Haemoglobin glycation index and risk for diabetes-related complications in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial

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Abstract

Aims/hypothesis

Previous studies have suggested that the haemoglobin glycation index (HGI) can be used as a predictor of diabetes-related complications in individuals with type 1 and type 2 diabetes. We investigated whether HGI was a predictor of adverse outcomes of intensive glucose lowering and of diabetes-related complications in general, using data from the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial.

Methods

We studied participants in the ADVANCE trial with data available for baseline HbA _1c and fasting plasma glucose (FPG) ( n = 11,083). HGI is the difference between observed HbA _1c and HbA _1c predicted from a simple linear regression of HbA _1c on FPG. Using Cox regression, we investigated the association between HGI, both categorised and continuous, and adverse outcomes, considering treatment allocation (intensive or standard glucose control) and compared prediction of HGI and HbA _1c.

Results

Intensive glucose control lowered mortality risk in individuals with high HGI only (HR 0.74 [95% CI 0.61, 0.91]; p = 0.003), while there was no difference in the effect of intensive treatment on mortality in those with high HbA _1c. Irrespective of treatment allocation, every SD increase in HGI was associated with a significant risk increase of 14–17% for macrovascular and microvascular disease and mortality. However, when adjusted for identical covariates, HbA _1c was a stronger predictor of these outcomes than HGI.

Conclusions/interpretation

HGI predicts risk for complications in ADVANCE participants, irrespective of treatment allocation, but no better than HbA _1c. Individuals with high HGI have a lower risk for mortality when on intensive treatment. Given the discordant results and uncertain relevance beyond HbA _1c, clinical use of HGI in type 2 diabetes cannot currently be recommended.

Electronic supplementary material

The online version of this article (10.1007/s00125-017-4539-1) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

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Most cited references 23

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Red cell life span heterogeneity in hematologically normal people is sufficient to alter HbA1c.

P. Ciraolo, Clinton Joiner, Lorraine P. Smith … (2008)

Although red blood cell (RBC) life span is a known determinant of percentage hemoglobin A1c (HbA1c), its variation has been considered insufficient to affect clinical decisions in hematologically normal persons. However, an unexplained discordance between HbA1c and other measures of glycemic control can be observed that could be, in part, the result of differences in RBC life span. To explore the hypothesis that variation in RBC life span could alter measured HbA1c sufficiently to explain some of this discordance, we determined RBC life span using a biotin label in 6 people with diabetes and 6 nondiabetic controls. Mean RBC age was calculated from the RBC survival curve for all circulating RBCs and for labeled RBCs at multiple time points as they aged. In addition, HbA1c in magnetically isolated labeled RBCs and in isolated transferrin receptor-positivereticulocytes was used to determine the in vivo synthetic rate of HbA1c. The mean age of circulating RBCs ranged from 39 to 56 days in diabetic subjects and 38 to 60 days in nondiabetic controls. HbA1c synthesis was linear and correlated with mean whole blood HbA1c (R(2) = 0.91). The observed variation in RBC survival was large enough to cause clinically important differences in HbA1c for a given mean blood glucose.

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Paget's Disease of the Mandible

Mayank Patel, Ashok Bhalla (2008)

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Racial and ethnic differences in the relationship between HbA1c and blood glucose: implications for the diagnosis of diabetes.

William Herman, Robert Cohen (2012)

Hemoglobin A1c (HbA1c) is widely used as an index of mean glycemia in diabetes, as a measure of risk for the development of diabetic complications, and as a measure of the quality of diabetes care. In 2010, the American Diabetes Association recommended that HbA1c tests, performed in a laboratory using a method certified by the National Glycohemoglobin Standardization Program, be used for the diagnosis of diabetes. Although HbA1c has a number of advantages compared to traditional glucose criteria, it has a number of disadvantages. Hemoglobinopathies, thalassemia syndromes, factors that impact red blood cell survival and red blood cell age, uremia, hyperbilirubinemia, and iron deficiency may alter HbA1c test results as a measure of average glycemia. Recently, racial and ethnic differences in the relationship between HbA1c and blood glucose have also been described. Although the reasons for racial and ethnic differences remain unknown, factors such as differences in red cell survival, extracellular-intracellular glucose balance, and nonglycemic genetic determinants of hemoglobin glycation are being explored as contributors. Until the reasons for these differences are more clearly defined, reliance on HbA1c as the sole, or even preferred, criterion for the diagnosis of diabetes creates the potential for systematic error and misclassification. HbA1c must be used thoughtfully and in combination with traditional glucose criteria when screening for and diagnosing diabetes.

