Is Gout A Deadly Disease?

A recently published study shows a clear association between gout and heart failure.¹ 

The researchers studied people who were originally part of the REasons for Geographic and Racial Differences In Stroke (REGARDS) project, a national observational study of 30,239 participants, sponsored by the National Institutes of Health (NIH).² The current gout study excluded prior study participants who already had a history of heart failure, coronary heart disease and stroke to yield a study group of 5,714 participants with a mean age of 72. With gout already being associated with these conditions, eliminating those with a previous history allowed a clean baseline from which to monitor future complications that might be linked to hyperuricemia.

Indeed, after following the new study participants via telephone interview during 2016, researchers found that patients diagnosed with gout also had a higher incidence of heart failure hospitalization, coronary heart disease and all-cause mortality versus their counterparts without gout.¹ However, after multivariable adjustment, study authors noted the only statistically significant association was one between gout and a higher risk for heart failure hospitalization. Thus, there was no statistically significant difference between patients with gout and those without gout in terms of risk for coronary heart disease, stroke and all-cause mortality. However, heart failure with reduced left ventricular ejection fraction (LVEF) had a significant association with gout.¹

The importance of this study is the discovery that gout is a risk factor for heart failure independent of other well-known risk factors such as hypertension, diabetes, cigarette smoking and obesity. In terms of heart failure, the researchers found an association with gout and reduced left ventricular ejection fraction, suggesting that different mechanisms might be involved. They point out that interleukin-1 is a key inflammatory marker involved in the development of gout flares, which has been demonstrated in recent clinical trials with interleukin-1 blockade.^3-5 Animal models point to an association between Interleukin-1 overexpression and the development of heart failure with preserved left ventricular ejection fraction.^6,7  In addition, research indicates that insulin resistance is common in adults with gout and that insulin resistance is associated with increased risk of heart failure and reduced left ventricular ejection fraction.^8,9

Gout affects four percent of the population in the United States and most likely represents an even larger percentage of patients in podiatric practice.¹⁰ Often times, a podiatric physician is the first health care provider who will diagnose gout in a particular patient. Podiatric physicians then must educate the patient about gout regarding etiology, treatment options and long-term prognosis. Although this has been previously reported in the literature, medical professionals may not be aware of an association between gout and an increased risk for atherosclerotic cardiovascular disease, including coronary heart disease (CHD) and stroke.^11-13 

This new study from Colantonio and colleagues seems to refute a direct association between gout, coronary heart disease and stroke.¹ Yet this study does verify a risk of hospitalization for heart failure in patients with gout. The authors also demonstrated that patients with gout tend to be overweight, hypertensive, have diabetes and lower levels of activity in comparison to patients without gout.¹ Thus, besides gout, these patients have other risk factors for cardiovascular disease.

It is incumbent on the podiatric physician -- whether diagnosing gout for the first time or seeing a patient with a long history of gout -- to educate the patient about the long-term ramifications of gout. Recognizing that patients with gout already have risk factors for heart disease and reinforcing that heart failure is a known complication of gout should be a cornerstone of the patient education interaction. Although it is not known whether controlling hyperuricemia will prevent heart failure, it would certainly be prudent to recommend this intervention to patients with gout as well as lifestyle changes already established as preventive measures for heart disease and stroke.

Dr. Richie is an Adjunct Associate Professor within the Department of Applied Biomechanics at the California School of Podiatric Medicine at Samuel Merritt University in Oakland, Calif. He is a Fellow and Past President of the American Academy of Podiatric Sports Medicine. Dr. Richie is a Fellow of the American College of Foot and Ankle Surgeons and the American Academy of Podiatric Sports Medicine. 

References

1. Colantonio LD, Saag KG, Singh JA, et al. Gout is associated with an increased risk for incident heart failure among older adults: the REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort study. Arthritis Res Ther. 2020;22(1):86.

2. Howard VJ, Cushman M, Pulley L, Gomez CR, Go RC, Prineas RJ, Graham A, Moy CS, Howard G. The reasons for geographic and racial differences in stroke study: objectives and design. Neuroepidemiology. 2005;25(3):135–143.

3. So A, De Smedt T, Revaz S, Tschopp J. A pilot study of IL-1 inhibition by anakinra in acute gout. Arthritis Res Ther. 2007;9(2):R28. 

4. Solomon DH, Glynn RJ, MacFadyen JG, et al. Relationship of interleukin-1beta blockade with incident gout and serum uric acid levels: exploratory analysis of a randomized controlled trial. Ann Intern Med. 2018;169(8):535–542. 

5. Sundy JS, Schumacher HR, Kivitz A, et al. Rilonacept for gout flare prevention in patients receiving uric acid lowering therapy: results of RESURGE, a phase III, international safety study. J Rheumatol. 2014;41(8):1703–1711.

6. Isoda K, Kamezawa Y, Tada N, Sato M, Ohsuzu F. Myocardial hypertrophy in transgenic mice overexpressing human interleukin 1alpha. J Card Fail. 2001;7(4):355–364. 

7. Nishikawa K, Yoshida M, Kusuhara M, et al. Left ventricular hypertrophy in mice with a cardiac-specific overexpression of interleukin-1. Am J Physiol Heart Circ Physiol. 2006;291(1): H176–183

8. Yoo HG, Lee SI, Chae HJ, Park SJ, Lee YC, Yoo WH. Prevalence of insulin resistance and metabolic syndrome in patients with gouty arthritis. Rheumatol Int. 2011;31(4):485–491. 

9. Saag KG, Choi H. Epidemiology, risk factors, and lifestyle modifications for gout. Arthritis Res Ther. 2006;8(Suppl 1):S2.

10. Khanna D, Fitzgerald JD, Khanna PP, et al. 2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res. 2012;64(10):1431–1446.

11. Liu SC, Xia L, Zhang J, et al. Gout and risk of myocardial infarction: a systematic review and meta-analysis of cohort studies. PLoS One. 2015;10(7):e0134088. 

12. Kim SY, Guevara JP, Kim KM, Choi HK, Heitjan DF, Albert DA. Hyperuricemia and risk of stroke: a systematic review and meta-analysis. Arthritis Rheum. 2009;61(7):885–892. 

13. Singh JA, Ramachandaran R, Yu S, et al. Is gout a risk equivalent to diabetes for stroke and myocardial infarction? A retrospective claims database study. Arthritis Res Ther. 2017;19(1):228.