Table 2.
Antidiabetic and lipid metabolism drugs in the preclinical stage
| Class | Targets | Drug name | Experimental models | Outcome | Ref. |
|---|---|---|---|---|---|
| Antidiabetic drugs | PPARα agonist | Bezafibrate | MCD diet-fed male KK-Ay/TaJcl (KK-Ay) mouse model |
↓Lipid accumulation ↓Hepatic inflammation ↓Fibrosis ↓Plasma ALT, TG ↑Hepatic fatty acid β-oxidative genes Bezafibrate reduced the mRNA levels of profibrogenic and fibrogenic genes in TGF-β1-stimulated RI-T cells |
147,149 |
| GW7647 | Choline-deficient L-amino acid–defined diet containing 45% fat (HF-CDAA) diet-fed mouse model |
↓Liver/BW ratio ↓Serum TG ↓Liver steatosis |
148 | ||
| Gemcabene | STAM™ murine model of NASH | ↓Hepatic mRNA markers of inflammation, lipogenesis and lipid modulation, fibrosis | 150 | ||
| PPARδ agonist | Seladelpar (MBX-8025) | Atherogenic diet-fed Alms1 mutant (foz/foz) mouse model |
↓Hyperglycemia, hyperinsulinemia, and whole-body insulin resistance ↓Blood glucose, ALT ↓Apoptosis ↓Inflammation ↓NAS |
151 | |
| Antidiabetic drugs | GLP agonist | Dulaglutide (LY2189265) | HFHC diet-fed mouse model |
↓Body weight ↓AST, glucose levels ↓Inflammation No effects on NAS Score and liver TG. |
606,607 |
| GLP-1/GLP-2R dual agonist | GLP-1/2-Fc fusion | Choline-deficient high-fat diet with high fructose and sucrose water (CDHF-FC)-fed mouse model |
↓Body weight, glucose levels, hepatic TG, and cellular apoptosis. ↓Liver fibrosis, insulin sensitivity. |
608 | |
| GCGR and GLP-1R dual agonist | Oxyntomodulin (OXM) analog | Diabetogenic diet-induced obese (DIO) mouse model |
↓Liver lipid content ↓Fat mass |
609 | |
| Lipid metabolism | ACC inhibitor | ND-630 | HFD or HSD diet-rat model |
↓Hepatic steatosis ↑Insulin sensitivity ↓Weight gain |
610 |
| ND-654 | Diethylnitrosamine (DEN) induced HCC rat model |
↓Hepatic DNL ↓Development of HCC |
611 | ||
| WZ66 | HFD-diet mouse model |
↓Seatosis ↓KCs and HSCs activation ↓Hepatic TGs and other lipids including diglycerides (DGs), phosphatidylcholine (PC), and sphingomyelin (SM) ↓Allobaculum, Mucispirillum, and Prevotella genera as well as Mucispirillum schaedleri species in gut microbiota. |
612 | ||
| ALOX12-ACC inhibitor | IMA-1 |
High-fat/high-cholesterol (HFHC) diet-induced NASH mouse model HFHC diet-induced NASH Cynomolgus macaque model |
↓NASH progression | 613 | |
| Lipid metabolism | Hepatic stimulator substance (HSS) | Overexpression of HSS | HFD or MCD diet-fed HSS gene-transfected mouse mode |
↓Hepatic steatosis ↓Hepatic inflammation ↑Activity of CPT-1 |
614 |
| ACLY inhibitor | Hydroxy citrate | HFD-fed rat model |
↓ALT, AST ↓GGT, LDH |
82 | |
| Bempedoic acid (ETC-1002) | HFD-fed mouse model |
↓Body weight ↑Glycemic control ↓Hepatic TG and TC ↓Inflammatory, fibrosis ↓NAS score |
79 | ||
| Lipid metabolism | SREBP inhibitor | 25-HL |
Western-type diet (WD)-fed mouse model Amylin liver NASH model (AMLN) diet-fed Ldlr−/− male mice mouse model |
↑Energy expenditure ↓TC and TG in serum and liver ↓Hepatic steatosis, inflammation, and fibrosis |
615 |
|
Lipid metabolism (target on adipocytes) |
Adipocytes targets | Leukemia inhibitory factor (LIF) | HFD-fed Adipoq-Cre; Lifrfl/fl mouse model | ↓Hepatic TG | 616 |
|
Lipid metabolism (target on bile acids) |
FXR agonists | Tiliamsoine | HFD-fed, DEN-induced nonalcoholic steatohepatitis rat model |
↓Plasma levels of transaminases, phosphatase, and LDH ↓TNFα |
617 |
| GC-1 (sobetirome) | Choline-devoid methionine-deficient (CMD) diet-fed rat model | ↓Hepatic steatosis | 222,618 | ||
| MGL-3196 (resmetirom) | HFD-fed rat model | ↓TC, LDL-C | 220 | ||
| Lipid metabolism | FGF21 agonist | EPB-53 | HFD-fed mouse model |
↓Body weight ↓Glucose tolerance ↓Hepatic steatosis ↓Hypertriglyceridaemia |
619 |
| Lipid metabolism | P53 agonist | Doxorubicin |
HFD-fed mouse model MCD diet-fed mouse model |
↓Liver steatosis ↓Lipogenesis, inflammation, and ER stress ↓Liver damage |
329 |