HbA1c levels in non-diabetic older adults – No J-shaped associations with primary cardiovascular events, cardiovascular and all-cause mortality after adjustment for confounders in a meta-analysis of individual participant data from six cohort studies


Background:
To determine the shape of the associations of HbA1c with mortality and cardiovascular outcomes in non-diabetic individuals and explore potential explanations.

Methods:
The associations of HbA1c with all-cause mortality, cardiovascular mortality and primary cardiovascular events (myocardial infarction or stroke) were assessed in non-diabetic subjects ≥50 years from six population-based cohort studies from Europe and the USA and meta-analyzed. Very low, low, intermediate and increased HbA1cwere defined as <5.0, 5.0 to <5.5, 5.5 to <6.0 and 6.0 to <6.5 % (equals <31, 31 to <37, 37 to <42 and 42 to <48 mmol/mol), respectively, and low HbA1c was used as reference in Cox proportional hazards models.

Results:
Overall, 6,769 of 28,681 study participants died during a mean follow-up of 10.7 years, of whom 2,648 died of cardiovascular disease. Furthermore, 2,493 experienced a primary cardiovascular event. A linear association with primary cardiovascular events was observed. Adjustment for cardiovascular risk factors explained about 50 % of the excess risk and attenuated hazard ratios (95 % confidence interval) for increased HbA1c to 1.14 (1.03–1.27), 1.17 (1.00–1.37) and 1.19 (1.04–1.37) for all-cause mortality, cardiovascular mortality and cardiovascular events, respectively. The six cohorts yielded inconsistent results for the association of very low HbA1c levels with the mortality outcomes and the pooled effect estimates were not statistically significant. In one cohort with a pronounced J-shaped association of HbA1c levels with all-cause and cardiovascular mortality (NHANES), the following confounders of the association of very low HbA1c levels with mortality outcomes were identified: race/ethnicity; alcohol consumption; BMI; as well as biomarkers of iron deficiency anemia and liver function. Associations for very low HbA1c levels lost statistical significance in this cohort after adjusting for these confounders.

Conclusions:
A linear association of HbA1c levels with primary cardiovascular events was observed. For cardiovascular and all-cause mortality, the observed small effect sizes at both the lower and upper end of HbA1c distribution do not support the notion of a J-shaped association of HbA1c levels because a certain degree of residual confounding needs to be considered in the interpretation of the results.

KeywordsGlycated hemoglobin, Cardiovascular disease, Myocardial infarction, Stroke, Mortality, Cohort study, Meta-analysis


Autoři: Ben Schöttker 1,2*;  W. Rathmann 3;  C. Herder 4,5;  B. Thorand 6;  T. Wilsgaard 7;  I. Njølstad 7;  G. Siganos 8;  E. B. Mathiesen 8;  K. U. Saum 1;  A. Peasey 9;  E. Feskens 10;  P. Boffetta 11,12;  A. Trichopoulou 12;  K. Kuulasmaa 13;  F. Kee 14;  H. Brenner 1;  On Behalf Of The Chances Group
Působiště autorů: Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Im Neuenheimer Feld 1, 691 0 Heidelberg, Germany. 1;  Division of Human Nutrition, Wageningen University, PO Box 8 9, 6700 EV Wageningen, The Netherlands. 10;  Institute for Translational Epidemiology and The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 11;  Hellenic Health Foundation, Kaisareias and Alexandroupoleos, Athens 11527, Greece. 12;  National Institute for Health and Welfare (THL), PO Box 30, FI-00271 Helsinki, Finland. 13;  UKCRC Centre of Excellence for Public Health, Queen’s University Belfast, Belfast, Northern Ireland. 14;  Network Aging Research, University of Heidelberg, Bergheimer Straße 20, 6911 Heidelberg, Germany. 2;  Institute for Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Auf`m Hennekamp 6 , 022 Düsseldorf, Germany. 3;  Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Auf`m Hennekamp 6 , 4022 Düsseldorf, Germany. 4;  German Center for Diabetes Research (DZD), Ingolstädter Landstraße 1, 857 4 München-Neuherberg, Germany. 5;  Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Postfach 112 , Neuherberg, Germany. 6;  Epidemiology of Chronic Diseases Research Group, Department of Community Medicine, UiT The Arctic University of Norway, 037 Tromsø, Norway. 7;  Brain and Circulation Research Group, Department of Clinical Medicine, UiT The Arctic University of Norway, 037 Tromsø, Norway. 8;  Department of Epidemiology and Public Health, University College London, 1–19 Torrington Place, London WC1E 6BT, UK. 9
Vyšlo v časopise: BMC Medicine 2016, 14:26
Kategorie: Research article
prolekare.web.journal.doi_sk: 10.1186/s12916-016-0570-1

© 2016 Schöttker et al. 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. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
The electronic version of this article is the complete one and can be found online at: https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-016-0570-1

Souhrn

Background:
To determine the shape of the associations of HbA1c with mortality and cardiovascular outcomes in non-diabetic individuals and explore potential explanations.

Methods:
The associations of HbA1c with all-cause mortality, cardiovascular mortality and primary cardiovascular events (myocardial infarction or stroke) were assessed in non-diabetic subjects ≥50 years from six population-based cohort studies from Europe and the USA and meta-analyzed. Very low, low, intermediate and increased HbA1cwere defined as <5.0, 5.0 to <5.5, 5.5 to <6.0 and 6.0 to <6.5 % (equals <31, 31 to <37, 37 to <42 and 42 to <48 mmol/mol), respectively, and low HbA1c was used as reference in Cox proportional hazards models.

Results:
Overall, 6,769 of 28,681 study participants died during a mean follow-up of 10.7 years, of whom 2,648 died of cardiovascular disease. Furthermore, 2,493 experienced a primary cardiovascular event. A linear association with primary cardiovascular events was observed. Adjustment for cardiovascular risk factors explained about 50 % of the excess risk and attenuated hazard ratios (95 % confidence interval) for increased HbA1c to 1.14 (1.03–1.27), 1.17 (1.00–1.37) and 1.19 (1.04–1.37) for all-cause mortality, cardiovascular mortality and cardiovascular events, respectively. The six cohorts yielded inconsistent results for the association of very low HbA1c levels with the mortality outcomes and the pooled effect estimates were not statistically significant. In one cohort with a pronounced J-shaped association of HbA1c levels with all-cause and cardiovascular mortality (NHANES), the following confounders of the association of very low HbA1c levels with mortality outcomes were identified: race/ethnicity; alcohol consumption; BMI; as well as biomarkers of iron deficiency anemia and liver function. Associations for very low HbA1c levels lost statistical significance in this cohort after adjusting for these confounders.

Conclusions:
A linear association of HbA1c levels with primary cardiovascular events was observed. For cardiovascular and all-cause mortality, the observed small effect sizes at both the lower and upper end of HbA1c distribution do not support the notion of a J-shaped association of HbA1c levels because a certain degree of residual confounding needs to be considered in the interpretation of the results.

KeywordsGlycated hemoglobin, Cardiovascular disease, Myocardial infarction, Stroke, Mortality, Cohort study, Meta-analysis


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