Efficacy and safety of linagliptin in subjects with type 2 diabetes mellitus and poor glycemic control: Pooled analysis of data from three placebo-controlled phase III trials ☆ Stefano Del Prato a, ⁎, Marja-Riitta Taskinen b , David R. Owens c , Maximilian von Eynatten d , Angela Emser d , Yan Gong d , Silvia Chiavetta e , Sanjay Patel f , Hans-Juergen Woerle d a Department of Endocrinology and Metabolism, Section of Diabetes, University of Pisa, Pisa, Italy b Helsinki University Central Hospital, Institute of Clinical Medicine, Helsinki, Finland c Institute of Molecular and Experimental Medicine, Cardiff University, Cardiff, UK d Boehringer Ingelheim, Ingelheim, Germany e Boehringer Ingelheim, Milan, Italy f Boehringer Ingelheim, Bracknell, UK abstract article info Article history: Received 13 August 2012 Received in revised form 28 November 2012 Accepted 28 November 2012 Available online 9 February 2013 Keywords: Combination therapy DPP-4 inhibitor Linagliptin Poor glycemic control Type 2 diabetes mellitus Aims: To evaluate the efficacy/safety of dipeptidyl peptidase-4 inhibitor, linagliptin, in subjects with insufficiently controlled type 2 diabetes mellitus (T2DM), and factors influencing treatment response. Methods: Pooled analysis of data from 2258 subjects in three 24-week phase III, randomized, placebo- controlled, parallel-group studies, who received oral linagliptin (5 mg/day) or placebo as monotherapy, added-on to metformin, or added-on to metformin plus sulfonylurea was performed. Results: Among 388 subjects with HbA1c ≥9.0%, adjusted mean baseline HbA1c (9.4% both groups) declined to 8.3% in linagliptin group and 9.1% in placebo group at 24 weeks (P b .0001) and adjusted mean change from baseline was 1.2% (vs. 0.4%, placebo). Linagliptin significantly lowered fasting plasma glucose levels vs. placebo (1.6 mmol/l vs. 0.4 mmol/l); treatment difference, 1.1 mmol/l (95% CI, −1.7 to −0.5). Treatment and washout of previous oral antidiabetes drugs were the only factors to independently affect HbA1c change at week 24. Adverse event rates were similar for linagliptin (61.9%) and placebo (62.7%). Hypoglycemia was rare with linagliptin monotherapy/add-on to metformin (≤1%) and increased when linagliptin was added to metformin plus sulfonylurea (linagliptin, 17.9% vs. placebo, 8.3%). Conclusions: Linagliptin was an effective, well-tolerated treatment in subjects with T2DM and insufficient glycemic control, both as monotherapy or added-on to metformin/metformin plus sulfonylurea. © 2013 Elsevier Inc. All rights reserved. 1. Introduction Linagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor recently approved for the treatment of type 2 diabetes. The molecule has a unique xanthine-based structure and is a highly selective, competitive inhibitor of DPP-4 (Thomas, Eckhardt, Langkopf, Tadayyon, Himmelsbach, & Mark, 2008), the enzyme responsible for degradation of endogenously released glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP). The safety and efficacy of linagliptin 5 mg in people with T2DM and insufficient glycemic control (HbA1c ≥ 6.5% [48 mmol/mol] or ≥ 7.0% [53 mmol/mol] to ≤ 10.0% [86 mmol/mol]) have been demonstrated in four phase III clinical trials: as monotherapy (Del Prato, Barnett, Huisman, Neubacher, Woerle, & Dugi, 2011), add-on to metformin (Taskinen et al., 2011), or add-on to metformin and sulfonylurea (Owens, Swallow, Dugi, & Woerle, 2011), and in combination with pioglitazone (Gomis, Espadero, Jones, Woerle, & Dugi, 2011). These four phase III clinical trials recruited subjects with different degrees of glycemic control but did not address in a specific manner whether treatment with linagliptin remained efficacious in patients with poor glycemic control and to what extent some factors could be affecting the safety/efficacy profile in these individuals. Therefore, the aim of this pooled analysis was to Journal of Diabetes and Its Complications 27 (2013) 274–279 ☆ Conflicts of interest: Stefano Del Prato has received fees for speaking by Novartis Pharmaceuticals, Merck & Co., Bristol-Myers Squibb, Astra Zeneca; sanofi-aventis, Novo Nordisk; fees for consulting from Boehringer Ingelheim, Novartis Pharmaceuticals, Merck & Co., Roche Pharmaceuticals, Eli Lilly and Co., Bristol-Myers Squibb, Astra Zeneca, GlaxoSmithKline, Takeda Pharmaceuticals, Novo Nordisk, Intarcia; funds for reasearch from Merck & Co., Takeda Pharmaceuticals, and Novo Nordisk. Marja-Ritta Taskinen has received reimbursement for attending symposia when acting as a speaker, in addition to fees for consulting, and funds for research and support for associated staff. David Owens has received honoraria for lecturing from Roche and Sanofi, in addition to fees for advisory board activities from Roche, Sanofi and Boehringer Ingelheim. Maximilian von Eynatten, Angela Emser, Yan Gong, Sylvia Chiavetta, Sanjay Patel, and Hans-Juergen Woerle are employees of Boehringer Ingelheim. ⁎ Corresponding author. Tel.: +39 050 995103; fax: +39 050 541521. E-mail address: stefano.delprato@med.unipi.it (S. Del Prato). 1056-8727/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jdiacomp.2012.11.008 Contents lists available at SciVerse ScienceDirect Journal of Diabetes and Its Complications journal homepage: WWW.JDCJOURNAL.COM