Safety and efficacy of liraglutide in patients with type 2 diabetes and elevated liver enzymes: individual patient data meta-analysis of the LEAD program

Background Non-alcoholic fatty liver disease has reached epidemic proportions in type 2 diabetes (T2D). Glucagon-like peptide-1 analogues are licensed in T2D, yet little data exist on efficacy and safety in liver injury. Aim To assess the safety and efficacy of 26-week liraglutide on liver parameters in comparison with active-placebo. Methods Individual patient data meta-analysis was performed using patient-level data combined from six 26-week, phase-III, randomised controlled T2D trials, which comprise the Liraglutide Effect and Action in Diabetes (LEAD) program. The LEAD-2 sub-study was analysed to assess the effect on CT-measured hepatic steatosis. Results Of 4442 patients analysed, 2241 (50.8%) patients had an abnormal ALT at baseline [mean ALT 33.8(14.9)IU/L in females; 47.3(18.3)IU/L in males]. Liraglutide 1.8mg reduced ALT in these patients vs. placebo (-8.20 vs. -5.01IU/L; P=0.003), and was dose-dependent (no significant differences vs. placebo with liraglutide 0.6 or 1.2mg). This effect was lost after adjusting for liraglutide's reduction in weight (mean ALT difference vs. placebo -1.41IU/L, P=0.21) and HbA1c (+0.57IU/L, P=0.63). Adverse effects with 1.8mg liraglutide were similar between patients with and without baseline abnormal ALT. In LEAD-2 sub-study, liraglutide 1.8mg showed a trend towards improving hepatic steatosis vs. placebo (liver-to-spleen attenuation ratio +0.10 vs. 0.00; P=0.07). This difference was reduced when correcting for changes in weight (+0.06, P=0.25) and HbA1c (0.00, P=0.93). Conclusions Twenty-six weeks' liraglutide 1.8mg is safe, well tolerated and improves liver enzymes in patients with type 2 diabetes. This effect appears to be mediated by its action on weight loss and glycaemic control.