Clinical and Metabolic Characterization of Adults with Type 2 Diabetes by Age in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) Study Cohort

Objective: Differences in type 2 diabetes phenotype by age are described, but it is not known whether these differences are seen in a more uniformly defined adult population at a common early stage of care. We characterize age-related clinical and metabolic characteristics of adults with type 2 diabetes on metformin monotherapy, prior to treatment intensification. Research Design and Methods: The Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) Study enrolled participants with type 2 diabetes duration <10 years, A1c 6.8-8.5%, on metformin monotherapy, and randomly assigned to one of four additional glucose-lowering medications. We compared baseline clinical and metabolic characteristics across age categories (<45; 45-<55; 55-<65; ≥65 years) using ANOVA and Pearson’s chi-squared tests.. Results: Within the GRADE cohort (n=5,047), we observed significant differences by age with younger adults having greater racial diversity, fewer medications for common comorbidities, lower prevalence of CVD, higher weight and BMI, more pronounced hyperglycemia and diabetic dyslipidemia, with metabolic profile indicating lower insulin sensitivity (1/fasting insulin, HOMA-2S, Matsuda index) and inadequate β cell response (oral disposition index) (p < 0.05 across age categories). Conclusions: Clinical and metabolic characteristics of type 2 diabetes differ by age within the GRADE cohort. Younger adults exhibit more prominent obesity-related characteristics, including higher obesity levels, lower insulin sensitivity and beta cell compensation. Given the increasing burden of type 2 diabetes and complications, particularly among younger populations, these age-related distinctions may inform risk factor management approaches and treatment priorities. Further study will determine whether age-related differences impact response to therapy.