Improvements in Liver Enzymes with Empagliflozin in the EMPA-REG OUTCOME Trial

Abstract

Empagliflozin (EMPA) reduces weight and HbA1c in patients with T2DM, but it is not known if it leads to reductions in elevated liver enzymes reflective of liver fat. We investigated the effect of EMPA on liver transaminases in the EMPA-REG OUTCOME trial. Patients with T2DM and established CV disease were randomized to receive EMPA 10 mg, EMPA 25 mg, or placebo (PBO) in addition to standard of care. Changes from baseline in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were assessed in all treated patients (N=7020) and in tertiles by baseline ALT or AST. In the EMPA group, ALT decreased from baseline to week 28 and then remained stable. In the PBO group, ALT declined steadily to a lesser extent. Reductions in ALT were greatest in the highest tertile of baseline ALT (tertile 3). In the lowest tertile, changes in ALT were similar between EMPA and PBO. AST decreased from baseline to week 28 and then remained stable with EMPA; there were no relevant changes with PBO. Changes from baseline in AST were generally similar between EMPA and PBO at weeks 28 and 164 in the second and third tertiles, but were greater with EMPA than PBO in the highest tertile by baseline AST. Similar patterns were observed in analysis of pooled Phase III trial data and a trial of EMPA vs. glimepiride. In conclusion, EMPA reduced ALT and AST vs. PBO in the EMPA-REG OUTCOME trial, with greater reductions in ALT than AST, in a pattern consistent with a reduction in liver fat. Table. Changes in ALT and AST in the EMPA-REG OUTCOME trial.ALT (U/L)AST (U/L)Week 28PBOEMPAPBOEMPAAll patientsChange from baseline-0.73 (0.25)-2.96 (0.18)-0.31 (0.20)-1.32 (0.14)Difference vs PBO-2.22 (-2.83, -1.62)***-1.01 (-1.48, -0.54)***Tertile 1Change from baseline1.57 (0.51)1.51 (0.36)1.88 (0.38)1.72 (0.27)Difference vs PBO-0.06 (-1.27, 1.15)-0.16 (-1.08. 0.75)Tertile 2Change from baseline0.29 (0.51)-1.15 (0.35)0.70 (0.36)-0.03 (0.26)Difference vs PBO-1.45 (-2.65, -0.24)*-0.73 (-1.61, 0.14)Tertile 3Change from baseline-3.96 (0.48)-8.33 (0.35)-3.15 (0.34)-4.69 (0.24)Difference vs PBO-4.36 (-5.51, -3.21)***-1.53 (-2.35, -0.72)***Week 164All patientsChange from baseline-1.80 (0.36)-3.(0.25)-0.51 (0.33)-1.17 (0.23)Difference vs PBO-1.26 (-2.12, -0.40)**-0.66 (-1.45, 0.13)Tertile 1Change from baseline2.46 (0.72)2.32 (0.49)2.69 (0.67)2.51 (0.45)Difference vs PBO-0.13 (-1.84, 1.58)-0.18 (-1.75, 1.39)Tertile 2Change from baseline0.04 (0.71)-0.86 (0.48)1.17 (0.61)0.73 (0.42)Difference vs PBO-0.91 (-2.59, 0.77)-0.44 (-1.88, 1.00)Tertile 3Change from baseline-7.33 (0.65)-9.54 (0.46)-4.51 (0.57)-5.50 (0.39)Difference vs PBO-2.22 (-3.78, -0.66)**-0.99 (-2.34, 0.36)Mixed model repeated measures analysis in patients treated with ≥1 dose of study drug based on observed cases. Changes from baseline are adjusted mean (standard error). Differences vs PBO are adjusted mean (95% confidence interval). Tertile 3 indicates the highest tertile by baseline value. All patients: N=2333 for PBO; N=4686 for EMPA. *p<0.05; **p<0.01; ***p<0.001 Disclosure N. Sattar: Advisory Panel; Self; Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Boehringer Ingelheim GmbH, Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S, Eli Lilly and Company. Research Support; Self; Boehringer Ingelheim GmbH. Advisory Panel; Self; Amgen Inc.. Speaker's Bureau; Self; Amgen Inc., AstraZeneca, Mitsubishi Tanabe Pharma Corporation, Medscape, Sanofi-Aventis Deutschland GmbH. D.H. Fitchett: Advisory Panel; Self; Boehringer Ingelheim GmbH, Eli Lilly and Company. Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; Amgen Inc., Sanofi. S. Hantel: Employee; Self; Boehringer Ingelheim GmbH. J.T. George: Employee; Self; Boehringer Ingelheim GmbH. B. Zinman: Consultant; Self; Novo Nordisk A/S, Boehringer Ingelheim Pharmaceuticals, Inc., AstraZeneca, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Sanofi, Merck & Co., Inc., Abbott.