Efficacy and Tolerability of the DPP-4 Inhibitor Alogliptin Combined with Pioglitazone, in Metformin-Treated Patients with Type 2 Diabetes

Context: Optimal management of type 2 diabetes remains an elusive goal. Combination therapy addressing the core defects of impaired insulin secretion and insulin resistance shows promise in maintaining glycemic control. Objective: The aim of the study was to assess the efficacy and tolerability of alogliptin combined with pioglitazone in metformin-treated type 2 diabetic patients. Design, Setting, and Patients: We conducted a multicenter, randomized, double-blind, placebo-controlled, parallel-arm study in patients with type 2 diabetes. Interventions: The study consisted of 26-wk treatment with alogliptin (12.5 or 25 mg qd) alone or combined with pioglitazone (15, 30, or 45 mg qd) in 1554 patients on stable-dose metformin monotherapy (>= 1500 mg) with inadequate glycemic control. Main Outcome Measure: The primary endpoint was change in glycosylated hemoglobin (HbA(1c)) from baseline to wk 26. Secondary endpoints included changes in fasting plasma glucose and beta-cell function. Primary analyses compared pioglitazone therapy [all doses pooled, pioglitazone alone (Pio alone); n = 387] with alogliptin 12.5 mg plus any dose of pioglitazone (A12.5 + P; n = 390) or alogliptin 25 mg plus any dose of pioglitazone (A25 + P; n = 390). Results: When added to metformin, the least squares mean change (LSM Delta) from baseline HbA(1c) was -0.9 +/- 0.05% in the Pio-alone group and -1.4 +/- 0.05% in both the A12.5 + P and A25 + P groups (P < 0.001 for both comparisons). A12.5 + P and A25 + P produced greater reductions in fasting plasma glucose (LSM Delta = -2.5 +/- 0.1 mmol/liter for both) than Pio alone (LSM Delta = -1.6 +/- 0.1 mmol/liter; P < 0.001). A12.5 + P and A25 + P significantly improved measures of beta-cell function (proinsulin: insulin and homeostasis model assessment of beta-cell function) compared to Pio alone, but had no effect on homeostasis model assessment of insulin resistance. The LSM Delta body weight was 1.8 +/- 0.2, 1.9 +/- 0.2, and 1.5 +/- 0.2 kg in A12.5 +/- P, A25 + P, and Pio-alone groups, respectively. Hypoglycemia was reported by 1.0, 1.5, and 2.1% of patients in the A12.5 + P, A25 + P, and Pio-alone groups, respectively. Conclusions: In type 2 diabetic patients inadequately controlled by metformin, the reduction in HbA(1c) by alogliptin and pioglitazone was additive. The decreases in HbA(1c) with A12.5 + P and A25 + P were similar. All treatments were well tolerated. (J Clin Endocrinol Metab 97: 1615-1622, 2012)