Background There is a lack of consensus across international organizations regarding definitions of prediabetes. Associations with complications can inform the comparative value of different prediabetes definitions. Methods We conducted a prospective cohort study of 10,844 Atherosclerosis Risk in Communities (ARIC) study participants without diagnosed diabetes who attended visit 2 (1990–92) and 7,194 who attended visit 4 (1996–98). Fasting glucose and HbA1c were measured at visit 2 and fasting glucose and 2-hour glucose were measured at visit 4. We compared prediabetes definitions based on fasting glucose (American Diabetes Association [ADA] 5.6–6.9 mmol/L and World Health Organization [WHO] 6.1–6.9 mmol/L), HbA1c (ADA 39–46 mmol/mol and International Expert Committee [IEC] 42–46 mmol/mol), and 2-hour glucose (ADA/WHO 7.8–11.0 mmol/L). Findings ADA fasting glucose-defined prediabetes (prevalence 37.9%) was the most sensitive for major clinical outcomes, while ADA and IEC HbA1c and WHO fasting glucose-based definitions (prevalence 18.7%, 9.0%, 11.2%, respectively) were more specific. After demographic adjustment, HbA1c-based definitions of prediabetes had higher hazard ratios and demonstrated better risk discrimination for chronic kidney disease, cardiovascular disease, peripheral arterial disease, and all-cause mortality compared to fasting glucose (modestly larger C-statistics, all p<0.05). For example, the C-statistic for incident chronic kidney disease was 0.636 for ADA fasting glucose categories and 0.640 for ADA HbA1c clinical categories (difference −0.005, 95%CI −0.008, −0.001). Additionally, ADA HbA1c-defined prediabetes also demonstrated significant overall improvement in the net reclassification index for cardiovascular outcomes and death compared to glucose-based definitions. Comparing ADA and WHO fasting glucose and ADA/WHO 2-hour did not reveal statistically significant differences in risk discrimination for chronic kidney disease, cardiovascular, or mortality outcomes. Interpretation Our results suggest that HbA1c-defined prediabetes definitions were more specific and provided modest improvements in risk discrimination for clinical complications. ADA fasting glucose was a more sensitive definition overall.

Severe hypoglycemia is clearly indicative of declining health and is a potent marker of high absolute risk of cardiovascular events and mortality.

The reference intervals for these biomarkers should inform their clinical use. Diagnostic cutpoint equivalents for fructosamine and glycated albumin could be useful to identify persons with hyperglycemia in settings where fasting glucose or HbA1c are not available or where the interpretation of these traditional measures is problematic.

Diabetes is an important risk factor for kidney function decline. Those with diagnosed diabetes declined almost twice as rapidly as those without diabetes. Among people with diagnosed diabetes, steeper declines were seen in those with modifiable risk factors, including hypertension and glycemic control, suggesting areas for continued targeting in kidney disease prevention.

In older adults with severe or very severe CKD, HbA1c, glycated albumin, and fructosamine were not highly correlated with fasting glucose. The results suggest there may be no particular advantage of glycated albumin or fructosamine over HbA1c for monitoring glycemic control in CKD.