Hemoglobin glycation index, calculated from a single fasting glucose value, as a prediction tool for severe hypoglycemia and major adverse cardiovascular events in DEVOTE

Abstract

Introduction: Hemoglobin glycation index (HGI) is the difference between observed and predicted glycated hemoglobin A1c (HbA_1c), derived from mean or fasting plasma glucose (FPG). In this secondary, exploratory analysis of data from DEVOTE, we examined: whether insulin initiation/titration affected the HGI; the relationship between baseline HGI tertile and cardiovascular and hypoglycemia risk; and the relative strengths of HGI and HbA_1c in predicting these risks.

Research design and methods: In DEVOTE, a randomized, double-blind, cardiovascular outcomes trial, people with type 2 diabetes received once per day insulin degludec or insulin glargine 100 units/mL. The primary outcome was time to first occurrence of a major adverse cardiovascular event (MACE), comprising cardiovascular death, myocardial infarction or stroke; severe hypoglycemia was a secondary outcome. In these analyses, predicted HbA_1c was calculated using a linear regression equation based on DEVOTE data (HbA_1c=0.01313 FPG (mg/dL) (single value)+6.17514), and the population data were grouped into HGI tertiles based on the calculated HGI values. The distributions of time to first event were compared using Kaplan-Meier curves; HRs and 95% CIs were determined by Cox regression models comparing risk of MACE and severe hypoglycemia between tertiles.

Results: Changes in HGI were observed at 12 months after insulin initiation and stabilized by 24 months for the whole cohort and insulin-naive patients. There were significant differences in MACE risk between baseline HGI tertiles; participants with high HGI were at highest risk (low vs high, HR: 0.73 (0.61 to 0.87)_{95% CI}; moderate vs high, HR: 0.67 (0.56 to 0.81)_{95% CI}; p<0.0001). No significant differences between HGI tertiles were observed in the risk of severe hypoglycemia (p=0.0911). With HbA_1c included within the model, HGI no longer significantly predicted MACE.

Conclusions: High HGI was associated with a higher risk of MACE; this finding is of uncertain significance given the association of HGI with insulin initiation and HbA_1c.

Trial registration number: NCT01959529.

Keywords: diabetes mellitus; type 2.

Figure 1

HGI variability over time in the whole trial population and in insulin-naive participants. (A) HGI variability over the trial period in the whole trial population. Data are mean±SEM. Red lines represent the boundaries of each HGI tertile. For HGI tertiles, black lines represent a random sample of 60 participants; blue lines represent a mean of the whole trial population in each tertile. (B) HGI variability over the trial period in insulin-naive participants. Data are mean±SEM. Red lines represent the boundaries of each HGI tertile. For HGI tertiles, black lines represent a random sample of 60 participants; blue lines represent a mean of the insulin-naive participants in each tertile. (C) Migration in HGI tertile groups over the trial period in the whole trial population and in insulin-naive participants. Data are observed proportions. HGI, hemoglobin glycation index.

Figure 2

Kaplan–Meier curves for time to first MACE and severe hypoglycemia. (A) Time to first occurrence of EAC-confirmed MACE across the whole trial population; (B) time to first occurrence of EAC-confirmed MACE in insulin-naive participants; (C) time to first EAC-confirmed severe hypoglycemic event in the whole trial population; (D) time to first adjudicated severe hypoglycemic event in insulin-naive participants; (E) time to first occurrence of EAC-confirmed MACE by baseline HbA_1c in the whole trial population. Numbers of patients at each time point are shown under each graph. EAC, event adjudication committee; HbA_1c, glycated hemoglobin A1c; HGI, hemoglobin glycation index; MACE, major adverse cardiovascular event.