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.

Early investigational drugs targeting PPAR-α for the treatment of metabolic disease

“…Studies in the db/db diabetic mouse showed GFT505 reduced fasting glucose and HbA1c and improved insulin sensitivity similar to the PPAR-g agonist rosiglitazone or dual-PPAR-a/-g agonist aleglitazar, but GFT505 did not have the adverse cardiac effects of the PPAR-g-activating drugs [70]. The absence of cardiac effects of GFT505 was confirmed in 12-month studies in cynomolgus monkeys [70].…”

“…The liver-protective effects of GFT505 were demonstrated in various animal models of NAFLD/NASH and liver fibrosis including WD-fed hApoE2 KI transgenic mice and the benefits were shown to be partly related to PPAR-a effects and partly due to PPAR-a-independent mechanisms [69]. Studies in the db/db diabetic mouse showed GFT505 reduced fasting glucose and HbA1c and improved insulin sensitivity similar to the PPAR-g agonist rosiglitazone or dual-PPAR-a/-g agonist aleglitazar, but GFT505 did not have the adverse cardiac effects of the PPAR-g-activating drugs [70]. The absence of cardiac effects of GFT505 was confirmed in 12-month studies in cynomolgus monkeys [70].…”

Current and upcoming pharmacotherapy for non-alcoholic fatty liver disease

“…Elafibranor (GFT-505) is a dual PPARα/δ agonist, aiming to combine the beneficial effects of activating the two receptors. Animal data demonstrate that a beneficial effect of elafibranor on serum triglycerides, cholesterol and high density lipoprotein (HDL), and a reduction in hepatic fat that is mediated, at least in part, by non-PPARα-dependent mechanism 22 23. Post hoc analysis of short-term (4–12 weeks) phase II clinical trials using elafibranor for the treatment of metabolic syndrome demonstrated a significant reduction in ALT in subjects in the top two quartiles at baseline22 24 and has shown an improvement in liver, adipose and peripheral tissue insulin sensitivity,24 making it a potentially attractive therapeutic agent for NASH.…”

Novel therapeutics in hypertriglyceridemia

“…There was, however, a higher incidence of hypoglycemia and muscle events in the aleglitazar group, and peripheral edema, although not heart failure [21]. The dual PPAR-a and PPAR-d agonist, GFT505, has promise for treating diabetes, lipids, and potentially NAFLD, with recent promising animal data [25,45]. Human data are also promising, with small clinical trials demonstrating triglyceride reduction of 16.7-21% in various patient populations with abdominal obesity, with no major safety concerns [23,24].…”