Inhibition of sodium-glucose cotransporter-2 and... : Hepatology (original) (raw)

Original Articles: Steatohepatitis

Chung, Sung Won1,2; Moon, Hye-Sung3; Shin, Hyunjae1; Han, Hyein4; Park, Sehoon5; Cho, Heejin1; Park, Jeayeon1; Hur, Moon Haeng1; Park, Min Kyung1; Won, Sung-Ho3,4,6,7; Lee, Yun Bin1; Cho, Eun Ju1; Yu, Su Jong1; Kim, Dong Ki5; Yoon, Jung-Hwan1; Lee, Jeong-Hoon1,8; Kim, Yoon Jun1

1Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea

2Division of Gastroenterology, Liver Center, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea

3RexSoft Inc., Seoul, South Korea

4Department of Public Health Sciences, Graduate School of Public Health, Seoul National University, Seoul, South Korea

5Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea

6Interdisciplinary Program for Bioinformatics, College of Natural Science, Seoul National University, Seoul, South Korea

7Institute of Health and Environment, Seoul National University, Seoul, South Korea

8Inocras, Inc., San Diego, California, USA

Abbreviations: aHR, adjusted hazard ratio; AMPK, adenosine monophosphate–activated protein kinase; DPP4i, dipeptidyl peptidase-4 inhibitor; GLP-1, glucagon-like peptide; GRS, genetic risk score; GWAS, genome-wide association study; IVW, inverse-variance weighted; MASLD, metabolic dysfunction–associated steatotic liver disease; MetALD, metabolic dysfunction associated and alcohol associated liver disease; MR, Mendelian randomization; NHIS, National Health Insurance Service; OAD, oral antidiabetic drug; SGLT2i, sodium-glucose cotransporter-2 inhibitor; SLD, steatotic liver disease; T2DM, type 2 diabetes mellitus; UKB, UK Biobank.

Sung Won Chung, Hye-Sung Moon, and Hyunjae Shin equally contributed as co-first authors.

Jeong-Hoon Lee and Yoon Jun Kim equally contributed as co-corresponding authors.

Correspondence Yoon Jun Kim, Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea. Email: [email protected]

Jeong-Hoon Lee, Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea. Email: [email protected]; [email protected]

Supplemental Digital Content is available for this article. Direct URL citations are provided in the HTML and PDF versions of this article on the journal's website, www.hepjournal.com.

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.

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