Correlation Among Hypoglycemia, Glycemic Variability, and C-Peptide Preservation After Alefacept Therapy in Patients with Type 1 Diabetes Mellitus: Analysis of Data from the Immune Tolerance Network T1DAL Trial

Abstract

Purpose 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. Methods 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). Findings 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. Implications 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.

Random non-fasting C-peptide testing can identify patients with insulin-treated type 2 diabetes at high risk of hypoglycaemia

“…The relationship between C-peptide and glucose variability in previous literature is continuous but non-linear, with a very strong association at low but not high C-peptide levels [28, 29, 36]. This is similar to the relationship observed with self-reported hypoglycaemia in our cohort (ESM Fig.…”

Persistent C‐peptide is associated with reduced hypoglycaemia but not HbA1c in adults with longstanding Type 1 diabetes: evidence for lack of intensive treatment in UK clinical practice?

“…The limitation of achieving optimal glycaemic control with intensive treatment in Type 1 diabetes is usually hypoglycaemia, which prevents up-titration of insulin doses. The reduced glucose variability and better hypoglycaemia counter-regulation associated with preservation of endogenous insulin secretion [16,[23][24][25] means that with intensive treatment an adult with retained endogenous insulin secretion can obtain a lower HbA 1c at an acceptable level of hypoglycaemia than would be possible where endogenous insulin is absent. Our findings are consistent with previous research on the clinical impact of C-peptide.…”

Hypoglycemia and Glucagon Utilization in Insulin-Treated Diabetic Patients

“…Several investigations suggest that patients with preservation of C-peptide values (measure that represents endogenous insulin production) have significant correlation with better glycemic control, including lower hypoglycemia episode rates. Furthermore, higher values of C-peptide are connected with increased sensor glucose levels in the target range and lower glucose variability [20][21][22]. In addition, progressive insulin deficiency and longer duration of the disease in type 2 diabetic patients increase overall risk of hypoglycemia episodes [23].…”