Antidiabetic Therapy in the Treatment of Nonalcoholic Steatohepatitis

Abstract

Liver-related diseases are the third-leading causes (9.3%) of mortality in type 2 diabetes (T2D) in Japan. T2D is closely associated with nonalcoholic fatty liver disease (NAFLD), which is the most prevalent chronic liver disease worldwide. Nonalcoholic steatohepatitis (NASH), a severe form of NAFLD, can lead to hepatocellular carcinoma (HCC) and hepatic failure. No pharmacotherapies are established for NASH patients with T2D. Though vitamin E is established as a first-line agent for NASH without T2D, its efficacy for NASH with T2D recently failed to be proven. The effects of pioglitazone on NASH histology with T2D have extensively been established, but several concerns exist, such as body weight gain, fluid retention, cancer incidence, and bone fracture. Glucagon-like peptide 1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors are Int.expected to ameliorate NASH and NAFLD (LEAN study, LEAD trial, and E-LIFT study). Among a variety of SGLT2 inhibitors, dapagliflozin has already entered the phase 3 trial (DEAN study). A key clinical need is to determine the kinds of antidiabetic drugs that are the most appropriate for the treatment of NASH to prevent the progression of hepatic fibrosis, resulting in HCC or liver-related mortality without increasing the risk of cardiovascular or renal events. Combination therapies, such as glucagon receptor agonist/GLP-1 or gastrointestinal peptide/GLP-1, are under development. This review focused on antidiabetic agents and future perspectives on the view of the treatment of NAFLD with T2D.

Hepatic Antifibrotic Pharmacotherapy: Are We Approaching Success?

“…38 In addition, a phase III trial (AURORA, NCT03028740) is ongoing, and reports of the side effects of cenicriviroc are worthy of continuous follow-up. In the same way, cenicriviroc can also inhibit inflammation and reduce fibrosis by inhibiting hepatocyte death, 39 balancing metabolism, 40 or regulating the "gut-liver axis", 41 which are also promising treatment strategies.…”

Glucagon-like peptide-1 receptor agonists in non-alcoholic fatty liver disease: An update

“…Long-acting GLP1-RAs, such as dulaglutide and semaglutide, seem an appealing therapeutic option. Dulaglutide pharmacotherapy combines the beneficial effects of short-acting liraglutide on ameliorating anthropometric and laboratory parameters, such as body mass and ALT serum levels respectively, with the significant advantage of weekly injection administration[ 42 , 60 ]. Beyond the latter advantage, disposable and prefilled devises for dulaglutide medication are also available[ 60 ].…”

Common Drug Pipelines for the Treatment of Diabetic Nephropathy and Hepatopathy: Can We Kill Two Birds with One Stone?

“…Since NASH/NAFLD is considered to be a multifactorial disease, the importance of combining therapies that engage with different targets and which have synergistic benefits for individual therapies has been highlighted. NASH/NAFLD patients with T2D should be preferentially treated with novel drugs licensed for diabetes treatment such as GLP-1RA and SGLT2 inhibitors [ 120 ], because these agents also have hepatoprotective [ 146 ] and nephroprotective efficacy [ 119 , 131 ]. Among a variety of SGLT2 inhibitors, dapagliflozin has entered phase 3 trials for patients with biopsy-proven NASH (DEAN study) or nondiabetic CKD (DAPA-CKD study) [ 133 ].…”

“…SGLT2 inhibits glucose reabsorption in the proximal tubule, leading to glucouria and plasma glucose reduction. Therefore, SGLT2 inhibitors have become promising therapeutic agents in NASH and NAFLD patients [ 120 ]. Several pilot studies or open randomized controlled trials (RCTs) have found a significant reduction in transaminase activity, body weight, hepatic steatosis, fatty liver index and liver histology (steatosis and fibrosis) in NAFLD patients [ 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 ].…”