The dipeptidyl peptidase‐4 inhibitor PHX1149 improves blood glucose control in patients with type 2 diabetes mellitus

Abstract

Addition of the DPP4 inhibitor PHX1149 to a stable regimen of metformin or metformin plus a glitazone in patients with type 2 diabetes was well tolerated and improved blood glucose control.

Evaluation of the potential for pharmacokinetic and pharmacodynamic interactions between dutogliptin, a novel DPP4 inhibitor, and metformin, in type 2 diabetic patients

“…No SAEs were reported. It should be noted that in a 4-week study with 174 patients with T2DM who were on a background of metformin 12 and in a 12-week study with 423 patients with T2DM who were on a background medication of metformin 27 , there was no clear difference in adverse events between the dutogliptin treated groups and the placebo group.…”

“…Any change in the plasma AUC of dutogliptin or metformin within the 0.50-2.0 bound was predefined as lack of a clinically meaningful pharmacokinetic interaction based on the following. Single doses of dutogliptin of up to 3200 mg/day, eight times the highest anticipated clinical dose level, were well tolerated by 53 healthy volunteers 26 , while a lower dose of 200 mg still resulted in near complete DPP4 inhibition and showed changes of HbA 1c 12,27 . For metformin, the typically administered dose range is from 500 mg to 2550 mg/day [28][29] .…”

“…These are desirable properties as they retain dutogliptin in the extracellular compartment where DPP4, the regulator of GLP-1 degradation, is located. Studies in normal volunteers and in diabetic patients have shown a dose-dependent increase of plasma dutogliptin concentrations which correlate with ex vivo DPP4 inhibition [12][13] . Furthermore, a dosedependent increase of intact GLP-1 concentrations, reduced postprandial glucose excursion, and improved glycemic control have been demonstrated in patients with T2DM 12 .…”

“…In patients with T2DM, GLP-1 release is decreased and therefore stimulation of insulin production and secretion occurs at a lower concentration [8][9][10] . Enhancement of the half-life of GLP-1 by blocking its degrading enzyme, DPP4, is a clinically validated approach in treatment of diabetes [10][11][12] . Three DPP4 inhibitors, sitagliptin, vildagliptin and saxagliptin, have been approved in the US or Europe for the treatment of patients with T2DM since October 2006.…”

Novel Pharmacological Approaches to the Treatment of Type 2 Diabetes

“…A reduction in the dose of sulfonylureas is usually recommended (risk of hypoglycemia) when DPP-4 inhibitors are added (pharmacodynamic rather than a pharmacokinetic interaction) (Scheen, 2010a). (Garcia-Soria et al, 2008;Pattzi et al, 2010); efficacy and tolerability are positive (O'Farrell et al, 2007;GarciaSoria et al, 2008;Rosenberg et al, 2010). Dutogliptin is highly water soluble (Ͼ2000 mg/ml), has low cellular permeability, is rapidly absorbed (with a T max of 3 to 4 h), has a half-life of 10 to 13 h, exhibits low plasma protein binding (11%) (Pattzi et al, 2010), is not metabolized (Pattzi et al, 2010), and is excreted renally.…”