Association Between Haemoglobin A1c and All-Cause and Cause-Speci�c Mortality in Middle-Aged and Older Koreans: A Prospective Cohort Study

Background This study aimed to examine associations between haemoglobin A1c (HbA 1c ) levels over time and all-cause and cause-speci�c mortality in middle-aged and older Koreans. Methods Using data from the Korean Genome and Epidemiology Study, we analysed 9,294 40–69-year-old participants with no history of cardiovascular disease (CVD) or cancer. HbA 1c levels were measured at baseline and at each biennial follow-up examination. Participants were divided into one group of participants with known diabetes and �ve groups of participants without known diabetes classi�ed according to HbA 1c levels: <31 mmol/mol (5.0%), 31–36 mmol/mol (5.0%–5.4%), 37–41 mmol/mol (5.5%–5.9%), 42–47 mmol/mol (6.0%–6.4%), and ≥ 48 mmol/mol (6.5%). Hazard ratios (HRs) for all-cause and cause-speci�c mortality associated with HbA 1c levels were calculated using a time-dependent Cox proportional hazards model adjusting for several variables. Restricted cubic spline models were �tted to investigate the relationship between continuous HbA 1c levels and mortality among people without known diabetes. Subgroup analyses were performed for age, sex, smoking, hypertension, liver diseases, and red blood cell (RBC) counts. Results During a median follow-up period of 15.7 years, there were 944 deaths, including 185, 359, and 400 from CVD, cancer, and other causes, respectively. Compared with participants with HbA 1c levels of 37–41 mmol/mol, multivariate-adjusted HRs and 95% con�dence intervals for all-cause death of participants with levels <31 mmol/mol, 31–36 mmol/mol, 42–47 mmol/mol, and ≥ 48 mmol/mol and participants with known diabetes were 1.84 (1.35–2.51), 1.13 (0.95–1.34), 1.30 (1.04– 1.62), 1.37 (0.97–1.93), and 2.03 (1.70–2.44), respectively. There was a U-shaped association between HbA 1c levels over time and all-cause and cause-speci�c mortality. When we performed diverse subgroup analyses, low HbA 1c levels were strongly associated with mortality in participants with low RBC counts or liver diseases. Conclusions We found U-shaped associations between HbA 1c levels over time and all-cause and cause-speci�c mortality in middle-aged and older Koreans. In particular, people with low RBC counts or liver diseases and low HbA 1c levels had a high risk of mortality. Therefore, more careful management of these groups is recommended to decrease the risk of mortality. respectively. Participants with higher HbA 1c levels tended to be older and had higher BMIs, waist circumferences, RBC counts, hypertension and dyslipidaemia prevalences, proportion of current smokers, and fasting glucose, haemoglobin, haematocrit, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and a lower total bilirubin level, prevalence of anaemia, proportion of current alcohol drinkers, and education level. On the other hand, participants with lower HbA 1c levels tended to have lower RBC counts and higher prevalences of anaemia and liver diseases. 31–36 (5.0–5.4%), 42–47 mmol/mol (6.0–6.4%), ≥ 48 mmol/mol (6.5%), and known diabetes were at a 74%, 20%, 50%, 62%, and 130%, respectively, increased risk of all-cause mortality. This was after adjusting for age, sex, residential area, BMI, smoking, alcohol use, regular exercise, education, hypertension, and dyslipidaemia. When we considered changes in HbA 1c levels and other covariates during follow-up in a time-dependent Cox regression analysis, HbA 1c levels <31 mmol/mol (5.0%) were associated with 84% and 121% increased risks of all-cause and cancer deaths, respectively. Risks of all-cause and non-CVD/non-cancer mortality were signi�cantly elevated in patients with HbA 1c levels of 42–47 mmol/mol (6.0–6.4%). A signi�cantly increased risk of CVD mortality was associated with HbA 1c levels ≥ 48 mmol/mol ( ≥ 6.5%). Known diabetes signi�cantly increased the risk of all-cause and cause-speci�c mortality. �ndings suggest that people with low HbA 1c levels, as well as those with high HbA 1c levels, have an increased risk of mortality. HbA 1c testing may improve the identi�cation of individuals with a high risk of mortality. In particular, for people with low RBC counts or liver diseases and low HbA 1c levels, more careful management is recommended to decrease the risk of mortality. Causal mechanisms underlying the increased cause-speci�c mortality risk in