Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study

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
Baseline Characteristics
Characteristic Pioglitazone

(n = 26)

Placebo

(n = 26)

Demographics
Age (yr) 50 (11) 52 (12)
Male sex (%) 18 (69%) 13 (50%)
Race
White 23 (88%) 23 (88%)
Asian 1 (4%) 1 (4%)
Black 1 (4%) 0 (0%)
Comorbidities
Type 2 diabetes 9 (35%) 8 (31%)
Hyperlipidemia 9 (35%) 7 (27%)
Hypertension 15 (58%) 14 (54%)
Metabolic factors
Glycated HbA1c (%) 5.9% 6.0%
BMI (kg/m2) 34.2 37.7
Liver histology
Definite non-alcoholic steatohepatitis 26 (100%) 26 (100%)
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.

References

  1. 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.
  2. 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.
  3. Armstrong MJ, Adams LA, Canbay A, et al. Extra-hepatic complications of nonalcoholic fatty liver disease. Hepatology 2014; 59: 1174–97.
  4. 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.
  5. Sanyal AJ, Chalasani N, Kowdley KV, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010; 362: 1675–85.
  6. Ratziu V. Pharmacological agents for NASH. Nat Rev Gastroenterol Hepatol 2013; 10: 676–85.
  7. Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology 2007; 132: 2131–57.

 

 

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