LAUSR

Gout is a common hyperuricaemic metabolic condition that leads to painful inflammatory arthritis and a high comorbidity burden, especially cardiometabolic-renal (CMR) conditions, including hypertension, myocardial infarction, stroke, obesity, hyperlipidaemia, type 2 diabetes mellitus and chronic kidney disease. Substantial advances have been made in our understanding of the excess CMR burden in gout, ranging from pathogenesis underlying excess CMR comorbidities, inferring causal relationships from Mendelian randomization studies, and potentially discovering urate crystals in coronary arteries using advanced imaging, to clinical trials and observational studies. Despite many studies finding an independent association between blood urate levels and risk of incident CMR events, Mendelian randomization studies have largely found that serum urate is not causal for CMR end points or intermediate risk factors or outcomes (such as kidney function, adiposity, metabolic syndrome, glycaemic traits or blood lipid concentrations). Although limited, randomized controlled trials to date in adults without gout support this conclusion. If imaging studies suggesting that monosodium urate crystals are deposited in coronary plaques in patients with gout are confirmed, it is possible that these crystals might have a role in the inflammatory pathogenesis of increased cardiovascular risk in patients with gout; removing monosodium urate crystals or blocking the inflammatory pathway could reduce this excess risk. Accordingly, data for CMR outcomes with these urate-lowering or anti-inflammatory therapies in patients with gout are needed. In the meantime, highly pleiotropic CMR and urate-lowering benefits of sodium–glucose cotransporter 2 (SGLT2) inhibitors and key lifestyle measures could play an important role in comorbidity care, in conjunction with effective gout care based on target serum urate concentrations according to the latest guidelines. In this Review, Choi et al. review the pathogenesis of cardiometabolic-renal comorbidities of gout and discuss potential therapies to concurrently reduce serum urate concentrations and risk of gout cardiometabolic-renal comorbidities. Exacerbated by the ‘Western’ lifestyle and obesity epidemics, the frequency and burden of gout, a hyperuricaemic metabolic condition complicated by excess cardiometabolic-renal (CMR) comorbidities and sequelae, have risen worldwide for decades. Many prospective studies have associated blood urate levels with the development of incident CMR events, but evidence from Mendelian randomization studies and randomized controlled trials does not support a causal effect for serum (soluble) urate. In addition to activating inflammasome pathways and inducing gout flares in joints, monosodium urate crystals might also deposit in coronary plaques and have pro-inflammatory roles in the pathogenesis of excess cardiovascular risk associated with gout, analogous to cholesterol crystals. Sodium–glucose cotransporter 2 (SGLT2) inhibitors, with their highly pleiotropic CMR and urate-lowering benefits, are an attractive alternative or adjunct therapy for patients with gout, although more evidence of their effects in gout populations is needed. The downstream effects of weight loss and lifestyle modification, including adherence to healthy cardiometabolic diets, should simultaneously reduce CMR risk and serum urate concentrations and the risk of incident gout. Pharmacotherapy and diet and lifestyle recommendations for gout prevention and management can be guided by concurrent CMR comorbidities and shared decision-making that reflects patient preferences.