title: Efficacy and tolerability of the DPP-4 inhibitor alogliptin combined with pioglitazone, in metformin-treated patients with type 2 diabetes.
abstract: BACKGROUND
  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.
  
  
  METHODS
  We conducted a multicenter, randomized, double-blind, placebo-controlled, parallel-arm study in patients with type 2 diabetes.
  
  
  METHODS
  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.
  
  
  METHODS
  The primary endpoint was change in glycosylated hemoglobin (HbA(1c)) 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).
  
  
  RESULTS
  When added to metformin, the least squares mean change (LSMΔ) 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 (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.
  
  
  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.
authors.affiliation: University of Texas Health Sciences Center, Diabetes Division, 7703 Floyd Curl Drive, San Antonio, Texas 78229, USA. albarado@uthscsa.edu
authors.forename: R A
authors.initials: RA
authors.lastname: DeFronzo
authors.forename: C F
authors.initials: CF
authors.lastname: Burant
authors.forename: P
authors.initials: P
authors.lastname: Fleck
authors.forename: C
authors.initials: C
authors.lastname: Wilson
authors.forename: Q
authors.initials: Q
authors.lastname: Mekki
authors.forename: R E
authors.initials: RE
authors.lastname: Pratley
mesh_terms: D000328:Adult; D000368:Aged; D001786:Blood Glucose; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination / Q000009:adverse effects; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D008297:Male; D008687:Metformin / Q000008:administration & dosage / Q000627:therapeutic use*; D008875:Middle Aged; D000077205:Pioglitazone; D010880:Piperidines / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000627:therapeutic use*; D014498:Uracil / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D010880:Piperidines; D045162:Thiazolidinediones; D014498:Uracil; D008687:Metformin; C520853:alogliptin; D000077205:Pioglitazone