original article Diabetes, Obesity and Metabolism 12: 348 – 355, 2010.  2010 Blackwell Publishing Ltd original article Dutogliptin, a selective DPP4 inhibitor, improves glycaemic control in patients with type 2 diabetes: a 12-week, double-blind, randomized, placebo-controlled, multicentre trial H. M. R. Pattzi 1 , S. Pitale 2 , M. Alpizar 3 , C. Bennett 4 , A. M. O’Farrell 4 , J. Li 4 , J. M. Cherrington 4 , H.-P. Guler 4 & PHX1149-PROT202 Study Group 1 Instituto Mexicano de Investigaciones Clinicas, Mexico City, Mexico 2 Pitale’s Clinic, Dhantoli, Nagpur, India 3 CEDOPEC, Mexico City, Mexico 4 Phenomix Corporation, San Diego, CA, USA Aim: To determine efficacy and tolerability of dutogliptin, a dipeptidyl peptidase 4 (DPP4) inhibitor, in patients with type 2 diabetes mellitus. Methods: This was a 12-week, multicentre, randomized, double-blind, placebo-controlled trial in 423 patients with type 2 diabetes with suboptimal metabolic control. Following a 2-week single-blind placebo run-in, patients aged 18–75 years with a body mass index of 25–48 kg/m 2 and baseline HbA1c of 7.3–11.0% were randomized 2:2:1 to receive once-daily oral therapy with either dutogliptin (400 or 200 mg) or placebo on a background medication of either metformin alone, a thiazolidinedione (TZD) alone or a combination of metformin plus a TZD. Results: Average HbA1c at baseline was 8.4%. Administration of dutogliptin 400 and 200 mg for 12 weeks decreased HbA1c by −0.52% (p < 0.001) and −0.35% (p = 0.006), respectively (placebo-corrected values), with absolute changes in HbA1c for the 400 mg, 200 mg and placebo groups of −0.82, −0.64 and −0.3%, respectively. The proportion of patients achieving an HbA1c <7% was 27, 21 and 12% at dutogliptin doses of 400 and 200 mg or placebo, respectively (p = 0.008 for comparison of 400 mg vs. placebo). Fasting plasma glucose (FPG) levels were significantly reduced in both active treatment groups compared to placebo: the placebo-corrected difference was −1.00 mmol/l (p < 0.001) for the 400 mg group and −0.88 mmol/l (p = 0.003) for the 200 mg group. Dutogliptin caused significantly greater reductions in postprandial glucose AUC 0–2h in both the 400 and 200 mg groups (placebo corrected values −2.58 mmol/l/h, p < 0.001 and −1.63 mmol/l/h, p = 0.032, respectively). In general, patients tolerated the study drug well. There were minor, not clinically meaningful differences in adverse events (AEs) between dutogliptin-treated patients and placebo controls, and 60% of all reported AEs were mild. Vital signs and body weight were stable, and routine safety laboratory parameters did not change compared with placebo. Trough ex vivo DPP4 inhibition at the end of the 12-week treatment period was 80 and 70%, at the 400 and 200 mg doses of dutogliptin, respectively. Conclusions: Dutogliptin treatment for 12 weeks improved glycaemic control in patients with type 2 diabetes who were on a background medication of metformin, a TZD or metformin plus a TZD. Tolerability was favourable for both doses tested. The 400 mg dose of dutogliptin resulted in larger changes of HbA1c and FPG and more subjects reached an HbA1c target of <7% than the 200 mg dose. Keywords: diabetes mellitus treatment, DPP4 inhibition, dutogliptin, HbA1c, incretins Date submitted 1 November 2009; date of first decision 19 December 2009; date of final acceptance 21 December 2009 Introduction Dutogliptin is a novel, orally available, potent and selective dipeptidyl peptidase-4 (DPP4) enzyme inhibitor. DPP4 is a serine protease that cleaves polypeptide substrates, including glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). GLP-1 and GIP increase insulin synthesis and release in response to food ingestion and Correspondence to: Hans-Peter Guler, MD, Phenomix Corporation, 5930 Cornerstone Court West, Suite 230, San Diego, CA 92121, USA. E-mail: hans-peter.guler@phenomixcorp.com decrease glucagon secretion in a glucose-dependent manner; these combined effects result in improved blood glucose control, primarily in the postprandial phase [1 – 3]. Continuous subcutaneous infusion of GLP-1 to patients with type 2 diabetes results in markedly improved glycaemic control [4]. In patients with type 2 diabetes, the endogenous GLP-1 response is blunted, leading to inappropriately reduced insulin secretion [5]. GLP-1 has a short half-life; therefore, strategies to inhibit the degradation of GLP-1 thereby enhancing its half-life have been developed in the last decade [6]. DPP4 inhibitors as well as GLP-1 analogues resistant to degradation by DPP4 are now available for the treatment of type 2 diabetic