Synergistic effect of the human GLP-1 analogue liraglutide and a dual PPARα/γ agonist on glycaemic control in Zucker diabetic fatty rats

Aim/Hypothesis Combination therapies are increasingly common in the clinical management of type 2 diabetes. We investigated to what extent combined treatment with the human glucagon-like peptide-1 (GLP-1) analogue liraglutide and the dual PPAR alpha/gamma agonist ragaglitazar would improve glycaemic control in overtly diabetic Zucker diabetic fatty (ZDF) rats. Methods Ninety overtly diabetic male ZDF rats were stratified into groups with matched haemoglobin A1c (HbA(1c)) (9.0 +/- 0.1%). Liraglutide (15 and 50 mu g/kg subcutaneously twice daily), ragaglitazar (1 and 3 mg/kg perorally once daily) and their vehicles were studied as monotherapy and in combination in a 3 x 3 factorial design. Results After 4-week treatment, synergistic effects on HbA(1c), non-fasting morning blood glucose (BG) and/or 24-h BG profiles were observed with three of the four combinations. The relationship between plasma insulin and BG in combination-treated animals approached that of historical lean ZDF rats representing normal glucose homeostasis, suggesting that insulin secretion and insulin sensitivity were markedly improved. Increased insulin immunostaining in islets further supports the improved beta-cell function and/or insulin sensitivity in combination-treated animals. The synergistic effect on glycaemic control was found without a similar synergistic increase in beta-cell mass in the combination groups. Conclusions/Interpretation Our data demonstrate that combination treatment with a human GLP-1 analogue and a dual PPAR alpha/gamma agonist through distinct mechanism of actions synergistically improves glycaemic control in the ZDF rat.