title: Insulin Dose and Cardiovascular Mortality in the ACCORD Trial.
abstract: OBJECTIVE
  In the ACCORD trial, intensive treatment of patients with type 2 diabetes and high cardiovascular (CV) risk was associated with higher all-cause and CV mortality. Post hoc analyses have failed to implicate rapid reduction of glucose, hypoglycemia, or specific drugs as the causes of this finding. We hypothesized that exposure to injected insulin was quantitatively associated with increased CV mortality.
  
  
  METHODS
  We examined insulin exposure data from 10,163 participants with a mean follow-up of 5 years. Using Cox proportional hazards models, we explored associations between CV mortality and total, basal, and prandial insulin dose over time, adjusting for both baseline and on-treatment covariates including randomized intervention assignment.
  
  
  RESULTS
  More participants allocated to intensive treatment (79%) than standard treatment (62%) were ever prescribed insulin in ACCORD, with a higher mean updated total daily dose (0.41 vs. 0.30 units/kg) (P < 0.001). Before adjustment for covariates, higher insulin dose was associated with increased risk of CV death (hazard ratios [HRs] per 1 unit/kg/day 1.83 [1.45, 2.31], 2.29 [1.62, 3.23], and 3.36 [2.00, 5.66] for total, basal, and prandial insulin, respectively). However, after adjustment for baseline covariates, no significant association of insulin dose with CV death remained. Moreover, further adjustment for severe hypoglycemia, weight change, attained A1C, and randomized treatment assignment did not materially alter this observation.
  
  
  CONCLUSIONS
  These analyses provide no support for the hypothesis that insulin dose contributed to CV mortality in ACCORD.
authors.affiliation: Temple University School of Medicine, Philadelphia, PA esiraj@temple.edu.
authors.forename: Elias S
authors.initials: ES
authors.lastname: Siraj
authors.affiliation: Temple University School of Medicine, Philadelphia, PA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rubin
authors.affiliation: Oregon Health & Science University School of Medicine, Portland, OR.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Riddle
authors.affiliation: Wake Forest School of Medicine, Winston-Salem, NC.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Miller
authors.affiliation: Wake Forest School of Medicine, Winston-Salem, NC.
authors.forename: Fang-Chi
authors.initials: FC
authors.lastname: Hsu
authors.affiliation: Case Western Reserve University School of Medicine, Cleveland, OH.
authors.forename: Faramarz
authors.initials: F
authors.lastname: Ismail-Beigi
authors.affiliation: Wake Forest School of Medicine, Winston-Salem, NC.
authors.forename: Shyh-Huei
authors.initials: SH
authors.lastname: Chen
authors.affiliation: Wake Forest School of Medicine, Winston-Salem, NC.
authors.forename: Walter T
authors.initials: WT
authors.lastname: Ambrosius
authors.affiliation: Henry Ford Medical Center, Detroit, MI.
authors.forename: Abraham
authors.initials: A
authors.lastname: Thomas
authors.affiliation: Holston Medical Group, Kingsport, TN.
authors.forename: William
authors.initials: W
authors.lastname: Bestermann
authors.affiliation: University of North Carolina School of Medicine, Chapel Hill, NC.
authors.forename: John B
authors.initials: JB
authors.lastname: Buse
authors.affiliation: Case Western Reserve University School of Medicine, Cleveland, OH.
authors.forename: Saul
authors.initials: S
authors.lastname: Genuth
authors.affiliation: Memorial University Health Sciences Centre, St. John's, NL, Canada.
authors.forename: Carol
authors.initials: C
authors.lastname: Joyce
authors.affiliation: Memorial University Health Sciences Centre, St. John's, NL, Canada.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Kovacs
authors.affiliation: HealthPartners Institute for Education and Research, Minneapolis, MN.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: O'Connor
authors.affiliation: University of Calgary Cumming School of Medicine, Calgary, AB, Canada.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Sigal
authors.affiliation: Veterans Affairs Medical Center and University of Tennessee Health Science Center, Memphis, TN.
authors.forename: Sol
authors.initials: S
authors.lastname: Solomon
mesh_terms: D000328:Adult; D000368:Aged; D002318:Cardiovascular Diseases / Q000401:mortality*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000401:mortality*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007003:Hypoglycemia / Q000139:chemically induced / Q000453:epidemiology; D007004:Hypoglycemic Agents / Q000008:administration & dosage*; D007328:Insulin / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D012307:Risk Factors
chemical_list: D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin