American Diabetes Association
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The Association of Baseline Factors with Glycemic Outcomes in the GRADE Study: A Comparative Effectiveness Randomized Clinical Trial

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posted on 2024-01-29, 19:46 authored by W. Timothy Garvey, Robert M. Cohen, Nicole M. Butera, Erin J. Kazemi, Naji Younes, Samuel P. Rosin, Andrew J. Ahmann, Priscilla A Hollander, Jonathan Krakoff, Catherine L. Martin, Elizabeth Seaquist, Michael W. Steffes, John M. Lachin

Objective: To describe the individual and joint associations of baseline factors with glycemia, and with differential effectiveness of medications added to metformin.

Research Design and Methods: GRADE participants (type 2 diabetes for <10 years, HbA1c 6.8%-8.5% on metformin, N=5047) were randomly assigned to a basal insulin (glargine), sulfonylurea (glimepiride), glucagon-like peptide-1 agonist (liraglutide), or dipeptidyl peptidase-4 inhibitor (sitagliptin). The glycemic outcome was HbA1c ≥7.0%, subsequently confirmed. Univariate, multivariate regression, and Classification and Regression Tree (CART) analyses described the association of baseline factors with the glycemic outcome at years 1 and 4.

Results: In univariate analyses at baseline, younger age (<58 years), Hispanic ethnicity, high fasting glucose and triglyceride levels, lower insulin secretion, and relatively greater insulin resistance were associated with the glycemic outcome at years 1 and 4. No factors were associated with differential effectiveness of the medications by year 4. In multivariate analyses, treatment group, younger age, and higher baseline HbA1c and fasting glucose were jointly associated with the glycemic outcome by year 4. The superiority of glargine and liraglutide at year 4 persisted after controlling for multiple baseline factors. CART analyses indicated that younger participants and those with baseline HbA1c ≥7.4% were more likely to fail by year 4.

Conclusions: Several baseline factors were associated with the glycemic outcome but not with differential effectiveness of the four medications. Failure to maintain HbA1c <7% was largely driven by younger age and higher HbA1c at baseline. Factors that predict earlier glycemic deterioration could help target patients for more aggressive management.


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, UL1 TR001449, UL1 TR002243, UL1 TR002345, UL1 TR002378, UL1 TR002489, UL1 TR002529, UL1 TR002535, UL1 TR002537, 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, NovoNordisk, 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.


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