Low-Dose Anti-Thymocyte Globulin (ATG) Preserves β-Cell Function and Improves HbA1c in New-Onset Type 1 Diabetes

Type 1 Diabetes TrialNet ATG-GCSF Study Group; Michael J Haller; Desmond A Schatz; Jay S Skyler; Jeffrey P Krischer; Brian N Bundy; Jessica L Miller; Mark A Atkinson; Dorothy J Becker; David Baidal; Linda A DiMeglio; Stephen E Gitelman; Robin Goland; Peter A Gottlieb; Kevan C Herold; Jennifer B Marks; Antoinette Moran; Henry Rodriguez; William Russell; Darrell M Wilson; Carla J Greenbaum; Polly Bingley

doi:10.2337/dc18-0494

Low-Dose Anti-Thymocyte Globulin (ATG) Preserves β-Cell Function and Improves HbA1c in New-Onset Type 1 Diabetes

Type 1 Diabetes TrialNet ATG-GCSF Study Group, Michael J Haller, Desmond A Schatz, Jay S Skyler, Jeffrey P Krischer, Brian N Bundy, Jessica L Miller, Mark A Atkinson, Dorothy J Becker, David Baidal, Linda A DiMeglio, Stephen E Gitelman, Robin Goland, Peter A Gottlieb, Kevan C Herold, Jennifer B Marks, Antoinette Moran, Henry Rodriguez, William Russell, Darrell M WilsonCarla J Greenbaum, Polly Bingley

Research output: Contribution to journal › Article (Academic Journal) › peer-review

Abstract

OBJECTIVE: A pilot study suggested that combination therapy with low-dose anti-thymocyte globulin (ATG) and pegylated granulocyte colony-stimulating factor (GCSF) preserves C-peptide in established type 1 diabetes (T1D) (duration 4 months to 2 years). We hypothesized that 1) low-dose ATG/GCSF or 2) low-dose ATG alone would slow the decline of β-cell function in patients with new-onset T1D (duration <100 days).

RESEARCH DESIGN AND METHODS: A three-arm, randomized, double-masked, placebo-controlled trial was performed by the Type 1 Diabetes TrialNet Study Group in 89 subjects: 29 subjects randomized to ATG (2.5 mg/kg intravenously) followed by pegylated GCSF (6 mg subcutaneously every 2 weeks for 6 doses), 29 to ATG alone (2.5 mg/kg), and 31 to placebo. The primary end point was mean area under the curve (AUC) C-peptide during a 2-h mixed-meal tolerance test 1 year after initiation of therapy. Significance was defined as one-sided P value < 0.025.

RESULTS: The 1-year mean AUC C-peptide was significantly higher in subjects treated with ATG (0.646 nmol/L) versus placebo (0.406 nmol/L) (P = 0.0003) but not in those treated with ATG/GCSF (0.528 nmol/L) versus placebo (P = 0.031). HbA1c was significantly reduced at 1 year in subjects treated with ATG and ATG/GCSF, P = 0.002 and 0.011, respectively.

CONCLUSIONS: Low-dose ATG slowed decline of C-peptide and reduced HbA1c in new-onset T1D. Addition of GCSF did not enhance C-peptide preservation afforded by low-dose ATG. Future studies should be considered to determine whether low-dose ATG alone or in combination with other agents may prevent or delay the onset of the disease.

Original language	English
Pages (from-to)	1917-1925
Number of pages	9
Journal	Diabetes Care
Volume	41
Issue number	9
DOIs	https://doi.org/10.2337/dc18-0494
Publication status	Published - 1 Sep 2018

Bibliographical note

Keywords

Adolescent
Adult
Antilymphocyte Serum/administration & dosage
C-Peptide/blood
Child
Cytoprotection/drug effects
Diabetes Mellitus, Type 1/drug therapy
Dose-Response Relationship, Drug
Double-Blind Method
Drug Therapy, Combination
Female
Glycated Hemoglobin A/drug effects
Granulocyte Colony-Stimulating Factor/administration & dosage
Humans
Insulin-Secreting Cells/drug effects
Male
Pilot Projects
Polyethylene Glycols/administration & dosage
Recombinant Proteins/administration & dosage
Young Adult

