Future Perspectives on GLP-1 Receptor Agonists and GLP-1/glucagon Receptor Co-agonists in the Treatment of NAFLD

Abstract

Along the obesity pandemic, the prevalence of non-alcoholic fatty liver disease (NAFLD), often regarded as the hepatic manifestation of the metabolic syndrome, increases worldwide representing now the prevalent liver disease in western countries. No pharmacotherapy is approved for the treatment of NAFLD and, currently, the cornerstone treatment is lifestyle modifications focusing on bodyweight loss, notoriously difficult to obtain and even more difficult to maintain. Thus, novel therapeutic approaches are highly demanded. Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) are approved for the treatment of type 2 diabetes and obesity. They exert their body weight-lowering effect by reducing satiety and food intake. GLP-1RAs have also been shown to reduce liver inflammation and fibrosis. Furthermore, glucagon receptor agonism is being investigated for the treatment of NAFLD due to its appetite and food intake-reducing effects, as well as its ability to increase lipid oxidation and thermogenesis. Recent studies suggest that glucagon receptor signaling is disrupted in NAFLD, indicating that supra-physiological glucagon receptor agonism might represent a new NAFLD treatment target. The present review provides (1) an overview in the pathophysiology of NAFLD, including the potential involvement of GLP-1 and glucagon, (2) an introduction to the currently available GLP-1RAs and (3) outlines the potential of emerging GLP-1RAs and GLP-1/glucagon receptor co-agonists in the treatment of NAFLD.

Fatty liver disease and primary liver cancer: disease mechanisms, emerging therapies and the role of bariatric surgery

“…Liraglutide, an antidiabetic GLP-1 agonist, in a phase 2 clinical trial, resulted in histological resolution of NASH in 39% of patients, compared with only 9% of patients treated with placebo [35]. More recent studies, in several different countries, have found similar results [36][37][38][39]. Pioglitazone, a PPARγ agonist, improved NASH histology both in patients with prediabetics and with type 2 diabetes, with a greater improvement in fibrosis in those with type 2 diabetes [40], and is endorsed by multiple international societies for the treatment of patients with NAFLD [41][42][43][44].…”

“…The molecular underpinnings of the evolution from NAFLD to NASH to liver cancer (with or without cirrhosis) are well understood [5,19,52], and multiple studies are underway targeting specific parts of this progression [30,[36][37][38][39]53]. NAFLD and NASH typically occur in patients with metabolic syndrome.…”

Enhanced GIP Secretion in Obesity Is Associated with Biochemical Alteration and miRNA Contribution to the Development of Liver Steatosis

“…The pathophysiology of NAFLD includes (apart from dietary fat contribution) proinflammatory cytokines, hepatic and adipose tissue insulin resistance, lipotoxicity, and oxidative stress. A reduced hepatic glucagon resistance, together with an impaired incretin effect, may be additional mechanisms [53]. Although the functional receptor for GIP (GIPR) was not found in the liver, this incretin hormone may play a role in hepatic steatosis exerting pleiotropic effects in other tissues.…”

Kardiovaskuläre Effekte von GLP-1-Rezeptoragonisten

“…20 % aggraviert die Fettlebererkrankung zu einer Steatohepatitis (NASH), die durch eine vermehrte Produk-tionreaktiverSauerstoffspezies(ROS)mitErhöhungpro-inflammatorischerZytokinesowieverminderterVerfügbarkeit antiinflammatorischer Adipokine bedingt wird [38]. Eine Therapie mit GLP-1-Rezeptoragonisten könnte diesen pathophysiologischen Teufelskreis auf verschiedene Arten durchbrechen (Gewichtsabnahme durch zentrale Regulation der Nahrungsaufnahme, Reduktion der Lipogenese und der freien Fettsäuren, Erhöhung der Insulinsensitivität,ReduktionproinflammatorischerZytokine, Erhöhung des Adiponektin/Leptin-Verhältnisses) [38]. Erste vielversprechende Daten zeigen, dass Liraglutid vs.…”

“…Placebo eine deutliche histologische Remission der NASH (39%vs.9%,p=0,019)bewirkenkann [39].WeitereStudien zu Semaglutid und Dualen-Agonisten (wie beispielsweise GLP-1/GIPR oder GLP-1/GCGR-Co-Agonisten) wurden initiiert bzw. sind in Vorbereitung [38].…”