title: 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.
  
  
  OBJECTIVE
  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.
authors.affiliation: Centre for Liver Research and NIHR Liver Biomedical Research Unit, University of Birmingham, Birmingham, UK. mattyarm@doctors.org.uk
authors.forename: M J
authors.initials: MJ
authors.lastname: Armstrong
authors.forename: D D
authors.initials: DD
authors.lastname: Houlihan
authors.forename: I A
authors.initials: IA
authors.lastname: Rowe
authors.forename: W H O
authors.initials: WH
authors.lastname: Clausen
authors.forename: B
authors.initials: B
authors.lastname: Elbrønd
authors.forename: S C L
authors.initials: SC
authors.lastname: Gough
authors.forename: J W
authors.initials: JW
authors.lastname: Tomlinson
authors.forename: P N
authors.initials: PN
authors.lastname: Newsome
mesh_terms: D000410:Alanine Transaminase / Q000378:metabolism*; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D005234:Fatty Liver / Q000188:drug therapy* / Q000201:enzymology; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D000069450:Liraglutide; D008099:Liver / Q000201:enzymology*; D008111:Liver Function Tests; D008297:Male; D065626:Non-alcoholic Fatty Liver Disease; D016032:Randomized Controlled Trials as Topic; D016896:Treatment Outcome; D015431:Weight Loss
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1; D000410:Alanine Transaminase