Table 1.
Old and new glucose-lowering agents as potential treatments for adult patients with biopsy-proven NASH
| Drug target | Drug | Population | Intervention use/dosage/patients | Duration | Hepatic outcomes & plasma lipids |
Metabolic Outcomes | Reference | ||
|---|---|---|---|---|---|---|---|---|---|
| Liver enzyme plasma lipids | Resolution of NASH without worsening of fibrosis | Improvement in fibrosis stage of ≥1 without worsening of NASH | |||||||
| Pan-PPAR agonist | Lanifibranor | 247 biopsy-proven NASH patients | Oral: (A) 1,200 mg/day (n=83); (B) 800 mg/day (n=83); (C) placebo (n=81) | 24 weeks | ↓AST, ↓ALT, ↓γ-GT, ↓LDL, ↓TG, ↑HDL-C | Yes (49% 1,200-mg lanifibranor vs. 22% placebo) | Yes (48% 1,200-mg lanifibranor vs. 29% placebo) | ↓FPG, ↓HOMAIR, ↓Fasting insulin | [46] |
| Dual PPARα/δ agonist | Elafibranor | 276 biopsy-proven NASH patients (F0-F3 stages) | Oral: (A) 80 mg/day (n=93); (B) 120 mg/day (n=91); (C) placebo (n=92) | 52 weeks | ↓ALT, ↓γ-GT, ↓ALP, ↓TC, ↓LDL-C, ↑HDL-C | Yes (19% 120-mg elafibranor vs. 12% placebo) | No | ↓FPG, ↓HbA1c, ↓HOMA-IR,↑Scr | [49] |
| Elafibranor (NCT02704403) | 2,157 biopsy-proven NASH patients (NAS score ≥4) | Oral: (A) 120 mg/day (n=717); (B) placebo (n=253) (970 patients recruited) | 72 weeks | -TC, -HDL, -LDL | No | No | -HOMA-IR, -HbA1c | [52] | |
| PPAR-γ agonist | Pioglitazone | 101 biopsy-proven NASH patients with prediabetes or T2DM | Oral: (A) 45 mg/day (n=50); (B) placebo (n=51) | 18 months | ↓AST, ↓ALT, ↓TG, ↑HDL-C | Yes (51% 45-mg pioglitazone vs. 19% placebo) | No | ↑Weight gain, ↓FPG, ↓HbA1c | [58] |
| GLP-1RA | Semaglutide | 320 biopsy-proven NASH patients (F1-F3 stages) | Subcutaneous: (A) 0.1 mg/day (n=80); (B) 0.2 mg/day (n=78); (C) 0.4 mg/day (n=82); (D) placebo (n=80) | 72 weeks | ↓ALT, ↓AST | Yes (59% 0.4-mg semaglutide vs. 17% placebo) | No | ↓Weight loss, ↓HbA1c | [73] |
| Liraglutide | 52 biopsy-proven NASH patients | Subcutaneous: (A) 1.8 mg/day (n=26); (B) placebo (n=26) | 48 weeks | ↓AST, ↓γ-GT, ↑HDL-C | Yes (39% 1.8-mg liraglutide vs. 9% placebo) | No | ↓Weight loss, ↓HbA1c, ↓FPG | [75] | |
NASH, non-alcoholic steatohepatitis; PPAR, peroxisome proliferator–activated receptor; ↓, decrease; AST, aspartate aminotransferase; ALT, alanine aminotransferase; γ-GT, gammaglutamyltransferase; LDL, low-density lipoprotein; TG, triglyceride; ↑, increase; HDL-C, high-density lipoprotein cholesterol; FPG, fasting plasma glucose; HOMA-IR, homeostasis model assessment of insulin resistance; ALP, alkaline phosphatase; TC, total cholesterol; LDL-C, low-density lipoprotein cholesterol; HbA1c, hemoglobin A1c; Scr, serum creatinine; NAS, NAFLD Activity Score; -, no change.