hyperuricemia and coronary artery disease in elderly patients without comorbidities. Oncotarget. 2017;8(46):80688–99.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Tu W, Wu J, Jian G, Lori J, Tang Y, Cheng H, et al. Asymptomatic hyperuricemia and incident stroke in elderly Chinese patients without comorbidities. Eur J Clin Nutr. 2019;73(10):1392–402.

    Article  CAS  PubMed  Google Scholar 

  14. Upadhya B, Kitzman DW. Heart failure with preserved ejection fraction in older adult. Heart Fail Clin. 2017;13(3):485–502.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Otaki Y, Watanabe T, Kinoshita D, Yokoyama M, Takahashi T, Toshima T, et al. Association of plasma xanthine oxidoreductase activity with severity and clinical outcome in patients with chronic heart failure. Int J Cardiol. 2017;228:151–7.

    Article  PubMed  Google Scholar 

  16. Ambrosio G, Crespo Leiro MG, Lund LH, Coiro S, Cardona A, Filippatos G, et al. Serum uric acid and outcomes in patients with chronic heart failure through the whole spectrum of ejection fraction phenotypes: analysis of the ESC-EORP Heart Failure Long-Term (HF LT) Registry. Eur J Intern Med. 2021;89:65–75.

    Article  CAS  PubMed  Google Scholar 

  17. Coiro S, Carluccio E, Biagioli P, Alunni G, Murrone A, D’Antonio A, et al. Elevated serum uric acid concentration at discharge confers additive prognostic value in elderly patients with acute heart failure. Nutr Metab Cardiovasc Dis. 2018;28(4):361–8.

    Article  CAS  PubMed  Google Scholar 

  18. Dalbeth N, Gosling AL, Gaffo A, Abhishek A. Gout. Lancet. 2021;397(10287):1843–55.

    Article  CAS  PubMed  Google Scholar 

  19. Richette P, Bardin T. Gout. Lancet. 2010;375(9711):318–28.

    Article  CAS  PubMed  Google Scholar 

  20. Scheepers LEJ, Boonen A, Dagnelie PC, Schram MT, van der Kallen CJH, Henry RMA, et al. Uric acid and blood pressure: exploring the role of uric acid production in the Maastricht study. J Hypertens. 2017;35(10):1968–75.

    Article  CAS  PubMed  Google Scholar 

  21. Dalbeth N, Stamp L. Hyperuricaemia and gout: time for a new staging system? Ann Rheum Dis. 2014;73(9):1598–600.

    Article  PubMed  Google Scholar 

  22. Kuo CF, Grainge MJ, Zhang W, Doherty M. Global epidemiology of gout: prevalence, incidence and risk factors. Nat Rev Rheumatol. 2015;11(11):649–62.

    Article  PubMed  Google Scholar 

  23. Stamp LK, Chapman PT. Urate-lowering therapy: current options and future prospects for elderly patients with gout. Drugs Aging. 2014;31(11):777–86.

    Article  CAS  PubMed  Google Scholar 

  24. Disveld IJM, Fransen J, Rongen GA, Kienhorst LBE, Zoakman S, Janssens HJEM, et al. crystal-proven gout and characteristic gout severity factors are associated with cardiovascular disease. Rheumatology. 2018;45(6):858–63.

    CAS  Google Scholar 

  25. Chowalloor P, Raymond WD, Cheah P, Keen H. The burden of subclinical intra-articular inflammation in gout. Int J Rheum Dis. 2020;23(5):661–8.

    Article  CAS  PubMed  Google Scholar 

  26. Mason JC, Libby P. Cardiovascular disease in patients with chronic inflammation: mechanisms underlying premature cardiovascular events in rheumatologic conditions. Eur Heart J. 2015;36(8):482–9.

    Article  PubMed  Google Scholar 

  27. 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(1):210–7.

    Article  PubMed  Google Scholar 

  28. Bardin T, Richette P. Impact of comorbidities on gout and hyperuricaemia: an update on prevalence and treatment options. BMC Med. 2017;15(1):123.

    Article  PubMed  PubMed Central  Google Scholar 

  29. 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(1):31–8.

    Article  PubMed  Google Scholar 

  30. FitzGerald JD, Dalbeth N, Mikuls T, Brignardello-Petersen R, Guyatt G, Abeles AM, et al. 2020 American College of Rheumatology guideline for the management of gout. Arthritis Rheumatol. 2020;72(6):879–95.

