TABLE 3.
Placebo‐controlled or active‐controlled RCTs with different GLP‐1RAs for the treatment of NAFLD or NASH
| Study | RCT characteristics | Interventions (n), RCT duration | Efficacy outcomes | Major adverse effects |
|---|---|---|---|---|
| Armstrong et al. 78 UK, LEAN trial | Patients with biopsy‐confirmed NASH. Mean age: 51 years; men: 60%; BMI: 36 kg/m2; fibrosis F3‐F4 (on histology:) 52%; pre‐existing T2DM: 33% | A. Liraglutide 1.8 mg/day (n = 26). B. Placebo (n = 26). Duration: 48 weeks | GLP‐1RAs versus placebo. 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. Adjustment for weight loss result in non significant effect of GLP‐1RA | Gastrointestinal side effects GLP‐1RA vs. placebo: 81% vs. 65%, respectively |
| Dutour et al. 79 France | Patients with T2DM, 95% of whom had NAFLD assessed by MRS. Mean age: 52 years; men: 48%; BMI: 36 kg/m2 | A. Exenatide 5–10 mcg bd (n = 22). B. Placebo (n = 22). Duration: 26 weeks | GLP‐1RAs versus placebo. Reduction in liver fat content when compared with placebo (liver fat content: −23.8 ± 9.5% vs. +12.5 ± 9.6%, p = 0.007). Weight loss (−5.5 ± 1.2 kg vs. −0.2 ± 0.8 kg; p = 0.001 for difference between groups) | Not reported |
| Yan et al. 80 China | Patients with T2DM and NAFLD were assessed by MRI‐PDFF. Mean age: 44 years; men: 69%; BMI: 29.8 kg/m2 | A. Liraglutide 1.8 mg/day (n = 24). B. Insulin glargine 0.2 IU/kg/day (n = 24). C. Sitagliptin 100 mg/day (n = 27). Duration: 26 weeks | Compared to baseline. In the liraglutide and sitagliptin groups, liver fat content significantly decreased from baseline to week 26 (liraglutide: from 15.4 ± 5.6% to 12.5 ± 6.4%, p < 0.001; sitagliptin: from 15.5 ± 5.6% to 11.7 ± 5.0%, p = 0.001). Body weight was significantly decreased in the liraglutide and sitagliptin groups | Not reported |
| Khoo et al. 81 Singapore | Non‐diabetic patients with obesity and NAFLD assessed by MRI‐PDFF. Mean age: 41 years; men: 90%; BMI: 33 kg/m2 | A. Liraglutide 3.0 mg/day (n = 15). B. Lifestyle modifications (diet+exercise) (n = 15) Duration: 26 weeks | Compared to baseline. At 26 weeks, the two treatment groups showed significant (p < 0.01) but similar reductions in liver fat content (−8.1 ± 13.2 vs. ‐7.0 ± 7.1%). | Gastrointestinal side effects more common in the liraglutide group |
| Liu et al. 82 ; China | Patients with T2DM and NAFLD were assessed by MRI‐PDFF. Mean age: 48 years; men: 50%; BMI: 28 kg/m2 | A. Exenatide 1.8 mg/day (n = 38). B. Insulin glargine 0.2 IU/kg/day (n = 38). Duration: 24 weeks | Liver fat content was significantly reduced after exenatide treatment (change of liver fat: −17.6 ± 12.9%). Exenatide resulted in greater reductions in visceral adipose tissue (ΔVAT −43.6 ± 68.2 cm2) | Not different between groups |
| Bizino et al. 83 Netherlands | Patients with T2DM and NAFLD were assessed by MRS. Mean age: 60 years; men: 59%; BMI: 32 kg/m2 | A. Liraglutide 1.8 mg/day (n = 23). B. Placebo (n = 26) Duration: 26 weeks | Liver fat content not different between groups (liraglutide: from 18.1 ± 11.2% to 12.0 ± 7.7%; placebo: from 18.4 ± 9.4% to 14.7 ± 10.0%; estimated treatment effect −2.1% [95% CI ‐5.3 to 1.0]). Compared to placebo, liraglutide significantly reduced body weight (liraglutide: from 98.4 ± 13.8 kg to 94.3 ± 14.9 kg; placebo: from 94.5 ± 13.1 kg to 93.9 ± 3.2 kg; estimated treatment effect −4.5 kg [95% CI ‐6.4 to −2.6]) | No serious drug‐related adverse events |
