Anti-thymocyte globulin/G-CSF treatment preserves β cell function in patients with established type 1 diabetes

J Clin Invest. 2015 Jan;125(1):448-55. doi: 10.1172/JCI78492. Epub 2014 Dec 15.

Abstract

Background: Previous efforts to preserve β cell function in individuals with type 1 diabetes (T1D) have focused largely on the use of single immunomodulatory agents administered within 100 days of diagnosis. Based on human and preclinical studies, we hypothesized that a combination of low-dose anti-thymocyte globulin (ATG) and pegylated granulocyte CSF (G-CSF) would preserve β cell function in patients with established T1D (duration of T1D >4 months and <2 years).

Methods: A randomized, single-blinded, placebo-controlled trial was performed on 25 subjects: 17 subjects received ATG (2.5 mg/kg intravenously) followed by pegylated G-CSF (6 mg subcutaneously every 2 weeks for 6 doses) and 8 subjects received placebo. The primary outcome was the 1-year change in AUC C-peptide following a 2-hour mixed-meal tolerance test (MMTT). At baseline, the age (mean ± SD) was 24.6 ± 10 years; mean BMI was 25.4 ± 5.2 kg/m²; mean A1c was 6.5% ± 1.1%; insulin use was 0.31 ± 0.22 units/kg/d; and length of diagnosis was 1 ± 0.5 years.

Results: Combination ATG/G-CSF treatment tended to preserve β cell function in patients with established T1D. The mean difference in MMTT-stimulated AUC C-peptide between treated and placebo subjects was 0.28 nmol/l/min (95% CI 0.001-0.552, P = 0.050). A1c was lower in ATG/G-CSF-treated subjects at the 6-month study visit. ATG/G-CSF therapy was associated with relative preservation of Tregs.

Conclusions: Patients with established T1D may benefit from combination immunotherapy approaches to preserve β cell function. Further studies are needed to determine whether such approaches may prevent or delay the onset of the disease.

Trial registration: Clinicaltrials.gov NCT01106157.

Funding: The Leona M. and Harry B. Helmsley Charitable Trust and Sanofi.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Antilymphocyte Serum / therapeutic use*
  • C-Peptide / blood
  • Child
  • Diabetes Mellitus, Type 1 / blood
  • Diabetes Mellitus, Type 1 / drug therapy*
  • Drug Combinations
  • Female
  • Glycated Hemoglobin A / metabolism
  • Granulocyte Colony-Stimulating Factor / therapeutic use*
  • Humans
  • Hypoglycemic Agents / therapeutic use*
  • Insulin / therapeutic use
  • Insulin-Secreting Cells / physiology*
  • Male
  • Middle Aged
  • Polyethylene Glycols / therapeutic use*
  • Single-Blind Method
  • Treatment Outcome
  • Young Adult

Substances

  • Antilymphocyte Serum
  • C-Peptide
  • Drug Combinations
  • Glycated Hemoglobin A
  • Hypoglycemic Agents
  • Insulin
  • hemoglobin A1c protein, human
  • pegylated granulocyte colony-stimulating factor, human
  • Granulocyte Colony-Stimulating Factor
  • Polyethylene Glycols

Associated data

  • ClinicalTrials.gov/NCT01106157