Inhibition of sodium-glucose cotransporter-2 and liver-related complications in individuals with diabetes: a Mendelian randomization and population-based cohort study

Sung Won Chung; Hye-Sung Moon; Hyunjae Shin; Hyein Han; Sehoon Park; Heejin Cho; Jeayeon Park; Moon Haeng Hur; Min Kyung Park; Sung-Ho Won; Yun Bin Lee; Eun Ju Cho; Su Jong Yu; Dong Ki Kim; Jung-Hwan Yoon; Jeong-Hoon Lee; Yoon Jun Kim

doi:10.1097/HEP.0000000000000837

Inhibition of sodium-glucose cotransporter-2 and liver-related complications in individuals with diabetes: a Mendelian randomization and population-based cohort study

Hepatology. 2024 Mar 11. doi: 10.1097/HEP.0000000000000837. Online ahead of print.

Authors

Sung Won Chung^{1

2}, Hye-Sung Moon³, Hyunjae Shin¹, Hyein Han⁴, Sehoon Park⁵, Heejin Cho¹, Jeayeon Park¹, Moon Haeng Hur¹, Min Kyung Park¹, Sung-Ho Won^{3

4

6

7}, Yun Bin Lee¹, Eun Ju Cho¹, Su Jong Yu¹, Dong Ki Kim⁵, Jung-Hwan Yoon¹, Jeong-Hoon Lee^{1

8}, Yoon Jun Kim¹

Affiliations

¹ Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea.
² Division of Gastroenterology, Liver Center, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
³ RexSoft Inc., Seoul, South Korea.
⁴ Department of Public Health Sciences, Graduate School of Public Health, Seoul National University, Seoul, South Korea.
⁵ Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea.
⁶ Interdisciplinary Program for Bioinformatics, College of Natural Science, Seoul National University, Seoul, South Korea.
⁷ Institute of Health and Environment, Seoul National University, Seoul, South Korea.
⁸ Inocras, Inc., San Diego, California, USA.

PMID: 38466796
DOI: 10.1097/HEP.0000000000000837

Abstract

Background and aims: No medication has been found to reduce liver-related events. We evaluated the effect of sodium-glucose cotransporter-2 inhibitor (SGLT2i) on liver-related outcomes.

Approach and results: Single nucleotide polymorphisms associated with SGLT2 inhibition were identified, and a genetic risk score (GRS) was computed using the UK Biobank data (n=337,138). Two-sample Mendelian randomization (MR) was conducted using the FinnGen (n=218,792) database and the UK Biobank data. In parallel, a nationwide population-based study using the Korean National Health Insurance Service (NHIS) database was conducted. The development of liver-related complications (ie, hepatic decompensation, HCC, liver transplantation, and death) was compared between individuals with type 2 diabetes mellitus and steatotic liver diseases treated with SGLT2i (n=13,208) and propensity score-matched individuals treated with dipeptidyl peptidase-4 inhibitor (n=70,342). After computing GRS with 6 single nucleotide polymorphisms (rs4488457, rs80577326, rs11865835, rs9930811, rs34497199, and rs35445454), GRS-based MR showed that SGLT2 inhibition (per 1 SD increase of GRS, 0.1% lowering of HbA1c) was negatively associated with cirrhosis development (adjusted odds ratio=0.83, 95% CI=0.70-0.98, p =0.03) and this was consistent in the 2-sample MR (OR=0.73, 95% CI=0.60-0.90, p =0.003). In the Korean NHIS database, the risk of liver-related complications was significantly lower in the SGLT2i group than in the dipeptidyl peptidase-4 inhibitor group (adjusted hazard ratio=0.88, 95% CI=0.79-0.97, p =0.01), and this difference remained significant (adjusted hazard ratio=0.72-0.89, all p <0.05) across various sensitivity analyses.

Conclusions: Both MRs using 2 European cohorts and a Korean nationwide population-based cohort study suggest that SGLT2 inhibition is associated with a lower risk of liver-related events.