    Article  PubMed  Google Scholar 

  31. Bredemeier M, Lopes LM, Eisenreich MA, Hickmann S, Bongiorno GK, d’ Avila R, et al. Xanthine oxidase inhibitors for prevention of cardiovascular events: a systematic review and meta-analysis of randomized controlled trials. BMC Cardiovasc Disord. 2018;18(1):24.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Sapankaew T, Thadanipon K, Ruenroengbun N, Chaiyakittisopon K, Ingsathit A, Numthavaj P, et al. Efficacy and safety of urate-lowering agents in asymptomatic hyperuricemia: systematic review and network meta-analysis of randomized controlled trials. BMC Nephrol. 2022;23(1):223.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Mackenzie IS, Hawkey CJ, Ford I, Greenlaw N, Pigazzani F, Rogers A, et al. ALL-HEART Study Group. Allopurinol versus usual care in UK patients with ischaemic heart disease (ALL-HEART): a multicentre, prospective, randomised, open-label, blinded-endpoint trial. Lancet. 2022;400(10359):1195–205.

    Article  CAS  PubMed  Google Scholar 

  34. Huang WS, Lin CL, Tsai CH, Chang KH. Association of gout with CAD and effect of antigout therapy on CVD risk among gout patients. J Investig Med. 2020;68(5):972–9.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Chen JH, Lan JL, Cheng CF, Liang WM, Lin HY, Tsay GJ, et al. Effect of urate-lowering therapy on the risk of cardiovascular disease and all-cause mortality in patients with gout: a case-matched cohort study. J Rheumatol. 2015;42(9):1694–701.

    Article  CAS  PubMed  Google Scholar 

  36. Lin HC, Daimon M, Wang CH, Ho Y, Uang YS, Chiang SJ, et al. Allopurinol, benzbromarone and risk of coronary heart disease in gout patients: a population-based study. Int J Cardiol. 2017;15(233):85–90.

    Article  Google Scholar 

  37. Joo K, Kwon SR, Lim MJ, Jung KH, Joo H, Park W. Prevention of comorbidity and acute attack of gout by uric acid lowering therapy. J Korean Med Sci. 2014;29(5):657–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Pérez Ruiz F, Richette P, Stack AG, Karra Gurunath R, García de Yébenes MJ, Carmona L. Failure to reach uric acid target of < 0.36 mmol/L in hyperuricaemia of gout is associated with elevated total and cardiovascular mortality. RMD Open. 2019;5(2):e001015.

    Article  PubMed  PubMed Central  Google Scholar 

  39. 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. 2019;58(12):2122–9.

    Article  CAS  PubMed  Google Scholar 

  40. White WB, Saag KG, Becker MA, Borer JS, Gorelick PB, Whelton A, CARES Investigators, et al. Cardiovascular safety of febuxostat or allopurinol in patients with gout. N Engl J Med. 2018;378(13):1200–10.

    Article  CAS  PubMed  Google Scholar 

  41. 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(11):1116–26.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Mackenzie IS, Ford I, Nuki G, Hallas J, Hawkey CJ, Webster J, et al. FAST Study Group. 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.

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  44. Wang M, Zhang Y, Zhang M, Li H, Wen C, Zhao T, et al. The major cardiovascular events of febuxostat versus allopurinol in treating gout or asymptomatic hyperuricemia: a systematic review and meta-analysis. Ann Palliat Med. 2021;10(10):10327–37.

    Article  PubMed  Google Scholar 

  45. Guan X, Zhang S, Liu J, Wu F, Zhou L, Liu Y, et al. Cardiovascular safety of febuxostat and allopurinol in patients with gout: a meta-analysis. Front Pharmacol. 2022;30(13): 998441.

