Aderonke Adeboye, PharmD Mercer University College of Pharmacy
Non-alcoholic steatohepatitis is stated to be the most common cause of liver disease.2 Researchers have found that patients with non-alcoholic steatohepatitis are at greater risk of morbidity and mortality related to liver and cardiovascular complications.3 Per guidelines for the management of non-alcoholic fatty liver disease, lifestyle modifications associated with maintaining dietary and weight loss goals are the mainstay of treatment.2
Previous studies utilizing treatment with pioglitazone, vitamin E (PIVENS trial), and obeticholic acid (FLINT trial) compared to placebo were associated with improvements in liver histology.4,5 It is suggested that concerns for the long-term safety profile of both pioglitazone and vitamin E have limited the use of both agents.6 With the correlation of metabolic syndrome to non-alcoholic steatohepatitis, researchers have found that there is growing rationale for therapies utilizing glucagon-like peptide-1 (GLP-1).7
|Title: Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study|
|Design||Multicenter, double-blind, randomized, placebo controlled; N = 52|
|Objective||Assess the safety and efficacy of the long-acting GLP-1 analogue, liraglutide, in patients with non-alcoholic steatohepatitis|
|Study Groups||Liraglutide (n = 26); placebo (n = 26)|
|Methods||Patients where randomly assigned in a 1:1 ratio to receive either once-daily subcutaneous injections of 1.8 mg liraglutide or placebo. To improve gastrointestinal tolerability ,all enrolled patients underwent a 14 day dose titration until the maximum dose of 1.8 mg daily was achieved.
|Duration||August 1, 2010 to May 31, 2013|
|Primary Outcome Measure||Improvement in liver histology from baseline to end of treatment|
|Results||In an intent to treat analysis, resolution of definite non-alcoholic steatohepatitis from baseline to end of treatment occurred in 9 (39%) of 23 patients in the liraglutide group and in 2 (9%) of 23 patients in the placebo group (relative risk 4.3; 95% CI interval, 1.0 to 17.7; p = 0.019).|
|Adverse Events||Common Adverse Events: gastrointestinal disorders (81%), nausea (46%), diarrhea (l38%)|
|Serious Adverse Events: N/A|
|Percentage that Discontinued due to Adverse Events: liraglutide (8%)|
|Study Author Conclusions||Liraglutide was safe, well tolerated, and its use led to histological resolution of non-alcoholic steatohepatitis.|
The LEAN study was the first randomized, placebo controlled, trial to report the effects of a GLP-1 analogue on liver histology in patients with non-alcoholic steatohepatitis. In comparison to the PIVENS trial and FLINT trial, this study included patients with only non-alcoholic steatohepatitis by maintaining two independent blinded central assessments of liver biopsies at baseline and at the end of treatment. A limitation of this study would be its smaller sample size compared to later stage phase II studies. For future studies, a focus on a larger sample size may further strengthen the findings in this trial.
- Armstrong MJ, Gaunt P, Aithal GP, et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet. 2016;387(10019):679-90.
- Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology. Gastroenterology 2012; 142: 1592–609.
- Armstrong MJ, Adams LA, Canbay A, et al. Extra-hepatic complications of nonalcoholic fatty liver disease. Hepatology 2014; 59: 1174–97.
- Neuschwander-Tetri BA, Loomba R, Sanyal AJ, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 2015; 385: 956–65.
- Sanyal AJ, Chalasani N, Kowdley KV, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010; 362: 1675–85.
- Ratziu V. Pharmacological agents for NASH. Nat Rev Gastroenterol Hepatol 2013; 10: 676–85.
- Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology 2007; 132: 2131–57.