title: 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.
abstract: 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 HbA1c were 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.
authors: Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Im Neuenheimer Feld 581, 69120, Heidelberg, Germany. b.schoettker@dkfz.de.|Network Aging Research, University of Heidelberg, Bergheimer Straße 20, 69115, Heidelberg, Germany. b.schoettker@dkfz.de.
authors: Ben
authors: B
authors: Schöttker
authors: Institute for Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Auf`m Hennekamp 65, 40225, Düsseldorf, Germany.
authors: W
authors: W
authors: Rathmann
authors: Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Auf`m Hennekamp 65, 40225, Düsseldorf, Germany.|German Center for Diabetes Research (DZD), Ingolstädter Landstraße 1, 85764, München-Neuherberg, Germany.
authors: C
authors: C
authors: Herder
authors: Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Postfach 1129, Neuherberg, Germany.
authors: B
authors: B
authors: Thorand
authors: Epidemiology of Chronic Diseases Research Group, Department of Community Medicine, UiT The Arctic University of Norway, 9037, Tromsø, Norway.
authors: T
authors: T
authors: Wilsgaard
authors: Epidemiology of Chronic Diseases Research Group, Department of Community Medicine, UiT The Arctic University of Norway, 9037, Tromsø, Norway.
authors: I
authors: I
authors: Njølstad
authors: Brain and Circulation Research Group, Department of Clinical Medicine, UiT The Arctic University of Norway, 9037, Tromsø, Norway.
authors: G
authors: G
authors: Siganos
authors: Brain and Circulation Research Group, Department of Clinical Medicine, UiT The Arctic University of Norway, 9037, Tromsø, Norway.
authors: E B
authors: EB
authors: Mathiesen
authors: Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Im Neuenheimer Feld 581, 69120, Heidelberg, Germany.
authors: K U
authors: KU
authors: Saum
authors: Department of Epidemiology and Public Health, University College London, 1-19 Torrington Place, London, WC1E 6BT, UK.
authors: A
authors: A
authors: Peasey
authors: Division of Human Nutrition, Wageningen University, PO Box 8129, 6700 EV, Wageningen, The Netherlands.
authors: E
authors: E
authors: Feskens
authors: Institute for Translational Epidemiology and The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Hellenic Health Foundation, Kaisareias 13 and Alexandroupoleos, Athens, 11527, Greece.
authors: P
authors: P
authors: Boffetta
authors: Hellenic Health Foundation, Kaisareias 13 and Alexandroupoleos, Athens, 11527, Greece.
authors: A
authors: A
authors: Trichopoulou
authors: National Institute for Health and Welfare (THL), PO Box 30, FI-00271, Helsinki, Finland.
authors: K
authors: K
authors: Kuulasmaa
authors: UKCRC Centre of Excellence for Public Health, Queen's University Belfast, Belfast, Northern Ireland.
authors: F
authors: F
authors: Kee
authors: Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Im Neuenheimer Feld 581, 69120, Heidelberg, Germany.
authors: H
authors: H
authors: Brenner
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000097:blood*; D002318:Cardiovascular Diseases / Q000097:blood* / Q000453:epidemiology* / Q000401:mortality; D002423:Cause of Death; D015331:Cohort Studies; D015986:Confounding Factors, Epidemiologic; D005060:Europe / Q000453:epidemiology; D005260:Female; D006442:Glycated Hemoglobin / Q000032:analysis*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009749:Nutrition Surveys; D016016:Proportional Hazards Models; D012307:Risk Factors; D014481:United States / Q000453:epidemiology
chemical_list: D006442:Glycated Hemoglobin; C517652:hemoglobin A1c protein, human