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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

2019; American Diabetes Association; Volume: 42; Issue: 9 Linguagem: Inglês

10.2337/dc19-0556

1935-5548

David A. Ehrmann, Karla A. Temple, Abby Rue, Elena Barengolts, Babak Mokhlesi, Eve Van Cauter, Susan Sam, M. Annette Miller, Steven E. Kahn, Karen M. Atkinson, Jerry P. Palmer, Kristina M. Utzschneider, Tsige Gebremedhin, Abigail Kernan‐Schloss, Alexandra Kozedub, Brenda K. Montgomery, Emily J. Morse, Kieren J. Mather, Tammy Garrett, Tamara S. Hannon, Amale Lteif, Aniket Patel, Robin Chisholm, Karen Moore, Vivian Pirics, Linda Pratt, Kristen J. Nadeau, Susan Gross, Philip Zeitler, Jayne Williams, Melanie Cree‐Green, Yesenia Garcia‐Reyes, Krista Vissat, Silva Arslanian, Kathleen Brown, Nancy Guerra, Kristin E. Porter, Sonia Caprio, Mary Savoye, Bridget Pierpont, Thomas A. Buchanan, Anny H. Xiang, Enrique Trigo, Elizabeth Beale, Ting Chow, Fadi N. Hendee, Namir Katkhouda, Krishan Nayak, Mayra P. Martinez, Cortney Montgomery, Xinhui Wang, Jun Wu, Sharon L. Edelstein, John M. Lachin, Ashley H. Tjaden, Santica M. Marcovina, Jessica Harting, John J. Albers, Dave Hill, Peter J. Savage, Ellen W. Leschek,

Metabolism, Diabetes, and Cancer

OBJECTIVE The Restoring Insulin Secretion (RISE) Adult Medication Study compared pharmacological approaches targeted to improve β-cell function in individuals with impaired glucose tolerance (IGT) or treatment-naive type 2 diabetes of <12 months duration. 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. β-Cell function was assessed using hyperglycemic clamps at baseline, 12 months (on treatment), and 15 months (3 months off treatment). The primary outcome was β-cell function at 15 months compared with baseline. RESULTS All three active treatments produced on-treatment reductions in weight and improvements in HbA1c 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 β-cell function in any treatment group. CONCLUSIONS In adults with IGT or recently diagnosed type 2 diabetes, interventions that improved β-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 β-cell dysfunction in IGT or early type 2 diabetes.