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.

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.

© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Figures

Figure 1

Smoothing curves for association between updated, average A1C (%) and updated, average total insulin dose (units/kg) for the two treatment strategies over the range of average A1C from 6.0 to 9.0% (42 to 75 mmol/mol). The bold red line represents the intensive treatment group, and the bold dashed blue line represents the standard group. The finer-colored lines represent the 95% CIs for each group. The association between A1C level and insulin dose in the intensive group was marginally different compared with the association in the standard group (P for interaction = 0.065). In the stratified analysis, an increase in updated, average A1C was associated with an increase in updated, average insulin dose within each treatment group (regression coefficient estimates are 0.20 and 0.18 for the intensive group and the standard group, respectively; both P < 0.001).

Figure 2

Spline curves displaying the risk of CV mortality with the two treatment strategies over the range of updated, average total insulin dose (units/kg). The curves represent the linear part of the Cox proportional hazards models derived from values for updated, average total insulin from model 4. The bold red line represents the intensive treatment group, the bold dashed blue line represents the standard group, and the finer-colored lines represent the 95% CIs for each group. The reference group is for an updated, average total insulin of 0 in the standard group. There was no evidence that the shape of the curves was statistically different between treatment groups (P for interaction = 0.358), and there was no evidence of nonlinearity within each treatment group (intensive P = 0.375; standard P = 0.523) or evidence of a nonzero slope within groups (intensive P = 0.975; standard P = 0.930).