American Diabetes Association
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Impact of insulin sensitivity and β-cell function over time on glycemic outcomes in the GRADE (Glycemia Reduction Approaches in Type 2 Diabetes: A Comparative Effectiveness) Study: differential treatment effects of dual therapy.

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posted on 2024-01-08, 21:04 authored by Kristina M Utzschneider, Naji Younes, Nicole M Butera, Ashok Balasubramanyam, Richard M Bergenstal, Joshua Barzilay, Cyrus DeSouza, Ralph A. DeFronzo, Tom Elasy, Jonathan Krakoff, Steven E Kahn, Neda Rasouli, Willy M. Valencia, William I Sivitz

Objective: Compare the effects of insulin sensitivity and β-cell function over time on HbA1c and durability of glycemic control in response to dual therapy. Design and Methods: GRADE Study participants were randomized to glimepiride (n=1254), liraglutide (n=1262), or sitagliptin (n=1268) added to baseline metformin and followed for 5.0±1.3 years with HbA1c quarterly and OGTTs at baseline, 1, 3, and 5 years. We related time-varying insulin sensitivity (HOMA2-%S) and early (0-30 min) and total (0-120 min) C-peptide (CP) responses to changes in HbA1c and glycemic failure (primary: HbA1c≥7% (53 mmol/mol) and secondary outcome: HbA1c>7.5% (58 mmol/mol)) and examined differential treatment responses. Results: Higher HOMA2-%S was associated with greater initial HbA1c lowering (3 months) but not subsequent HbA1c rise. Greater CP responses were associated with a larger initial treatment response and slower subsequent HbA1c rise. Higher HOMA2-%S and CP responses were each associated with lower risk of primary and secondary outcomes. These associations differed by treatment. In the sitagliptin group, HOMA2-%S and CP responses had greater impact on initial HbA1c reduction (test heterogeneity p=0.009 HOMA2-%S; p=0.018 early CP; p=0.001 total CP) and risk of primary outcome (p=0.005 HOMA2-%S; p=0.11 early CP; p=0.025 total CP), but lower impact on HbA1c rise (p=0.175 HOMA2-%S; p=0.006 early CP; p<0.001 total CP) compared to glimepiride and liraglutide. There were no differential treatment effects on secondary outcome. Conclusion: Insulin sensitivity and β-cell function affected treatment outcomes irrespective of drug assignment, with greater impact in the sitagliptin group on initial (short-term) HbA1c response compared to glimepiride and liraglutide.


Funding: The GRADE Study was supported by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health under Award Number U01DK098246. The planning of GRADE was supported by a U34 planning grant from the NIDDK (U34-DK-088043). The American Diabetes Association supported the initial planning meeting for the U34 proposal. The National Heart, Lung, and Blood Institute and the Centers for Disease Control and Prevention also provided funding support. The Department of Veterans Affairs provided resources and facilities. Additional support was provided by grant numbers P30 DK017047, P30 DK020541-44, P30 DK020572, P30 DK072476, P30 DK079626, P30 DK092926, U54 GM104940, UL1 TR000439, UL1 TR000445, UL1 TR001108, UL1 TR001409, 2UL1TR001425, UL1 TR001449, UL1 TR002243, UL1 TR002345, UL1 TR002378, UL1 TR002489, UL1 TR002529, UL1 TR002535, UL1 TR002537, 2UL1 TR001425 and UL1 TR002548. Educational materials have been provided by the National Diabetes Education Program. Material support in the form of donated medications and supplies has been provided by Becton, Dickinson and Company, Bristol-Myers Squibb, Merck & Co., Inc., Novo Nordisk, Roche Diagnostics, and Sanofi. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The GRADE Study Research Group is deeply grateful to our participants whose loyal dedication made GRADE possible.


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