Table 1.
Published phase II or II placebo or active-controlled randomized clinical trials evaluating GLP-1RAs for the treatment of MASLD/MASH.
| Author/Ref. | Country/Publication Year | Phase and Design of Study | Study Population | Mean Age, Mean BMI, Gender, T2DM (%) | Intervention; Duration; Assessment | Outcomes |
|---|---|---|---|---|---|---|
| Armstrong et al. [88] | United Kingdom, 2016 |
Phase 2, double-blind, placebo-controlled | 52 overweight patients with biopsy-confirmed MASH | 51 yo, 36 kg/m2, 60% male, 33% with T2DM | Liraglutide 1.8 mg/day (n = 26) vs. placebo (n = 26); 48 weeks; Liver Biopsy | Greater MASH resolution in the liraglutide group: 39% vs. 9% in the placebo group (p = 0.019). Less liver fibrosis progression with liraglutide: 9% vs. 36% in the placebo group (p = 0.04). |
| Bizino et al. [89] |
Netherlands, 2020 |
Phase 2, double-blind, placebo-controlled (sub-analysis of the MGNA VICTORIA study) | 49 patients with T2DM | 60 yo, 32 kg/m2, 59% male, 100% with T2DM | Liraglutide 1.8 mg/day (n = 23) vs. placebo (n = 26); 26 weeks; MRI | LFC reduction was not significantly different between groups; liraglutide was associated with significantly greater body weight and subcutaneous fat reduction |
| Yan et al. [90] |
China, 2019 |
Phase 2, open-label, active-controlled | 75 patients with T2DM and MASLD, with inadequate glycemic control by metformin | 44 yo, 30 kg/m2, 69% male, 100% with T2DM | Liraglutide 1.8 mg/day (n = 24) vs. insulin glargine 0.2 IU/kg/day (n = 24) vs. sitagliptin 100 mg/day (n = 27) (adds-on metformin); 26 weeks; MRI | When combined with metformin, both sitagliptin and liraglutide but not insulin glargine resulted in a significant decrease in LFC; liraglutide group: from 15.4% [SD 5.6] to 12.5% [SD 6.4] (p < 0·001). |
| Guo et al. [91] |
China, 2020 |
Phase 2, open-label, placebo-controlled | 96 patients with T2DM and MASLD with inadequate glycemic control by metformin | 52 yo, 29 kg/m2, 56% male, 100% with T2DM | Liraglutide 1.8 mg/day (n = 32) vs. insulin glargine once daily (n = 32) vs. placebo (n = 32) (adds-on metformin); 26 weeks; MRI | When combined with metformin, liraglutide significantly reduced steatosis from 26.4% [SD 3.2] to 20.6% [SD 3.9] (p < 0·05). |
| Khoo et al. [92] |
Singapore, 2019 |
Phase 2, open-label, active-controlled | 30 patients with obesity and MASLD | 41 yo, 33 kg/m2, 90% male, 0% with T2DM | Liraglutide 3 mg/day (n = 15) vs. lifestyle modifications: diet and exercise (n = 15); 26 weeks; MRI | Both liraglutide and lifestyle modifications resulted in significant hepatic fat reduction vs. baseline: −7.0% [SD 7.1] and −8.1% [SD 13.2], respectively. These benefits were not sustained in the liraglutide group in a 6-month period. |
| Zhang et al. [93] |
China, 2020 |
Phase 2, open-label, active-controlled | 60 patients with T2DM and MASLD | 51 yo, 27 kg/m2, 47% male, 100% with T2DM | Liraglutide 1.2 mg/day (n = 30) vs. pioglitazone 30 mg/day (n = 30) (add-on to usual care); 24 weeks; MRI |
The addition of liraglutide was associated with a significant reduction in LFC from 24.1% [SD 3.0] to 20.1% [SD 3.8] (p < 0·05). This reduction was significantly greater compared with the addition of pioglitazone. |
| Dutour et al. [94] |
France, 2016 |
Phase 2, open-label, active-controlled | 44 patients with obesity and T2DM, with inadequate glycemic control by oral antidiabetic therapy (MASLD in 95% of them) | 52 yo, 36 kg/m2, 48% male, 100% with T2DM | Exenatide 5–10 μg twice/day (n = 22) vs. reference treatment according to local guidelines (n = 22); 26 weeks; MRI | Exenatide resulted in a significant decrease in hepatic triglyceride content: −23.8% [SD 9.5] vs. +12.5% [SD 9.6] in the placebo group (p = 0.007). |
| Liu et al. [95] |
China, 2020 |
