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

IntroductionHemoglobin 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 methodsIn 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.ResultsChanges 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.ConclusionsHigh 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 numberNCT01959529.

High Hemoglobin glycation index is associated with telomere attrition independent of HbA1c, mediating by TNFα

Context The hemoglobin glycation index(HGI) is correlated with metabolic diseases and inflammations. Whether the HGI is associated with the ageing process and how inflammation and oxidative stress affect the relationship remain unclear. Objective We aim to analyze links between HGI and ageing biomarkers, and to explore a potential role of inflammation and oxidative stress in the correlations. Methods A cross-sectional study of 434 subjects with different glucose intolerances in a rural community was enrolled. The HGI was calculated as the difference between the measured and predicted hemoglobin A1c(HbA1c). The population was categorized into tertiles of HGI. Telomere length(LTL) and mitochondrial DNA copy number(mtDNAcn) determined by PCR assay. Tumor necrosis factor α(TNFα) and interleukin 6(IL-6), 8-oxo-2′-deoxyguanosine(8-oxo-dG), superoxide dismutase(SOD) activities and glutathione reductase(GR) were measured. Result Participants in the high HGI group were older and reported a shorter LTL, higher levels of TNFα, SOD activities and HbA1c. Correlation analyses demonstrated that HGI was correlated with LTL(r=-0.25,p&lt;0.001) and TNFα(r=0.19,p&lt;0.001) regardless of HbA1c levels. No relationship was found between HGI and mtDNAcn. HGI(β=-0.238,95%CI(-0.430,-0.046),p=0.015) and TNFα(β=-0.02,95%CI(-0.030,-0.014),p&lt;0.001) were proved to be correlated with LTL independently using multiple linear regression analysis. Ordinal logistic regression models showed that compared with subjects in High-HGI, the possibilities of a higher-level LTL was 5.29-fold in Low-HGI(OR5.29,95%CI(2.45,11.41),p&lt;0.001), 2.41-fold in Moderate-HGI (OR2.41,95%CI(1.35,4.30),p=0.003) after controlling for confounding variables. Mediation analyses indicated that TNFα accounted for 30.39% effects of HGI on LTL. Conclusion HGI was negatively related to telomere attrition, independent of HbA1c. TNFα acted as a mediator of the relationship between HGI and LTL.

Association Between Hemoglobin Glycation Index and Risk of Cardiovascular Disease and All Cause Mortality in Type 2 Diabetic Patients: A Meta-Analysis

Background: The hemoglobin glycation index (HGI) has been proposed as a marker to quantify inter-individual variation in hemoglobin glycosylation. However, whether HGI is associated with an increased risk of diabetic complications independent of glycated hemoglobin (HbA1c) remains unclear. This meta-analysis aimed to determine the association between HGI and the risk of all cause mortality and composite cardiovascular disease (CVD).Methods: PubMed, and EMBASE databases were searched for related studies up to March 31, 2021. Observational studies reported associations between HGI levels and composite CVD and all cause mortality were included for meta-analysis. A random effect model was used to calculate the hazard ratios (HRs) and 95% confidence intervals (CI) for higher HGI.Results: A total of five studies, comprising 22,035 patients with type two diabetes mellitus were included for analysis. The median follow-up duration was 5.0 years. After adjusted for multiple conventional cardiovascular risk factors, an increased level of HGI was associated with a higher risk of composite CVD (per 1 SD increment: HR = 1.14, 95% CI = 1.04–1.26) and all cause mortality (per 1 SD increment: HR = 1.18, 95% CI = 1.05–1.32). However, when further adjusted for HbA1c, the association between HGI and risk of composite CVD (per 1 SD increment of HGI: HR = 1.01, 95% CI = 0.93–1.10) and all cause mortality (per 1 SD increment of HGI: HR = 1.03, 95% CI = 0.96–1.10) became insignificant.Conclusions: High HGI was associated with an increased risk of composite CVD and all cause mortality after adjustment for multiple conventional cardiovascular risk factors. However, the association was mainly mediating by the level of HbA1c.

Postchallenge glucose increment was associated with hemoglobin glycation index in subjects with no history of diabetes

We investigated the association between postchallenge glucose increment and hemoglobin glycation index (HGI), the difference between observed and predicted glycated hemoglobin (HbA1c), in subjects with no history of diabetes. We enrolled 1381 subjects who attended our outpatient clinic for an oral glucose tolerance test (OGTT) to screen for diabetes. HGI was defined as observed HbA1c minus predicted HbA1c. The predicted HbA1c was calculated by entering fasting plasma glucose (FPG) level into an equation [HbA1c(%)=FPG(mg/dL)*0.029+2.9686] determined from an HbA1c versus FPG regression analysis using data from an independent cohort of 2734 subjects with no history of diabetes. The association between 2-hour glucose increment and HGI was analyzed using linear regression analyses with adjustment of relevant parameters. Overall, the proportions of subjects with normal glucose tolerance, pre-diabetes, and newly diagnosed diabetes were 42.3%, 41.3%, and 16.4%, respectively. Compared with subjects who had an HGI≤0, subjects with an HGI>0 had a lower FPG (95.0±13.3 vs 98.5±15.3 mg/dL, p<0.001) but a higher 2-hour plasma glucose (151.1±52.8 vs 144.6±51.4 mg/dL, p=0.027) and 2-hour glucose increment (56.1±46.1 vs 46.1±45.0 mg/dL, p<0.001). The 2-hour glucose increment after an OGTT was independently associated with HGI (β coefficient 0.003, 95% CI 0.002 to 0.003, p<0.001). Our findings suggested that postchallenge glucose increment was independently associated with HGI in subjects with no history of diabetes.