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Excess comorbidities in gout: the causal paradigm and pleiotropic approaches to care

Abstract

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.

Key points

  • 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.

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Fig. 1: Contemporary prevalence and trends of cardiometabolic-renal conditions in gout populations.
Fig. 2: Causal pathways of gout CMR comorbidities and pleiotropic effects of CMR pharmacotherapies.
Fig. 3: Pleiotropic benefits of SGLT2 inhibitors in gout and CMR comorbidities.
Fig. 4: Shared inflammasome-pathway hypothesis: inflammation in gout and cardiovascular disease.
Fig. 5: Proposed personalized medicine framework for comorbidity care in gout.

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Acknowledgements

H.K.C. is supported by National Institutes of Health grants R01-AR065944 and P50-AR060772. N.M. is supported by a Fellowship Award from the Canadian Institutes of Health Research. C.Y. is supported by a Scientist Development Award from the Rheumatology Research Foundation.

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All authors researched data for the article. H.K.C. contributed substantially to discussion of the content. All authors wrote the article and reviewed and/or edited the manuscript before submission.

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H.K.C. reports research support from Ironwood and Horizon, and consulting fees from Ironwood, Selecta, Horizon, Takeda, Kowa and Vaxart. N.M. and C.Y. declare no competing interests.

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Glossary

Instrumental variables

Variables (for example, single or multiple genetic variants) that function as a proxy for the exposure of interest and must be associated with the exposure but cannot be independently associated with the outcome of interest (that is, outside its association with the exposure itself).

Non-pleiotropic variants

A genetic variant associated only with the exposure of interest (for example, serum urate levels) and not directly associated with the outcome of interest (for example, fasting insulin levels) or other traits that could be causal for the outcome of interest through a different pathway (for example, triglycerides).

Horizontal pleiotropy

When genetic variants can affect the outcome of interest through more than one biological pathway, including those that are independent of the exposure of interest.

Pleiotropic variants

Genetic variants associated with the exposure of interest (for example, serum urate levels) but also directly associated with additional traits (for example, triglyceride levels) that could affect the outcome of interest (for example, fasting insulin levels) independently of the main exposure.

Beam-hardening artefacts

Phenomena that occur when lower energy photons are selectively attenuated as they pass through a dense object.

Partial volume effects

Phenomena that occur when tissues of widely different absorption are included in the same CT voxel, producing a beam attenuation that is proportional to the average value of the tissues within the voxel.

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Choi, H.K., McCormick, N. & Yokose, C. Excess comorbidities in gout: the causal paradigm and pleiotropic approaches to care. Nat Rev Rheumatol 18, 97–111 (2022). https://doi.org/10.1038/s41584-021-00725-9

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