Liraglutide resolved NASH in 39% of patients in small UK trial

A phase 2 trial in the United Kingdom found that the GLP-1 drug liraglutide resolved non-alcoholic steatohepatitis (NASH) in 39 percent of patients who received it, compared with 9 percent of those on placebo, according to results published Nov. 20, 2015 ^[1].

The study, called LEAN, was a multicentre, double-blind, randomised, placebo-controlled phase 2 trial run at four UK medical centers. Researchers enrolled 52 overweight patients with clinical evidence of NASH and assigned 26 to daily subcutaneous liraglutide 1.8 mg and 26 to placebo. Treatment lasted 48 weeks. The main measure was resolution of definite NASH with no worsening of fibrosis, judged centrally by two independent pathologists who did not know which treatment each patient had received. Enrollment ran from Aug. 1, 2010, to May 31, 2013. The design required 8 of 21 successes (38 percent) in the liraglutide group for the effect to count as clinically significant ^[1].

Among patients who had an end-of-treatment liver biopsy, 9 of 23 in the liraglutide group (39 percent) had resolution of definite NASH, compared with 2 of 22 in the placebo group (9 percent). The relative risk was 4.3, with a 95 percent confidence interval of 1.0 to 17.7 (p=0.019). Fibrosis got worse in 2 of 23 liraglutide patients (9 percent) and 8 of 22 placebo patients (36 percent) (0.2, 95 percent CI 0.1-1.0; p=0.04) ^[1].

Side effects were mostly mild (grade 1) to moderate (grade 2), short-lived, and similar between groups for all organ classes and symptoms except gastrointestinal problems, which occurred in 21 of 23 liraglutide patients (81 percent) and 17 of 22 placebo patients (65 percent). These included diarrhoea (10 patients, 38 percent, on liraglutide vs 5, 19 percent, on placebo), constipation (7, 27 percent, vs none) and loss of appetite (8, 31 percent, vs 2, 8 percent) ^[1].

The authors concluded that liraglutide was safe and well tolerated and led to histological resolution of NASH, and said the findings warranted extensive, longer-term studies. The trial was funded by the Wellcome Trust, the National Institute for Health Research and Novo Nordisk ^[1].

Why it matters for patients

When the trial began, GLP-1 analogs were licensed for type 2 diabetes and their effectiveness in NASH was unknown ^[1]. The results are the kind of early signal that can lead to larger studies, but a 52-person phase 2 trial is not proof that a drug treats liver disease. Only 23 liraglutide patients and 22 placebo patients had the biopsy used for the main result ^[1].

The confidence interval for the main result ran from 1.0 to 17.7, meaning the data are consistent with anything from almost no advantage to a large one ^[1].

The trial tested liraglutide only. Whether the liver findings extend to semaglutide (sold as Ozempic, Wegovy and Rybelsus) or tirzepatide (sold as Mounjaro and Zepbound) is not established by this publication, which tested none of those medicines ^[1]. People taking a GLP-1 medicine for diabetes or weight loss cannot assume a liver benefit from this trial, and the publication records no approved liver indication for liraglutide ^[1].

What happens next

The trial is registered with ClinicalTrials.gov as NCT01237119 ^[1]. The authors' stated next step was extensive, longer-term research ^[1]. The Lancet published a commentary on the trial in February 2016 and correspondence about it in June 2016 ^[1]. Whether any larger follow-up liver study of liraglutide was completed, and what it found, is not reported in the trial publication ^[1].