Coding variants in PNPLA3 and TM6SF2 are risk factors for hepatic steatosis and elevated serum alanine aminotransferases caused by a glucagon receptor antagonist

Cristina B Guzman; Suman Duvvuru; Anthony Akkari; Pallav Bhatnagar; Chakib Battioui; Wendra Foster; Xiaotian Michelle Zhang; Sudha S Shankar; Mark A Deeg; Naga Chalasani; Thomas A Hardy; Christof M Kazda; Sreekumar G Pillai

doi:10.1002/hep4.1171

Coding variants in PNPLA3 and TM6SF2 are risk factors for hepatic steatosis and elevated serum alanine aminotransferases caused by a glucagon receptor antagonist

Hepatol Commun. 2018 Mar 23;2(5):561-570. doi: 10.1002/hep4.1171. eCollection 2018 May.

Authors

Cristina B Guzman^{1

2}, Suman Duvvuru^{1

3}, Anthony Akkari⁴, Pallav Bhatnagar¹, Chakib Battioui¹, Wendra Foster¹, Xiaotian Michelle Zhang⁵, Sudha S Shankar^{1

6}, Mark A Deeg^{1

7}, Naga Chalasani⁸, Thomas A Hardy¹, Christof M Kazda⁹, Sreekumar G Pillai¹

Affiliations

¹ Eli Lilly and Company Indianapolis IN.
² Present address: Enanta Pharmaceuticals Inc Watertown MA.
³ Present address: Amazon Seattle WA.
⁴ Cabernet Pharmaceuticals Durham NC.
⁵ Eli Lilly and Company Toronto Canada.
⁶ Present address: NGM Biopharmaceuticals San Francisco CA.
⁷ Present address: Regulus Pharmaceuticals San Diego CA.
⁸ Indiana University Department of Medicine Indianapolis IN.
⁹ Eli Lilly and Company Neuilly sur Seine France.

Abstract

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 (PNPLA3) (rs738409 and rs738491), transmembrane 6 superfamily member 2 (TM6SF2) (rs58542926), peroxisome proliferative activated receptor gamma coactivator 1 alpha (PPARGC1A) (rs4361373, rs3774921, rs2970849), adenylate cyclase 3 (ADCY3) (rs713586), and insulin-like growth factor 1 (IGF-1) (rs1520220). In GLDI, PNPLA3 I148M (P = 0.001) and TM6SF2 E167K (P = 0.001) were significantly associated with an increase in ALT at 6 weeks for LY2409021 but not for placebo. In GLDJ, PNPLA3 I148M showed the same effect (P = 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 PNPLA3 and/or TM6SF2 risk alleles showed significantly increased ALT (GLDI, +13.28 U/L in carriers versus +4.84 U/L in noncarriers, P = 4 × 10^-5; GLDJ, +14.6 U/L in carriers versus +1.7 in noncarriers, P = 0.0018) and HFF (GLDJ, +5.35% in carriers versus 2.38% in noncarriers, P = 0.048). Elevation of transaminase and HFF were also noted in the noncarriers but at a significantly lower degree. Conclusion: The carriers of PNPLA3 and/or TM6SF2 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. (Hepatology Communications 2018;2:561-570).