Addition of a dipeptidyl peptidase-4 inhibitor, sitagliptin, to ongoing therapy with the glucagon- like peptide-1 receptor agonist liraglutide: A randomized controlled trial in patients with type 2 diabetes

Aim: To determine whether the addition of sitagliptin to pre- existing therapy with liraglutide changes glycaemic excursions after a mixed meal. Methods: A total of 16 patients with type 2 diabetes treated with metformin and liraglutide ( 1.2 mg/ d for >= 2 weeks) were randomized ( sealed envelopes), within a cross- over design, to be studied on two occasions, after an overnight fast, with ( 1) sitagliptin ( 100 mg orally) and ( 2) placebo ( patients and care givers blinded) administered 60 minutes before a mixed meal, or vice versa. Glucose excursions ( incremental area under the curve [AUC]; primary endpoint) and insulin, C- peptide, glucagon and incretin concentrations were measured. The study setting was a metabolic study unit at a specialized diabetes hospital. Results: All 16 patients completed the study and were analysed. Glucose ( AUC(glucose) 319 +/- 30 [placebo] vs 315 +/- 18 mmol. L-1. min(-1) [sitagliptin], Delta 7 [95% confidence interval - 50 to 63] mmol. L-1. min-1), insulin, C-peptide and glucagon concentrations were not affected significantly by sitagliptin treatment (P =.60-1.00). Intact glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) concentrations were augmented by sitagliptin, by 78.4% and 90.2%, respectively (both P < .0001). The influence of sitagliptin treatment on incretin plasma concentrations was similar to previously published results obtained in patients with type 2 diabetes on metformin treatment only. Conclusions: Sitagliptin, in patients already treated with a GLP-1 receptor agonist (liraglutide), increased intact GLP-1 and GIP concentrations, but with marginal, non-significant effects on glycaemic control. GLP-1 receptors have probably been maximally stimulated by liraglutide. Our findings do not support combination treatment with GLP-1 receptor agonists and DPP-4 inhibitors, but longer-term trials are needed to support clinical recommendations.