The hemoglobin glycation index identifies subpopulations with harms or benefits from intensive treatment in the ACCORD trial

Abstract

Objective: This study tested the hypothesis that intensive treatment in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial disproportionately produced adverse outcomes in patients with diabetes with a high hemoglobin glycation index (HGI = observed HbA1c - predicted HbA1c).

Research design and methods: ACCORD was a randomized controlled trial of 10,251 patients with type 2 diabetes assigned to standard or intensive treatment with HbA1c goals of 7.0% to 7.9% (53 to 63 mmol/mol) and less than 6% (42 mmol/mol), respectively. In this ancillary study, a linear regression equation (HbA1c = 0.009 × fasting plasma glucose [FPG] [mg/dL] + 6.8) was derived from 1,000 randomly extracted participants at baseline. Baseline FPG values were used to calculate predicted HbA1c and HGI for the remaining 9,125 participants. Kaplan-Meier and Cox regression were used to assess the effects of intensive treatment on outcomes in patients with a low, moderate, or high HGI.

Results: Intensive treatment was associated with improved primary outcomes (composite of cardiovascular events) in the low (hazard ratio [HR] 0.75 [95% CI 0.59-0.95]) and moderate (HR 0.77 [95% CI 0.61-0.97]) HGI subgroups but not in the high HGI subgroup (HR 1.14 [95% CI 0.93-1.40]). Higher total mortality in intensively treated patients was confined to the high HGI subgroup (HR 1.41 [95% CI 1.10-1.80]). A high HGI was associated with a greater risk for hypoglycemia in the standard and intensive treatment groups.

Conclusions: HGI calculated at baseline identified subpopulations in ACCORD with harms or benefits from intensive glycemic control. HbA1c is not a one-size-fits-all indicator of blood glucose control, and taking this into account when making management decisions could improve diabetes care.

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

Assessment of HbA1c and FPG at baseline. The low, moderate, and high HGI subgroups have green, blue, or red lines, respectively. A: Distribution of HbA1c by HGI subgroup. B: Distribution of FPG by HGI subgroup. C: The red dotted line is the simple linear population regression line.

Figure 2

HbA1c and FPG disparity among HGI subgroups. Mean (± 95% CI) HbA1c (□) and FPG levels (■) for low, moderate, and high HGI subgroups after 1 year of standard (A) or intensive (B) glycemia treatment. For each panel, HbA1c or FPG values with different superscripts (a, b, c) are significantly different (P < 0.05). The dotted lines denote protocol-mandated HbA1c treatment-intensification thresholds.

Figure 3

Kaplan-Meier curves for primary outcomes, total mortality, and hypoglycemia requiring any assistance. Proportions of participants free of the specified outcome over time are compared between standard and intensive treatment groups (panels A, C, D) and among the HGI subgroups (panels B, D, F). Standard treatment is depicted by orange dashed lines and intensive treatment by solid purple lines. Low, moderate, and high HGI subgroups have green, blue, or red lines, respectively.