Intralymphatic GAD-Alum (Diamyd®) Improves Glycemic Control in Type 1 Diabetes With HLA DR3-DQ2.

Cristina Hernandez, Johnny Ludvigsson, Rosaura Casas, Ulf Hannelius, Sara Puente-Marin, Fabricia Dietrich, Stepanka Pruhova, Theo Sas, Marta Ferrer Lozano, Ana Gómez-Gila, Maria Clemente-León, Christoph Nowak, Ragnar Hanas, Jeanette Wahlberg, MariSol Ruiz de Adana, Maria A Martínez-Brocca, Itxaso Rica, Elena Lundberg, Lía Nattero-Chavez, Terezie Pelikanova, Zdenek Sumnik, Marcus Lind

Journal: The Journal of clinical endocrinology and metabolism 2022;107(9):2644-2651

PMID: 35665810

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Abstract

AIMS

Residual beta cell function in type 1 diabetes (T1D) is associated with lower risk of complications. Autoantigen therapy with GAD-alum (Diamyd) given in 3 intralymphatic injections with oral vitamin D has shown promising results in persons with T1D carrying the human leukocyte antigen (HLA) DR3-DQ2 haplotype in the phase 2b trial DIAGNODE-2. We aimed to explore the efficacy of intralymphatic GAD-alum on blood glucose recorded by continuous glucose monitoring (CGM).

METHODS

DIAGNODE-2 (NCT03345004) was a multicenter, randomized, placebo-controlled, double-blind trial of 109 recent-onset T1D patients aged 12 to 24 years with GAD65 antibodies and fasting C-peptide > 0.12 nmol/L, which randomized patients to 3 intralymphatic injections of 4 μg GAD-alum and oral vitamin D, or placebo. We report results for exploratory endpoints assessed by 14-day CGM at months 0, 6, and 15. Treatment arms were compared by mixed-effects models for repeated measures adjusting for baseline values.

RESULTS

We included 98 patients with CGM recordings of sufficient quality (DR3-DQ2-positive patients: 27 GAD-alum-treated and 15 placebo-treated). In DR3-DQ2-positive patients, percent of time in range (TIR, 3.9-10 mmol/L) declined less between baseline and month 15 in GAD-alum-treated compared with placebo-treated patients (-5.1% and -16.7%, respectively; P = 0.0075), with reduced time > 13.9 mmol/L (P = 0.0036), and significant benefits on the glucose management indicator (P = 0.0025). No differences were detected for hypoglycemia. GAD-alum compared to placebo lowered the increase in glycemic variability (standard deviation) observed in both groups (P = 0.0219). Change in C-peptide was correlated with the change in TIR.

CONCLUSIONS

Intralymphatic GAD-alum improves glycemic control in recently diagnosed T1D patients carrying HLA DR3-DQ2.

Address: Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, 14183 Huddinge, Sweden.; Diamyd Medical AB, 11135 Stockholm, Sweden.; Department of Molecular and Clinical Medicine, University of Gothenburg, 41345 Gothenburg, Sweden, Sahlgrenska University Hospital, Gothenburg and NU-Hospital Group, S41553, Uddevalla, Sweden.; Department of Pediatrics, 2nd Faculty of Medicine, Charles University and Motol University Hospital, 15000 Prague, Czech Republic.; Diabetes Centre of the Institute of Clinical and Experimental Medicine, 14000 Prague, Czech Republic.; Department of Endocrinology and Nutrition, Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain.; Institution of Clinical Science, Department of Pediatrics, Umeå University, Norrland University Hospital, 93451 Umeå, Sweden.; Department of Pediatric Endocrinology, Cruces University Hospital, 48902 Bilbao, Ciberdem, Spain.; Department of Endocrinology, Virgen Macarena Hospital, Department of Endocrinology and Nutrition, Virgen Macarena University Hospital, 41009 Sevilla, Spain.; Diabetes Unit, Department of Endocrinology and Nutrition, Ibima, Ciberdem, General University Hospital, 29010 Malaga, Spain.; Department of Endocrinology in Linköping and Department of Health, Medicine and Caring Sciences, Linköping University, 58183 Linköping, Sweden.; Department of Internal Medicine, School of Health and Medical Sciences, Örebro University, 70281 Örebro, Sweden.; Department of Pediatrics, NU Hospital Group, 45153 Uddevalla, Sweden.; Department of Endocrinology and Nutrition, Vall d'Hebron Hospital, 08035 Barcelona, Ciberdem, Spain.; Department of Endocrinology, Pediatric Service, Vall d'Hebron Hospital, 08035 Barcelona, CibererSpain.; Pediatric Endocrinology Service, Virgen del Rocío University Hospital, 41013 Sevilla, Spain.; Department of Pediatric Endocrinology, Miguel Servet University Hospital, 50009 Zaragoza, Spain.; Diabeter, National Treatment and Research Center for Children, Adolescents and Young Adults with type 1 diabetes, and Department of Pediatric Endocrinology, Erasmus University Medical Center, 3015 Rotterdam, The Netherlands.; Division of Pediatrics, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, 58183 Linköping, Sweden.; Division of Pediatrics, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences and Crown Princess Victoria Children´s Hospital, Linköping University, 58183 Linköping, Sweden.

DOI: 10.1210/clinem/dgac343

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MeSH Terms: Adolescent, Alum Compounds, Blood Glucose, Blood Glucose Self-Monitoring, C-Peptide, Child, Diabetes Mellitus, Type 1, Glutamate Decarboxylase, Glycemic Control, HLA-DR3 Antigen, Humans, Vitamin D, Young Adult