Recombinant human glutamic acid decarboxylase may preserve C-peptide in type 1 diabetes
Recombinant human glutamic acid decarboxylase formulated with aluminum hydroxide may preserve C-peptide and improve HbA1c for people with type 1 diabetes carrying a specific genotype, according to findings from a meta-analysis.
“The correlation between 15-month effects on C-peptide and HbA1c suggests that therapeutically preserved C-peptide in recent-onset type 1 diabetes might improve glycemic control — likely at least for antigen-specific immunotherapies, as immunomodulatory drugs with consistent C-peptide effects have not shown convincing effects on HbA1c,” Johnny Ludvigsson, MD, PhD, professor emeritus in the division of pediatrics, department of biomedical and clinical sciences, at Crown Princess Victoria Children’s Hospital and Linköping University in Sweden, and colleagues wrote. “Whether this discrepancy is due to disease heterogeneity requiring subgroup-targeted approaches as for glutamic acid decarboxylase in alum or because HbA1c is affected by complex factors remains open.”
Researchers conducted a meta-analysis of four phase 2 and phase 3 randomized controlled trials in which 627 people with recent-onset type 1 diabetes received subcutaneous or intralymphatic glutamic acid decarboxylase (GAD65) in alum or placebo. Participants were classified according to whether they carried HLA DR3-DQ2 and whether they received placebo, two injections or three to four injections. Mixed-meal tolerance tests were conducted to measure meal-stimulated C-peptide. Mean HbA1c changes from baseline were analyzed using a restricted maximum likelihood-based repeated measures approach that was adjusted for the fixed effects of baseline C-peptide, treatment, HLA DR3-DQ2 subgroup, visit, country, sex and age, as well as the interaction of baseline C-peptide by visit and treatment by HLA DR3-DQ2 subgroup.
The findings were published in Diabetes, Obesity and Metabolism.
Researchers observed a positive association on C-peptide and HbA1c for participants receiving three to four doses of GAD65. No association was found for those receiving two doses. Those who received three to four doses had a 40% preservation of C-peptide and a 2.4% reduction in HbA1c compared with placebo.
The associations among participants with HLA DR3-DQ2 were also significant with three to four doses, but not two doses. Sensitivity meta-analyses confirmed treatment benefits in people with HLA DR3-DQ2 receiving three or four doses of GAD65. In a separate analysis substituting HbA1c for the secondary endpoints of insulin dose-adjusted HbA1c and insulin dose, similar trends were observed.
“Preservation of C-peptide using GAD-alum correlates with effects on HbA1c in individuals with recent-onset type 1 diabetes carrying HLA DR3-DQ2,” the researchers wrote. “These findings will be evaluated in a confirmatory phase 3 trial and support using C-peptide as a clinically relevant surrogate endpoint for endogenous insulin production-preserving therapies.”