Table Info

Table 1.

Placebo-controlled or active-controlled RCTs of GLP-1 RAs for treatment of NAFLD or NASH (ordered by publication year)

Author, year, country (Ref)	Study characteristics	Interventions (n), trial length (weeks)	*Efficacy and/or effectiveness outcomes A vs.* B (or vs. C)**	Major adverse effects	Cochrane RCT’s quality scale
Shao et al. 2014; China [18]	Patients with T2DM and NAFLD on ultrasound Mean age: 43 years; male sex: 48%; BMI 30 kg/m²; HbA1c 7.6%; ALT 166 IU/L; AST 123 IU/L	A. Exenatide + glargine (n = 30) B. Intensive insulin: insulin aspart + insulin glargine (n = 30) Length: 12 weeks	Reversal rate of NAFLD on ultrasound (A vs. B): 93% vs. 67%, P < 0.01 Differences in body weight change post-treatment vs. pre- treatment: −7.8 kg vs. 3.3 kg, P < 0.001 No difference in changes in HbA1c between the groups	Not reported	Random sequence generation (selection bias): unclear Allocation concealment (selection bias): unclear Blinding of participants and researchers (performance bias): unclear Blinding of outcome assessment (detection bias): unclear Incomplete outcome data (attrition bias): unclear Selective reporting (reporting bias): unclear Other bias: unclear
Armstrong et al. 2016; UK [19]	Patients with biopsy-proven NASH (i.e. LEAN trial) Mean age: 51 years; male sex: 60%; BMI 36 kg/m²; ALT 71 IU/L; AST 51 IU/L; fibrosis F3-F4 (on histology) 52%; pre-existing diabetes: 33%	A. Liraglutide 1.8 mg (n = 26) B. Placebo (n = 26) Length: 48 weeks	Histologic resolution of NASH: 39% vs. 9%, P = 0.019 Change in histologic NAS score: −1.3 vs. −0.8, P = 0.24 Change in fibrosis stage: −0.2 vs. 0.2, P = 0.11 Fibrosis improvement: 26% vs. 14%, P = 0.46 Fibrosis worsening: 9% vs. 36%, P = 0.04 Change in serum ALT: −26.6 UI/L vs. −10.2 UI/L, P = 0.16 Change in serum AST: −27 UI/L vs. +9 IU/L, P = 0.02	Gastro-intestinal disorders in the liraglutide vs. placebo: 81% vs. 65%	Random sequence generation (selection bias): low Allocation concealment (selection bias): low Blinding of participants and researchers (performance bias): low Blinding of outcome assessment (detection bias): low Incomplete outcome data (attrition bias): low Selective reporting (reporting bias): low Other bias: low
Dutour et al. 2016; France [20]	Patients with T2DM, 95% of whom had NAFLD on MR spectroscopy Mean age: 52 years; male sex: 48%; BMI 36 kg/m2; HbA1c 7.5%; ALT 29 IU/L; AST 22 IU/L	A: Exenatide 5–10 mcg bid (n = 22) B: Placebo (n = 22) Length: 26 weeks	Exenatide and reference treatment had a similar improvement in terms of HbA1c values (−0.7 ± 0.3% vs. −0.7 ± 0.4%; P = 0.29) Significant weight loss was observed in the exenatide group (–5.5 ± 1.2 kg vs. −0.2 ± 0.8 kg, P = 0.001 for difference between groups) When compared with the reference therapy, exenatide induced a significant reduction in liver fat content (–23.8 ± 9.5% vs. 12.5 ± 9.6%, P = 0.007)	Not reported	Random sequence generation (selection bias): unclear Allocation concealment (selection bias): unclear Blinding of participants and researchers (performance bias): unclear Blinding of outcome assessment (detection bias): unclear Incomplete outcome data (attrition bias): unclear Selective reporting (reporting bias): unclear Other bias: unclear
Feng et al. 2017; China [21]	Patients with T2DM and NAFLD on ultrasound Mean age: 47 years; male sex: 75%; BMI 28 kg/m²; HbA1c 9.1%; ALT 49 IU/mL; AST 31 IU/L	A. Liraglutide up to 1.8 mg/d (n = 31) B. Metformin up to 2000 mg/d (n = 31) C. Gliclazide 60–120 mg/d (n = 31) Length: 24 weeks	Liver fat content decreased in all groups as follows: from 36.7 ± 3.6% to 13.1 ± 1.8% in the liraglutide group; from 33.0 ± 3.5% to 19.6 ± 2.1% in the gliclazide group, and from 35.1 ± 2.3% to 18.4 ± 2.2% in the metformin group (P < 0.001 for all treatment groups, final vs. baseline) Reduction in liver fat content following liraglutide treatment was greater when compared to that following gliclazide treatment (P = 0.001) Both liraglutide and metformin treatments reduced body weight and improved serum liver enzymes HbA1c levels were lower in the liraglutide and metformin groups than in the gliclazide group	Not reported	Random sequence generation (selection bias): unclear Allocation concealment (selection bias): unclear Blinding of participants and researchers (performance bias): unclear Blinding of outcome assessment (detection bias): unclear Incomplete outcome data (attrition bias): unclear Selective reporting (reporting bias): unclear Other bias: unclear