| Kuchay et al. 84 India, D‐LIFT trial | Patients with T2DM and NAFLD were assessed by MRI‐PDFF. Mean age: 47 years; men: 70%; BMI: 29.7 kg/m2 | A. Dulaglutide 1.5 mg/week (n = 32). B. Placebo (n = 32) Duration: 24 weeks open‐label trial (add‐on to usual care) | Dulaglutide treatment resulted in a control‐corrected absolute change in liver fat content of −3.5% (95% CI −6.6 to −0.4; p = 0.025) and relative change of −26.4% (95% CI ‐44.2 to −8.6; p = 0.004). Absolute changes in liver stiffness on Fibroscan (−1.31 kPa [−2.99 to 0.37]; p = 0.12) were not significant between two groups | No serious drug‐related adverse events |
| Guo et al. 85 China | Patients with T2DM (treated with metformin) and NAFLD assessed by MRS. Mean age: 52 years; men: 56%; BMI: 28.7 kg/m2 | A. Liraglutide 1.8 mg/week (n = 32). B. Glargine (n = 32). C. Placebo (n = 32). Duration: 26 weeks | Liraglutide treatment resulted in a control‐corrected absolute change in liver fat content of −6.3% (p < 0.05) and relative change of −24% (p < 0.05). N.B. although this change in liver fat was greater with liraglutide than with insulin glargine, there was no significant difference between the groups (−6.3 vs. −3.4%; p > 0.05). In the liraglutide group, there were significant decreases in body weight and waist circumference (weight, 84.3 ± 10.8 kg to 79.4 ± 9.3 kg, p < 0.05; and waist circumference, 95.5 ± 8.0 cm to 89.6 ± 9.3 cm, p < 0.05) | Mild‐to‐moderate gastrointestinal side effects were noted with liraglutide |
| Zhang et al. 86 China | Patients with T2DM (treated with metformin) and NAFLD assessed by MRS. Mean age: 51 years; men: 47%; BMI: 27.3 kg/m2 | A. Liraglutide 1.8 mg/week (n = 30). B. Pioglitazone 30 mg/day (n = 30). Duration: 24 weeks open‐label trial (add‐on to usual care) | Liraglutide treatment resulted in a control‐corrected absolute change in liver fat content of −4% (95% CI −6.6 to −0.4; p < 0.05) and relative change of −17% (p < 0.05). This change in liver fat content was greater with liraglutide than pioglitazone (e.g., 1H‐MRS (%) liraglutide baseline 24.1 ± 3.0 versus the end of study 20.1 ± 3.8; pioglitazone baseline 23.9 ± 3.8 versus the end of study 22.4 ± 3.5). In the liraglutide groups, there were significant decreases in body weight and waist circumference (weight: 79.3 ± 8.8 kg to 69.2 ± 10 kg, p < 0.05; and waist circumference, 93.2 ± 4.6 cm to 84.4 ± 4.0 cm, p < 0.05) | Mild‐to‐moderate gastrointestinal events were reported in the liraglutide group |
| Newsome et al. 87 Multinational cohort of individuals from 16 countries | Patients with biopsy‐confirmed NASH and fibrosis. Mean age: 55 years; men: 41%; BMI 35.7 kg/m2; pre‐existing T2DM: 62% | A. Semaglutide 0.1 mg/day (n = 80). B. Semaglutide 0.2 mg/day (n = 78). C. Semaglutide 0.4 mg/day (n = 82). D. Placebo (n = 80) Length: 72 weeks | Amongst patients with stage F2 or F3 fibrosis, the percentage of patients in whom NASH resolution was achieved with no worsening of fibrosis was 40% in the 0.1‐mg group, 36% in the 0.2‐mg group, 59% in the 0.4‐mg group, and 17% in the placebo group (p < 0.001 for semaglutide 0.4 mg vs. placebo). Improvement in the fibrosis stage occurred in 43% of the patients in the 0.4‐mg group and in 33% of the patients in the placebo group (p = 0.48). Mean percent weight loss was 13% in the 0.4‐mg group and 1% in the placebo group (p < 0.001) | Gastrointestinal side effects were more common in the 0.4‐mg group than in the placebo group |
Abbreviations: BMI, body mass index; CI, confidence interval; MRS, magnetic resonance spectroscopy; MRI‐PDFF, magnetic resonance imaging‐proton density fat fraction; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; T2DM, type 2 diabetes mellitus.