title: Pioglitazone as monotherapy or in combination with sulfonylurea or metformin enhances insulin sensitivity (HOMA-S or QUICKI) in patients with type 2 diabetes.
abstract: BACKGROUND
  Miyazaki et al. demonstrated using the hyperinsulinemic, euglycemic clamp that pioglitazone (PIO) enhanced insulin sensitivity in patients (n = 23) with type 2 diabetes (T2D). Although considered the reference method for measuring insulin sensitivity, the clamp is seldom used in large clinical trials because of its complexity. The Homeostasis Model Assessment Insulin Sensitivity (HOMA-S) and Quantitative Insulin Sensitivity Check Index (QUICKI) are two alternative insulin sensitivity surrogates that correlate with the clamp method and are suitable for use with large study populations.
  
  
  OBJECTIVE
  To evaluate the effect of PIO monotherapy and in combination therapy with sulfonylurea (SU) or metformin (MET) on insulin sensitivity as assessed by HOMA-S and QUICKI in a large group of patients (approximately 1000).
  
  
  METHODS
  Patient data from three randomized, double blind, multicenter, parallel group, placebo-controlled registration trials (Studies-001 PIO monotherapy and 010 and 027 combination therapy with SU or MET, respectively) were analyzed for this study. We evaluated insulin sensitivity for all three studies using HOMA-S and QUICKI.
  
  
  RESULTS
  PIO 15, 30 and 45 mg enhanced HOMA-S compared with baseline (56.9-63.6%, p = 0.0298); (53.7-64.7%, p = 0.0008); (59.0-75.9%, p < 0.0001), respectively. Only the 45 mg dose showed a difference from placebo (p = 0.0025). Similarly, PIO enhanced QUICKI versus baseline (0.290-0.296, p = 0.0026); (0.287-0.299, p = 0.0001); (0.290-0.306, p = 0.0001), respectively. Both the 30 and 45 mg doses were different from placebo for QUICKI (p = 0.0005, p < 0.0001). PIO 15 and 30 mg plus SU enhanced HOMA-S compared with baseline (58.4-66.7%, p = 0.0007; 53.2-68.4%, p < 0.0001) and placebo plus SU (p = 0.0129, p < 0.0001, respectively). Likewise, PIO 15 and 30 mg plus SU enhanced QUICKI versus baseline (0.289-0.300, p = 0.0001; 0.287-0.305, p = 0.0001, respectively). Both doses had different effects from placebo plus SU (p = 0.0001) for QUICKI. PIO 30mg combined with MET enhanced HOMA-S versus baseline (66.2-82.2%, p < 0.0001) and placebo plus MET (p = 0.0002). Similarly, PIO 30 mg plus MET enhanced QUICKI compared with baseline (0.295-0.309, p = 0.0001) and placebo plus MET (p = 0.0001).
  
  
  CONCLUSIONS
  PIO monotherapy and combination therapy with SU or MET enhanced insulin sensitivity as evaluated by HOMA-S and QUICKI. Both measures can detect changes in sensitivity for large numbers of subjects when the reference method hyperinsulinemic euglycemic clamp, or other complex methods are not feasible.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. tan_meng@lilly.com
authors.forename: Meng H
authors.initials: MH
authors.lastname: Tan
authors.forename: N Bradly
authors.initials: NB
authors.lastname: Glazer
authors.forename: Don
authors.initials: D
authors.lastname: Johns
authors.forename: Mario
authors.initials: M
authors.lastname: Widel
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Gilmore
mesh_terms: D000704:Analysis of Variance; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007333:Insulin Resistance; D008297:Male; D008687:Metformin / Q000627:therapeutic use*; D000077205:Pioglitazone; D013453:Sulfonylurea Compounds / Q000627:therapeutic use*; D045162:Thiazolidinediones / Q000627:therapeutic use*
chemical_list: D007004:Hypoglycemic Agents; D013453:Sulfonylurea Compounds; D045162:Thiazolidinediones; D008687:Metformin; D000077205:Pioglitazone