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

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

APPROACH RESULTS: Single nucleotide polymorphisms (SNPs) associated with SGLT2 inhibition were identified, and a genetic risk score (GRS) was computed using the UK Biobank (UKB) data (n=337,138). Two-sample Mendelian randomization (MR) was conducted using the FinnGen (n=218,792) database and UKB 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 (i.e., hepatic decompensation, hepatocellular carcinoma, 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 (DPP4i) (n=70,342). After computing GRS with six SNPs (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% confidence interval [CI]=0.70-0.98, p=0.03) and this was consistent in two-sample MR (odds ratio=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 DPP4i group (adjusted hazard ratio [aHR]=0.88, 95% CI=0.79-0.97, p=0.01), and this difference remained significant (aHR=0.72-0.89, all p<0.05) across various sensitivity analyses.

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