Epidemiologic relationships between A1C and all-cause mortality during a median 3.4-year follow-up of glycemic treatment in the ACCORD trial

Abstract

Objective: Randomized treatment comparing an intensive glycemic treatment strategy with a standard strategy in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial was ended early because of an unexpected excess of mortality in the intensive arm. As part of ongoing post hoc analyses of potential mechanisms for this finding, we explored whether on-treatment A1C itself had an independent relationship with mortality.

Research design and methods: Participants with type 2 diabetes (n = 10,251 with mean age 62 years, median duration of diabetes 10 years, and median A1C 8.1%) were randomly assigned to treatment strategies targeting either A1C <6.0% (intensive) or A1C 7.0-7.9% (standard). Data obtained during 3.4 (median) years of follow-up before cessation of intensive treatment were analyzed using several multivariable models.

Results: Various characteristics of the participants and the study sites at baseline had significant associations with the risk of mortality. Before and after adjustment for these covariates, a higher average on-treatment A1C was a stronger predictor of mortality than the A1C for the last interval of follow-up or the decrease of A1C in the first year. Higher average A1C was associated with greater risk of death. The risk of death with the intensive strategy increased approximately linearly from 6-9% A1C and appeared to be greater with the intensive than with the standard strategy only when average A1C was >7%.

Conclusions: These analyses implicate factors associated with persisting higher A1C levels, rather than low A1C per se, as likely contributors to the increased mortality risk associated with the intensive glycemic treatment strategy in ACCORD.

Trial registration: ClinicalTrials.gov NCT00000620.

Figure 1

Spline curves displaying the risk of all-cause mortality with the two treatment strategies over the range of average A1C from 6.0 to 9.0%. The curves represent the linear part of the proportional hazards models derived from values for intervals of average A1C from model 3. For clarity, the figure omits values <6 and >9%; ∼5% of deaths are excluded from this plot at the lower end and also at the higher end of the A1C range, but these data are included in the models. The bold orange line represents the intensive treatment strategy group, the bold blue line represents the standard group, and the finer colored lines represent the 95% CIs for each group.

Figure 2

Curves displaying all-cause mortality rates by treatment for the whole period of follow-up, over a range of decreases in A1C from baseline in the 1st year of treatment (as a percentage of A1C). The figure omits values <5th and >95th percentiles of A1C changes. The full range of values was from −6.8 (an increase) to 7.4% (a decrease) from baseline. The calculations used a Poisson regression model with data from model 3. The bold orange line represents the intensive treatment group, the bold blue line represents the standard group, and the finer colored lines represent the 95% CIs for each group.