The Hemoglobin Glycation Index Identifies Subpopulations With Harms or Benefits From Intensive Treatment in the ACCORD Trial

Abstract

OBJECTIVEThis 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 METHODSACCORD 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.RESULTSIntensive 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.CONCLUSIONSHGI 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.

Association between hemoglobin glycation index and hepatic steatosis in non-diabetic individuals

“…HGI represents a measure of the degree of non-enzymatic glycation of hemoglobin and it has been found to be positively associated with diabetic complications [21,22]. In patients with type 1 diabetes participating to the Diabetes Control and Complications Trial (DCCT) it has been observed that a higher HGI, calculated by using mean blood glucose levels, was associated with a greater risk of retinopathy and nephropathy [21].…”

“…In patients with type 1 diabetes participating to the Diabetes Control and Complications Trial (DCCT) it has been observed that a higher HGI, calculated by using mean blood glucose levels, was associated with a greater risk of retinopathy and nephropathy [21]. Furthermore, it has been recently reported that a higher HGI value, calculated by using fasting plasma glucose in patients with type 2 diabetes participating to the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, was associated with diabetic complications and with greater mortality in the intensive treatment group [22]. However, whether HGI is associated with organ damage also in subjects without diabetes has not been investigated to date.…”

“…A predicted value of HbA1c was calculated by inserting fasting plasma glucose concentration into the sub-sample linear regression equation (HbA1c = 0.0158 * fasting glucose levels (mg/dl) +4.0311). HGI was calculated by subtracting the predicted value of HbA1c from the observed HbA1c level for all participants, as previously described [22,27]. Study participants (1120 subjects) were stratified into quartiles according to their HGI value.…”

Glucose Control and Vascular Outcomes in Type 2 Diabetes: Is the Picture Clear?

“…In ACCORD, excess mortality was found in those who showed an increase in HbA 1c with intensive glucose control (39); thus, people with worsening glycemic control when exposed to intensive treatment should be set less stringent glucose targets. Additionally, intensive treatment was associated with improved primary outcomes in people with low and moderate hemoglobin glycation index (HGI) (HGI = observed HbA 1c 2 predicted HbA 1c ) but not with high HGI at baseline, and higher total mortality in intensively treated patients was confined to the high-HGI subgroup (40). A high HGI was also associated with greater risk for hypoglycemia (40).…”

“…Additionally, intensive treatment was associated with improved primary outcomes in people with low and moderate hemoglobin glycation index (HGI) (HGI = observed HbA 1c 2 predicted HbA 1c ) but not with high HGI at baseline, and higher total mortality in intensively treated patients was confined to the high-HGI subgroup (40). A high HGI was also associated with greater risk for hypoglycemia (40). Finally, a retrospective subgroup analysis of the ACCORD data set, assessing the impact and tolerability of intensive glucose management in older versus younger adults ($65 vs. ,65 years), showed a 71% increased risk of cardiovascular mortality in the intensive arm for the younger subgroup (41).…”