HbA _1c measured in stored erythrocytes is positively linearly associated with mortality in individuals with diabetes mellitus

Introduction: Observational studies have shown that glycated haemoglobin (HbA _1c) is related to mortality, but the shape of the association is less clear. Furthermore, disease duration and medication may modify this association. This observational study explored the association between HbA _1c measured in stored erythrocytes and mortality. Secondly, it was assessed whether disease duration and medication use influenced the estimates or were independently associated with mortality. Methods: Within the European Prospective Investigation into Cancer and Nutrition a cohort was analysed of 4,345 individuals with a confirmed diagnosis of diabetes at enrolment. HbA _1c was measured in blood samples stored up to 19 years. Multivariable Cox proportional hazard regression models for all-cause mortality investigated HbA _1c in quartiles as well as per 1% increment, diabetes medication in seven categories of insulin and oral hypoglycaemic agents, and disease duration in quartiles. Results: After a median follow-up of 9.3 years, 460 participants died. Higher HbA _1c was associated with higher mortality: Hazard Ratio for 1%-increase was 1.11 (95% CI 1.06, 1.17). This association was linear (P-nonlinearity =0.15) and persistent across categories of medication use, disease duration, and co-morbidities. Compared with metformin, other medication types were not associated with mortality. Longer disease duration was associated with mortality, but not after adjustment for HbA _1c and medication. Conclusion: This prospective study showed that persons with lower HbA _1c had better survival than those with higher HbA _1c. The association was linear and independent of disease duration, type of medication use, and presence of co-morbidities. Any improvement of HbA _1c appears to be associated with reduced mortality risk.