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Despite being one of the most common inflammatory diseases, misconceptions regarding gout still remain. Among some patients and clinicians, gout has the reputation of a self-inflicted disease, the consequence of exercise, and dietary choices.1 It is also thought of a disease that mainly causes pain to the joint of the great toe. However, as with other rheumatic diseases, systemic inflammation from a gout flare can greatly influence patients’ cardiovascular (CV) health.2
With the prevalence of gout having increased by more than 7% in the past 20 years,3 further understanding is necessary to treat patients with gout and CV comorbidities. Hypertension, smoking, diabetes mellitus, dyslipidemia, age, and obesity are risk factors for CV disease, and are all common comorbidities in patients with gout.4 Increased levels of uric acid that leads to chronic inflammation may also contribute to associated higher CV burden in patients with gout.5
To further explore the link between CV health and gout, researchers conducted a retrospective observational study to examine the association between gout flare and CV event occurrence. They found that patients with gout who experienced a CV event had significantly higher odds of experiencing a recent gout flare in the preceding days compared with those who did not experience a CV event.6 These findings were published in Journal of the American Medical Association.
We spoke with Robert Keenan, MD, to get further insights into the study results. Dr Keenan is an associate professor of medicine at the Duke University School of Medicine and the vice chief of Clinical Affairs for the Division of Rheumatology. He is also a member of the International Advisory Council for the Gout Education Society.
This study reports that among patients with newly diagnosed gout, those who experienced CV events had significantly increased odds of a gout flare during the preceding 120 days compared with patients who did not experience CV events. Overall, these findings suggest that gout flares are associated with a transient increase in CV events following flares. Can you please elaborate on the study outcomes?
Dr Keenan: This study retrospectively examined newly diagnosed patients with gout during a 24-year period. More than 10,000 patients with either an acute myocardial infarction or stroke were compared with more than 52,000 patients with newly diagnosed gout who did not experience a CV event. The patients who experienced a CV event had a higher incidence of smoking and higher CV risks compared with the control group. However, despite adjusting for these variables plus other CV risk factors (such as hypercholesterolemia or hypertension), [patients] still had significantly higher odds of having a gout flare within 120 days prior.
The risk for gout flare prior to the CV event was highest within 60 days (fewer than2 times more likely), while the likelihood of having a gout flare between 61 to 120 days of a CV event was still 1.5 times higher. There was no difference in the odds of a gout flare within the prior 121 to 180 days of a CV event.
The results bring up an important question in the relationship between the increased systemic inflammatory state with an acute gout flare above that of baseline gout, its impact on CV events, and whether it provides a potential trigger for the CV event.
This is a well-done retrospective analysis in a very large cohort spanning more than 2 decades, which adds validity to the results.
What are some preventative measures clinicians can take to ensure patients with a history of gout who have experienced an acute CV event can minimize the risk for a flare?
Dr Keenan: Treating to a serum urate target of less than 6 mg/dL — or in some patients to less than 5 mg/dL — is the ultimate way to assure flare resolution over time. By keeping serum urate levels well below the limit of solubility (approximately 6 mg/dL), crystal dissolution occurs and the nidus for flares resolves. Given it takes time for all of deposited crystals to fully dissolve, flares can continue to occur for a period of time even after a patient is at their targeted serum urate level. Therefore, it is important to reduce patients’ flare risk with prophylactic therapy — such as colchicine — for at least 6 months after they have reached their serum urate target, or 6 months after their last flare, whichever is longer.
Is there an argument to be made for medications such as colchicine or other anti-inflammatory medications to be used proactively after a CV event to reduce the risk for a flare?
Dr Keenan: Colchicine is used to prevent and treat gout flares, and has been shown in some studies to lower the incidence of CV events. Colchicine has also been used to prevent subsequent events and revascularization after a myocardial infarction if initiated within 30 days after the event.7,8
Other anti-inflammatory medications not currently approved for prophylaxis or treatment of gout flares in the US, including IL-1 inhibitors such as canakinumab, have been shown to prevent recurrent CV events.9 In contrast, typical nonsteroidal anti-inflammatory drugs (NSAIDs) and prednisone, also used to prevent and treat gout flares, do not have the same potential benefit and may actually increase risk for CV events in all patients with or without gout, especially with regular doses.
What should clinicians know about monitoring CV health in patients with gout?
Dr Keenan: We know that CV risk increases with age, as does gout and other comorbid illnesses such as hypertension. Although this study is not necessarily generalizable to all patients with gout, we can infer some things from the study.