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Type 1 Diabetes TrialNet ATG-GCSF Study Group, Haller, M. J., Schatz, D. A., Skyler, J. S., Krischer, J. P., Bundy, B. N., Miller, J. L., Atkinson, M. A., Becker, D. J., Baidal, D., DiMeglio, L. A., Gitelman, S. E., Goland, R., Gottlieb, P. A., Herold, K. C., Marks, J. B., Moran, A., Rodriguez, H., Russell, W., ... Bingley, P. (2018). Low-Dose Anti-Thymocyte Globulin (ATG) Preserves β-Cell Function and Improves HbA1c in New-Onset Type 1 Diabetes. Diabetes Care, 41(9), 1917-1925. https://doi.org/10.2337/dc18-0494

Type 1 Diabetes TrialNet ATG-GCSF Study Group ; Haller, Michael J ; Schatz, Desmond A ; Skyler, Jay S ; Krischer, Jeffrey P ; Bundy, Brian N ; Miller, Jessica L ; Atkinson, Mark A ; Becker, Dorothy J ; Baidal, David ; DiMeglio, Linda A ; Gitelman, Stephen E ; Goland, Robin ; Gottlieb, Peter A ; Herold, Kevan C ; Marks, Jennifer B ; Moran, Antoinette ; Rodriguez, Henry ; Russell, William ; Wilson, Darrell M ; Greenbaum, Carla J ; Bingley, Polly. / Low-Dose Anti-Thymocyte Globulin (ATG) Preserves β-Cell Function and Improves HbA1c in New-Onset Type 1 Diabetes. In: Diabetes Care. 2018 ; Vol. 41, No. 9. pp. 1917-1925.

@article{22951613a22e4c22bde5ef6d0c599603,

title = "Low-Dose Anti-Thymocyte Globulin (ATG) Preserves β-Cell Function and Improves HbA1c in New-Onset Type 1 Diabetes",

abstract = "OBJECTIVE: A pilot study suggested that combination therapy with low-dose anti-thymocyte globulin (ATG) and pegylated granulocyte colony-stimulating factor (GCSF) preserves C-peptide in established type 1 diabetes (T1D) (duration 4 months to 2 years). We hypothesized that 1) low-dose ATG/GCSF or 2) low-dose ATG alone would slow the decline of β-cell function in patients with new-onset T1D (duration <100 days).RESEARCH DESIGN AND METHODS: A three-arm, randomized, double-masked, placebo-controlled trial was performed by the Type 1 Diabetes TrialNet Study Group in 89 subjects: 29 subjects randomized to ATG (2.5 mg/kg intravenously) followed by pegylated GCSF (6 mg subcutaneously every 2 weeks for 6 doses), 29 to ATG alone (2.5 mg/kg), and 31 to placebo. The primary end point was mean area under the curve (AUC) C-peptide during a 2-h mixed-meal tolerance test 1 year after initiation of therapy. Significance was defined as one-sided P value < 0.025.RESULTS: The 1-year mean AUC C-peptide was significantly higher in subjects treated with ATG (0.646 nmol/L) versus placebo (0.406 nmol/L) (P = 0.0003) but not in those treated with ATG/GCSF (0.528 nmol/L) versus placebo (P = 0.031). HbA1c was significantly reduced at 1 year in subjects treated with ATG and ATG/GCSF, P = 0.002 and 0.011, respectively.CONCLUSIONS: Low-dose ATG slowed decline of C-peptide and reduced HbA1c in new-onset T1D. Addition of GCSF did not enhance C-peptide preservation afforded by low-dose ATG. Future studies should be considered to determine whether low-dose ATG alone or in combination with other agents may prevent or delay the onset of the disease.",

keywords = "Adolescent, Adult, Antilymphocyte Serum/administration & dosage, C-Peptide/blood, Child, Cytoprotection/drug effects, Diabetes Mellitus, Type 1/drug therapy, Dose-Response Relationship, Drug, Double-Blind Method, Drug Therapy, Combination, Female, Glycated Hemoglobin A/drug effects, Granulocyte Colony-Stimulating Factor/administration & dosage, Humans, Insulin-Secreting Cells/drug effects, Male, Pilot Projects, Polyethylene Glycols/administration & dosage, Recombinant Proteins/administration & dosage, Young Adult",