Frøssing et al. 2017; Denmark [22]	Women with polycystic ovary syndrome and NAFLD on MR spectroscopy Mean age: 47 years; female sex: 100%; BMI 33 kg/m²	A. Liraglutide 1.8 mg/d (n = 48) B. Placebo (n = 24) Length: 26 weeks	Liraglutide treatment reduced body weight by 5.2 kg (–5.6% from baseline), liver fat content by 44% (on MR spectroscopy) as well as NAFLD prevalence by roughly two-thirds (P < 0.01 for all) Liraglutide treatment reduced fasting plasma glucose and HbA1c [liraglutide vs. placebo, mean between-group difference (95% CI), −0.24 (–0.44 to −0.04) mmol/L; mean HbA1c (95% CI), −1.38 (–2.48 to −0.28) mmol/mol]	Nausea and constipation in the liraglutide group	Random sequence generation (selection bias): unclear Allocation concealment (selection bias): unclear Blinding of participants and researchers (performance bias): unclear Blinding of outcome assessment (detection bias): unclear Incomplete outcome data (attrition bias): unclear Selective reporting (reporting bias): unclear Other bias: unclear
Yan et al. 2019; China [23]	Patients with T2DM and NAFLD on MRI- PDFF Mean age: 44 years; male sex: 69%; BMI 29.8 kg/m²; HbA1c 7.7%; ALT 43 IU/L; AST 33 IU/L	A. Liraglutide 1.8 mg/d (n = 24) B. Insulin glargine 0.2 IU/kg/d (n = 24) C. Sitagliptin 100 mg/d (n = 27) Length: 26 weeks	In the liraglutide and sitagliptin groups, liver fat content decreased from baseline to week 26 (in particular, in the liraglutide group the reduction ranged from 15.4 ± 5.6% to 12.5 ± 6.4%, P < 0.001, while in the sitagliptin group the reduction ranged from 15.5 ± 5.6% to 11.7 ± 5.0%, P = 0.001) HbA1c levels decreased in all treatment groups (in particular, in the liraglutide group the reduction ranged from 7.8 ± 1.4% to 6.8 ± 1.7%, P < 0.001; in the sitagliptin group from 7.6 ± 0.9% to 6.6 ± 1.1%, P = 0.016; and in the insulin group from 7.7 ± 0.9% to 6.9% ± 1.1%, P = 0.013) Body weight decreased in the liraglutide and in the sitagliptin groups, but not in the insulin glargine group	Not reported	Random sequence generation (selection bias): unclear Allocation concealment (selection bias): unclear Blinding of participants and researchers (performance bias): unclear Blinding of outcome assessment (detection bias): unclear Incomplete outcome data (attrition bias): unclear Selective reporting (reporting bias): unclear Other bias: unclear
Liu et al. 2020; China [24]	Patients with T2DM and NAFLD on MRI- PDFF Mean age: 48 years; male sex: 50%; BMI 28 kg/m²; HbA1c 8.3%; ALT 38 IU/L; AST 28 IU/L	A. Exenatide 1.8 mg/d (n = 38) B. Insulin glargine 0.2 IU/kg/d (n = 38) Length: 24 weeks	Liver fat content was reduced after exenatide treatment (Δ liver fat −17.6 ± 12.9%). Exenatide treatment also led to a greater reduction in the visceral adipose tissue (ΔVAT −43.6 ± 68.2 cm²), serum ALT, AST, GGT levels, BMI and waist circumference than insulin glargine	Adverse events were comparable between the two groups	Random sequence generation (selection bias): unclear Allocation concealment (selection bias): unclear Blinding of participants and researchers (performance bias): unclear Blinding of outcome assessment (detection bias): unclear Incomplete outcome data (attrition bias): unclear Selective reporting (reporting bias): unclear Other bias: unclear

BMI: body mass index; HbA1c: hemoglobin A1c; MR: magnetic resonance; MRI-PDFF: magnetic resonance imaging-proton density fat fraction; VAT: visceral adipose tissue

Supplementary materials

The supplementary material for this article is available at:

https://www.explorationpub.com/uploads/Article/file/10018_sup_1.pdf

Declarations

Author contributions

AM and GT contributed to study concept and design, acquisition of data, and drafting of the manuscript. AM and GT contributed to statistical analysis of data. AM, GB, GP, FP, DS, and GT contributed to analysis and interpretation of data. GB, GP, FP, and DS contributed to critical revision of the manuscript for important intellectual content. AM and GT are the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

Not applicable.

Copyright

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