Abstract WE441: Progression and Risk of Type 2 Diabetes Mellitus According to Glycemic Phenotypes

Background: Heterogeneity in prediabetes (preDM) etiology may influence progression to type 2 diabetes mellitus (T2DM). Despite its clinical importance, longitudinal data on progression to diabetes according to baseline glycemic status remain limited. Methods: We included Framingham Heart Study Generation 3 based cohorts, free of diabetes who participated in an oral glucose tolerance test (OGTT, n=2,965). Participants with preDM were classified into four glycemic phenotype groups: impaired fasting glucose (IFG-only, 100-125 mg/dl), impaired glucose tolerance (IGT-only, 140-199 mg/dl on OGTT), impaired HbA1c (IA1c-only, 5.7-6.4%), and multiple abnormalities (≥2). We used multivariable Poisson regression models to estimate the risk of developing T2DM for each phenotype group, compared to normoglycemia (referent). Model 1 was adjusted for age, sex, smoking, and education. Fully adjusted model further included waist circumference, systolic blood pressure, hypertension and lipid medication use, and non-HDL cholesterol. Progression of preDM phenotype categories was evaluated in participants who completed a mixed meal tolerance test upon follow-up (n=2,077). Results: Among 2,965 FHS participants (Women 54.06%), the average age was 46 years and 26% had only one marker for preDM at baseline (12% IFG, 3% IGT, 11% IA1c); 11% had multiple abnormalities. Over a median follow-up of 14 years, 219 participants (7%) developed T2DM. Having multiple glycemic abnormalities, compared to normoglycemia, was associated with the highest risk of developing T2DM, followed by IFG, IGT, and IA1c ( Figure 1A ). Individuals with multiple abnormalities had a 19-fold higher incidence rate than normoglycemic participants (IRR 95% CI = 18.5 12.7, 27.0, model 1). IFG showed a 6-fold higher risk, IGT a 5-fold higher risk, and IA1c a 4-fold higher risk of developing T2DM compared with normoglycemic participants (p < 0.001). All associations were attenuated but remained significant in the full adjustment model. Progression of preDM phenotypes among a subset of participants with two glycemic challenges in Figure 1B demonstrates substantial instability in glycemic phenotype group membership. Conclusions: Diabetes incidence among middle-aged U.S. adults varied significantly by baseline glycemic phenotypes. These findings suggest that phenotype-specific T2DM prevention strategies may lead to more effective interventions and improved public health outcomes.