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 (HbA1c), 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 HbA1c 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 HbA1c was calculated using a linear regression equation based on DEVOTE data (HbA1c=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 HbA1c 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 HbA1c.

Trial registration number: NCT01959529.

Keywords: diabetes mellitus; type 2.

Conflict of interest statement

Competing interests: KRK was supported in this work from the University of North Carolina, Department of Medicine and School of Medicine Physician Scientist Training Programs; EF has participated in advisory panels for AstraZeneca, Bioton, Boehringer Ingelheim and Novo Nordisk and has received honoraria for serving on speakers’ bureaus for AstraZeneca, Bioton, Boehringer Ingelheim, Eli Lilly, Merck, Merck Sharp; SM has received personal fees from Abbott Vascular, Novo Nordisk, University of Oxford, AstraZeneca and Bristol-Myers Squibb; and research support from Novo Nordisk, The Medicines Company and Terumo Medical; TRP has received research support from Novo Nordisk and AstraZeneca and personal fees as a consultant from Adocia, Arecor, AstraZeneca, Eli Lilly, Novo Nordisk and Sanofi. TRP is also the Chief Scientific Officer of CBmed (Center for Biomarker Research in Medicine), a public-funded biomarker research company; REP reports grants from Hanmi Pharmaceutical Co; grants from Janssen; consulting fees from Merck; grants, speaker fees and consulting fees from Novo Nordisk; consulting fees from Pfizer; grants from Poxel SA; grants and consulting fees from Sanofi; consulting fees from Scohia Pharma Inc; and consulting fees from Sun Pharmaceutical Industries. REP’s services were paid for directly to AdventHealth, a nonprofit organization; AG is a full-time employee of, and holds stock in, Novo Nordisk A/S; KK is a full-time employee of, and holds stock in, Novo Nordisk A/S; JBB reports contracted consulting fees and travel support for contracted activities, which are paid to the University of North Carolina, by Adocia, AstraZeneca, Eli Lilly, Intarcia Therapeutics, MannKind, Novo Nordisk, Sanofi, Senseonics and vTv Therapeutics; he reports grant support from AstraZeneca, Dexcom, Eli Lilly, Intarcia Therapeutics, Johnson & Johnson, Lexicon, 477 NovaTarg, Novo Nordisk, Sanofi, Theracos, Tolerion and vTv Therapeutics; he has received fees for consultation from Anji Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, Cirius Therapeutics Inc, Dasman Diabetes Institute (Kuwait), Eli Lilly, Fortress Biotech, Glyscend, Janssen, Mellitus Health, Moderna, Pendulum Therapeutics, Praetego, Stability Health and Zealand Pharma; he holds stock/options in Mellitus Health, Pendulum Therapeutics, PhaseBio, Praetego and Stability Health; and he is supported by grants from the National Institutes of Health, ADA, JDRFI and PCORI.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

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 HbA1c in the whole trial population. Numbers of patients at each time point are shown under each graph. EAC, event adjudication committee; HbA1c, glycated hemoglobin A1c; HGI, hemoglobin glycation index; MACE, major adverse cardiovascular event.