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

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Summary

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.

Introduction

Prediabetes is a pressing clinical and public health problem that affects approximately 12–30% of US adults aged 18 years and older, depending on the definition used.1 International organisations largely agree on the clinical cutoff points for diagnosis of diabetes and, in 2010, HbA1c ≥6·5% (≥48 mmol/mol) was adopted for diagnosis of diabetes by many international groups, in part based on the association of HbA1c with retinopathy.2, 3, 4, 5 By contrast, the category of prediabetes does not have a uniform definition. The American Diabetes Association (ADA) recommends using the following criteria to identify people with prediabetes: fasting glucose concentration between 5·6 and 6·9 mmol/L (100–125 mg/dL; impaired fasting glucose), HbA1c of 5·7–6·4% (39–46 mmol/mol), or 2 h glucose concentration after a 75 g oral glucose tolerance test of 7·8–11·0 mmol/L (140–199 mg/dL; impaired glucose tolerance).6 WHO also recommends 2 h glucose of 7·8–11·0 mmol/L to identify impaired glucose tolerance, but recommends a fasting glucose concentration of 6·1–6·9 mmol/L (110–125 mg/dL) to identify impaired fasting glucose.2 In 2009, the International Expert Committee (IEC) recommended HbA1c of 6·0–6·4% (42–46 mmol/mol) for the identification of an intermediate risk group, which has been adopted by some organisations.5 Identification of individuals with prediabetes provides an opportunity for intervention through lifestyle modification and pharmacological interventions to prevent progression to diabetes.6, 7 Consensus on definitions of prediabetes could help guide resource allocation and aid public health efforts to identify people at risk of developing diabetes and its complications.

Research in context

Evidence before this study

We searched PubMed with the search terms “prediabetic state” OR “prediabetes”, “impaired fasting glucose” OR “impaired glucose tolerance”, AND “diabetes mellitus” OR “diabetes”, OR “cardiovascular diseases” OR “chronic renal insufficiency” OR “chronic kidney disease”, OR “peripheral vascular diseases” OR “peripheral arterial disease”, OR “all-cause mortality” OR “mortality”, AND “humans”, for papers published up to June, 2015. There were no date or language restrictions. Prediabetes is characterised by elevated levels of blood glucose or hyperglycaemia that falls below the diagnostic threshold for diabetes. The prognostic value of different clinical definitions of prediabetes has not previously been formally compared. Current definitions include those by the American Diabetes Association (ADA), which defines prediabetes as a fasting glucose concentration of 5·6–6·9 mmol/L, an HbA1c of 5·7–6·4% (39–46 mmol/L), or a 2 h glucose concentration of 7·8–11·0 mmol/L. WHO recommends the same 2 h glucose concentration cutoffs as the ADA, but recommends a fasting glucose concentration of 6·1–6·9 mmol/L as another definition for prediabetes. The International Expert Committee (IEC) defines prediabetes as an HbA1c of 6·0–6·4% (42–46 mmol/L).

Added value of this study

We compared the prognostic value of the ADA, WHO, and IEC definitions of prediabetes in the Atherosclerosis Risk in Communities (ARIC) study, a large, prospective cohort study of over 10 000 middle-aged adults followed-up for over two decades for health outcomes including incident diabetes, chronic kidney disease, atherosclerotic cardiovascular disease, peripheral arterial disease, and all-cause mortality. We found that WHO fasting glucose concentration cutoffs and HbA1c-based definitions of prediabetes result in lower prevalence estimates than ADA fasting glucose concentration cutoffs and ADA and WHO 2 h glucose concentration cutoffs, but were more specific in identifying people at risk for long-term outcomes. We also observed that ADA fasting glucose concentration and ADA and WHO 2 h glucose concentration-based definitions of prediabetes are more sensitive for long-term outcomes. We found that HbA1c-based definitions of prediabetes had stronger associations with long-term outcomes and provided modest, but statistically significantly more information for risk discrimination than fasting glucose-based definitions for many major clinical complications. We did not observe meaningful differences between definitions using both ADA and WHO fasting glucose concentrations compared with those using ADA and WHO 2 h glucose concentration cutoffs for long-term risk associations.

Implications of all the available evidence

Many considerations need to be accounted for in the selection of a definition of prediabetes for use in population screening or other settings, but long-term risk associations can and should be taken into account when reaching consensus on a definition for prediabetes.

Although the selection of biomarker cutoff points for screening or diagnosis requires a broad range of considerations, associations with clinical outcomes are an important factor.8 Therefore, the aim of this study was to compare the prognostic performance of the above-mentioned definitions of prediabetes in their associations with major clinical complications such as incident diabetes, chronic kidney disease, atherosclerotic cardiovascular disease, peripheral arterial disease, and all-cause mortality. We compared the risk of future outcomes across different definitions of prediabetes by 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.

Section snippets

Study design and participants

This prospective cohort study was based on the ARIC study, which originally enrolled 15 792 adults aged 45–64 years from the communities of Jackson, MS; Forsyth County, NC; suburban Minneapolis, MN; and Washington County, MD, USA. We excluded participants with prevalent diabetes, chronic kidney disease, atherosclerotic cardiovascular disease, or peripheral arterial disease, those who were missing variables of interest, or those who fasted for less than 10 h (see appendix for full details).

Results

In comparison with people with prediabetes defined using ADA fasting glucose concentration cutoffs at visit 2, use of ADA HbA1c cutoffs to define prediabetes was more likely to identify people who were women, black, current smokers, had hypertension, and who had less high-school education; it was less likely to identify current drinkers (table 1). In comparison with people defined using ADA fasting glucose concentration cutoffs at visit 4, use of ADA and WHO 2 h glucose concentration to define

Discussion

In this cohort study, we showed that prevalence of prediabetes and performance of various definitions of prediabetes were significantly different when analysed in the context of long-term complications. Use of ADA fasting glucose concentration cutoffs or ADA and WHO 2 h glucose concentration cutoffs to define prediabetes resulted in higher prevalence estimates than did use of WHO fasting glucose concentration cutoffs, ADA HbA1c cutoffs, or IEC HbA1c cutoffs. With the ADA fasting glucose

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