HbA1c and Risks of All-Cause and Cause-Specific Death in Subjects without Known Diabetes: A Dose-Response Meta-Analysis of Prospective Cohort Studies

Abstract

Whether HbA1c levels are associated with mortality in subjects without known diabetes remains controversial. Moreover, the shape of the dose-response relationship on this topic is unclear. Therefore, a dose-response meta-analysis was conducted. PubMed and EMBASE were searched. Summary hazard ratios (HRs) were calculated using a random-effects model. Twelve studies were included. The summary HR per 1% increase in HbA1c level was 1.03 [95% confidence interval (CI) = 1.01-1.04] for all-cause mortality, 1.05 [95% CI = 1.02-1.07) for cardiovascular disease (CVD) mortality, and 1.02 (95% CI = 0.99-1.07) for cancer mortality. After excluding subjects with undiagnosed diabetes, the aforementioned associations remained significant for CVD mortality only. After further excluding subjects with prediabetes, all aforementioned associations presented non-significance. Evidence of a non-linear association between HbA1c and mortality from all causes, CVD and cancer was found (all Pnon-linearity < 0.05). The dose-response curves were relatively flat for HbA1c less than around 5.7%, and rose steeply thereafter. In conclusion, higher HbA1c level is associated with increased mortality from all causes and CVD among subjects without known diabetes. However, this association is driven by those with undiagnosed diabetes or prediabetes. The results regarding cancer mortality should be treated with caution due to limited studies.

Figure 1. The flowchart of identifying relevant studies.

Figure 2

Meta-analysis on HbA_1c and all-cause mortality in (a) subjects without known diabetes, (b) those without diabetes, and (c) those with normal HbA_1c range. The squares represent the hazard ratio per 1% increase in HbA_1c level for each individual study, with the area reflecting the weight assigned to the study. The horizontal line across each square represents the 95% confidence interval. The diamond represents the summary hazard ratio per 1% increase in HbA_1c level, with width representing 95% confidence interval.

Figure 3

Meta-analysis on HbA_1c and cardiovascular disease mortality in (a) subjects without known diabetes, (b) those without diabetes, and (c) those with normal HbA_1c range. The squares represent the hazard ratio per 1% increase in HbA_1c level for each individual study, with the area reflecting the weight assigned to the study. The horizontal line across each square represents the 95% confidence interval. The diamond represents the summary hazard ratio per 1% increase in HbA_1c level, with width representing 95% confidence interval.

Figure 4

Meta-analysis on HbA_1c and cancer mortality in (a) subjects without known diabetes, (b) those without diabetes, and (c) those with normal HbA_1c range. The squares represent the hazard ratio per 1% increase in HbA_1c level for each individual study, with the area reflecting the weight assigned to the study. The horizontal line across each square represents the 95% confidence interval. The diamond represents the summary hazard ratio per 1% increase in HbA_1c level, with width representing 95% confidence interval.

Figure 5

Non-linear dose–response analyses on the association of HbA_1c level with mortality from (a) all causes, (b) cardiovascular disease, and (c) cancer.