Intralymphatic glutamic acid decarboxylase with vitamin d supplementation in recent-onset type 1 diabetes: A double-blind, randomized, placebo-controlled phase iib trial

Johnny Ludvigsson*, Zdenek Sumnik, Terezie Pelikanova, Lia Nattero Chavez, Elena Lundberg, Itxaso Rica, Maria A. Martínez-Brocca, Marisol Ruiz de Adana, Jeanette Wahlberg, Anastasia Katsarou, Ragnar Hanas, Cristina Hernandez, Maria Clemente León, Ana Gómez-Gila, Marcus Lind, Marta Ferrer Lozano, Theo Sas, Ulf Samuelsson, Stepanka Pruhova, Fabricia DietrichSara Puente Marin, Anders Nordlund, Ulf Hannelius, Rosaura Casas

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

31 Citations (Scopus)

Abstract

OBJECTIVE To evaluate the efficacy of aluminum-formulated intralymphatic glutamic acid de-carboxylase (GAD-alum) therapy combined with vitamin D supplementation in preserving endogenous insulin secretion in all patients with type 1 diabetes (T1D) or in a genetically prespecified subgroup. RESEARCH DESIGN AND METHODS In a multicenter, randomized, placebo-controlled, double-blind trial, 109 patients aged 12–24 years (mean ± SD 16.4 ± 4.1) with a diabetes duration of 7–193 days (88.8 ± 51.4), elevated serum GAD65 autoantibodies, and a fasting serum C-peptide >0.12 nmol/L were recruited. Participants were randomized to receive either three intralymphatic injections (1 month apart) with 4 μg GAD-alum and oral vitamin D (2,000 IE daily for 120 days) or placebo. The primary outcome was the change in stimulated serum C-peptide (mean area under the curve [AUC] after a mixed-meal tolerance test) between baseline and 15 months. RESULTS Primary end point was not met in the full analysis set (treatment effect ratio 1.091 [CI 0.845–1.408]; P = 0.5009). However, GAD-alum–treated patients carrying HLA DR3-DQ2 (n = 29; defined as DRB1*03, DQB1*02:01) showed greater preservation of C-peptide AUC (treatment effect ratio 1.557 [CI 1.126–2.153]; P = 0.0078) after 15 months compared with individuals receiving placebo with the same genotype (n = 17). Several secondary end points showed supporting trends, and a positive effect was seen in partial remission (insulin dose–adjusted HbA1c ≤9; P = 0.0310). Minor transient injection site reactions were reported. CONCLUSION Intralymphatic administration of GAD-alum is a simple, well-tolerated treatment that together with vitamin D supplementation seems to preserve C-peptide in patients with recent-onset T1D carrying HLA DR3-DQ2. This constitutes a disease-modifying treatment for T1D with a precision medicine approach.

Original languageEnglish
Pages (from-to)1604-1612
Number of pages9
JournalDiabetes Care
Volume44
Issue number7
DOIs
Publication statusPublished - 21 May 2021

Bibliographical note

Funding Information:
Acknowledgments. The authors thank all the participants who agreed to participate in the study. The authors are grateful to Dr. Joachim Davidsson (Department of Radiology, Linko€ping University Hospital, Linko€ping, Sweden) for skillful performance of the needle-guided lymph node injections and instructions to other centers. The authors also thank Isabel Leiva (Malaga, Spain) and all research nurses and physicians at the sites, as well as Ingela Johansson and Gosia Smolinska (Division of Pediatrics, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linko€ping University, Linko€ping, Sweden) for skillful laboratory work. Funding. This study was supported by Barn-diabetesfonden (Swedish Child Diabetes Foundation) and Diabetesfonden. Diamyd Medical provided GAD-alum, vitamin D, and matching placebos.

Publisher Copyright:
© 2021 by the American Diabetes Association.

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