Glucagon-like peptide-1 receptor agonists in non-alcoholic fatty liver disease: An update

Table 1 Characteristics and outcomes of clinical studies that evaluated the effects of exenatide, lisixenatide and dulaglutide on non-alcoholic fatty liver disease

Ref.	Type of study, country	Number of patients	Treatment	Effects on NAFLD
Gastaldelli et al[30], 2016	Randomized double-blind vs placebo/Pisa, Italy	15	Exenatide 5 μg vs placebo 30 min before a 75-g OGTT	Exenatide significantly ameliorated oral glucose absorption, hepatic glucose production, hepatic and adipose tissue insulin resistance, reduced insulin levels and increased hepatic glucose uptake
Dutour et al[31], 2016	Prospective randomized trial, France	44	Exenatide 5 μg twice daily for 4 wk, followed by 10 μg twice daily for additional 22 wk vs reference antidiabetic treatment according to French guidelines	Exenatide markedly reduced body weight, waist, thigh, hip circumference, fasting plasma insulin, total cholesterol and palmitoleic acid plasma levels
Blaslov et al[32], 2014	Open label parallel-group, uncontrolled study, Croatia	125	Exenatide (10 μg twice daily) on its own or in combination with other oral antidiabetic drugs vs other oral antidiabetic drugs without exenatide for 6 mo	Exenatide remarkably attenuated body mass index, waist circumference, ALP, ALT, intrahepatic fat accumulation assessed by fatty liver index
Cuthbertson et al[33], 2012	Prospective study, United Kingdom	25 [exenatide (n = 19), liraglutide (n = 6)]	Exenatide 5 μg twice daily titrated to 10 μg twice daily after one month; liraglutide 0.6 mg once daily, titrated to 1.2 mg once daily for 6 mo	GLP-1RA reduced, compared to baseline, abdominal visceral and subcutaneous adipose tissue, HbA1c, ALT, γ-GT and intrahepatic lipid content and increased adiponectin serum levels
Fan et al[34], 2013	Randomized clinical trial, China	117	Exenatide (5 μg for four weeks followed by 10 μg for additional 8 wk, two times daily) vs metformin (0.5-2 g/d)	Exenatide decreased body weight, waist-to-hip ratio, ALT, AST, AST/ALT ratio, γ-GT, 2-h postprandial glucose serum levels, CRP and increased adiponectin serum levels
Savvidou et al[35], 2016	Open label, randomized controlled intervention trial, Greece	120	Exenatide 5 μg twice daily for 4 wk and 10 μg twice daily as supplementation on glargine insulin vs intense self-regulated insulin therapy for 6 mo	Both therapies significantly increased adiponectin serum levels compared to baseline, but no significant change between the groups; Exenatide, compared to insulin group, reduced more robustly body weight but not HbA1c
Shao et al[37], 2014	Randomized controlled trial, China	60	Exenatide 5 μg twice daily, followed by 10 μg twice daily for additional 8 wk plus insulin glargine vs intensive insulin therapy with insulin glargine and insulin as part for a time period of 12 wk	Body weight, waist circumference, ALT, AST, γ-GT were markedly reduced in exenatide compared to insulin group, while levels of fasting blood glucose, postprandial blood glucose, HbA1c, triglyceride and total bilirubin were significantly reduced at both groups at 12 wk, compared to baseline
Bi et al[38], 2014	Randomized controlled trial, China	33	Exenatide 5 μg twice daily for 4 wk, followed by maximum 10 μg twice daily for 20 wk vs insulin vs pioglitazone 30 mg daily, titrated to 45 mg at fourth week, 6 mo study	Exenatide reduced, compared to baseline, intrahepatic fat, visceral and subcutaneous fat volumes, body weight, waist circumference, serum triglycerides, HbA1c, TNF-a
Sathyanarayana et al[39], 2011	Randomized controlled study, United States	21	Exenatide 10 μg twice daily plus pioglitazone 45 mg/d vs pioglitazone 45 mg/d for 12 mo	Combination pharmacotherapy with exenatide, compared to pioglitazone, significantly decreased serum ALT and triglyceride levels as well as intrahepatic fat content and increased adiponectin plasma levels
Gluud et al[41], 2014	Review, Denmark	15 studies included in this meta-analysis	12 randomized clinical trials on lisixenatide vs placebo and 3 randomized clinical trials on lisixenatide vs liraglutide, exenatide or sitagliptin	Lisixenatide markedly increased the proportion of overweight or obese patients with T2DM who achieved ALT levels normalization
Seko et al[42], 2017	Retrospective study, Japan	15	Dulaglutide 0.75 mg once weekly for 12 wk	Dulaglutide, compared to baseline, reduced body weight, ALT, AST, HbA1c and liver stiffness
Ghosh et al[43], 2019	Retrospective study, India	85 T2DM overweight patients	Dulaglutide 1.5 mg once weekly for 20 wk	Dulaglutide led to significant reductions in HbA1c, body weight, ALT and AST levels
Cusi et al[44], 2018	Post hoc analysis, multicenter	4 randomized, placebo-controlled trials with 1499 T2DM patients	Dulaglutide 1.5 mg once weekly for 6 mo	Dulaglutide, compared to placebo, significantly decreased ALT, AST, γ-GT, particularly in patients with elevated transaminase levels at the onset of the study

NAFLD: Non-alcoholic fatty liver disease; OGTT: Oral glucose tolerance test; ALP: Alkaline phosphatase; ALT: Alanine transaminase; GLP-1RA: Glucagon-like peptide-1 receptor agonists; AST: Aspartate aminotransferase; CRP: C-reactive protein; T2DM: Type 2 diabetes mellitus; γ-GT: γ-glutamyl-transferase.

