Research Article Details
| Article ID: | A02251 |
| PMID: | 34446271 |
| Source: | Clin Ther |
| Title: | Emerging and Established Therapeutic Approaches for Nonalcoholic Fatty Liver Disease. |
| Abstract: | PURPOSE: Nonalcoholic fatty liver disease (NAFLD), more recently referred to as metabolic-associated fatty liver disease, refers to a disease spectrum ranging from hepatic steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis, associated with hepatic complications (including liver fibrosis, cirrhosis, and hepatocellular carcinoma) and extrahepatic complications (particularly cardiometabolic complications, including type 2 diabetes and cardiovascular disease). Treatment options include lifestyle interventions (dietary modification and physical activity programs) and pharmacologic interventions. Treatment aims should be broad, with a hepatic focus (to improve/reverse hepatic inflammation, fibrosis, and steatohepatitis), ideally with additional extrahepatic effects affecting metabolic co-morbidities (eg, insulin resistance, glucose dysregulation, dyslipidemia), causing weight loss and affording cardiovascular protection. NASH and fibrosis represent the main histopathological features that warrant treatment to prevent disease progression. Despite a paucity of established treatments, the array of potential molecular targets, pathways, and potential treatments is continually evolving. The goal of this article was to provide a narrative review summarizing the emerging and more established therapeutic options considering the complex pathophysiology of NAFLD and the important long-term sequelae of this condition. METHODS: The literature was reviewed by using PubMed, conference abstracts, and press releases from early-phase clinical studies to provide an overview of the evidence. FINDINGS: As understanding of the pathophysiology of NASH/NAFLD evolves, drugs with different mechanisms of action, targeting different molecular targets and aberrant pathways that mediate hepatic steatosis, inflammation, and fibrosis, have been developed and are being tested in clinical trials. Pharmacologic therapies fall into 4 main categories according to the molecular targets/pathways they disrupt: (1) meta-bolic targets, targeting insulin resistance, hepatic de novo lipogenesis, or substrate utilization; (2) inflam-matory pathways, inhibiting inflammatory cell recruitment/signaling, reduce oxidative/endoplasmic reticulum stress or are antiapoptotic; (3) the liver-gut axis, which modulates bile acid enterohepatic circulation/signaling or alters gut microbiota; and (4) antifibrotic targets, targeting hepatic stellate cells, decrease collagen deposition or increase fibrinolysis. IMPLICATIONS: Lifestyle modification must remain the cornerstone of treatment. Pharmacologic treatment is reserved for NASH or fibrosis, the presence of which requires histopathological confirmation. The disease complexity provides a strong rationale for combination therapies targeting multiple pathways simultaneously. |
| DOI: | 10.1016/j.clinthera.2021.07.013 |
| Strategy ID | Therapy Strategy | Synonyms | Therapy Targets | Therapy Drugs | |
|---|---|---|---|---|---|
| S01 | Improve insulin resistance | insulin sensitizer; insulin resistance; glucose tolerance | Biguanide: increases 5-AMP activated protein kinase signaling; SGLT-2 inhibitor; Thiazalidinedione: selective PPAR-γ agonists; GLP-1 agonist | Metformin; Empagliflozin; Canagliflozin; Rosiglitazone; Pioglitazone; Liraglutide | Details |
| S03 | Anti-fibrosis | fibrosis | Angiotensin Receptor Blocker (ARB); CCR2/CCR5 antagonist; Thyroid receptor β agonist; PEGylated human FGF21 analogue; Monoclonal antibody to lysyl oxidase-like 2 (LOXL2); Galectin-3 inhibitor; FGF19 variant | Losartan; Cenicriviroc; VK-2809; MGL-3196; Pegbelfermin; Simtuzumab; GR-MD-02; NGM282 | Details |
| S05 | Anti-inflammatory | inflammatory | Bile acid; TNF-a inhibitor; Dual PPAR-α and -δ agonists; Toll-Like Receptor; (TLR)-4 antagonist; Caspase inhibitor; ASK-1 inhibitor | Ursodeoxycholic Acid; Pentoxifylline; Elafibranor; JKB-121; Emricasan; Selonsertib; | Details |
| S06 | Regulating intestinal flora | intestine gut microbiota; gut microbiota | farnesoid X receptor (FXR); fibroblast growth factor-19 (FGF19) | Probiotics; Prebiotics; Rifaximin; Yaq-001; Cilofexor; EDP-305; EYP001a; INT-767 | Details |
| S07 | Anti-lipogenesis | de novo lipogenesis; de novo lipogenesis; DNL; anti-lipogenic mechanisms; adipogenesis; anti-obesity | stearoyl-CoA desaturase 1 (SCD-1); Acetyl-coenzyme carboxylase; acyl-CoA carboxylase inhibitor (ACC inhibitor); stearoyl Coenzyme A desaturase inhibitor (SCD inhibitor); THR-beta selective agonist; DGAT2 inhibitor; FASN inhibitor | Aramchol; Firsocostat (GS-0976); VK-2809; ION 224 | Details |
| S08 | Lifestyle measures | Lifestyle intervention; weight loss; diet adaptation; dietary interventions; lifestyle modifications; Exercise | -- | -- | Details |
| Diseases ID | DO ID | Disease Name | Definition | Class | |
|---|---|---|---|---|---|
| I13 | 3146 | Lipid metabolism disorder | An inherited metabolic disorder that involves the creation and degradation of lipids. http://en.wikipedia.org/wiki/Lipid_metabolism | disease of metabolism/ inherited metabolic disorder | Details |
| I05 | 9352 | Type 2 diabetes mellitus | A diabetes that is characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both. A diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. http://en.wikipedia.org/wiki/Diabetes, http://en.wikipedia.org/wiki/Diabetes_mellitus_type_2 | disease of metabolism/inherited metabolic disorder/ carbohydrate metabolic disorder/glucose metabolism disease/diabetes/ diabetes mellitus | Details |
| Drug ID | Drug Name | Type | DrugBank ID | Targets | Category | Latest Progress | |
|---|---|---|---|---|---|---|---|
| D579 | Emfilermin | Miscellany | -- | adipocytes | Enhance lipid metabolism | Under investigation | Details |
| D328 | Serine | Chemical drug | DB00133 | SRR | Improve insulin resistance | Under clinical trials | Details |
| D010 | Amoxicillin | Chemical drug | DB01060 | -- | -- | Under clinical trials | Details |
| D080 | Citrulline | Chemical drug | DB00155 | -- | -- | Under clinical trials | Details |
| D182 | Insulin | Biological drug | DB00030 | INSR agonist; CPE modulator&product of | -- | Under clinical trials | Details |