Table 2.
Current randomized clinical studies evaluating double or triple incretin receptor agonists for the treatment of MASLD/MASH (or aspects of MASLD in non-MASLD cohorts).
| Author/Ref. | Country/Publication Year | Phase and Design of Study | Study Population | Mean Age, Mean BMI, Gender, T2DM (%) | Intervention; Duration; Assessment | Outcomes |
|---|---|---|---|---|---|---|
| Ludvik et al./ Hartman et al. [102,104] |
Multinational (13 countries), 2021 |
Phase 3, randomized, open-label, parallel-group, multicenter | 1444 overweight patients with T2DM | 57 yo, 33 kg/m2, 56% male, 100% with T2DM | Tirzepatide (5, 10, 15 mg) (n = 358, 360, 359) vs. insulin degludec (n = 360); 52 weeks; HbA1c and bodyweight reduction | Greater reduction in HbA1c vs. baseline [1.93%, 2.2%, 2.37% for 5, 10, and 15 mg, respectively (p = 0.05)] and body weight and lower risk of hypoglycemia; pooled tirzepatide group (10 mg and 15 mg) induced a greater LFC reduction compared with the insulin degludec group (−8.09% vs. −3.38%, p < 0.0001) |
| Hartman et al. [104] | USA/2020 | Phase 2, post-hoc analysis | 316 patients with T2DM | 57 yo, 32.6 kg/m2, 53% male | Tirzepatide (1, 5, 10, 15 mg) (n = 52, n = 55, n = 51, n = 53) vs. dulaglutide (n = 54) or placebo (n = 51); 26 weeks; hepatic dysfunction parameters | Greater decrease in ALT (−6.8 units/L and −6.4 units/L for tirzepatide 10 mg and 15 mg, respectively vs. dulaglutide, p < 0.05), K-18 (−135.2 units/L in the tirzepatide 10 mg vs. placebo group, p < 0.015) pro-C3 (−2.1 ng/mL in the tirzepatide 15 mg vs. placebo group, p = 0.041) |
| Nahra et al. [106] | Multinational (8 countries), 2021 |
Phase 2b, double-blind, placebo-controlled | 834 patients with T2DM and BMI ≥ 25 kg/m2 | ~56 yo, ~35 kg/m2, ~45% male, 100% with T2DM | Cotadutide 100 μg (n = 100), 200 μg (n = 256), or 300 μg (n = 256) vs. placebo (n = 110) or liraglutide 1.8 mg (n = 110); 54 weeks; HbA1c, body weight, hepatic parameters for liver fibrosis | Cotadutide (100, 200, or 300 mg) compared with the placebo group achieved greater reductions in AST (−1.77%, −6.22%, −9.14%, and 5.65%, respectively, p < 0.009), ALT (−7.52%, −12.01%, −14.15%, and 0.93%, respectively, p < 0.009), PRO-C3 (−0.38% in 300 mg cotadutide group vs. 13.04 in the placebo group, p = 0.0034), total and LDL cholesterol, triglycerides, and GGT levels, as well as in fatty liver index (−8.08, −6.73, −8.18, and −1.62, respectively, p < 0.001). |
| Haririson et al. [107] | United States, 2023 |
Randomized, double-blind, placebo-controlled | 94 patients with MASLD | 36 kg/m2, 29% with T2DM | Pemvidutide 1.2 mg, 1.8 mg, and 2.4 mg vs. placebo; 24 weeks; reduction in LFC, Ct1, ALT, body weight | Pemvidutide reduced LFC at 24 weeks vs. baseline, compared with the placebo group (−56.3%, −75.2%, −76.4%, and −14%, respectively). Dose-dependent reduction in ALT levels (−13.3 IU/L, −13.7 IU/L, −15.2 IU/L, −2.2 IU/L, respectively). |
| To et al. [108] | United States, 2023 |
Phase 1 | 18 overweight/obese patients with T2DM and MASLD | 100% with T2DM | DD01 1–80 mg (four once-weekly doses) vs. placebo; 36 days; MRI | Rapid reductions in hepatic steatosis assessed by MRI, HbA1c and greater weight loss. Over the four-week period of the study, patients treated with DD01 had a mean LFC reduction of 52% versus a 2.8% reduction in the placebo group. |
| Abdelmalek et al. [109,110] | United States, 2020 |
Phase 1b/2a, multicenter, randomized, placebo-controlled | 66 non-diabetic obese patients with MASLD | 46 yo; 50% men; mean BMI: 36 kg/m2, 0% with T2DM | HM15211 0.01, 0.02, 0.04, 0.06, and 0.08 mg/day vs. placebo; 12 weeks; MRI-PDFF | HM15211 reduced LFC vs. placebo in a dose-dependent manner (mean relative changes from baseline in liver fat at week 12 vs. baseline: −19.6% for 0.01 mg/kg, −36% for 0.02 mg/kg, −38% for 0.04 mg/kg, −59.3% for 0.06 mg/kg, and −5.7% for the placebo group, p < 0.05). HM15211 reduced body weight across all treatment dose groups compared with the placebo arm at week 12 vs. baseline [(placebo-corrected % reduction of body weight was −1.9%, −3.4%, −2.1%, −3.8%, and −5.1%) in 0.01 to 0.08 mg/kg dose cohorts, respectively, p < 0.05)] |
| Sanyal et al. [111] | United States, 2023 |
Phase 2 | 338 obese MASLD patients | 46.6 yo, 38.4 kg/m2, 53.1% males, 0% with T2DM | Retatrutide 1, 4, 8, and 12 mg/day vs. placebo; 48 weeks; liver fat change |
Retatrutide reduced mean relative LFC in comparison to placebo at 24 and 48 weeks of treatment vs. baseline [change from baseline at 24 weeks was −42.9% (1 mg), −57.0% (4 mg), −81.4% (8 mg), −82.4% (12 mg) and +0.3% (placebo), and at 48 weeks was −51.3% (1 mg), −59.0% (4 mg), −81.7% (8 mg), −86.0% (12 mg) and −4.6% (placebo), all p < 0.001 vs. placebo) |
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyl transferase; HbA1c, Hemoglobin A1C; LDL, low-density lipoprotein; LFC, liver fat content; 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.