title: 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: 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 mellitus (T1D), but it is unclear whether this is also true for drug-induced C-peptide preservation.
  
  
  
  We analyzed hypoglycemic events and glycemic control data from the T1DAL (Inducing Remission in New-Onset T1D with Alefacept) study, a trial of alefacept in new-onset T1D, which found significant C-peptide preservation at 1 and 2 years. We performed a post hoc analysis using mixed models of the association between the meal-stimulated 4-hour C-peptide AUC (4-hour AUC) and rates of major hypoglycemia, measures of glycemic control (glycosylated hemoglobin [HbA1c]; mean 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 and 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 association 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 2 measures of glycemic control: HbA1c and mean 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. None of these analyses found 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.
authors.affiliation: Federal Systems Division, Rho Inc, Chapel Hill, North Carolina.
authors.forename: Ashley
authors.initials: A
authors.lastname: Pinckney
authors.affiliation: Section of Pediatric Endocrinology and Diabetology, Department of Pediatrics, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Rigby
authors.affiliation: Federal Systems Division, Rho Inc, Chapel Hill, North Carolina.
authors.forename: Lynette
authors.initials: L
authors.lastname: Keyes-Elstein
authors.affiliation: Clinical Trials Group, Immune Tolerance Network, San Francisco, California.
authors.forename: Carol L
authors.initials: CL
authors.lastname: Soppe
authors.affiliation: Benaroya Research Institute at Virginia Mason, Seattle, Washington.
authors.forename: Gerald T
authors.initials: GT
authors.lastname: Nepom
authors.affiliation: Clinical Trials Group, Immune Tolerance Network, San Francisco, California. Electronic address: mehlers@immunetolerance.org.
authors.forename: Mario R
authors.initials: MR
authors.lastname: Ehlers
mesh_terms: D000293:Adolescent; D000328:Adult; D000077944:Alefacept; D001786:Blood Glucose / Q000032:analysis; D002096:C-Peptide / Q000378:metabolism*; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D004311:Double-Blind Method; D005260:Female; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D007003:Hypoglycemia / Q000188:drug therapy / Q000209:etiology; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D007108:Immune Tolerance; D007328:Insulin / Q000096:biosynthesis / Q000627:therapeutic use; D008297:Male; D011993:Recombinant Fusion Proteins / Q000009:adverse effects / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D000077944:Alefacept; D001786:Blood Glucose; D002096:C-Peptide; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D011993:Recombinant Fusion Proteins
keywords: alefacept; glycemic control; hypoglycemia; immune intervention; islet function; new-onset T1d