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

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.

Keywords: C-peptide; Diamyd; GAD-alum; GAD65; HLA DR3-DQ2; HbA1c; antigen-specific immune therapy; continuous glucose monitoring; type 1 diabetes.

© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Figures

Figure 1.

DIAGNODE-2 study visit schedule.

Figure 2.

Mean percent of time during the 14-day CGM recording periods spent in different glycemic ranges (individuals with HLA DR3-DQ2).

Figure 3.

Change in percent of time in range (3.9-10 mmol/L) during the study. The left panel shows the MMRM-predicted change where the difference between groups in the HLA DR3-DQ2 population reached statistical significance at months 6 (P = 0.0072) and 15 (P = 0.0075). The right shows the original data. Error bars represent standard errors.

Figure 4.

Scatterplots showing the association between AUC0-120min C-peptide (raw values in nmol/L) on the x-axis and percent spent in time in range (upper), >13.9 mmol/L (middle), and < 3 mmol/L (lower panel) on the y-axis. A locally estimated scatterplot smoothing regression line with 95% confidence interval has been fitted. All patients with CGM data are included, regardless of treatment condition.

Figure 5.

Scatterplot showing the association between change in AUC0-120min C-peptide (ratio between values at month 15 divided by baseline values in nmol/L) on the x-axis and change in time in range (difference between screening visit and month 15 in percent). Simple linear regression lines have been fitted. The figure suggests a positive correlation between preservation of C-peptide and reduced decline in TIR during the study period.