Differential Treatment Effects on β-Cell Function Using Model-Based Parameters in Type 2 Diabetes: Results From the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE)

OBJECTIVE To evaluate how model-based parameters of b-cell function change with glucose-lowering treatment and associate with glycemic deterioration in adults with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS In the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE), b-cell function parameters derived from mathematical modeling of oral glucose tolerance tests were assessed at baseline (N = 4,712) and 1, 3, and 5 years following randomization to insulin glargine, glimepiride, liraglutide, or si-tagliptin, added to baseline metformin. Parameters included insulin secretion rate (ISR), glucose sensitivity (insulin response to glucose), rate sensitivity (early insulin response), and potentiation. Linear mixed-effects models were used to compare changes across treatments. With Cox proportional hazards and Classifi-cation And Regression Tree (CART) analyses we evaluated associations between model parameters and glycemic failure (A1C >7.5%; 58.5 mmol/mol). RESULTS b-Cell function parameters increased variably at year 1 across treatments but subsequently declined for all treatments. Statistically significant changes were noted. Liraglutide led to the greatest increases in ISR, glucose sensitivity and po-tentiation, remaining above baseline at study end. Sitagliptin improved glucose sensitivity, with modest effects on other parameters. Glimepiride temporarily increased ISR and rate sensitivity but minimally increased glucose sensitivity or po-tentiation. Rate sensitivity increased most with glargine. Higher b-cell function parameters were protective against glycemic deterioration, but treatment did not alter the relationship between these parameters and glycemic outcomes. CONCLUSIONS Common glucose-lowering medications impact different physiologic components of b-cell function in T2D. Regardless of treatment modality, lower b-cell function associated with early glycemic failure, and b-cell function progressively declined after initial improvement.