Even after the authors adjusted for well-known comorbid risks, such as hypertension and hypercholesterolemia, patients had significantly higher odds of experiencing a CV event if they had a gout flare within the prior 120 days. As the epidemiologic evidence points to gout as an independent risk factor for CV disease, it is important to treat gout as such, regardless of the patient’s age or existence of any other risk factors. Gout and hyperuricemia should be considered risk factors for CV disease and be treated to a target (ie, serum urate level of less than 6 mg/dL or less than 5 mg/dL in some populations with chronic kidney disease) just as you would treat hypertension to a target.
How effective are standard lifestyle modifications (ie, diet, exercise, medication adherence, smoking cessation, etc) at minimizing the risk for gout flare post-acute CV event?
Dr Keenan: Lifestyle modifications such as diet, exercise, smoking cessation, and medication adherence all are important to minimize recurrent CV events, and possibly prevent gout flares at the same time. In some studies, weight loss has been shown to decrease serum urate levels and subsequent gout flares. While minimizing high-purine foods, such as red meat, may not be the most effective long-term way to treat gout and lower serum urate levels, it may be beneficial as part of an overall regimen of diet and exercise along with medications to treat gout and reduce CV events.
The study period spanned 24 years from 1997 to 2021. It is noted that during this time, the diagnosis and management of both gout and CV diseases have changed. Likewise, current treatment advances will influence how patients with gout are treated for CV events in the future. Are there any promising treatment advances that you can see improving outcomes for these patients?
Dr Keenan: Treatment advances in gout and CV disease have truly changed over the last few decades based on our better understanding of the pathophysiology and accumulated evidence on the effects of hyperuricemia, gout, and their effect on CV health and general morbidity. In addition to lowering glucose levels in patients with type 2 diabetes, sodium-glucose linked transporter 2 inhibitors have highlighted the potential CV and renal benefits of lowering serum urate levels. Additionally, there is evidence that uricosurics may slow the progression of renal disease and decrease CV risk. More studies and randomized controlled trials are needed to evaluate the long-term impact of uricosurics and xanthine oxidase inhibitors on CV disease.
Are there any aspects of this study that you would like to see further investigated?
Dr Keenan: It would be interesting to see if patients who experienced a CV event had further events with or without [previous] gout flares, and if serum urate levels had been at target. Also, it would be interesting to extend the study for another 10 to 20 years, identifying any control patients who had a CV event and if they had gout flare prior and/or hyperuricemia (not at target serum urate level of less than 6 mg/dL). Although this study evaluated colchicine, corticosteroid and NSAID use, I would be curious to see if patients receiving colchicine had decreased flare or CV risk, and if patients receiving corticosteroids and NSAIDs did as well.
References
1. Edwards NL, Lamoreaux B, Magerman A, et al. Does a gout stigma among rheumatologists influence perceptions of patients and treatment decisions? Annals of the Rheumatic Diseases. 2022;81:385-386. doi:10.1136/annrheumdis-2022-eular.1352
2. Cai K, Wu B, Mehta S, et al. Association between gout and cardiovascular outcomes in adults with no history of cardiovascular disease: large data linkage study in New Zealand. BMJ Medicine. Published online June 22, 2022. doi:10.1136/bmjmed-2021-000081
3. Ahmad MI, Masood S, Furlanetto DM, Nicolaou S. Urate crystals; beyond joints. Front Med (Lausanne). Published online June 4, 2021. doi:10.3389/fmed.2021.649505
4. Choi HK, Curhan G. Independent impact of gout on mortality and risk for coronary heart disease. Circulation. 2007;116:894-900. doi:10.1161/CIRCULATIONAHA.107.703389
5. Cox P, Gupta S, Zhao SS, Hughes DM. The incidence and prevalence of cardiovascular diseases in gout: a systematic review and meta-analysis. Rheumatol Int. 2021;41(7):1209-1219. doi:10.1007/s00296-021-04876-6
6. Cipolletta E, Tata LJ, Nakafero G, Avery AJ, Mamas MA, Abhishek A. Association between gout flare and subsequent cardiovascular events among patients with gout. JAMA. 2022;328(5):440-450. doi:10.1001/jama.2022.11390
7. Hansildaar R, Vedder D, Baniaamam M, Tausche AK, Gerritsen M, Nurmohamed MT. Cardiovascular risk in inflammatory arthritis: rheumatoid arthritis and gout. Lancet Rheumatol. 2021;3(1):e58-e70. doi:10.1016/S2665-9913(20)30221-6
8. Bouabdallaoui N, Tardif JC, Waters DD, et al. Time-to-treatment initiation of colchicine and cardiovascular outcomes after myocardial infarction in the Colchicine Cardiovascular Outcomes Trial (COLCOT). Eur Heart J. 2020;41(42):4092-4099. doi:10.1093/eurheartj/ehaa659
9. Ridker PM, Everett BM, Thuren TT, et al. Anti-inflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017;377:1119-1131. doi:10.1056/NEJMoa1707914
