title: Searching for the right outcome? A systematic review and meta-analysis of controlled trials using carotid intima-media thickness or pulse wave velocity to infer antiatherogenic properties of thiazolidinediones.
abstract: BACKGROUND
  Recent meta-analyses cast doubt over purported beneficial effects of Peroxisome Proliferator Activated Receptor-Gamma (PPAR-gamma) receptor agonists. Thiazolidinedione (TZD) trials using surrogate outcomes to postulate an antiatherogenic paradigm have been criticised as misinformative. We conducted an independent systematic review and meta-analysis of controlled TZD studies incorporating carotid intima-media thickness (CIMT) or pulse wave velocity (PWV) as primary outcome measures. The aim was to provide an evidence-based overview of TZD intervention studies using markers prospectively linked to vascular outcome in type 2 diabetes.
  
  
  METHODS
  Systematic search of known databases for TZD intervention trials using mean thickness CIMT(n = 9) and ankle-brachial PWV(n = 6) as primary outcome measures was performed. CIMT and PWV pooled weighted mean difference was calculated using a random effects model accounting for heterogeneity and publication bias. An indirect meta-analysis provided a comparison of rosiglitazone and pioglitazone effects.
  
  
  RESULTS
  A composite of combined placebo and comparator controlled trials demonstrated a significant weighted mean difference of-0.06 mm for CIMT (95% CI-0.09 to-0.02, p = 0.001) and-0.72 ms(-1) for PWV (95% CI-1.28 to-0.16, p = 0.011) in favour of thiazolidiendione treatment. No TZD intraclass variation in CIMT (p = 0.96) or PWV (p = 0.33) change was observed.
  
  
  CONCLUSIONS
  TZDs exhibit significant beneficial effects on aorto-carotid atherosclerosis when assessed using prospectively validated non-invasive techniques. Inferring clinical benefit in the absence of confirmatory outcome trials is questionable and caution should be exercised when interpreting intervention data with surrogate endpoints. TZD-induced congestive cardiac failure or other unknown PPAR-gamma adverse effects are plausible explanations for the conflicting results of intervention trials using markers of atherosclerosis and clinical event outcomes.
authors.affiliation: Department of Cardiovascular Sciences, Victoria Building, Leicester Royal Infirmary, Leicester LE1 5WW, UK. drw17@le.ac.uk
authors.forename: D R
authors.initials: DR
authors.lastname: Webb
authors.forename: M J
authors.initials: MJ
authors.lastname: Davies
authors.forename: L J
authors.initials: LJ
authors.lastname: Gray
authors.forename: K R
authors.initials: KR
authors.lastname: Abrams
authors.forename: B
authors.initials: B
authors.lastname: Srinivasan
authors.forename: S
authors.initials: S
authors.lastname: Das
authors.forename: N
authors.initials: N
authors.lastname: Taub
authors.forename: I
authors.initials: I
authors.lastname: Lawrence
authors.forename: S
authors.initials: S
authors.lastname: Sutton
authors.forename: K
authors.initials: K
authors.lastname: Khunti
mesh_terms: D055109:Ankle Brachial Index; D001783:Blood Flow Velocity / Q000502:physiology; D002339:Carotid Arteries / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D002340:Carotid Artery Diseases / Q000188:drug therapy* / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D003925:Diabetic Angiopathies / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects*; D045162:Thiazolidinediones / Q000009:adverse effects*; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology; D017540:Tunica Media / Q000187:drug effects / Q000473:pathology
chemical_list: D007004:Hypoglycemic Agents; D045162:Thiazolidinediones