Copyright ©The Author(s) 2020.
World J Hepatol. Aug 27, 2020; 12(8): 493-505
Published online Aug 27, 2020. doi: 10.4254/wjh.v12.i8.493
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, countryNumber of patientsTreatmentEffects on NAFLD
Gastaldelli et al[30], 2016Randomized double-blind vs placebo/Pisa, Italy15Exenatide 5 μg vs placebo 30 min before a 75-g OGTTExenatide 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], 2016Prospective randomized trial, France44Exenatide 5 μg twice daily for 4 wk, followed by 10 μg twice daily for additional 22 wk vs reference antidiabetic treatment according to French guidelinesExenatide markedly reduced body weight, waist, thigh, hip circumference, fasting plasma insulin, total cholesterol and palmitoleic acid plasma levels
Blaslov et al[32], 2014Open label parallel-group, uncontrolled study, Croatia125Exenatide (10 μg twice daily) on its own or in combination with other oral antidiabetic drugs vs other oral antidiabetic drugs without exenatide for 6 moExenatide remarkably attenuated body mass index, waist circumference, ALP, ALT, intrahepatic fat accumulation assessed by fatty liver index
Cuthbertson et al[33], 2012Prospective study, United Kingdom25 [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 moGLP-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], 2013Randomized clinical trial, China117Exenatide (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], 2016Open label, randomized controlled intervention trial, Greece120Exenatide 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 moBoth 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], 2014Randomized controlled trial, China60Exenatide 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 wkBody 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], 2014Randomized controlled trial, China33Exenatide 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 studyExenatide reduced, compared to baseline, intrahepatic fat, visceral and subcutaneous fat volumes, body weight, waist circumference, serum triglycerides, HbA1c, TNF-a
Sathyanarayana et al[39], 2011Randomized controlled study, United States21Exenatide 10 μg twice daily plus pioglitazone 45 mg/d vs pioglitazone 45 mg/d for 12 moCombination 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], 2014Review, Denmark15 studies included in this meta-analysis12 randomized clinical trials on lisixenatide vs placebo and 3 randomized clinical trials on lisixenatide vs liraglutide, exenatide or sitagliptinLisixenatide markedly increased the proportion of overweight or obese patients with T2DM who achieved ALT levels normalization
Seko et al[42], 2017Retrospective study, Japan15Dulaglutide 0.75 mg once weekly for 12 wkDulaglutide, compared to baseline, reduced body weight, ALT, AST, HbA1c and liver stiffness
Ghosh et al[43], 2019Retrospective study, India85 T2DM overweight patientsDulaglutide 1.5 mg once weekly for 20 wkDulaglutide led to significant reductions in HbA1c, body weight, ALT and AST levels
Cusi et al[44], 2018Post hoc analysis, multicenter4 randomized, placebo-controlled trials with 1499 T2DM patientsDulaglutide 1.5 mg once weekly for 6 moDulaglutide, compared to placebo, significantly decreased ALT, AST, γ-GT, particularly in patients with elevated transaminase levels at the onset of the study
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; countryNumber of patientsTreatmentEffects on NAFLD
Kahal et al[45], 2014Prospective; United Kingdom36Liraglutide 0.9 mg/d for 6 moSerum procollagen type 3 amino-terminal peptide levels, a marker of hepatic fibrosis, decreased in women with PCOS
Eguchi et al[46], 2014Prospective; Japan26Liraglutide 0.9 mg/d for 24-96 wkALT activity decreased. NASH decreased in 6/10 patients who underwent repeat biopsy at 96 wk
Suzuki et al[47], 2013Retrospective; Japan46Liraglutide 0.9 mg/d for 6 moLiver to kidney attenuation ratio in CT (an index of hepatic steatosis) increased
Ohki et al[48], 2012Retrospective; Japan82Liraglutide 0.9 mg/d for 340 d or sitagliptin 50-100 mg/d for 250 d or pioglitazone 15 mg/d for 1200 dALT activity was reduced with all agents. Liraglutide and pioglitazone but not sitagliptin reduced the APRI score
Jendle et al[49], 2009Randomized controlled; multicenter160Liraglutide 0.6, 1.2 or 1.8 mg/d or glimepiride 4 mg/d or placebo for 26 wkLiver 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], 2009Randomized controlled; Singapore30Liraglutide 3 mg/d for 16 wk or lifestyle modificationLiraglutide 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], 2017Randomized controlled; China87Liraglutide, metformin, or gliclazide for 24 wkLiraglutide 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], 2017Randomized controlled; Japan19Liraglutide 0.9 mg/d plus insulin or insulin alone for 14 wkLiraglutide reduces visceral fat, hepatic fat accumulation, albuminuria and micro-inflammation and improves QOL
Petit et al[53], 2017Prospective; France68Liraglutide 1.2 mg/d for 6 moLiraglutide significantly reduced liver fat content
Armstrong et al[54], 2016Double-blind, randomized, controlled; multicenter United Kingdom52Liraglutide 1.8 mg/d or placebo for 48 wkLiraglutide led to histological resolution of NASH
Smits et al[55], 2016Randomized placebo-controlled; Holland52Liraglutide 1.8 mg/d, sitagliptin 100 mg/d or placeboLiraglutide or sitagliptin treatment does not reduce hepatic steatosis or fibrosis
Zhang et al[56], 2016Randomized controlled; China835Liraglutide 1.2 mg/d or metformin 500 mg/3 times per dayLiraglutide improves the blood glucose and lipid levels as well as liver function
Tian et al[57], 2018Randomized controlled; China127Liraglutide 0.6-1.2 mg/d or metformin 1000-1500 mg/d for 12 wkLiraglutide decreases ALT levels and is more effective than metformin at alleviating liver inflammation and improving liver function
Cuthbertson et al[33], 2012Prospective; United Kingdom25Exenatide 10 mg twice daily or liraglutide 1.2 mg/dBoth liraglutide and exenatide reduce body weight, HbA1c and intrahepatic lipid accumulation
Newsome et al[58], 2019Retrospective (data from 2 trials); United Kingdom957 (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