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Brodosi et al. Hepatoma Res 2020;6:82 I http://dx.doi.org/10.20517/2394-5079.2020.88 Page 5 of 11

A beneficial role of liraglutide has been convincingly demonstrated in the pilot LEAN (Liraglutide Efficacy
[57]
and Action in NASH) study , a 48-week RCT in which liraglutide was tested vs. placebo in 52 patients
with biopsy-confirmed NASH. The study included patients with stage 3 fibrosis (38% in liraglutide vs.
8% in placebo) and cirrhosis (8% vs. 15%, respectively), and 35% of the liraglutide group had T2DM (vs.
31% in placebo). Liraglutide led to histologic NASH resolution in 35% of cases, compared with 8% of
placebo-treated patients [relative risk (RR) 4.5; 95%CI: 1.1-18.9; P = 0.017]. Specifically, liraglutide led to
the resolution of NASH in 3 out of 8 patients with T2DM (38%) (RR = 4.7, 95%CI: 0.3-75, P = 0.020), and
only 9% of patients in the liraglutide group vs. 36% in the placebo group had fibrosis progression during
treatment.

Less convincing data support a similar role for dulaglutide. A post-hoc analysis of the phase 3 AWARD
studies [Assessment of Weekly AdministRation of LY2189265 (Dulaglutide) in Diabetes], involving 760
patients with T2DM and high likelihood of NAFLD/NASH based on elevated ALT values and exclusion
of other hepatic diseases, showed a significantly greater reduction of ALT after 6-month treatment with
dulaglutide 1.5 mg once a week (-2.1 IU/L; 95%CI: -3.9 to -0.3; P = 0.022). Similar changes were observed
[58]
when the results were adjusted for body weight (-8.7 IU/L; 95%CI: -10.1 to -7.3) .
[59]
Exenatide also reduced ALT and AST levels in people with T2DM and elevated baseline ALT levels
in a case series of eight patients with NASH treated for 28 weeks. Some patients also experienced an
[60]
improvement in histological features, including fibrosis . Furthermore, the previously mentioned meta-
[48]
analysis by Carbone et al. showed a significant mean ALT reduction in both the liraglutide and exenatide
treated cohorts (mean 12.2 U/L; 95%CI: 4.9-19.4; P < 0.001). Finally, exenatide effectively reduced hepatic
triglyceride content compared to reference treatment (+12.5 ± 9.6%, P = 0.007, when assigned to 44 obese
[62]
[61]
subjects with T2DM , again in a weight loss-dependent manner; r = 0.47, P = 0.03). Cuthbertson et al.
reported a 42% median reduction of intracellular fat content (P < 0.0001), measured by magnetic resonance
spectroscopy (MRS), independently of weight loss, after six months of exenatide or liraglutide.

[63]
GLP-1RAs have also been investigated in combination with lifestyle interventions or other drugs. Fan et al.
found a significant reduction in ALT, AST, and gamma-glutamyl transpeptidase, and an increase in
the AST/ALT ratio in a cohort of 49 patients affected by both T2DM and NAFLD and treated by the
combination of exenatide and lifestyle interventions. The MRS-assessed hepatic content was significantly
higher in individuals receiving the combination of exenatide and pioglitazone for 12 months (12.1 ± 1.7 to 4.7
[64]
± 1.3%), however, compared with pioglitazone alone (11.0 ± 3.1 to 6.5 ± 1.9%) .

A phase 2 study of semaglutide, a longer-acting, weekly dosing GLP-1 analogue, has recently been completed.
A preliminary release reports that after 72 weeks of therapy with the highest dosage tested (0.4 mg),
33 of 56 patients (59%) with fibrosis stages F2 to F3 met the primary end-point of NASH resolution and no
worsening in liver fibrosis, vs. 10 of 58 patients (17%) in the control arm . Semaglutide is very effective on
[65]
body weight; a phase 3-4 trial in obesity reported a mean weight loss of 14.9% with semaglutide 2.4 mg/week
[66]
for 68 weeks, increasing to 17.4% at follow up . An oral formulation of semaglutide is also being tested in
[67]
pre-registration studies .

Concern on the use of GLP-1RA in NASH cirrhosis was recently raised by the observation that liraglutide.
While providing optimal control of blood glucose, HbA1c, and body weight in patients, it blunted the
[68]
effect of beta-blockers on heart rate, possibly indicating a raised bleeding risk after starting GLP-1RA .
The researchers proposed a mechanistic molecular explanation of how a GLP-1RA might prevent beta-
[69]
adrenergic receptor blockade . For this reason, the treatment of T2DM with GLP-1RA in subjects at risk
of bleeding requires additional studies.