Gout & Cardiometabolic Co-Morbidities

Chicago—Gout is a global scourge, affecting about 55 million people worldwide.¹ As many rheumatologists have observed clinically, gout and cardiometabolic diseases tend to swim in the same waters. With this in mind, the ACR Convergence 2025 session, Gazing into the Crystal Ball: Gout and Cardiometabolic Comorbidity Management, provided tremendous insights into this important topic.

Metabolic Syndrome & Gout

Dr. McCormick

The first speaker was Natalie McCormick, PhD, an instructor in medicine at Massachusetts General Hospital, Boston, and her talk focused on the metabolic syndrome (MetS) and its relationship to gout. MetS is a cluster of interrelated metabolic abnormalities—including central obesity, insulin resistance, dyslipidemia and hypertension—that together increase the risk of cardiovascular disease and type 2 diabetes. Several large cohort studies have demonstrated that individuals with MetS have a markedly higher risk of incident gout, with chronic MetS conferring up to a four-fold increased risk compared with those without MetS.^2,3 The risk of gout further rises with the number of MetS components present; among these components, hypertriglyceridemia and abdominal obesity show the strongest associations with gout.² Clinically, the coexistence of gout and MetS increases cardiovascular risk, a fact that highlights the need for systemic screening for MetS-related conditions in patients with gout.

Dr. McCormick went on to discuss her research on the interesting topic of how to assess the causal relationship between insulin resistance, hyperuricemia and gout using bidirectional Mendelian randomization, a research method that uses genetic variants as natural experiments to assess whether an observed association between a risk factor and a disease is likely to be causal. In other words, genetic data was used to figure out whether insulin resistance causes hyperuricemia and gout, or if high uric acid causes insulin resistance.

Dr. McCormick and her colleagues used genome-wide association data from the UK Biobank, which is a prospective cohort of approximately 500,000 individuals aged 40–69 years recruited across the United Kingdom. They also used individual-level, electronic medical record-linked data from the UK Biobank. The authors found that genetic risk for insulin resistance leads to higher uric acid levels and a greater risk of gout, but having genes for high uric acid does not cause insulin resistance. Put another way, insulin resistance can cause gout, but gout does not cause insulin resistance. This implies that treating insulin resistance (such as through diet, exercise or medications) could help lower uric acid and reduce the risk of gout.³

Cardiovascular Risk & Gout

Dr. Singh

The next speaker was Jasvinder Singh, MD, MPH, a professor of medicine and epidemiology and Musculoskeletal Outcomes Research Endowed Professor of Medicine at the University of Alabama in Birmingham, Ala., who lectured on cardiovascular morbidity and mortality as related to gout. Multiple large cohort studies and meta-analyses have consistently demonstrated gout is independently associated with an increased risk of myocardial infarction (MI), even after adjusting for traditional cardiovascular risk factors and comorbidities. For example, a meta-analysis of cohort studies found a pooled relative risk of 1.45 for MI in patients with gout compared with controls, and this association persisted after adjustment for confounders.⁵ Recent studies also show the risk of acute coronary events is amplified during periods of gout flare, likely due to heightened systemic inflammation and plaque destabilization.⁶

With respect to peripheral vascular disease, a case-control study including more than 150,000 gout patients found a significantly increased risk of peripheral arterial disease (PAD) compared with matched controls, with a hazard ratio of 1.52 even after adjusting for comorbidities.⁷ This is likely because both hyperuricemia and gout may promote vascular disease and atherosclerosis through chronic inflammation, oxidative stress and endothelial dysfunction, all of which are implicated in PAD pathogenesis.

Dr. Singh showed evidence gout is even an independent risk factor for atrial fibrillation, with hazard ratios for atrial fibrillation ranging from 1.09–1.83 in gout patients compared with matched controls (the association is observed across both sexes and across various patient ages).^7-9 Perhaps most importantly, Dr. Singh explained, is that gout is an independent risk factor for cardiovascular mortality, and the presence of tophi and elevated uric acid levels (i.e., evidence of poorly controlled disease) are independently associated with greater risk of death, especially from cardiovascular causes. In fact, the risk is additive: having multiple tophi further increases the likelihood of major adverse cardiovascular events.¹⁰

A key topic discussed by Dr. Singh was cardiovascular safety related to febuxostat. In 2019, the Food and Drug Administration (FDA) concluded there was an increased risk of death with febuxostat compared with allopurinol and, thus, added this information as a boxed warning.¹¹ This was primarily based on a study published by White and colleagues in The New England Journal of Medicine in 2018.¹² However, researchers have noted that the study (called the CARES trial) had a high loss to follow-up—approaching 50%—which raises concerns about the reliability of its findings. Subsequent studies, such as the FAST trial, have found no difference in cardiovascular events or mortality between febuxostat and allopurinol,¹³ leading some experts to question the FDA’s black-box warning for febuxostat and to call for its reconsideration in light of more recent evidence.

Gout’s Metabolic Risk Factors

Dr. Schlesinger

The final speaker was Naomi Schlesinger, MD, a professor of medicine, endowed chair and chief of the Division of Rheumatology at the Spencer Fox Eccles School of Medicine at the University of Utah, who talked about the treatment of gout and its metabolic risk factors. Dr. Schlesinger noted that colchicine has anti-inflammatory effects that are mediated by inhibition of microtubule polymerization and suppression of neutrophil and inflammasome activity. The use of colchicine has been shown to reduce major adverse cardiovascular events in large randomized trials of patients with coronary artery disease. The COLCOT and LoDoCo2 trials demonstrated that low-dose colchicine (0.5 mg daily) reduced the risk of MI, stroke, coronary revascularization and cardiovascular death by 23–31% compared with placebo, with benefits additive to standard therapies such as statins and antiplatelet agents.^14-15 In 2023, the FDA approved low-dose colchicine for secondary prevention in adults with established atherosclerotic disease or multiple cardiovascular risk factors.

