Hyperuricemia: contemporary treatment in patients with cardiovascular disease

The prevalence of hyperuricemia is due to the epidemic of obesity, changes in eating behavior in the population with the rise of purines, alcohol and fructose consumption, as well as the increased use of diuretics. It’s important to mention that over the past 20 years there has been an increase in the prevalence of such concomitant diseases and conditions as arterial hypertension (+15%), diabetes mellitus (+19%), decreased kidney function (+17%), hyperlipidemia (+40%) and obesity (+19%). Hyperuricemia (and/or gout) can be both a cause and a consequence of various comorbid conditions. That is why their treatment is closely connected with the treatments of hyperuricemia, especially of asymptomatic one.
It’s important to determine not only the upper limit of the uric acid in patients, when the therapy is being initiated, but to assess the target levels of uric acid, that must be achieved in patients receiving optimal treatment.
In this review article the main principles of both non-pharmacological and pharmacological treatment in patients with cardiovascular diseases are described. The need for medical treatment, target serum urate levels in patients with cardiovascular risk factors are discussed, as well as further perspectives in the field of research in patients with hyperuricemia and cardiovascular diseases.
Allopurinol is currently the key drug prescribed to patients with hyperuricemia and cardiovascular risk factors. The most important advantage is its safety profile. Patients receiving renal replacement therapy can also safely receive the drug.
The need to reduce the level of uric acid in patients with cardiovascular disease is currently beyond doubt. In the group of patients with additional risk factors, such as diabetes mellitus, metabolic syndrome and CKD, lifestyle modification in combination with urate-lowering therapy improves both the quality of life and prognosis. Currently, allopurinol is the drug of choice for the treatment of AH in combination with AH, taking into account both the efficacy and safety of its administration to this group of patients. However, it is obvious that further studies with clearer inclusion criteria are needed to analyze the effect of therapy on cardiovascular events, as well as combined endpoints.

1. Elfishawi MM, Zleik N, Kvrgic Z, Michet CJ, 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 [Internet]. 2018 Apr 1;45(4):574 LP -579. Available from: http:// www.jrheum.org/content/45/4/574.abstract, https://doi.org/10.3899/jrheum.170806

2. Zhu Y, Pandya BJ, Choi HK. Prevalence of gout and hyperuricemia in the US general population: the National Health and Nutrition Examination Survey 2007–2008. Arthritis Rheum. 2011;63(10):3136–41. https://doi.org/10.1002/art.30520

3. Pascart T, Lioté F. Gout: state of the art after a decade of developments. Rheumatology. 2019;58(1):27–44. https://doi.org/10.1093/rheumatology/key002

4. Lioté F, Pascart T. From hyperuricaemia to gout: what are the missing links? Nat Rev Rheumatol. 2018;14(8):448–9. https://doi.org/10.1038/s41584-018-0040-6

5. Bardin T, Richette P. Impact of comorbidities on gout and hyperuricaemia: an update on prevalence and treatment options. BMC Med. 2017;15(1):1-10. https://doi.org/10.1186/s12916-017-0890-9

6. 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(7):1122–32. https://doi.org/10.1002/art.40472

7. Bardin T. Hyperuricemia starts at 360 micromoles (6mg/dL). Jt Bone Spine. 2015;3(82):141–3. https://doi.org/10.1016/j.jbspin.2015.01.002

8. 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(1):29–42. https://doi.org/10.1136/annrheumdis-2016-209707

9. Chazova I.E., Zhernakova J.V., Kisliak O.A., Nedogoda S.V., Podzolkov V.I., Oshchepkova E.V., Medvedeva I.V., Mironova O.I., Blinova N.V. Consensus on patients with hyperuricemia and high cardiovascular risk treatment // Systemic Hypertension. 2019;16(4):8–21. (in Russ.). https://doi.org/10.26442/2075082X.2019.4.190686

10. Campion EW, Glynn RJ, Delabry LO. Asymptomatic hyperuricemia. Risks and consequences in the Normative Aging Study. Am J Med. 1987;82(3):421–6. https://doi.org/10.1016/0002-9343(87)90441-4

