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The Deterrence of Rapid Metabolic Decline within 3 Months after Teplizumab Treatment in Individuals at High Risk for Type 1 Diabetes

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posted on 22.09.2021, 16:45 by Emily K. Sims, David Cuthbertson, Kevan C. Herold, Jay M. Sosenko
Endpoints that provide an early identification of treatment effects are needed to implement type 1 diabetes prevention trials more efficiently. To this end, we assessed whether metabolic endpoints can be used to detect a teplizumab effect on rapid β-cell decline within 3 months after treatment in high-risk individuals in the TrialNet teplizumab trial. Glucose and C-peptide response curves (GCRCs) were constructed by plotting mean glucose and C-peptide values from 2-hour oral glucose tolerance tests on a 2-dimensional grid. Groups were compared visually for changes in GCRC shape and movement. GCRC changes reflected marked metabolic deterioration in the placebo group within 3 months of randomization. By 6 months, GCRCs resembled typical GCRCs at diagnosis. In contrast, GCRC changes in the teplizumab group suggested metabolic improvement. Quantitative comparisons, including two novel metabolic endpoints that indicate GCRC changes, the Within Quadrant Endpoint (WQE) and the Ordinal Directional Endpoint (ODE), were consistent with visual impressions of an appreciable treatment effect at 3 and 6-month timepoints. In conclusion, an analytic approach combining visual evidence with novel endpoints, demonstrated that Teplizumab delays rapid metabolic decline, and improves the metabolic state within 3 months after treatment; this effect extends for at least 6 months.

Funding

This manuscript was supported by funding from NIDDK U01 DK127786, R03 DK117253, and R01DK121929 to E.K.S., and funding from JDRF 2-SRA-2017-498-M-B to E.K.S. We acknowledge the support of the Type 1 Diabetes TrialNet Study Group, which identified study participants and provided samples and follow-up data for this study. Supported by the National Institutes of Health through the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute of Allergy and Infectious Diseases, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, through cooperative agreements U01 DK061010, U01 DK061034, U01 DK085461, U01 DK085465, U01 DK085466, U01 DK085476, U01 DK085509, U01 DK103266, U01 DK103282, U01 DK106984, U01 DK107013, U01 DK107014, UC4 DK097835, and UC4 DK106993; JDRF; and the American Diabetes Association. Additional support for clinical studies was provided by the National Center for Research Resources through Clinical Translational Science Awards UL1TR000142, UL1TR002366, UL1TR000445, UL1TR000064, UL1TR002537, UL1TR001082, UL1TR000114, UL1TR001857, UL1TR002529, UL1TR001872 and by the Immune Tolerance Network (UM1 AI09565).

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