Sodium-glucose cotransporter 1 inhibition and gout: Mendelian randomization study

Sizheng Steven Zhao, Skanda Rajasundaram, Ville Karhunen, Uazman Alam, Dipender Gill

Research output: Contribution to journalArticlepeer-review

Abstract

Objective. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) reduce serum urate, but their efficacy depends on renal function which is often impaired in patients with gout. SGLT1 is primarily expressed in the small intestine and its inhibition may be a more suitable target for gout. We aimed to investigate the association of genetically proxied SGLT1i with gout risk, serum urate levels and cardiovascular safety using Mendelian randomization (MR).

Methods. Leveraging data from a genome-wide association study of 344,182 individuals in the UK Biobank, we identified a missense variant in the SLC5A1 gene that associated with glycated haemoglobin (HbA1c) to proxy SGLT1i. Outcome genetic data comprised 13,179 gout cases and 750,634 controls, 457,690 individuals for serum urate levels, and up to 977,323 individuals for cardiovascular safety outcomes. We applied the Wald ratio method and investigated potential genetic confounding using colocalization.

Results. The rs17683430 missense variant was selected to instrument SGLT1i. Genetically proxied SGLT1i was associated with 75% reduction in gout risk (OR 0.25; 95%CI 0.06, 0.99; p=0.048) and 32.0μmol/L reduction in serum urate (95%CI -56.7, -7.3; p=0.01), per 6.7mmol/mol reduction in HbA1c. SGLT1i was associated with increased levels of low-density lipoprotein cholesterol (0.37mmol/L; 95%CI 0.17, 0.56; p=0.0002) but not coronary heart disease, stroke, or chronic kidney disease. Colocalization did not suggest that the results are attributable to genetic confounding.

Conclusion. SGLT1 inhibition may represent a novel therapeutic option for preventing gout in patients with or without comorbid diabetes. Randomised trials are needed to formally investigate efficacy and safety.

Keywords: Sodium-glucose cotransporter, gout, urate, cholesterol, SGLT1, glycated haemoglobin, diabetes.
Original languageEnglish
JournalSeminars in arthritis and rheumatism
Publication statusAccepted/In press - 27 Jun 2022

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