Insulin Dose and Cardiovascular Mortality in the ACCORD Trial

Diabetes Care. 2015 Nov;38(11):2000-8. doi: 10.2337/dc15-0598. Epub 2015 Oct 13.

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.

Research design and 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.

Trial registration: ClinicalTrials.gov NCT00000620.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Aged
  • Cardiovascular Diseases / mortality*
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / mortality*
  • Dose-Response Relationship, Drug
  • Female
  • Glycated Hemoglobin A / metabolism
  • Humans
  • Hypoglycemia / chemically induced
  • Hypoglycemia / epidemiology
  • Hypoglycemic Agents / administration & dosage*
  • Insulin / administration & dosage*
  • Male
  • Middle Aged
  • Proportional Hazards Models
  • Risk Factors

Substances

  • Glycated Hemoglobin A
  • Hypoglycemic Agents
  • Insulin

Associated data

  • ClinicalTrials.gov/NCT00000620