Gout & Cardiometabolic Co-Morbidities

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.