Effects of randomization to intensive glucose control on adverse events, cardiovascular disease, and mortality in older versus younger adults in the ACCORD Trial

Abstract

Objective: We explore the effect of randomized treatment, comparing intensive to standard glucose-lowering strategies on major cardiovascular outcomes, death, and severe adverse events in older versus younger participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.

Research design and methods: Participants with type 2 diabetes (n = 10,251) with a mean age of 62 years, a median duration of diabetes of 10 years, and a median A1C of 8.1% (65 mmol/mol) were randomized to treatment strategies targeting either A1C <6.0% (42 mmol/mol) or 7.0-7.9% (53-63 mmol/mol) and followed for a mean of 3.7 years. Outcomes were analyzed within subgroups defined by baseline age (<65 vs. ≥65 years).

Results: Older and younger ACCORD participants achieved similar intensive-arm A1C levels and between-arm A1C differences. Within the older subgroup, similar hazards of the cardiovascular primary outcome and total mortality were observed in the two arms. While there was no intervention effect on cardiovascular mortality in the older subgroup, there was an increased risk in the intensive arm for the younger subgroup (older hazard ratio [HR] = 0.97; younger HR = 1.71; P = 0.03). Regardless of intervention arm, the older subgroup experienced higher annualized rates of severe hypoglycemia (4.45% intensive and 1.36% standard) than the younger subgroup (2.45% intensive and 0.80% standard).

Conclusions: Intensive glucose lowering increased the risk of cardiovascular disease and total mortality in younger participants, whereas it had a neutral effect in older participants. The intensive to standard relative risk of severe hypoglycemia was similar in both age subgroups, with higher absolute rates in older participants within both treatment arms.

Trial registration: ClinicalTrials.gov NCT00000620.

Figure 1

Horizontal bars represent the 95% CI on the HR. Hosp, hospitalization.

Figure 2

Plots represent the proportion of participants reporting difficulty with either walking or activities at each follow-up visit. In the table below the figure, the number of participants providing data at each time point is presented in parentheses, after the percentage of participants reporting difficulty. M12, month 12; M24, month 24; M36, month 36; M48, month 48; Int, intensive; Std, standard; Gly, glycemia.

Figure 3

Spline curves of the risk of all-cause mortality with the two treatment strategies. A and B: The linear part of the PH model for average A1C from 6.0 to 9.0% (42 to 75 mmol/mol) for participants aged <65 and ≥65 years at randomization, respectively. For clarity, the figure omits values <6 (42 mmol/mol) and >9% (75 mmol/mol); approximately 5% of deaths are excluded from the plot at the lower and also at the higher end of the A1C range, but these data are included in the models. The plotted values are relative to a standard participant, aged <65 years at randomization and at an A1C of 6%. The dashed lines represent estimates and CIs for standard participants, solid lines are for intensive participants. C and D: The results from a Poisson regression model of all-cause mortality rates by treatment and age subgroup for the whole period of follow-up, over a range of decreases in A1C from baseline in the first year of treatment (as %A1C). The figures omit values beyond the 5th and 95th percentiles of A1C changes. The full range of values was from 6.8% (51 mmol/mol; an increase) to 7.4% (57 mmol/mol; a decrease) from baseline. The calculations used a Poisson regression model with data from model 3 of Riddle et al. (20).