11. 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(3):388–96. https://doi.org/10.3899/jrheum.160452

12. Dalbeth N, Phipps-Green A, Frampton C, Neogi T, Taylor WJ, Merriman TR. Relationship between serum urate concentration and clinically evident incident gout: an individual participant data analysis. Ann Rheum Dis. 2018;77(7):1048–52. https://doi.org/10.1136/annrheumdis-2017-212288

13. Saag KG, Mikuls TR, Abbott J. The epidemiology of gout and calcium pyrophosphate dihydrate deposition disease. In: Crystal-induced arthropathies. CRC Press; 2006. p. 25–54.

14. De Becker B, Borghi C, Burnier M, Van De Borne P. Uric acid and hypertension: a focused review and practical recommendations. J Hypertens. 2019;37(5):878–83. https://doi.org/10.1097/hjh.0000000000001980

15. Feig DI, Kang D-H, Johnson RJ. Uric acid and cardiovascular risk. N Engl J Med. 2008;359(17):1811–21. https://doi.org/10.1056/nejmra0800885

16. Borghi C, Rosei EA, Bardin T, Dawson J, Dominiczak A, Kielstein JT, et al. Serum uric acid and the risk of cardiovascular and renal disease. J Hypertens. 2015;33(9):1729–41. https://doi.org/10.1097/hjh.0000000000000701

17. El Din UAAS, Salem MM, Abdulazim DO. Uric acid in the pathogenesis of metabolic, renal, and cardiovascular diseases: A review. J Adv Res. 2017;8(5):537–48. https://doi.org/10.1016/j.jare.2016.11.004

18. Gagliardi ACM, Miname MH, Santos RD. Uric acid: a marker of increased cardiovascular risk. Atherosclerosis. 2009;202(1):11–7. https://doi.org/10.1016/j.atherosclerosis.2008.05.022

19. Kuwabara M, Hisatome I, Niwa K, Hara S, Roncal-Jimenez CA, Bjornstad P, et al. Uric acid is a strong risk marker for developing hypertension from prehypertension: a 5-year Japanese cohort study. Hypertension. 2018;71(1):78–86. https://doi.org/10.1161/hypertensionaha.117.10370

20. Feig DI. Uric acid-a novel mediator and marker of risk in chronic kidney disease? Curr Opin Nephrol Hypertens. 2009;18(6):526. https://doi.org/10.1097/mnh.0b013e328330d9d0

21. Desai RJ, Franklin JM, Spoendlin-Allen J, Solomon DH, Danaei G, Kim SC. An evaluation of longitudinal changes in serum uric acid levels and associated risk of cardio-metabolic events and renal function decline in gout. PLoS One. 2018;13(2):e0193622. https://doi.org/10.1371/journal.pone.0193622

22. Kuwabara M, Bjornstad P, Hisatome I, Niwa K, Roncal-Jimenez CA, Andres- Hernando A, et al. Elevated serum uric acid level predicts rapid decline in kidney function. Am J Nephrol. 2017;45(4):330–7. https://doi.org/10.1159/000464260

23. Zhao G, Huang L, Song M, Song Y. Baseline serum uric acid level as a predictor of cardiovascular disease related mortality and all-cause mortality: a meta-analysis of prospective studies. Atherosclerosis. 2013;231(1):61–8. https://doi.org/10.1016/j.atherosclerosis.2013.08.023

24. Kim SY, Guevara JP, Kim KM, Choi HK, Heitjan DF, Albert DA. Hyperuricemia and coronary heart disease: a systematic review and meta‐analysis. Arthritis Care Res Off J Am Coll Rheumatol. 2010;62(2):170–80.

