American Diabetes Association
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Longitudinal effects of glucose-lowering medications on β-cell responses and insulin sensitivity in type 2 diabetes: The GRADE randomized clinical trial

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posted on 2024-01-11, 23:30 authored by Neda Rasouli, Naji Younes, Alokananda Ghosh, Jeanine Albu, Robert M. Cohen, Ralph A. DeFronzo, Elsa Diaz, Laure Sayyed Kassem, José A. Luchsinger, Janet B. McGill, William I. Sivitz, William V. Tamborlane, Kristina M. Utzschneider, Steven E. Kahn

Objective: To compare the long-term effects of glucose-lowering medications (insulin glargine U-100, glimepiride, liraglutide, sitagliptin) when added to metformin on insulin sensitivity and β-cell function.

Research Design and Methods: In the GRADE cohort with type 2 diabetes (n=4,801), HOMA2 was used to estimate insulin sensitivity (HOMA2-%S) and fasting β-cell function (HOMA2-%B) at baseline and 1, 3, and 5 years on treatment. OGTT β-cell responses (C-peptide index [CPI] and total C-peptide response [incremental C-peptide/incremental glucose over 120 minutes]) were evaluated at the same timepoints. These responses adjusted for HOMA2-%S in regression analysis provided estimates of β-cell function.

Results: HOMA2-%S increased from baseline to year 1 with glargine and remained stable thereafter, while it did not change from baseline in the other treatment groups. HOMA2-%B and C-peptide responses increased to variable degrees at year 1 in all groups, but then declined progressively over time. At year 5, CPI was similar between liraglutide and sitagliptin, both higher than glargine and glimepiride (0.80, 0.87, 0.74, 0.64 (nmol/L)/(mg/dL)*100, respectively, p<0.001), while the total C-peptide response was greatest with liraglutide followed in descending order by sitagliptin, glargine and glimepiride (1.54, 1.25, 1.02, 0.87 (nmol/L)/(mg/dL)*100, respectively, p<0.001). After adjusting for HOMA2-%S to obtain an estimate of β-cell function, the nature of the change in β-cell responses reflected those in β-cell function.

Conclusion: The differential long-term effects on insulin sensitivity and β-cell function of four different glucose-lowering medications when added to metformin highlight the importance of the loss of β-cell function in the progression of type 2 diabetes.


he 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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