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GAD Treatment and Insulin Secretion in Recent-Onset Type 1 Diabetes.
Ludvigsson, Johnny M.D., Ph.D.; Faresjo, Maria Ph.D.; Hjorth, Maria M.Sc.; Axelsson, Stina M.Sc.; Cheramy, Mikael M.Sc.; Pihl, Mikael M.Sc.; Vaarala, Outi M.D., Ph.D.; Forsander, Gun M.D., Ph.D.; Ivarsson, Sten M.D., Ph.D.; Johansson, Calle M.D.; Lindh, Agne M.D.; Nilsson, Nils-Osten M.D.; Aman, Jan M.D., Ph.D.; Ortqvist, Eva M.D., Ph.D.; Zerhouni, Peter M.Sc.; Casas, Rosaura Ph.D.
[Article] New England Journal of Medicine. 359(18):1909-1920, October 30, 2008.

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Background: The 65-kD isoform of glutamic acid decarboxylase (GAD) is a major autoantigen in patients with type 1 diabetes mellitus. This trial assessed the ability of alum-formulated GAD (GAD-alum) to reverse recent-onset type 1 diabetes in patients 10 to 18 years of age.

Methods: We randomly assigned 70 patients with type 1 diabetes who had fasting C-peptide levels above 0.1 nmol per liter (0.3 ng per milliliter) and GAD autoantibodies, recruited within 18 months after receiving the diagnosis of diabetes, to receive subcutaneous injections of 20 [mu]g of GAD-alum (35 patients) or placebo (alum alone, 35 patients) on study days 1 and 30. At day 1 and months 3, 9, 15, 21, and 30, patients underwent a mixed-meal tolerance test to stimulate residual insulin secretion (measured as the C-peptide level). The effect of GAD-alum on the immune system was also studied.

Results: Insulin secretion gradually decreased in both study groups. The study treatment had no significant effect on change in fasting C-peptide level after 15 months (the primary end point). Fasting C-peptide levels declined from baseline levels significantly less over 30 months in the GAD-alum group than in the placebo group (-0.21 vs. -0.27 nmol per liter [-0.62 vs. -0.81 ng per milliliter], P=0.045), as did stimulated secretion measured as the area under the curve (-0.72 vs. -1.02 nmol per liter per 2 hours [-2.20 vs. -3.08 ng per milliliter per 2 hours], P=0.04). No protective effect was seen in patients treated 6 months or more after receiving the diagnosis. Adverse events appeared to be mild and similar in frequency between the two groups. The GAD-alum treatment induced a GAD-specific immune response.

Conclusions: GAD-alum may contribute to the preservation of residual insulin secretion in patients with recent-onset type 1 diabetes, although it did not change the insulin requirement. (ClinicalTrials.gov number, NCT00435981.)