title: The dual peroxisome proliferator-activated receptor alpha/delta agonist GFT505 exerts anti-diabetic effects in db/db mice without peroxisome proliferator-activated receptor gamma-associated adverse cardiac effects.
abstract: We report here the efficacy and safety of GFT505, a novel liver-targeted peroxisome proliferator-activated receptor alpha/delta (PPARα/δ) agonist, in the db/db mouse model of diabetes. Mice were treated with vehicle, GFT505, PPARγ agonist rosiglitazone or dual-PPARα/γ agonist aleglitazar for up to 8 weeks. All compounds comparably reduced fasting glycaemia and HbA1c and improved insulin sensitivity. The glucose-lowering effect of GFT505 was associated with decreased hepatic gluconeogenesis, correlating with reduced expression of gluconeogenic genes. In contrast with the PPARγ-activating drugs, treatment with GFT505 did not affect heart weight and did not increase plasma adiponectin concentrations. This absence of cardiac effects of GFT505 was confirmed after 12 months of administration in cynomolgus monkeys, by the absence of echocardiographic and histological findings. Moreover, long-term GFT505 administration to monkeys induced no change in haematological parameters or in bone marrow differential cell counts. Compared to PPARγ-activating drugs, the dual-PPARα/δ agonist GFT505 therefore shows an improved benefit/risk ratio, treating multiple features of type 2 diabetes without inducing the cardiac side-effects associated with PPARγ activation.
authors.affiliation: Genfit SA, Loos, France.
authors.forename: Rémy
authors.initials: R
authors.lastname: Hanf
authors.affiliation: Genfit SA, Loos, France.
authors.forename: Lesley J
authors.initials: LJ
authors.lastname: Millatt
authors.affiliation: Department of Endocrinology, l'Institut du Thorax, Nantes University Hospital, Nantes, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Cariou
authors.affiliation: Genfit SA, Loos, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Noel
authors.affiliation: Genfit SA, Loos, France.
authors.forename: Géraldine
authors.initials: G
authors.lastname: Rigou
authors.affiliation: Genfit SA, Loos, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Delataille
authors.affiliation: Genfit SA, Loos, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Daix
authors.affiliation: Genfit SA, Loos, France.
authors.forename: Dean W
authors.initials: DW
authors.lastname: Hum
authors.affiliation: Institut Pasteur de Lille, Lille, France Inserm, UMR 1011, Lille, France Université de Lille 2, Lille, France EGID, Lille, France bart.staels@pasteur-lille.fr.
authors.forename: Bart
authors.initials: B
authors.lastname: Staels
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D047188:Chalcones / Q000494:pharmacology / Q000627:therapeutic use*; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy*; D004353:Drug Evaluation, Preclinical; D008055:Lipids / Q000097:blood; D008297:Male; D051379:Mice; D047493:PPAR alpha / Q000819:agonists; D047494:PPAR delta / Q000819:agonists; D011422:Propionates / Q000494:pharmacology / Q000627:therapeutic use*; D011897:Random Allocation
chemical_list: C585906:2-(2,6-dimethyl-4-(3-(4-(methylthio)phenyl)-3-oxo-1-propenyl)phenoxyl)-2-methylpropanoic acid; D001786:Blood Glucose; D047188:Chalcones; D008055:Lipids; D047493:PPAR alpha; D047494:PPAR delta; D011422:Propionates
keywords: GFT505; PPAR; anti-diabetic; dual-PPAR agonist; lipid metabolism; safety