Coding variants in and are risk factors for hepatic steatosis and elevated serum alanine aminotransferases caused by a glucagon receptor antagonist.

LY2409021 is a glucagon receptor antagonist that was associated with hepatic steatosis and elevated aminotransferases in phase 2 diabetes studies. We investigated the relationship between selected genetic variants and hepatic steatosis and elevated alanine aminotransferases (ALTs) associated with LY2409021. Patients participated in a 6-week placebo-controlled trial (I1R-MC-GLDI [GLDI], n = 246) and a 52-week placebo- and active comparator-controlled trial (I1R-MC-GLDJ [GLDJ], n = 158). GLDJ had endpoints at 6 months, including measures of hepatic fat fraction (HFF) by magnetic resonance imaging. The five genes tested were patatin-like phospholipase domain containing 3 () (rs738409 and rs738491), transmembrane 6 superfamily member 2 () (rs58542926), peroxisome proliferative activated receptor gamma coactivator 1 alpha () (rs4361373, rs3774921, rs2970849), adenylate cyclase 3 () rs713586), and insulin-like growth factor 1 () (rs1520220). In GLDI, I148M ( = 0.001) and E167K ( = 0.001) were significantly associated with an increase in ALT at 6 weeks for LY2409021 but not for placebo. In GLDJ, I148M showed the same effect ( = 0.007) on ALT at 6 months but the placebo or sitagliptin did not. In GLDJ, both PNPLA3 and TM6SF2 risk-allele carriers showed increases in HFF that were numerically greater but not statistically significant. The carriers of and/or risk alleles showed significantly increased ALT (GLDI, +13.28 U/L in carriers versus +4.84 U/L in noncarriers, = 4 × 10; GLDJ, +14.6 U/L in carriers versus +1.7 in noncarriers, = 0.0018) and HFF (GLDJ, +5.35% in carriers versus 2.38% in noncarriers, = 0.048). Elevation of transaminase and HFF were also noted in the noncarriers but at a significantly lower degree. The carriers of and/or variant alleles are at risk for hepatic steatosis and elevated ALT levels caused by LY2409021, a glucagon receptor antagonist. More studies are needed to investigate if our observations are generalizable to hepatic steatosis caused by other medications. ( 2018;2:561-570).