Effects of ALT-801, a GLP-1 and glucagon receptor dual agonist, in a translational mouse model of non-alcoholic steatohepatitis

Abstract

Body weight loss of ≥ 10% improves the metabolic derangements and liver disease in the majority of non-alcoholic steatohepatitis (NASH) patients, suggesting metabolic modulators may be effective in controlling disease. The pharmacodynamics of ALT-801, a GLP-1/glucagon receptor dual agonist optimized for NASH and weight loss, were compared to semaglutide (GLP-1 receptor agonist) and elafibranor (peroxisome proliferator-activated receptor, PPAR-α/δ, agonist) in a biopsy-confirmed, diet-induced obese (DIO) mouse model of NASH (DIO-NASH). Male C57BL/6J mice were fed Amylin Liver NASH (AMLN) diet for 32 weeks. Animals with biopsy-confirmed steatosis and fibrosis received ALT-801, semaglutide, elafibranor, or vehicle daily for 12 weeks while maintained on the AMLN diet. Study endpoints included body and liver weight, liver and plasma total cholesterol and triglycerides, plasma aminotransferases, histological analysis of liver steatosis, inflammation (galectin-3) and fibrosis (collagen type 1 alpha 1), and evaluation of individual animal changes in composite Non-alcoholic Fatty Liver Disease Activity Score (NAS), and fibrosis stage. ALT-801 demonstrated significant reductions in body weight (approx. 25%), plasma aminotransferases, plasma total cholesterol and liver triglycerides/total cholesterol in conjunction with improved liver steatosis, with greater reductions (p < 0.05) compared to semaglutide and elafibranor. ALT-801 significantly reduced the inflammation marker galectin-3 and the fibrosis marker collagen type 1 alpha 1 vs. vehicle (p < 0.05), with ALT-801 producing greater reductions in galectin-3 vs. elafibranor (p < 0.05). Importantly, all animals treated with ALT-801 significantly improved composite NAS compared to the active controls. This study provides evidence for a potential role for ALT-801 in the therapeutic treatment of NASH.

Abolishing β‐arrestin recruitment is necessary for the full metabolic benefits of G protein‐biased glucagon‐like peptide‐1 receptor agonists

“…Importantly, differences in the extent of surface GLP-1R loss with each agonist were observed within the reported range of steady state plasma semaglutide concentrations achieved with 2.4 mg weekly dosing in humans, 29 and for mice after a single 10 nmol/kg dose as in our study. 30 We also assessed the same phenomenon in INS-1832/3 cells and intact mouse pancreatic islets using post-labelling with exendin-4-Cy5 6 ; here, with 4% supplemental HSA treatment, 100 nM SRB107 again led to moderately preserved surface GLP-1R compared with SRB106 (Figure 3C, D). We note that this difference was less marked than in SNAP-GLP-1R cells, which could reflect receptor species-related differences (as in Figure S2), other cellspecific differences in endocytosis machinery, or assay considerations: residual binding of SRB107 at the cell surface may have reduced exendin-4-Cy5 binding during the labelling phase as both compete for the GLP-1R orthosteric site.…”

Efficacy and Safety of Liraglutide and Semaglutide on Weight Loss in People with Obesity or Overweight: A Systematic Review

“…People with obesity or overweight have a severe impact on our physical health and lead to an increased incidence of various diseases, especially people with obesity or overweight and type 2 diabetes, which is often accompanied by complications such as cardiovascular disease. [1][2][3][4] GLP-1RA can bring us weight loss and achieve the effect of lowering blood sugar, reducing the death rate of Covid-19, 5 and has a protective effect on our cardiovascular. 11 The primary purpose of this study is to compare the efficacy and safety of two GLP-1RA for weight management (liraglutide and Semaglutide) that the FDA has approved and recommended in the 2022 American Diabetes Association's standards for diabetes care and provide evidence for individualized medication management in clinical practice.…”

“…Obesity is a chronic disease with serious health consequences; it can lead to insulin resistance, hypertension, and dyslipidemia, associated with complications such as type 2 diabetes, cardiovascular disease, and non-alcoholic fatty liver disease, and reduce life expectancy. [1][2][3][4] Recently, obesity has been associated with increased hospitalizations, the need for mechanical ventilation, and death in patients with coronavirus disease 2019 (Covid-19). 5,6 Weight loss of 5% to 10% has been shown to reduce obesityrelated complications and improve quality of life.…”

Research Progress on the GIP/GLP-1 Receptor Coagonist Tirzepatide, a Rising Star in Type 2 Diabetes

“…In recent years, numerous antidiabetic drugs, such as pioglitazone and GLP-1RAs, have exhibited improvements in liver enzymes; both reduce cardiovascular risk and improve liver histology in individuals with NAFLD [24]; SGLT2 receptor inhibitors may also improve the metabolic abnormalities of NAFLD to some extent [25]. Mechanistically, the protective effect of GIP and GLP-1 on the liver is indirect, as hepatocytes do not express GIP and typically GLP-1, and the role of GIP and GLP-1 expression in the liver is controversial [26][27][28][29]. However, it is worth noting that an effective treatment for NAFLD is weight loss, which has been shown to improve hepatic steatosis and fibrosis [30].…”