Phase 2, open-label, active-controlled | 76 patients with newly diagnosed T2DM and MASLD. Age: 48, BMI: 28, 50% male | 48 yo, 28 kg/m2, 50% male, 100% with T2DM | Exenatide 5–10 μg twice/day (n = 38) vs. insulin glargine 0.2 IU/kg/day (n = 38); 24 weeks; MRI and Fibroscan | Exenatide and insulin glargine both significantly reduced LFC, but exenatide induced a greater reduction in body weight, visceral adiposity, liver enzymes, and Fibrosis-4 (FIB-4) index. |
| Kuchay et al. [96] |
India, 2020 |
Phase 2, open-label, active-controlled | 64 patients with T2DM and MASLD | 47 yo, 30 kg/m2, 70% male, 100% with T2DM | Dulaglutide 1.5 mg/week adds-on usual care (n = 32) vs. usual care (n = 32); 24 weeks; MRI and Fibroscan | Addition of dulaglutide resulted in a 2.6-fold greater reduction in LFC and a significant improvement in serum GGT level vs. control group. Changes in liver stiffness on Fibroscan, serum AST, and ALT levels were not significant. |
| Newsome et al. [97] |
Multicenter, 2020 |
Phase 2, double-blind, placebo-controlled | 320 patients with biopsy-confirmed MASH and liver fibrosis of stage F1, F2, or F3 | 55 yo, 36 kg/m2, 41% male, 62% with T2DM | Semaglutide 0.1 mg/day (n = 80) vs. semaglutide 0,2 mg/day (n = 78) vs. semaglutide 0.4 mg/day (n = 82) vs. placebo (n = 80); 72 weeks; liver biopsy | The proportion of patients on semaglutide 0.4 mg/day with resolution of MASH without worsening of fibrosis was significantly higher compared with the placebo group: 59% vs. 17% (p < 0.001). Improvement of liver fibrosis was not significantly different between groups. |
| Flint et al. [98] |
Germany, 2021 |
Phase 1, double-blind, placebo-controlled | 67 patients with MASLD (assessed by MRI-PDFF and MRE) | 60 yo, >30 kg/m2, 70% male, 73% with T2DM | Semaglutide 0·4 mg/day (n = 34) vs. placebo (n = 33); 72 weeks, MRI | In the semaglutide group, hepatic steatosis presented a significantly greater decrease vs. placebo group at week 24 (−36% vs. −9%, p < 0.001), week 48 (−58% vs. −11%, p < 0.001), and week 72 (−58% vs. −17%, p < 0.001); no significant difference between groups was observed in changes of liver stiffness. |
| Loomba et al. [99] |
Multicenter, 2023 |
Phase 2, double-blind, placebo-controlled | 71 patients with biopsy-confirmed MASH-related cirrhosis and BMI ≥ 27 kg/m2 | 60 yo, 35 kg/m2, 31% male, 75% with T2DM | Semaglutide 2.4 mg/week (n = 47) vs. placebo (n = 24); 48 weeks, liver biopsy | Neither the proportion of patients with MASH resolution nor the proportion of patients with liver fibrosis improvement without worsening of MASH differed significantly between groups. |
| Alkhouri et al. [100] |
USA, 2022 |
Phase 2, open-label, active-controlled | 108 patients with MASH (assessed by liver biopsy or by MRI-PDFF ≥10% and Fibroscan measured liver stiffness ≥7 kPa) | 56 yo, 35 kg/m2, 30% male, 55% with T2DM | Semaglutide 2.4 mg/week (n = 21) vs. semaglutide 2.4 mg/week + cilofexor 30 mg/day (n = 22) vs. semaglutide 2.4 mg/week + cilofexor 100 mg/day (n = 22) vs. semaglutide 2.4 mg/week + firsocostat 20 mg/day (n = 22) vs. semaglutide 2.4 mg/week + cilofexor 30 mg/day + firsocostat 20 mg/day (n = 21); 24 weeks; MRI and Fibroscan | Overall, combination therapies resulted in a larger reduction in LFC and greater improvement in liver enzymes and liver fibrosis (as assessed by Fibroscan) than semaglutide alone. When compared to semaglutide monotherapy, the only treatment group with significantly different change in liver steatosis was semaglutide + firsocostat: −11% vs. −8% in the semaglutide monotherapy group (p = 0.035). |
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; MASLD, metabolic dysfunction-associated steatotic liver disease; MASH, metabolic dysfunction-associated steatohepatitis; MRI, magnetic resonance imaging; PDFF, proton density fat fraction; T2DM, type 2 diabetes mellitus; GGT, gamma-glutamyltransferase.