A very hot topic of late has been the role of sodium–glucose cotransporter 2 (SGLT2) inhibitors in the treatment of gout. Mechanistically, SGLT2 inhibitors lower serum urate by promoting glycosuria, which competes with urate for reabsorption in the proximal tubule and thus enhances urinary urate excretion. Additional anti-inflammatory effects, such as suppression of IL-1β and downregulation of xanthine oxidase via SIRT-1 signaling, may further contribute to reduced gout flares and cardiovascular risk. Meta-analyses of randomized controlled trials confirm that SGLT2 inhibitors significantly reduce the risk of composite gout outcomes, with dapagliflozin and canagliflozin showing particularly strong urate-lowering effects.^16-17 These benefits appear independent of baseline serum urate and are not limited to patients with diabetes, suggesting broader applicability in populations at risk for gout. Thus, SGLT2 inhibitors may offer dual benefit for patients with coexisting diabetes and gout, though the potential benefit for treating gout alone with these medications is less well established and should be considered adjunctive rather than primary therapy.

Even though gout is an old disease, the concepts covered by the speakers were timely and relevant to the clinical audience. Those in attendance looked into the crystal ball of gout and can see a future in which the disease continues to receive the research attention it deserves, leading to improvements in patient care.

Jason Liebowitz, MD, FACR, is an assistant professor of medicine in the Division of Rheumatology at Columbia University Vagelos College of Physicians and Surgeons, New York.

References

1. GBD 2021 Gout Collaborators. Global, regional, and national burden of gout, 1990-2020, and projections to 2050: a systematic analysis of the Global Burden of Disease Study 2021. Lancet Rheumatol. 2024 Aug;6(8):e507-e517.
2. Eun Y, Han K, Lee SW, et al. Altered Risk of Incident Gout According to Changes in Metabolic Syndrome Status: A Nationwide, Population-Based Cohort Study of 1.29 Million Young Men. Arthritis Rheumatol. 2023 May;75(5):806-815.
3. Eun Y, Han K, Lee SW, et al. Increased risk of incident gout in young men with metabolic syndrome: A nationwide population-based cohort study of 3.5 million men. Front Med (Lausanne). 2022 Nov 14;9:1010391.
4. McCormick N, O’Connor MJ, Yokose C, et al. Assessing the Causal Relationships Between Insulin Resistance and Hyperuricemia and Gout Using Bidirectional Mendelian Randomization. Arthritis Rheumatol. 2021 Nov;73(11):2096-2104.
5. 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 Jul 31;10(7):e0134088.
6. Cipolletta E, Tata LJ, Nakafero G, et al. Association Between Gout Flare and Subsequent Cardiovascular Events Among Patients With Gout. JAMA. 2022 Aug 2;328(5):440-450.
7. Ferguson LD, Molenberghs G, Verbeke G, et al. Gout and incidence of 12 cardiovascular diseases: a case-control study including 152 663 individuals with gout and 709 981 matched controls. Lancet Rheumatol. 2024 Mar;6(3):e156-e167.
8. Kuo CF, Grainge MJ, Mallen C, et al. Impact of gout on the risk of atrial fibrillation. Rheumatology (Oxford). 2016 Apr;55(4):721-8.
9. Sedighi J, Luedde M, Gaensbacher-Kunzendorf J, et al. The association between gout and subsequent cardiovascular events: a retrospective cohort study with 132,000 using propensity score matching in primary care outpatients in Germany. Clin Res Cardiol. 2025 Sep;114(9):1185-1190.
10. Wang Y, Deng X, Zhang X, et al. Presence of tophi and carotid plaque were risk factors of MACE in subclinical artherosclerosis patients with gout: a longitudinal cohort study. Front Immunol. 2023 Apr 18;14:1151782.
11. 2019, February 21. FDA adds Boxed Warning for increased risk of death with gout medicine Uloric (febuxostat). FDA.
12. White WB, Saag KG, Becker MA, et al. Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout. N Engl J Med. 2018 Mar 29;378(13):1200-1210.
13. Mackenzie IS, Ford I, Nuki G, et al. 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 Nov 28;396(10264):1745-1757.
14. Tardif JC, Kouz S, Waters DD, et al. Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction. N Engl J Med. 2019 Dec 26;381(26):2497-2505.
15. Nidorf SM, Fiolet ATL, Mosterd A, et al. Colchicine in Patients with Chronic Coronary Disease. N Engl J Med. 2020 Nov 5;383(19):1838-1847.
16. Banerjee M, Pal R, Maisnam I, et al. Serum uric acid lowering and effects of sodium-glucose cotransporter-2 inhibitors on gout: A meta-analysis and meta-regression of randomized controlled trials. Diabetes Obes Metab. 2023 Sep;25(9):2697-2703.
17. Hu Q, Yang S, Zhang B, et al. Effects of sodium-glucose cotransporter-2 inhibitors on serum urate levels and gout in patients with and without type 2 diabetes: a systematic review and network meta-analysis. Int J Clin Pharm. 2025 Oct;47(5):1162-1176.