title: Double-blind, randomized, multicentre, and active comparator controlled investigation of the effect of pioglitazone, metformin, and the combination of both on cardiovascular risk in patients with type 2 diabetes receiving stable basal insulin therapy: the PIOCOMB study.
abstract: BACKGROUND
  We analyzed specific effects of an add-on therapy with pioglitazone compared to metformin and their combination in patients with basal insulin treatment on biomarkers of CV risk.
  
  
  METHODS
  In this double-blind, randomized, multicentre, active comparator controlled trial, 121 patients with type 2 diabetes were enrolled. Inclusions: treatment with basal insulin, HbA(1C) 6.5%-8.5%, age 30-75 years. After glargine therapy over 2 weeks for titration towards FBG ≤ 7.8 mmol/L, patients received either (A) bid 850 mg metformin (n = 42), (B) bid 15 mg pioglitazone (n = 40), or (C) 30 mg pioglitazone plus 1.7 g metformin (n = 39) over 6 months. Matrix Metal Proteinase 9 (MMP-9) was primary objective, together with biomarkers of CV risk.
  
  
  RESULTS
  Pioglitazone (B) reduced MMP-9 versus baseline by 54.1 ± 187.1 ng/mL, with metformin (A) it was increased by 49.6 ± 336.2 ng/mL (p = 0.0345; B vs. A), and with the combination of both (C) it was decreased by 67.8 ± 231.4 ng/mL (A vs. C: p = 0.0416; B vs. C: p = 0.8695). After logarithmic transformation due to high variances the exploratory results showed significance for A vs. B (p = 0.0043) and for A vs. C (p = 0.0289).Insulin dosage was reduced by 7.3 units in group B (p < 0.0001), by 6.0 units in C (p = 0.0004), but was increased by 2.5 units (p = 0.1539) in A at follow up. Reduction in hs-CRP was significant within treatment groups for B (p = 0.0098) and C (p < 0.0001), and between the groups for A vs. C (p = 0.0124). All three single regimens reduced PAI-1. Adiponectin was significantly elevated in B and C (p < 0.0001) and between-groups. HbA(1C) was only significantly decreased in the combination group. No significant effects were observed for NFkB and PGFα. peripheral edema were seen in 11.9% vs. 40.0% vs. 20.5%, and weight change was -0.7 kg vs. +4.3 kg vs. +2.7 kg (A vs. B vs. C).
  
  
  CONCLUSIONS
  Addition of pioglitazone but not of metformin reduces MMP-9, hs-CRP and increased insulin sensitivity and adiponectin in this study. The combination of both had no additional effect on inflammation. Pioglitazone is suggested to be a rational add-on therapy to basal insulin in patients with high CV risk.
authors.affiliation: GWT-TUD mbH, Fiedlerstr. 34, 01307 Dresden, Germany. hanefeld@gwtonline-zks.de
authors.forename: Markolf
authors.initials: M
authors.lastname: Hanefeld
authors.forename: Andreas
authors.initials: A
authors.lastname: Pfützner
authors.forename: Thomas
authors.initials: T
authors.lastname: Forst
authors.forename: Iris
authors.initials: I
authors.lastname: Kleine
authors.forename: Winfried
authors.initials: W
authors.lastname: Fuchs
mesh_terms: D052242:Adiponectin / Q000097:blood; D000328:Adult; D000368:Aged; D002097:C-Reactive Protein / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000453:epidemiology*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications* / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D007328:Insulin / Q000097:blood; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000097:blood; D008687:Metformin / Q000009:adverse effects / Q000627:therapeutic use*; D008875:Middle Aged; D000077205:Pioglitazone; D012307:Risk Factors; D045162:Thiazolidinediones / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D052242:Adiponectin; D002097:C-Reactive Protein; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D020780:Matrix Metalloproteinase 9; D008687:Metformin; D000077205:Pioglitazone; D045162:Thiazolidinediones