Glycated Hemoglobin and Prediabetes: A Systematic Review of HbA1c Thresholds for Type 2 Diabetes Prevention

Background/Objectives: HbA1c is widely used to identify adults at increased risk of type 2 diabetes mellitus (T2DM), but major guidance differs on whether the lower limit of an HbA1c-defined risk range should be 5.7% (39 mmol/mol) or 6.0% (42 mmol/mol). This systematic review evaluated the prognostic and screening utility of HbA1c 5.7–6.4% compared with HbA1c 6.0–6.4% and examined whether available evidence supports threshold-based allocation of preventive interventions. Methods: The review was reported in accordance with PRISMA 2020 and registered in PROSPERO (CRD42019134344). PubMed/MEDLINE, Embase and the Cochrane Library were searched for studies published from 1 January 2016 to 1 January 2026. Eligible evidence comprised human studies in English, French, Hebrew, Italian or Spanish that evaluated HbA1c ranges below the diabetes diagnostic threshold in adults aged at least 40 years or younger adults with established risk factors. Two reviewers independently screened records and extracted data. Risk of bias was assessed using an adapted QUADAS-2 framework for threshold-performance evidence, supplemented by CASP-informed appraisal, and certainty was rated with GRADE domains. Narrative synthesis was selected because populations, thresholds, comparator tests, follow-up and outcome ascertainment were heterogeneous. Results: Seven studies were included. Evidence consistently supported a graded risk continuum rather than a single biological cut point. HbA1c 5.7–6.4% identifies more adults but includes many at low short-term absolute risk, whereas HbA1c 6.0–6.4%, especially 6.2–6.4% or combined HbA1c and fasting glucose abnormality, identifies fewer adults at higher near-term risk. Direct evidence comparing 5.7% versus 6.0% thresholds came mainly from one UK cohort, with supportive but indirect evidence from meta-analysis, routine-care cohorts and reversion studies. No trial randomized adults to intervention by HbA1c threshold, and eligible evidence did not directly address early diabetes-related morbidity by threshold. Conclusions: HbA1c below the diabetes diagnostic threshold should be interpreted as risk strata, not as a binary disease label. HbA1c 5.7–6.4% is defensible for broad, low-intensity preventive advice, while HbA1c 6.0–6.4% can be used to prioritize structured prevention and closer follow-up. The proposed tiered approach is a pragmatic, hypothesis-generating interpretation of the available evidence rather than a trial-validated intervention algorithm.