June 20, 2016
Better blood glucose control is correlated with C-peptide preservation, a marker of natural insulin production, in individuals with type 1 diabetes who participated in the Immune Tolerance Network’s T1DAL Study [Inducing Remission in New Onset T1DM with Alefacept (Amevive®)]. This secondary analysis of T1DAL data is the first to demonstrate the correlation between insulin preservation and glycemic control in a clinical trial with an immune-targeting drug in type 1 diabetes. The data are published in the June 17th Diabetes Mellitus Topic Update in Clinical Therapeutics. The T1DAL Study was led by Dr. Mark Rigby (Riley Children’s Hospital, Indiana University, Indianapolis) and conducted by the Immune Tolerance Network (ITN).
The T1DAL study randomized 49 adolescents and adults with new-onset type 1 diabetes 2:1 to an immune-targeting agent, alefacept (LFA3-Ig fusion protein; Astellas Pharma Inc.) or placebo, and demonstrated significant preservation of C-peptide in the alefacept group compared to placebo at one and two years.
The post-hoc analysis published in Clinical Therapeutics used a mixed-model statistical approach to assess whether C-peptide preservation was correlated with clinical outcomes such as hypoglycemic events and variability in blood glucose levels. T1DAL participants used identical home glucometers to track blood glucose data, which was downloaded at every clinic visit, enabling standardized quantification of glycemic variability across the course of the trial.
The model found that C-peptide levels at baseline and one year were a significant predictor of the number of hypoglycemic events that occurred during the subsequent year (p=0.03), with higher C-peptide associated with fewer events. There was also a significant inverse association between C-peptide and the magnitude of variation in glucose readings as measured by the standard deviation (p<0.001), meaning better C-peptide preservation was associated with less variability in glucose levels. The model assessed other indicators of glycemic control, including glycated hemoglobin (HbA1c) and average glucometer readings, finding similar associations.
Though these findings seem intuitive, i.e., preservation of insulin production is associated with clinical benefits such as improved glycemic control, this is the first clinical trial using an immune-targeting therapeutic in type 1 diabetes to demonstrate this correlation. Further, this analysis was possible due to the comprehensive and systematic collection of longitudinal blood glucose data, something that has not been achieved in other immune intervention trials in type 1 diabetes.
“These results demonstrate, for the first time, that preserving endogenous insulin production with an immune intervention reduces hypoglycemia and improves glycemic control in type 1 diabetes,” said Dr. Mario Ehlers, Deputy Director of the ITN Clinical Trials Group. “Over the years, there has been skepticism that C-peptide secretion is a meaningful surrogate of clinical benefit, but our data show that there is a continuous relationship between higher C-peptide levels and better glycemic control.”
The data suggest that immune-targeting agents may be a viable strategy to realize the long-term clinical benefits associated with residual natural islet function, particularly when insulin replacement technology remains an imperfect alternative to blood glucose management.
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