Trial shortcomings make GABA benefits unclear in early type 1 diabetes
medwireNews: The limitations of a clinical trial of gamma aminobutyric acid (GABA) on the progression of newly diagnosed type 1 diabetes may have precluded any positive results, say the researchers.
Reporting the largely negative findings at the 55th EASD Annual Meeting in Barcelona, Spain, researcher Kenneth McCormick (University of Alabama at Birmingham, USA) listed multiple limitations, key of which was that the US FDA mandated a maximum twice-daily dose of 1 g/m2 per day, to a maximum of 1.5 g/day.
McCormick said this dose was very low compared with those used in preclinical studies, which he noted had mostly significant results. He suggested that the dose used lies on the lower threshold of efficacy, explaining why the researchers saw trends toward a positive effect on some outcomes. He added that GABA is freely available to purchase and has an excellent safety profile.
The primary endpoint of C-peptide response to a mixed meal tolerance test was negative, with no difference seen at 1 year between 39 study participants randomly assigned to receive GABA, 22 who received GABA plus glutamic acid decarboxylase ( GAD; which catalyzes the conversion of glutamate to GABA), and 30 given placebo.
The study participants were between 4 and 18 years old (around 11 years on average) and had been diagnosed with type 1 diabetes within the preceding 5 weeks.
Another limitation McCormick noted was that GABA has a relatively short half-life, suggesting that it may need to be administered thrice daily for the best effect. But medication adherence was an issue even at the twice-daily dose, and “especially daunting insofar as approximately 35% of the patients were teenagers,” he said.
Also confounding the treatment effect was the “fairly unique” placebo group, said the presenter, noting that the group had “remarkably high” baseline C-peptide levels and that the C-peptide response remained high or actually improved over time in seven children in this group.
There were no differences between the groups in glycated hemoglobin levels, but there was a trend toward a lower insulin dose needed at 12 months for the GABA plus GAD group versus the placebo group.
However, significant treatment differences did emerge for glucagon, with fasting and post-prandial levels both significantly lower in the GABA plus GAD group than in the placebo group by the end of the study and lower or verging on it in the GABA-only group. Normally there is a progressive increase in fasting and post-prandial glucagon levels during the first year after diabetes diagnosis, as was indeed observed for the placebo group, McCormick explained.
Stressing the “insufferable” limitations of the trial, he concluded that larger studies using a higher, thrice-daily dose are warranted.
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