Table 2 Characteristics and outcomes of clinical studies that evaluated the effects of liraglutide and semaglutide on non-alcoholic fatty liver disease

Ref.	Type of study; country	Number of patients	Treatment	Effects on NAFLD
Kahal et al[45], 2014	Prospective; United Kingdom	36	Liraglutide 0.9 mg/d for 6 mo	Serum procollagen type 3 amino-terminal peptide levels, a marker of hepatic fibrosis, decreased in women with PCOS
Eguchi et al[46], 2014	Prospective; Japan	26	Liraglutide 0.9 mg/d for 24-96 wk	ALT activity decreased. NASH decreased in 6/10 patients who underwent repeat biopsy at 96 wk
Suzuki et al[47], 2013	Retrospective; Japan	46	Liraglutide 0.9 mg/d for 6 mo	Liver to kidney attenuation ratio in CT (an index of hepatic steatosis) increased
Ohki et al[48], 2012	Retrospective; Japan	82	Liraglutide 0.9 mg/d for 340 d or sitagliptin 50-100 mg/d for 250 d or pioglitazone 15 mg/d for 1200 d	ALT activity was reduced with all agents. Liraglutide and pioglitazone but not sitagliptin reduced the APRI score
Jendle et al[49], 2009	Randomized controlled; multicenter	160	Liraglutide 0.6, 1.2 or 1.8 mg/d or glimepiride 4 mg/d or placebo for 26 wk	Liver to spleen attenuation ratio in CT (a marker of hepatic steatosis) increased in patients treated with liraglutide 1.8 mg/d and did not change in those treated with lower doses of liraglutide or glimepiride. ALT activity showed comparable decreases with both agents
Khoo et al[50], 2009	Randomized controlled; Singapore	30	Liraglutide 3 mg/d for 16 wk or lifestyle modification	Liraglutide was effective for decreasing weight, hepatic steatosis and hepatocellular apoptosis, but benefits were not sustained after discontinuation, in contrast with lifestyle modification
Feng et al[51], 2017	Randomized controlled; China	87	Liraglutide, metformin, or gliclazide for 24 wk	Liraglutide has better results in improving liver function, reductions in intrahepatic fat content and HbA1c level, and weight loss than metformin and gliclazide
Bouchi et al[52], 2017	Randomized controlled; Japan	19	Liraglutide 0.9 mg/d plus insulin or insulin alone for 14 wk	Liraglutide reduces visceral fat, hepatic fat accumulation, albuminuria and micro-inflammation and improves QOL
Petit et al[53], 2017	Prospective; France	68	Liraglutide 1.2 mg/d for 6 mo	Liraglutide significantly reduced liver fat content
Armstrong et al[54], 2016	Double-blind, randomized, controlled; multicenter United Kingdom	52	Liraglutide 1.8 mg/d or placebo for 48 wk	Liraglutide led to histological resolution of NASH
Smits et al[55], 2016	Randomized placebo-controlled; Holland	52	Liraglutide 1.8 mg/d, sitagliptin 100 mg/d or placebo	Liraglutide or sitagliptin treatment does not reduce hepatic steatosis or fibrosis
Zhang et al[56], 2016	Randomized controlled; China	835	Liraglutide 1.2 mg/d or metformin 500 mg/3 times per day	Liraglutide improves the blood glucose and lipid levels as well as liver function
Tian et al[57], 2018	Randomized controlled; China	127	Liraglutide 0.6-1.2 mg/d or metformin 1000-1500 mg/d for 12 wk	Liraglutide decreases ALT levels and is more effective than metformin at alleviating liver inflammation and improving liver function
Cuthbertson et al[33], 2012	Prospective; United Kingdom	25	Exenatide 10 mg twice daily or liraglutide 1.2 mg/d	Both liraglutide and exenatide reduce body weight, HbA1c and intrahepatic lipid accumulation
Newsome et al[58], 2019	Retrospective (data from 2 trials); United Kingdom	957 (trial 1) and 3297 (trial 2)	Semaglutide 0.05, 0.1, 0.2, 0.3 or 0.4 mg/d for 52 wk (trial 1) and semaglutide 0.5 or 1.0 mg/wk for 104 wk (trial 2)	Semaglutide significantly reduced ALT and hsCRP in clinical trials in subjects with obesity and/or type 2 diabetes

PCOS: Polycystic ovary syndrome; NAFLD: Non-alcoholic fatty liver disease; ALT: Alanine transaminase; hsCRP: High-sensitivity C-reactive protein; NASH: Non-alcoholic steatohepatitis; CT: Computed tomography; APRI: AST to platelet count ratio index.