author = "{Type 1 Diabetes TrialNet ATG-GCSF Study Group} and Haller, {Michael J} and Schatz, {Desmond A} and Skyler, {Jay S} and Krischer, {Jeffrey P} and Bundy, {Brian N} and Miller, {Jessica L} and Atkinson, {Mark A} and Becker, {Dorothy J} and David Baidal and DiMeglio, {Linda A} and Gitelman, {Stephen E} and Robin Goland and Gottlieb, {Peter A} and Herold, {Kevan C} and Marks, {Jennifer B} and Antoinette Moran and Henry Rodriguez and William Russell and Wilson, {Darrell M} and Greenbaum, {Carla J} and Polly Bingley",

note = "{\textcopyright} 2018 by the American Diabetes Association.",

year = "2018",

month = sep,

day = "1",

doi = "10.2337/dc18-0494",

language = "English",

volume = "41",

pages = "1917--1925",

journal = "Diabetes Care",

issn = "0149-5992",

publisher = "American Diabetes Association Inc.",

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Type 1 Diabetes TrialNet ATG-GCSF Study Group, Haller, MJ, Schatz, DA, Skyler, JS, Krischer, JP, Bundy, BN, Miller, JL, Atkinson, MA, Becker, DJ, Baidal, D, DiMeglio, LA, Gitelman, SE, Goland, R, Gottlieb, PA, Herold, KC, Marks, JB, Moran, A, Rodriguez, H, Russell, W, Wilson, DM, Greenbaum, CJ & Bingley, P 2018, 'Low-Dose Anti-Thymocyte Globulin (ATG) Preserves β-Cell Function and Improves HbA1c in New-Onset Type 1 Diabetes', Diabetes Care, vol. 41, no. 9, pp. 1917-1925. https://doi.org/10.2337/dc18-0494

Low-Dose Anti-Thymocyte Globulin (ATG) Preserves β-Cell Function and Improves HbA1c in New-Onset Type 1 Diabetes. / Type 1 Diabetes TrialNet ATG-GCSF Study Group; Haller, Michael J; Schatz, Desmond A; Skyler, Jay S; Krischer, Jeffrey P; Bundy, Brian N; Miller, Jessica L; Atkinson, Mark A; Becker, Dorothy J; Baidal, David; DiMeglio, Linda A; Gitelman, Stephen E; Goland, Robin; Gottlieb, Peter A; Herold, Kevan C; Marks, Jennifer B; Moran, Antoinette; Rodriguez, Henry; Russell, William; Wilson, Darrell M; Greenbaum, Carla J; Bingley, Polly.

In: Diabetes Care, Vol. 41, No. 9, 01.09.2018, p. 1917-1925.

Research output: Contribution to journal › Article (Academic Journal) › peer-review

TY - JOUR

T1 - Low-Dose Anti-Thymocyte Globulin (ATG) Preserves β-Cell Function and Improves HbA1c in New-Onset Type 1 Diabetes