25. Yu W, Cheng J-D. Uric acid and cardiovascular disease: an update from molecular mechanism to clinical perspective. Front Pharmacol. 2020;1607. https://doi.org/10.3389/fphar.2020.582680

26. Paul BJ, Anoopkumar K, Krishnan V. Asymptomatic hyperuricemia: is it time to intervene? Clin Rheumatol. 2017;36(12):2637–44. https://doi.org/10.1007/s10067-017-3851-y

27. Lopez-Pineda A, Cordero A, Carratala-Munuera C, Orozco-Beltran D, Quesada JA, Bertomeu-Gonzalez V, et al. Hyperuricemia as a prognostic factor after acute coronary syndrome. Atherosclerosis. 2018;269:229-35. https://doi.org/10.1016/j.atherosclerosis.2018.01.017

28. Andrés M, Quintanilla M, Sivera F, Sánchez‐Payá J, Pascual E, Vela P, et al. Silent monosodium urate crystal deposits are associated with severe coronary calcification in asymptomatic hyperuricemia: an exploratory study. Arthritis Rheumatol. 2016;68(6):1531–9.

29. Neogi T. Asymptomatic hyperuricemia: cardiovascular and renal implications. In: Gout & other crystal arthropathies. Elsevier; 2012. p. 226–38.

30. Grassi D, Desideri G, Giacomantonio D, Vittoria A, Di Giosia P, Ferri C. Hyperuricemia and cardiovascular risk. High Blood Press Cardiovasc Prev. 2014;21(4):235–42. https://doi.org/10.1007/s40292-014-0046-3

31. Maloberti A, Giannattasio C, Bombelli M, Desideri G, Cicero AFG, Muiesan ML, et al. Hyperuricemia and risk of cardiovascular outcomes: the experience of the URRAH (uric acid right for heart health) project. High Blood Press Cardiovasc Prev. 2020;27(2):121–8. https://doi.org/10.1007/s40292-020-00368-z

32. Soletsky B, Feig DI. Uric acid reduction rectifies prehypertension in obese adolescents. Hypertension. 2012;60(5):1148–56. https://doi.org/10.1161/hypertensionaha.112.196980

33. Akkineni R, Tapp S, Tosteson ANA, Lee A, Miller KL, Choi HK, et al. Treatment of asymptomatic hyperuricemia and prevention of vascular disease: a decision analytic approach. J Rheumatol. 2014;41(4):739–48. https://doi.org/10.3899/jrheum.121231

34. Gaffo AL, Edwards NL, Saag KG. Gout. Hyperuricemia and cardiovascular disease: how strong is the evidence for a causal link? Arthritis Res Ther. 2009;11(4):1–7. https://doi.org/10.1186/ar2761

35. Yuan H, Yu C, Li X, Sun L, Zhu X, Zhao C, et al. Serum uric acid levels and risk of metabolic syndrome: a dose-response meta-analysis of prospective studies. J Clin Endocrinol Metab. 2015;100(11):4198–207. https://doi.org/10.1210/jc.2015-2527

36. Bombelli M, Quarti-Trevano F, Tadic M, Facchetti R, Cuspidi C, Mancia G, et al. Uric acid and risk of new-onset metabolic syndrome, impaired fasting glucose and diabetes mellitus in a general Italian population: data from the Pressioni Arteriose Monitorate E Loro Associazioni study. J Hypertens. 2018;36(7):1492–8. https://doi.org/10.1097/hjh.0000000000001721

37. Choi HK. A prescription for lifestyle change in patients with hyperuricemia and gout. Curr Opin Rheumatol. 2010;22(2):165–72. https://doi.org/10.1097/bor.0b013e328335ef38

38. Rasheed H, Hsu A, Dalbeth N, Stamp LK, McCormick S, Merriman TR. The relationship of apolipoprotein B and very low density lipoprotein triglyceride with hyperuricemia and gout. Arthritis Res Ther. 2014;16(6):1–10. https://doi.org/10.1186/s13075-014-0495-z

39. Juraschek SP, Gelber AC, Choi HK, Appel LJ, Miller III ER. Effects of the Dietary Approaches to Stop Hypertension (DASH) diet and sodium intake on serum uric acid. Arthritis Rheumatol. 2016;68(12):3002–9. https://doi.org/10.1002/art.39813

40. Tang O, Miller ER, Gelber AC, Choi HK, Appel LJ, Juraschek SP. DASH diet and change in serum uric acid over time. Clin Rheumatol. 2017;36(6):1413–7. https://doi.org/10.1007/s10067-017-3613-x

