Intralymphatic Glutamic Acid Decarboxylase With Vitamin D Supplementation in Recent-Onset Type 1 Diabetes: A Double-Blind, Randomized, Placebo-Controlled Phase IIb Trial
Open accessAbstract
OBJECTIVE: To evaluate the efficacy of aluminum-formulated intralymphatic glutamic acid decarboxylase (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.
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GAD65-based therapies delivered via subcutaneous or intralymphatic administration have been tested in multiple clinical trials; overall efficacy in preserving insulin secretion was not shown.
“GAD₆₅based therapies delivered via subcutaneous or intralymphatic administration have been tested in multiple clinical trials.[24][25][26] Overall efficacy in preserving insulin secretion was not shown.”
From The future of type 1 diabetes therapy (2025) · cites this paper as [26]
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- Authors
- Ludvigsson, J., Sumnik, Z., Pelikanova, T., Nattero Chavez, L., Lundberg, E., Rica, I., Martínez-Brocca, M. A., Ruiz de Adana, M., Wahlberg, J., Katsarou, A., Hanas, R., Hernandez, C., Clemente León, M., Gómez-Gila, A., Lind, M., Lozano, M. F., Sas, T., Samuelsson, U., Pruhova, S., Dietrich, F., Puente Marin, S., Nordlund, A., Hannelius, U., & Casas, R.
- Affiliations
- Linköping University (SE)
- Department of Pediatrics, 2nd Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic
- Diabetes Centre of the Institute of Clinical and Experimental Medicine, Prague, Czech Republic
- Department of Endocrinology and Nutrition, Hospital Universitario Ramón y Cajal, Madrid, Spain
- University Hospital of Umeå (SE)
- Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas (ES)
- Department of Endocrinology, Virgen Macarena Hospital, Sevilla, Spain
- Department of Adult Endocrinology and Diabetology, General University Hospital, Instituto de Biomedicina de Málaga, CIBERDEM, Malaga, Spain
- Skåne University Hospital (SE)
- Department of Pediatrics, NU Hospital Group, Uddevalla, Sweden
- Department of Endocrinology and Nutrition, Vall d’Hebron Hospital, CIBERDEM, Barcelona, Spain
- Hospital Universitario Virgen del Rocío (ES)
- Uddevalla sjukhus (SE)
- Hospital Universitario Miguel Servet (ES)
- Erasmus MC (NL)
- Division of Pediatrics, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden
- Trial Form Support, Lund, Sweden
- Mertiva (Sweden) (SE)
- Corresponding author
- Ludvigsson, Johnny
- ORCID
- Venue
- Diabetes Care
- Publisher
- American Diabetes Association
- Published
- 2021-05-21
- Volume
- 44
- Issue
- 7
- Pages
- 1604-1612
- ISSN
- 0149-5992 (ISSN-L)
- 1935-5548
- PMC
- PMC8323180
- OpenAlex
- W3163253720
- Cited by
- 58
- References
- 37
- Citations by year
- 2026: 4 · 2025: 11 · 2024: 12 · 2023: 17 · 2022: 13 · 2021: 1
- FWCI
- 6.08
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Diabetes Care (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
- RISalud Institutional Health Repository of Andalucía (submittedVersion, other-oa)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- Funders
- Barndiabetesfonden
- Diabetesfonden
- Faculty of Medicine and Health, University of Sydney
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Keywords
- type 1 diabetes, recent-onset type 1 diabetes, intralymphatic injection, glutamic acid decarboxylase, alum adjuvant, vitamin D supplementation, insulin secretion, HLA-DR3-DQ2, HLA-DRB1*03, disease-modifying therapy
- MeSH terms
- C-Peptide, Diabetes Mellitus, Type 1, Double-Blind Method, Glutamate Decarboxylase, Humans, Vitamin D, Dietary Supplements
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