AU - Type 1 Diabetes TrialNet ATG-GCSF Study Group

AU - Haller, Michael J

AU - Schatz, Desmond A

AU - Skyler, Jay S

AU - Krischer, Jeffrey P

AU - Bundy, Brian N

AU - Miller, Jessica L

AU - Atkinson, Mark A

AU - Becker, Dorothy J

AU - Baidal, David

AU - DiMeglio, Linda A

AU - Gitelman, Stephen E

AU - Goland, Robin

AU - Gottlieb, Peter A

AU - Herold, Kevan C

AU - Marks, Jennifer B

AU - Moran, Antoinette

AU - Rodriguez, Henry

AU - Russell, William

AU - Wilson, Darrell M

AU - Greenbaum, Carla J

AU - Bingley, Polly

PY - 2018/9/1

Y1 - 2018/9/1

N2 - OBJECTIVE: A pilot study suggested that combination therapy with low-dose anti-thymocyte globulin (ATG) and pegylated granulocyte colony-stimulating factor (GCSF) preserves C-peptide in established type 1 diabetes (T1D) (duration 4 months to 2 years). We hypothesized that 1) low-dose ATG/GCSF or 2) low-dose ATG alone would slow the decline of β-cell function in patients with new-onset T1D (duration <100 days).RESEARCH DESIGN AND METHODS: A three-arm, randomized, double-masked, placebo-controlled trial was performed by the Type 1 Diabetes TrialNet Study Group in 89 subjects: 29 subjects randomized to ATG (2.5 mg/kg intravenously) followed by pegylated GCSF (6 mg subcutaneously every 2 weeks for 6 doses), 29 to ATG alone (2.5 mg/kg), and 31 to placebo. The primary end point was mean area under the curve (AUC) C-peptide during a 2-h mixed-meal tolerance test 1 year after initiation of therapy. Significance was defined as one-sided P value < 0.025.RESULTS: The 1-year mean AUC C-peptide was significantly higher in subjects treated with ATG (0.646 nmol/L) versus placebo (0.406 nmol/L) (P = 0.0003) but not in those treated with ATG/GCSF (0.528 nmol/L) versus placebo (P = 0.031). HbA1c was significantly reduced at 1 year in subjects treated with ATG and ATG/GCSF, P = 0.002 and 0.011, respectively.CONCLUSIONS: Low-dose ATG slowed decline of C-peptide and reduced HbA1c in new-onset T1D. Addition of GCSF did not enhance C-peptide preservation afforded by low-dose ATG. Future studies should be considered to determine whether low-dose ATG alone or in combination with other agents may prevent or delay the onset of the disease.

AB - OBJECTIVE: A pilot study suggested that combination therapy with low-dose anti-thymocyte globulin (ATG) and pegylated granulocyte colony-stimulating factor (GCSF) preserves C-peptide in established type 1 diabetes (T1D) (duration 4 months to 2 years). We hypothesized that 1) low-dose ATG/GCSF or 2) low-dose ATG alone would slow the decline of β-cell function in patients with new-onset T1D (duration <100 days).RESEARCH DESIGN AND METHODS: A three-arm, randomized, double-masked, placebo-controlled trial was performed by the Type 1 Diabetes TrialNet Study Group in 89 subjects: 29 subjects randomized to ATG (2.5 mg/kg intravenously) followed by pegylated GCSF (6 mg subcutaneously every 2 weeks for 6 doses), 29 to ATG alone (2.5 mg/kg), and 31 to placebo. The primary end point was mean area under the curve (AUC) C-peptide during a 2-h mixed-meal tolerance test 1 year after initiation of therapy. Significance was defined as one-sided P value < 0.025.RESULTS: The 1-year mean AUC C-peptide was significantly higher in subjects treated with ATG (0.646 nmol/L) versus placebo (0.406 nmol/L) (P = 0.0003) but not in those treated with ATG/GCSF (0.528 nmol/L) versus placebo (P = 0.031). HbA1c was significantly reduced at 1 year in subjects treated with ATG and ATG/GCSF, P = 0.002 and 0.011, respectively.CONCLUSIONS: Low-dose ATG slowed decline of C-peptide and reduced HbA1c in new-onset T1D. Addition of GCSF did not enhance C-peptide preservation afforded by low-dose ATG. Future studies should be considered to determine whether low-dose ATG alone or in combination with other agents may prevent or delay the onset of the disease.

KW - Adolescent

KW - Adult

KW - Antilymphocyte Serum/administration & dosage

KW - C-Peptide/blood

KW - Child

KW - Cytoprotection/drug effects

KW - Diabetes Mellitus, Type 1/drug therapy

KW - Dose-Response Relationship, Drug

KW - Double-Blind Method

KW - Drug Therapy, Combination

KW - Female

KW - Glycated Hemoglobin A/drug effects

KW - Granulocyte Colony-Stimulating Factor/administration & dosage

KW - Humans

KW - Insulin-Secreting Cells/drug effects

KW - Male

KW - Pilot Projects

KW - Polyethylene Glycols/administration & dosage

KW - Recombinant Proteins/administration & dosage

KW - Young Adult

U2 - 10.2337/dc18-0494

DO - 10.2337/dc18-0494

M3 - Article (Academic Journal)

C2 - 30012675

VL - 41

SP - 1917

EP - 1925

JO - Diabetes Care

JF - Diabetes Care

SN - 0149-5992

IS - 9

ER -