Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin added to pioglitazone in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled study

Objectives: To evaluate the efficacy and safety of alogliptin in patients with type 2 diabetes inadequately controlled by therapy with a thiazolidinedione (TZD). Research design and methods: In a multicenter, double-blind, placebo-controlled clinical study, 493 patients 18-80 years old with inadequate glycemic control after stabilization (i.e., glycosylated hemoglobin [HbA(1c)] 7.0-10.0%) despite ongoing treatment with a TZD were randomly assigned (2:2:1) to treatment with pioglitazone plus alogliptin 12.5 mg, alogliptin 25 mg or placebo once daily. Concomitant therapy with metformin or sulfonylurea at prestudy doses was permitted. Main outcome measures: The primary efficacy endpoint was change in HbA(1c) from baseline to Week 26. Secondary end-points included changes in fasting plasma glucose (FPG) and body weight, and incidences of marked hyperglycemia (FPG >= 200 mg/dL [11.10 mmol/L]) and rescue for hyperglycemia. Results: Least squares (LS) mean change in HbA1c was significantly (p < 0.001) greater for alogliptin 12.5 mg (-0.66%) or 25 mg (-0.80%) than for placebo (-0.19%). A significantly (p <= 0.016) larger proportion of patients achieved HbA(1c) <= 7% with alogliptin 12.5 mg (44.2%) or 25 mg (49.2%) than with placebo (34.0%). LS mean decreases in FPG were significantly (p=0.003) greater with alogliptin 12.5 mg (-19.7 mg/dL [-1.09 mmol/L]) or 25 mg (-19.9 mg/dL [-1.10 mmol/L]) than with placebo (-5.7 mg/dL [-0.32 mmol/L]). The percentage of patients with marked hyperglycemia was significantly (p < 0.001) lower for alogliptin (<= 25.0%) than placebo (44.3%). The incidences of overall adverse events and hypoglycemia were similar across treatment groups, but cardiac events occurred more often with active treatment than placebo. Conclusions: Addition of alogliptin to pioglitazone therapy significantly improved glycemic control in patients with type 2 diabetes and was generally well tolerated. The study did not evaluate the effect of combination therapy on long-term clinical outcomes and safety.