2-Year effects of pioglitazone add-on to sulfonylurea or metformin on oral glucose tolerance in patients with Type 2 diabetes § Jochen Seufert a, *, Richard Urquhart b a Division of Endocrinology and Diabetology, Department of Internal Medicine II, University Hospital of Freiburg, Hugstetter Strasse 55, 79106 Freiburg, Germany b Research & Development, Takeda Europe R&D Centre Ltd., London, United Kingdom diabetes research and clinical practice 79 (2008) 453–460 article info Article history: Received 2 November 2006 Accepted 26 November 2007 Published on line 26 December 2007 Keywords: Metformin Oral glucose tolerance testing Pioglitazone Sulfonylurea Type 2 diabetes abstract Aim: We report the effectiveness of the thiazolidinedione, pioglitazone, as add-on medica- tion to metformin or sulfonylurea in reducing post-load serum glucose levels, as assessed by 3-h oral glucose tolerance testing (OGTT). Methods: Adult patients with Type 2 diabetes took part in one of two large-scale, 2-year clinical trials. One study compared pioglitazone treatment as add-on to failing metformin therapy (N = 317) with add-on gliclazide treatment to metformin (N = 313). The other study compared combination therapy with pioglitazone added to existing failing sulfonylurea therapy (N = 319) with metformin treatment in addition to sulfonylurea (N = 320). HbA 1c and fasting plasma glucose concentrations were measured at baseline and throughout the study and at the final visit at week 104. At selected centers (N = 299 patients), a 3-h OGTT was performed at baseline and at week 104. Results: At week 104, mean HbA 1c reduction from baseline was 0.89% for pioglitazone and 0.77% for gliclazide addition to metformin ( p = 0.200) and 1.03% with pioglitazone and 1.16% with metformin addition to sulfonylurea ( p = 0.173) in the total patient cohort. In the 299 patients who underwent OGTT, 2 years of treatment with pioglitazone, whether added to existing metformin or sulfonylurea medication, resulted in decreases in glucose excursions after an oral glucose load without increasing post-load serum insulin concentrations. In contrast, gliclazide in combination with metformin therapy caused increases in both post- load serum glucose and insulin excursions after 2 years, whereas metformin add-on to sulfonylurea did not have a significant effect on post-load serum glucose concentrations and resulted in an increase in insulin levels. Conclusions: There were no significant differences in HbA 1c levels between groups. However, 2-year treatment with pioglitazone as an add-on to either failing metformin or sulfonylurea therapy improved post-load glucose excursions without affecting insulin secretion. In contrast, glucose excursions were not improved by gliclazide or metformin add-on therapy, despite increases in post-load insulin levels. These data suggest that pioglitazone reduces peripheral insulin resistance via mechanisms different from those of metformin. # 2007 Elsevier Ireland Ltd. All rights reserved. § A preliminary report of this analysis was presented at the 64th Scientific Sessions of the American Diabetes Association (G. Edwards, et al., Diabetes 53 (Suppl. 2) (2004) A1223, 522-P) and at the 40th Annual Meeting of the European Association for the Study of Diabetes (G. Belcher, et al., Diabetologia 47 (Suppl. 1) (2004) A254, P702). * Corresponding author. Tel.: +49 761 270 3634; fax: +49 761 270 3413. E-mail address: jochen.seufert@uniklinik-freiburg.de (J. Seufert). Abbreviations: AUC, area under the concentration curve; FPG, fasting plasma glucose; HbA 1c , glycosylated hemoglobin; ITT, intent-to- treat; LOCF, last observation carried forward; OGTT, oral glucose tolerance testing. available at www.sciencedirect.com journal homepage: www.elsevier.com/locate/diabres 0168-8227/$ – see front matter # 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.diabres.2007.11.014