Lack of Durable Improvements in β-Cell Function Following Withdrawal of Pharmacological Interventions in Adults With Impaired Glucose Tolerance or Recently Diagnosed Type 2 Diabetes

OBJECTIVE The Restoring Insulin Secretion (RISE) Adult Medication Study compared pharmacological approaches targeted to improve beta-cell function in individuals with impaired glucose tolerance (IGT) or treatment-naive type 2 diabetes of RESEARCH DESIGN AND METHODS A total of 267 adults with IGT (n = 197, 74%) or recently diagnosed type 2 diabetes (n = 70, 26%) were studied. Participants were randomized to receive 12 months of metformin alone, 3 months of insulin glargine with a target fasting glucose <5 mmol/L followed by 9 months of metformin, 12 months of liraglutide combined with metformin, or 12 months of placebo. beta-Cell function was assessed using hyperglycemic clamps at baseline, 12 months (on treatment), and 15 months (3 months off treatment). The primary outcome was beta-cell function at 15 months compared with baseline. RESULTS All three active treatments produced on-treatment reductions in weight and improvements in HbA(1c) compared with placebo; the greatest reductions were seen in the liraglutide plus metformin group. At 12 months, glucose-stimulated C-peptide responses improved in the three active treatment groups and were greatest in the liraglutide plus metformin group, but the arginine-stimulated incremental C-peptide response was reduced in the liraglutide plus metformin group. Despite on-treatment benefits, 3 months after treatment withdrawal there were no sustained improvements in beta-cell function in any treatment group. CONCLUSIONS In adults with IGT or recently diagnosed type 2 diabetes, interventions that improved beta-cell function during active treatment failed to produce persistent benefits after treatment withdrawal. These observations suggest that continued intervention may be required to alter the progressive beta-cell dysfunction in IGT or early type 2 diabetes.