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

Abstract

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 1.8 mg reduced ALT in these patients vs. placebo (−8.20 vs. −5.01 IU/L; P = 0.003), and was dose‐dependent (no significant differences vs. placebo with liraglutide 0.6 or 1.2 mg). This effect was lost after adjusting for liraglutide's reduction in weight (mean ALT difference vs. placebo −1.41 IU/L, P = 0.21) and HbA1c (+0.57 IU/L, P = 0.63). Adverse effects with 1.8 mg liraglutide were similar between patients with and without baseline abnormal ALT. In LEAD‐2 sub‐study, liraglutide 1.8 mg 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 HbA_1c (0.00, P = 0.93). Conclusions Twenty‐six weeks' liraglutide 1.8 mg 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.