title: Pioglitazone Prevents Diabetes in Patients With Insulin Resistance and Cerebrovascular Disease.
abstract: The Insulin Resistance Intervention after Stroke (IRIS) trial recently found that pioglitazone reduced risk for stroke and myocardial infarction in patients with insulin resistance but without diabetes who had had a recent ischemic stroke or transient ischemic attack (TIA). This report provides detailed results on the metabolic effects of pioglitazone and the trial's prespecified secondary aim of diabetes prevention.
  
  
  
  A total of 3,876 patients with recent ischemic stroke or TIA, no history of diabetes, fasting plasma glucose (FPG) <126 mg/dL, and insulin resistance by homeostasis model assessment of insulin resistance (HOMA-IR) score >3.0 were randomly assigned to pioglitazone or placebo. Surveillance for diabetes onset during the trial was accomplished by periodic interviews and annual FPG testing.
  
  
  
  At baseline, the mean FPG, HbA1c, insulin, and HOMA-IR were 98.2 mg/dL (5.46 mmol/L), 5.8% (40 mmol/mol), 22.4 μIU/mL, and 5.4, respectively. After 1 year, mean HOMA-IR and FPG decreased to 4.1 and 95.1 mg/dL (5.28 mmol/L) in the pioglitazone group and rose to 5.7 and 99.7 mg/dL (5.54 mmol/L), in the placebo group (all P < 0.0001). Over a median follow-up of 4.8 years, diabetes developed in 73 (3.8%) participants assigned to pioglitazone compared with 149 (7.7%) assigned to placebo (hazard ratio [HR] 0.48 [95% CI 0.33-0.69]; P < 0.0001). This effect was predominately driven by those with initial impaired fasting glucose (FPG >100 mg/dL [5.6 mmol/L]; HR 0.41 [95% CI 0.30-0.57]) or elevated HbA1c (>5.7% [39 mmol/mol]; HR 0.46 [0.34-0.62]).
  
  
  
  Among patients with insulin resistance but without diabetes who had had a recent ischemic stroke or TIA, pioglitazone decreased the risk of diabetes while also reducing the risk of subsequent ischemic events. Pioglitazone is the first medication shown to prevent both progression to diabetes and major cardiovascular events as prespecified outcomes in a single trial.
authors.affiliation: Yale School of Medicine, New Haven, CT silvio.inzucchi@yale.edu.
authors.forename: Silvio E
authors.initials: SE
authors.lastname: Inzucchi
authors.affiliation: Yale School of Medicine, New Haven, CT.
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Viscoli
authors.affiliation: Yale School of Medicine, New Haven, CT.
authors.forename: Lawrence H
authors.initials: LH
authors.lastname: Young
authors.affiliation: Alpert Medical School of Brown University, Providence, RI.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Furie
authors.affiliation: Vermont College of Medicine, Burlington, VT.
authors.forename: Mark
authors.initials: M
authors.lastname: Gorman
authors.affiliation: Yale School of Medicine, New Haven, CT.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Lovejoy
authors.affiliation: University of Tennessee Health Science Center, Memphis, TN.
authors.forename: Samuel
authors.initials: S
authors.lastname: Dagogo-Jack
authors.affiliation: Case Western Reserve University and VA Medical Center, Cleveland, OH.
authors.forename: Faramarz
authors.initials: F
authors.lastname: Ismail-Beigi
authors.affiliation: University of Pittsburgh School of Medicine, Pittsburgh, PA.
authors.forename: Mary T
authors.initials: MT
authors.lastname: Korytkowski
authors.affiliation: Florida Hospital, Orlando, FL.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Pratley
authors.affiliation: VA Medical Center and University of Colorado School of Medicine, Denver, CO.
authors.forename: Gregory G
authors.initials: GG
authors.lastname: Schwartz
authors.affiliation: Yale School of Medicine, New Haven, CT.
authors.forename: Walter N
authors.initials: WN
authors.lastname: Kernan
mesh_terms: D000368:Aged; D001786:Blood Glucose / Q000378:metabolism; D003920:Diabetes Mellitus / Q000517:prevention & control*; D003924:Diabetes Mellitus, Type 2 / Q000517:prevention & control; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007333:Insulin Resistance / Q000502:physiology; D002546:Ischemic Attack, Transient; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000517:prevention & control*; D000077205:Pioglitazone; D020521:Stroke / Q000517:prevention & control*; D045162:Thiazolidinediones / Q000627:therapeutic use*
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D000077205:Pioglitazone