Research has supported the increased risk for hypertension and cardiovascular disease (CVD) in patients with gout, according to results from a review published in Drugs.1 In particular, data from randomized controlled trials have demonstrated that hyperuricemia, a precursor to gout, may be associated with an increased risk for myocardial infarction (MI), coronary heart disease, and cerebrovascular accidents, in addition to renal diseases.2

Several epidemiological studies have also established an association of asymptomatic hyperuricemia with the frequently occurring comorbidities that increase CVD risk with gout.3 Finally, Ando and colleagues found that increased serum uric acid (SUA) levels are associated with percentage lipid volume inversely correlated with percentage fibrous volume, which could lead to increased plaque fragility and possibly arterial obstruction.4

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Uncertainties about the causal relationship between hyperuricemia and CVD led many investigators to use Mendelian randomization to examine the effect of urate-governing genetic variants on various CVD outcomes with mixed results. Yan and colleagues found that SUA was significantly associated with diabetic macrovascular disease among Chinese women with type 2 diabetes mellitus.5

This indicates a strong case for a biological basis of a potential causal role of SUA in atherosclerosis and other metabolic diseases.6 The effects of SUA in the intracellular environment promote oxidative stress, endothelial dysfunction, vasoconstriction, and inflammation of lipid oxidation, which contributes to the development of atheroma.

As gout is associated with metabolic syndrome and both are established risk factors for CVD, there is an increased risk for cardiovascular (CV) events. A pathologic explanation for the increased incidence for CV events could be endothelial dysfunction, increased oxidized lipoproteins, dyslipidemia, as well as chronic or acute systemic inflammations that are associated with hyperuricemia. Targeting systemic markers of inflammation has been shown to decrease the risk for CV events.7

An important potential explanation for the associations between CVD and hyperuricemia could be addressed by the effects of urate-lowering therapies (ULTs), according to several studies. Larsen and colleagues found that treatment with allopurinol was associated with a decreased CVD risk among patients with hyperuricemia.8 Singh and colleagues found that compared with patients on Medicare who did not take allopurinol, patients who took allopurinol for >2 years had a 28% decreased risk for MI.9

In their meta-analysis of trials examining the effects of xanthine oxidase inhibitors on mortality in patients with CVD, Zhang and colleagues found that xanthine oxidase inhibitors did not exert a large reduction in mortality but that the possibility of substantial harm or benefit cannot be excluded.10 In a comparison of the efficacy of febuxostat vs allopurinol, Zhang and colleagues found similar but not statistically significant incidence rates of MI.11 Finally, Kim and colleagues found that treatment with probenecid was associated with a modestly decreased risk for CV events compared with allopurinol.12

At the same time, more research is needed to evaluate whether more aggressive dosing of ULT is needed to treat gout and hyperuricemia.13 Such measures would likely influence the magnitude of effects on CV events in patients with gout treated with ULTs.

“I think recommendation (of treatment with ULT) for cardioprotective purposes at this time in gout patients may be a bit premature,” said Jasvinder Singh, MD, MPH, Endowed Professor, Musculoskeletal Outcomes Research at the Division of Clinical Immunology and Rheumatology, and director of the Gout Clinic at the University of Alabama Health Services Foundation.

“I think tophaceous gout with elevated inflammatory markers with ongoing joint destruction in people with moderate-high cardiac risk or those with known cardiac disease might be the only instance; however, this is not supported by data at present. We really need data from prospective trials and studies of benefit that is reproducible,” he concluded.

References

1. Gupta MK, Singh JA. Cardiovascular disease in gout and the protective effect of treatments including urate-lowering therapy. Drugs. 2019;79(5):531-541.

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

3. Zhu Y, Pandya BJ, Choi HK. Prevalence of gout and hyperuricemia in the US general population: the National Health and Nutrition Examination Study. Arthritis Rheum. 2011;63(10):3136-3141.

4. Ando K, Takahashi H, Watanabe T, et al. Impact of serum uric acid levels on coronary plaque stability evaluated using integrated backscatter intravascular ultrasound in patients with coronary artery disease. J Atheroscler Thromb. 2016;23(8):932-939.

5. Yan D, Wang J, Jiang F, et al. A causal relationship between uric acid and diabetic macrovascular disease in Chinese type 2 diabetes patients: a Mendelian randomization analysis. Int J Cardiol. 2016;214:194-199.

6. Morbidoni L, Olivari D. Gout, hyperuricemia, and cardio-vascular risk. Ital J Med. 2018;12(3):190-202.

7. Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017;377(12):1119-1131.

8. Larsen KS, Pottegard 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.

9. Singh JA, Yu S. Allopurinol reduces the risk of myocardial infarction (MI) in the elderly: a study of Medicare claims. Arthritis Res Ther. 2016;18(1):209.

10. Zhang J, Dierckx R, Mohee K, Clark AL, Cleland JG. Xanthine oxidase inhibition for the treatment of cardiovascular disease: an updated systematic review and meta-analysis. ESC Heart Fail. 2017;4(1):40-45.

11. Zhang M, Solomon DH, Desai RJ, et al. Assessment of cardiovascular risk in older patients with gout initiating febuxostat versus allopurinol. Circulation. 2018;138(11):1116-1126.

12. Kim SC, Neogi T, Kang EH, et al. Cardiovascular risks of probenecid versus allopurinol in older patients with gout. J Am Coll Cardiol. 2018;71(9):994-1004.

13. Juraschek SP, Kovell LC, Miller ER 3rd, Gelber AC. Gout, urate-lowering therapy, and uric acid levels among adults in the United States. Arthritis Care Res (Hoboken). 2015;67(4):588-592.