    Article  Google Scholar 

  46. Saag KG, Becker MA, White WB, Whelton A, Borer JS, Gorelick PB, CARES Investigators, et al. Evaluation of the relationship between serum urate levels, clinical manifestations of gout, and death from cardiovascular causes in patients receiving febuxostat or allopurinol in an outcomes trial. Arthritis Rheumatol. 2022;74(9):1593–601.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Kim SC, Neogi T, Kang EH, Liu J, Desai RJ, Zhang M, et al. cardiovascular risks of probenecid versus allopurinol in older patients with gout. J Am Coll Cardiol. 2018;71(9):994–1004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Uhlig T, Karoliussen LF, Sexton J, Borgen T, Haavardsholm EA, Kvien TK, et al. 12-month results from the real-life observational treat-to-target and tight-control therapy NOR-Gout study: achievements of the urate target levels and predictors of obtaining this target. RMD Open. 2021;7(1): e001628.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Yin R, Li L, Cui Z, Zhang Q, Fu T, Cao H, et al. Rate of adherence to urate-lowering therapy among patients with gout: a systematic review and meta-analysis. BMJ Open. 2018;8(4):e017542.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Ninčević V, Omanović Kolarić T, Roguljić H, Kizivat T, Smolić M, Bilić ĆI. Renal benefits of SGLT 2 inhibitors and GLP-1 receptor agonists: evidence supporting a paradigm shift in the medical management of type 2 diabetes. Int J Mol Sci. 2019;20(23):5831.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Banerjee M, Pal R, Mukhopadhyay S. Can SGLT2 inhibitors prevent incident gout? A systematic review and meta-analysis. Acta Diabetol. 2022;59(6):783–91.

    Article  CAS  PubMed  Google Scholar 

  52. Verma S, McMurray JJV. SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review. Diabetologia. 2018;61(10):2108–17.

    Article  CAS  PubMed  Google Scholar 

  53. Butt JH, Docherty KF, Claggett BL, Desai AS, Petersson M, Langkilde AM, et al. Association of dapagliflozin use with clinical outcomes and the introduction of uric acid-lowering therapy and colchicine in patients with heart failure with and without gout: a patient-level pooled meta-analysis of DAPA-HF and DELIVER. JAMA Cardiol. 2023;8(4):386–93.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Janssens HJ, Arts PG, Schalk BW, Biermans MC. Gout and rheumatoid arthritis, both to keep in mind in cardiovascular risk management: a primary care retrospective cohort study. Jt Bone Spine. 2017;84(1):59–64.

    Article  Google Scholar 

  55. Vedder D, Heslinga M, Wijbrandts CA, Nurmohamed MT, Gerritsen M. Cardiovascular risk management in gout patients: do patients benefit from screening in secondary care? Clin Exp Rheumatol. 2023. https://doi.org/10.55563/clinexprheumatol/38fbvd. (Online ahead of print).

    Article  PubMed  Google Scholar 

  56. van Dis I, Kromhout D, Geleijnse JM, Boer JM, Verschuren WM. Evaluation of cardiovascular risk predicted by different SCORE equations: the Netherlands as an example. Eur J Cardiovasc Prev Rehabil. 2010;17(2):244–9.

    Article  PubMed  Google Scholar 

  57. Ahmadi SF, Streja E, Zahmatkesh G, Streja D, Kashyap M, Moradi H, et al. reverse epidemiology of traditional cardiovascular risk factors in the geriatric population. J Am Med Dir Assoc. 2015;16(11):933–9.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Williamson JD, Supiano MA, Applegate WB, Berlowitz DR, Campbell RC, Chertow GM, et al. Intensive vs standard blood pressure control and cardiovascular disease outcomes in adults aged ≥75 years: a randomized clinical trial. JAMA. 2016;315:2673–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Gencer B, Marston NA, Im K, Cannon CP, Sever P, Keech A, et al. Efficacy and safety of lowering LDL cholesterol in older patients: a systematic review and meta-analysis of randomised controlled trials. Lancet. 2020;396(10263):1637–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Aimo A, Pascual Figal DA, Bayes-Genis A, Emdin M, Georgiopoulos G. Effect of low dose colchicine in acute and chronic coronary syndromes: a systematic review and meta-analysis. Eur J Clin Investig. 2021;51(4): e13464.

    Article  CAS  Google Scholar 

  61. Ridker PM, Everett BM, Thuren T, MacFayden JG, Chang WH, Ballantyne C, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. NEJM. 2017;377:1119–31.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Martijn Gerritsen.

Ethics declarations

Funding

The authors certify that no funding has been received in the preparation of this manuscript.

Conflict of interest

M.G. received research funding from Horizon Therapeutics. M.T.N. has no conflicts of interest to declare.

Ethics approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Availability of data and materials

Not applicable.

Code availability

Not applicable.

Author contributions

Both authors contributed significantly to the manuscript.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gerritsen, M., Nurmohamed, M.T. The Effects of Pharmacological Urate-Lowering Therapy on Cardiovascular Disease in Older Adults with Gout. Drugs Aging 41, 319–328 (2024). https://doi.org/10.1007/s40266-024-01098-w

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40266-024-01098-w

Navigation