2-Year effects of pioglitazone add-on to sulfonylurea or metformin on oral glucose tolerance in patients with Type 2 diabetes

Aim: We report the effectiveness of the thiazolidinedione, pioglitazone, as add-on medication 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. (C) 2007 Elsevier Ireland Ltd. All rights reserved.