Comparative prognostic performance of definitions of prediabetes: a prospective cohort analysis of the Atherosclerosis Risk in Communities (ARIC) study

BACKGROUND: No consensus on definitions of prediabetes exists among international organisations. Analysis of associations with different definitions and clinical complications can inform the comparative value of different prediabetes definitions. We compared the risk of future outcomes across different prediabetes definitions based on fasting glucose concentration, HbA1c, and 2 h glucose concentration during over two decades of follow-up in the community-based Atherosclerosis Risk in Communities (ARIC) study. We aimed to analyse the associations of definitions with outcomes to provide a comparison of different definitions. METHODS: We did a prospective cohort study of participants in the ARIC study who did not have diagnosed diabetes and who attended visit 2 (1990-92; n=10 844) and who attended visit 4 (1996-98; n=7194). ARIC participants were enrolled from four communities across the USA. Fasting glucose concentration and HbA1c were measured at visit 2 and fasting glucose concentration and 2 h glucose concentration were measured at visit 4. We compared prediabetes definitions based on fasting glucose concentration (American Diabetes Association [ADA] fasting glucose concentration cutoff 5·6-6·9 mmol/L and WHO fasting glucose concentration cutoff 6·1-6·9 mmol/L), HbA1c (ADA HbA1c cutoff 5·7-6·4% [39-46 mmol/mol] and International Expert Committee [IEC] HbA1c cutoff 6·0-6·4% [42-46 mmol/mol]), and 2 h glucose concentration (ADA and WHO 2 h glucose concentration cutoff 7·8-11·0 mmol/L). FINDINGS: Prediabetes defined using the ADA fasting glucose concentration cutoff (prevalence 4112 [38%] of 10 844 people; 95% CI 37·0-38·8) was the most sensitive for major clinical outcomes, whereas using the ADA HbA1c cutoff (2027 [19%] of 10 884 people; 18·0-19·4) and IEC HbA1c cutoff (970 [9%] of 10 844 people; 8·4-9·5), and the WHO fasting glucose concentration cutoff (1213 [11%] of 10 844 people; 10·6-11·8) were more specific. After demographic adjustment, HbA1c-based definitions of prediabetes had higher hazard ratios and better risk discrimination for chronic kidney disease, cardiovascular disease, peripheral arterial disease, and all-cause mortality than did fasting glucose concentration-based definitions (all p<0·05). The C-statistic for incident chronic kidney disease was 0·636 for ADA fasting glucose concentration clinical categories and 0·640 for ADA HbA1c clinical categories (difference -0·005, 95% CI -0·008 to -0·001). The C-statistics were 0·662 for ADA fasting glucose clinical concentration categories and 0·672 for ADA HbA1c clinical categories for atherosclerotic cardiovascular disease, 0·701 for ADA fasting glucose concentration clinical categories and 0·722 for ADA HbA1c clinical categories for peripheral arterial disease, and 0·683 for ADA fasting glucose concentration clinical categories and 0·688 for ADA HbA1c clinical categories for all-cause mortality. Prediabetes defined using the ADA HbA1c cutoff showed a significant overall improvement in the net reclassification index for cardiovascular outcomes and death compared with prediabetes defined with glucose-based definitions. ADA fasting glucose concentration clinical categories, WHO fasting glucose concentration clinical categories, and ADA and WHO 2 h glucose concentrations clinical categories were not significantly different in terms of risk discrimination for chronic kidney disease, cardiovascular outcomes, or mortality outcomes. INTERPRETATION: Our results suggest that prediabetes definitions using HbA1c were more specific and provided modest improvements in risk discrimination for clinical complications. The definition of prediabetes using the ADA fasting glucose concentration cutoff was more sensitive overall. FUNDING: US National Institutes of Health.