Zhao, S. S., Rajasundaram, S., Karhunen, V., Alam, U., & Gill, D. (2022). Sodium-glucose cotransporter 1 inhibition and gout: Mendelian randomisation study. Seminars in Arthritis and Rheumatism, 56, 152058. https://doi.org/10.1016/j.semarthrit.2022.152058
Sodium-glucose cotransporter 1 inhibition and gout : Mendelian randomisation study
|Author:||Zhao, Sizheng Steven1; Rajasundaram, Skanda2,3; Karhunen, Ville4,5;|
1Centre for Epidemiology Versus Arthritis, Division of Musculoskeletal and Dermatological Science, School of Biological Sciences, Faculty of Biological Medicine and Health, The University of Manchester, Manchester Academic Health Science Centre, Stopford Building, Oxford Road, Manchester M13 9PT, UK
2Centre for Evidence-Based Medicine, University of Oxford, Oxford, UK
3Faculty of Medicine, Imperial College London, London, UK
4Research Unit of Mathematical Sciences, University of Oulu, Oulu, Finland
5Center for Life Course Health Research, University of Oulu, Oulu, Finland
6Institute of Life Course and Medical Sciences and the Pain Research Institute, University of Liverpool, Liverpool, UK
7Department of Diabetes & Endocrinology, Liverpool University Hospital NHS Foundation Trust, Liverpool, UK
8Division of Diabetes, Endocrinology and Gastroenterology, Institute of Human Development, University of Manchester, Manchester, UK
9Centre of Excellence in Genetics, Novo Nordisk Research Centre Oxford, Oxford, UK
10Department of Epidemiology and Biostatistics, Imperial College London, London, UK
11Medical Research Council Biostatistics Unit, University of Cambridge, Cambridge, UK
|Online Access:||PDF Full Text (PDF, 0.9 MB)|
|Persistent link:|| http://urn.fi/urn:nbn:fi-fe2022122873962
|Publish Date:|| 2022-12-28
Objective: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) reduce serum urate, but their efficacy depends on renal function which is often impaired in people with gout. SGLT1 is primarily expressed in the small intestine and its inhibition may be a more suitable therapeutic target. We aimed to investigate the association of genetically proxied SGLT1i with gout risk, serum urate levels and cardiovascular safety using Mendelian randomisation (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 32.0 μmol/L reduction in serum urate (95%CI −56.7, −7.3; p = 0.01), per 6.7 mmol/mol reduction in HbA1c. SGLT1i was associated with increased levels of low-density lipoprotein cholesterol (0.37 mmol/L; 95%CI 0.17, 0.56; p = 0.0002) but not risk of coronary heart disease, stroke, or chronic kidney disease. Colocalization did not suggest that results are attributable to genetic confounding.
Conclusion: SGLT1 inhibition may represent a novel therapeutic option for preventing gout in people with or without comorbid diabetes. Randomised trials are needed to formally investigate efficacy and safety.
Seminars in arthritis and rheumatism
|Type of Publication:||
A1 Journal article – refereed
|Field of Science:||
3121 General medicine, internal medicine and other clinical medicine
All summary statistics used in this study are publicly available, with relevant citations detailed. UK Biobank data are available to all bona fide researchers for use in health-related research that is in the public interest. The application procedure is described at www.ukbiobank.ac.uk. The current analysis was performed under application number 72723.
© 2022 The Author(s). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).