Liver-targeting drugs and their effect on blood glucose and hepatic lipids

Abstract

The global epidemic of non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) and the high prevalence among individuals with type 2 diabetes has attracted the attention of clinicians specialising in liver disorders. Many drugs are in the pipeline for the treatment of NAFLD/NASH, and several glucose-lowering drugs are now being tested specifically for the treatment of liver disease. Among these are nuclear hormone receptor agonists (e.g. peroxisome proliferator-activated receptor agonists, farnesoid X receptor agonists and liver X receptor agonists), fibroblast growth factor-19 and -21, single, dual or triple incretins, sodium-glucose cotransporter inhibitors, drugs that modulate lipid or other metabolic pathways (e.g. inhibitors of fatty acid synthase, diacylglycerol acyltransferase-1, acetyl-CoA carboxylase and 11β-hydroxysteroid dehydrogenase type-1) or drugs that target the mitochondrial pyruvate carrier. We have reviewed the metabolic effects of these drugs in relation to improvement of diabetic hyperglycaemia and fatty liver disease, as well as peripheral metabolism and insulin resistance.

Keywords: Farnesoid X receptor agonists; Fibrosis; Hepatokines; Incretins; Insulin resistance; Non-alcoholic fatty liver disease; Non-alcoholic steatohepatitis; Peroxisome proliferator-activated receptor (PPAR) agonists; Review; SGLT2 inhibitors.

Fig. 1

Pharmacological treatments that directly or indirectly target hepatic glucose and lipid metabolism, inflammation and fibrosis. The arrows indicate the different actions on insulin exerted by some glucose-lowering drugs on hepatic metabolism. GLP-1RA, dual GIP/GLP-1 agonists, DPP4 inhibitors and sulfonylureas increase insulin levels by stimulating insulin release, while during treatment with SGLT-2 inhibitors the insulin levels are reduced. GK, glucokinase; GKRP, glucokinase regulatory protein; MPC, mitochondrial pyruvate carrier. This figure is available as a downloadable slide