41. Beyl Jr RN, Hughes L, Morgan S. Update on importance of diet in gout. Am J Med. 2016;129(11):1153–8. https://doi.org/10.1016/j.amjmed.2016.06.040

42. Chatzipavlou M, Magiorkinis G, Koutsogeorgopoulou L, Kassimos D. Mediterranean diet intervention for patients with hyperuricemia: a pilot study. Rheumatol Int. 2014;34(6):759–62. https://doi.org/10.1007/s00296-013-2690-7

43. Guasch-Ferré M, Bulló M, Babio N, Martínez-González MA, Estruch R, Covas M-I, et al. Mediterranean diet and risk of hyperuricemia in elderly participants at high cardiovascular risk. Journals Gerontol Ser A Biomed Sci Med Sci. 2013;68(10):1263–70. https://doi.org/10.1093/gerona/glt028

44. Holland R, McGill NW. Comprehensive dietary education in treated gout patients does not further improve serum urate. Intern Med J. 2015;45(2):189–94. https://doi.org/10.1111/imj.12661

45. Moi JHY, Sriranganathan MK, Falzon L, Edwards CJ, van der Heijde DM, Buchbinder R. Lifestyle interventions for the treatment of gout: a summary of 2 Cochrane systematic reviews. J Rheumatol Suppl. 2014;92:26–32. https://doi.org/10.3899/jrheum.140459

46. Abhishek A, Doherty M. Education and non-pharmacological approaches for gout. Rheumatology. 2018;57(suppl_1):i51–8. https://doi.org/10.1093/rheumatology/kex421

47. Nielsen SM, Bartels EM, Henriksen M, Wæhrens EE, Gudbergsen H, Bliddal H, et al. Weight loss for overweight and obese individuals with gout: a systematic review of longitudinal studies. Ann Rheum Dis. 2017;76(11):1870–82. https://doi.org/10.1136/annrheumdis-2017-211472

48. Kawamoto R, Katoh T, Ninomiya D, Kumagi T, Abe M, Kohara K. Synergistic association of changes in serum uric acid and triglycerides with changes in insulin resistance after walking exercise in community- dwelling older women. Endocr Res. 2016;41(2):116–23. https://doi.org/10.3109/07435800.2015.1094085

49. Chen J-H, Wen CP, Wu SB, Lan J-L, Tsai MK, Tai Y-P, et al. Attenuating the mortality risk of high serum uric acid: the role of physical activity underused. Ann Rheum Dis. 2015;74(11):2034–42. https://doi.org/10.1136/annrheumdis-2014-205312

50. Badve S V, Brown F, Hawley CM, Johnson DW, Kanellis J, Rangan GK, et al. Challenges of conducting a trial of uric-acid-lowering therapy in CKD. Nat Rev Nephrol. 2011;7(5):295–300. https://doi.org/10.1038/nrneph.2010.186

51. Chalès G. How should we manage asymptomatic hyperuricemia? Jt Bone Spine. 2019;86(4):437–43. https://doi.org/10.1016/j.jbspin.2018.10.004

52. Larsen KS, Pottegård A, Lindegaard HM, Hallas J. Effect of allopurinol on cardiovascular outcomes in hyperuricemic patients: a cohort study. Am J Med. 2016;129(3):299–306. https://doi.org/10.1016/j.amjmed.2015.11.003

53. Cicero AFG, Fogacci F, Cincione RI, Tocci G, Borghi C. Clinical effects of xanthine oxidase inhibitors in hyperuricemic patients. Med Princ Pract. 2021;30(2):122–30. https://doi.org/10.1159/000512178

54. Givertz MM, Anstrom KJ, Redfield MM, Deswal A, Haddad H, Butler J, et al. Effects of xanthine oxidase inhibition in hyperuricemic heart failure patients: the xanthine oxidase inhibition for hyperuricemic heart failure patients (EXACT-HF) study. Circulation. 2015;131(20):1763–71. https://doi.org/10.1161/circulationaha.114.014536

