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

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.

Figures

Figure 3. AUC C-peptide at baseline and 1 year following ATG/G-CSF compared with placebo.

Data from each subject is shown. Subjects are separated by study drug assignment. Subjects depicted by solid black lines had sustained or increased AUC C-peptide over 1 year. Subjects depicted by dashed gray lines had a reduction in AUC C-peptide over 1 year. AUC C-peptide is shown as the AUC divided by 120 minutes.

Figure 2. Preservation of C-peptide following combination therapy with low-dose ATG and G-CSF.

The combination of ATG and G-CSF resulted in a significant preservation of AUC C-peptide when compared with placebo therapy. On average, subjects who received placebo experienced a 39% reduction in AUC C-peptide over 1 year, while subjects who received ATG and G-CSF experienced a 4.3% increase in AUC C-peptide over the same time period. AUC C-peptide is shown as the AUC divided by 120 minutes. Data were analyzed via 2-sample 2-sided t test and are presented as mean ± SD.

Figure 1. ATG/G-CSF combination therapy consort diagram.