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Author and article information

Contributors

Sigrid C. van Steen: s.c.vansteen@amc.uva.nl

Journal

Journal ID (nlm-ta): Diabetologia

Journal ID (iso-abbrev): Diabetologia

Title: Diabetologia

Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )

ISSN (Print): 0012-186X

ISSN (Electronic): 1432-0428

Publication date (Electronic): 8 January 2018

Publication date PMC-release: 8 January 2018

Publication date (Print): 2018

Volume: 61

Issue: 4

Pages: 780-789

Affiliations

[1 ]ISNI 0000000084992262, GRID grid.7177.6, Department of Endocrinology, Academic Medical Centre, , University of Amsterdam, ; Postbus 22660, 1100 DD Amsterdam, the Netherlands

[2 ]ISNI 0000 0004 1936 834X, GRID grid.1013.3, The George Institute for Global Health, , University of Sydney, ; Sydney, NSW Australia

[3 ]ISNI 0000 0001 2171 9311, GRID grid.21107.35, Department of Epidemiology, , Johns Hopkins University, ; Baltimore, MD USA

[4 ]ISNI 0000 0001 2149 7878, GRID grid.410511.0, Department of Endocrinology, Hôpital Bichat-Claude Bernard, , Université Paris, ; Paris, France

[5 ]ISNI 0000 0000 9760 5620, GRID grid.1051.5, Diabetes Domain, Baker IDI Heart and Diabetes Institute, ; Melbourne, VIC Australia

[6 ]ISNI 0000 0001 0743 2111, GRID grid.410559.c, Centre de Rechercher, , Centre Hospitalier de l’Université de Montréal (CRCHUM), ; Montréal, Québec Canada

[7 ]ISNI 0000 0001 2174 1754, GRID grid.7563.7, Department of Medicine and Surgery, , University of Milan-Bicocca, ; Milan, Italy

[8 ]ISNI 0000 0004 1757 9530, GRID grid.418224.9, Istituto Auxologico Italiano, ; Milan, Italy

[9 ]ISNI 0000 0004 1936 834X, GRID grid.1013.3, Boden Institute of Obesity, Nutrition and Exercise, , University of Sydney, ; Sydney, NSW Australia

[10 ]ISNI 0000 0001 2116 3923, GRID grid.451056.3, National Institute of Health Research UCL Hospitals Biomedical Research Centre, ; London, UK

[11 ]Julius Clinical, Zeist, the Netherlands

[12 ]ISNI 0000000090126352, GRID grid.7692.a, Julius Centre for Health Sciences and Primary Care, , University Medical Centre Utrecht, ; Utrecht, the Netherlands

Article

Publisher ID: 4539

DOI: 10.1007/s00125-017-4539-1

PMC ID: 6448976

PubMed ID: 29308539

SO-VID: f5558559-79d5-46bf-b98f-50e63f696fe1

License:

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

History

Date received : 4 July 2017

Date accepted : 21 November 2017

Funding

Funded by: Academic Medical Center (AMC)

Custom metadata

ScienceOpen disciplines: Endocrinology & Diabetes

Keywords: (blood) glucose,cardiovascular complications,diabetes mellitus, type 2,hba1c,hypoglycaemia,mortality

Data availability:

ScienceOpen disciplines: Endocrinology & Diabetes

Keywords: (blood) glucose, cardiovascular complications, diabetes mellitus, type 2, hba1c, hypoglycaemia, mortality

Haemoglobin glycation index and risk for diabetes-related complications in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial

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Abstract

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Methods

Results

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Electronic supplementary material

Related collections

Journal of the ASEAN Federation of Endocrine Societies

Most cited references 23

Red cell life span heterogeneity in hematologically normal people is sufficient to alter HbA1c.

Paget's Disease of the Mandible

Racial and ethnic differences in the relationship between HbA1c and blood glucose: implications for the diagnosis of diabetes.

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