In natural history studies, maintenance of higher levels of C-peptide secretion (a measure of endogenous insulin production) correlates with a lower incidence of major hypoglycemic events in patients with type 1 diabetes (T1D), but is unclear whether this will also be true for drug-induced C-peptide preservation.
We analyzed hypoglycemic events and glycemic control data from the T1DAL study, a trial of alefacept in new-onset T1D, which demonstrated significant C-peptide preservation at 1 and 2 years. We performed a post hoc analysis using mixed models of the relationship between the meal-stimulated 4-hour C-peptide area under the curve (4-hour AUC) and rates of major hypoglycemia, measures of glycemic control (HbA1c; average glucometer readings) and variability (glucometer SDs; highest and lowest readings), and an index of partial remission (insulin dose-adjusted HbA1c, IDAA1C).
Data from 49 participants (33 in the alefacept group, 16 in the placebo group) were analyzed at baseline and 12 and 24 months. We found that the 4-hour AUC at baseline and at 1 year was a significant predictor of the number of hypoglycemic events during the ensuing 12-month interval (p=0.030). There was a strong relationship between the 4-hour AUC and glucometer SDs (p<0.001), highest readings (p<0.001), and lowest readings (p=0.03), all measures of glycemic variability. There was a strong inverse correlation between the 4-hour AUC and two measures of glycemic control: HbA1c and average glucometer readings (both p<0.001). There was also a strong inverse correlation between the 4-hour AUC and IDAA1C values (p<0.001), as well as a strong correlation between IDAA1C values and glucometer SDs (p<0.001), suggesting that reduced glycemic variability is associated with a trend toward partial remission. For none of these analyses was there a significant difference between the alefacept and placebo groups.
Measures of glycemic variability and control, including rates of hypoglycemia, are significantly correlated with preservation of C-peptide regardless of whether this is achieved by immune intervention with alefacept or natural variability in patients with new-onset T1D. Thus, preservation of endogenous insulin production by an immunomodulatory drug may confer clinical benefits similar to those seen in patients with higher C-peptide secretion due to slow disease progression.