55. Borghi C, Palazzuoli A, Landolfo M, Cosentino E. Hyperuricemia: a novel old disorder—relationship and potential mechanisms in heart failure. Heart Fail Rev. 2020;25(1):43–51. https://doi.org/10.1007/s10741-019-09869-z

56. Siu Y-P, Leung K-T, Tong MK-H, Kwan T-H. Use of allopurinol in slowing the progression of renal disease through its ability to lower serum uric acid level. Am J Kidney Dis. 2006;47(1):51–9. https://doi.org/10.1053/j.ajkd.2005.10.006

57. Feig DI, Soletsky B, Johnson RJ. Effect of allopurinol on blood pressure of adolescents with newly diagnosed essential hypertension: a randomized trial. Jama. 2008;300(8):924–32. https://doi.org/10.1001/jama.300.8.924

58. Doehner W, Schoene N, Rauchhaus M, Leyva-Leon F, Pavitt D V, Reaveley DA, et al. Effects of xanthine oxidase inhibition with allopurinol on endothelial function and peripheral blood flow in hyperuricemic patients with chronic heart failure: results from 2 placebo-controlled studies. Circulation. 2002;105(22):2619–24. https://doi.org/10.1161/01.cir.0000017502.58595.ed

59. Kanbay M, Huddam B, Azak A, Solak Y, Kadioglu GK, Kirbas I, et al. A randomized study of allopurinol on endothelial function and estimated glomular filtration rate in asymptomatic hyperuricemic subjects with normal renal function. Clin J Am Soc Nephrol. 2011;6(8):1887–94. https://doi.org/10.2215/cjn.11451210

60. Jalal DI, Decker E, Perrenoud L, Nowak KL, Bispham N, Mehta T, et al. Vascular function and uric acid-lowering in stage 3 CKD. J Am Soc Nephrol. 2017;28(3):943–52. https://doi.org/10.1681/asn.2016050521

61. Liu P, Wang H, Zhang F, Chen Y, Wang D, Wang Y. The effects of allopurinol on the carotid intima-media thickness in patients with type 2 diabetes and asymptomatic hyperuricemia: a three-year randomized parallel-controlled study. Intern Med. 2015;54(17):2129–37. https://doi.org/10.2169/internalmedicine.54.4310

62. Takir M, Kostek O, Ozkok A, Elcioglu OC, Bakan A, Erek A, et al. Lowering uric acid with allopurinol improves insulin resistance and systemic inflammation in asymptomatic hyperuricemia. J Investig Med. 2015;63(8):924–9. https://doi.org/10.1097/JIM.0000000000000242

63. Liu P, Chen Y, Wang B, Zhang F, Wang D, Wang Y. Allopurinol treatment improves renal function in patients with type 2 diabetes and asymptomatic hyperuricemia: 3‐year randomized parallel‐controlled study. Clin Endocrinol (Oxf). 2015;83(4):475–82. https://doi.org/10.1111/cen.12673

64. Waheed Y, Yang F, Sun D. Role of asymptomatic hyperuricemia in the progression of chronic kidney disease and cardiovascular disease. Korean J Intern Med. 2021;36(6):1281. https://doi.org/10.3904/kjim.2020.340

65. Piani F, Cicero AFG, Borghi C. Uric acid and hypertension: prognostic role and guide for treatment. J Clin Med. 2021;10(3):448. https://doi.org/10.3390/jcm10030448

66. Borghi C, Verardi FM, Pareo I, Bentivenga C, Cicero AFG. Hyperuricemia and cardiovascular disease risk. Expert Rev Cardiovasc Ther. 2014;12(10):1219–25. https://doi.org/10.1586/14779072.2014.957675

67. Brucato A, Cianci F, Carnovale C. Management of hyperuricemia in asymptomatic patients: a critical appraisal. Eur J Intern Med. 2020;74:8-17. https://doi.org/10.1016/j.ejim.2020.01.001

68. van der Pol KH, Wever KE, Verbakel M, Visseren FLJ, Cornel JH, Rongen GA. Allopurinol to reduce cardiovascular morbidity and mortality: A systematic review and meta-analysis. PLoS One. 2021;16(12):e0260844. https://doi.org/10.1371/journal.pone.0260844