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

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. The aim of the study was to assess the efficacy and tolerability of alogliptin combined with pioglitazone in metformin-treated type 2 diabetic patients. We conducted a multicenter, randomized, double-blind, placebo-controlled, parallel-arm study in patients with type 2 diabetes. 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. The primary endpoint was change in glycosylated hemoglobin (HbA1c) from baseline to wk 26. Secondary endpoints included changes in fasting plasma glucose and β-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). When added to metformin, the least squares mean change (LSMΔ) from baseline HbA1c 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 (LSMΔ = −2.5 ± 0.1 mmol/liter for both) than Pio alone (LSMΔ = −1.6 ± 0.1 mmol/liter; P < 0.001). A12.5+P and A25+P significantly improved measures of β-cell function (proinsulin:insulin and homeostasis model assessment of β-cell function) compared to Pio alone, but had no effect on homeostasis model assessment of insulin resistance. The LSMΔ 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. In type 2 diabetic patients inadequately controlled by metformin, the reduction in HbA1c by alogliptin and pioglitazone was additive. The decreases in HbA1c with A12.5+P and A25+P were similar. All treatments were well tolerated.