Short-acting exenatide fails to benefit glucose profile in type 1 diabetes
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Adults with type 1 diabetes on multiple daily injection therapy saw no benefit in glycemic measures when adding on preprandial injections of short-acting exenatide, according to findings from a phase 2a study published in The Lancet Diabetes & Endocrinology.
“In a 26-week study investigating the efficacy and safety of short-acting exenatide administered three times daily with main meals as an add-on to standard insulin therapy in dysregulated patients with type 1 diabetes, we did not show improved HbA1c, but observed reduced body weight and insulin requirements compared with placebo without increasing the risk of hypoglycemia,” Filip K. Knop, MD, PhD, director of the Center for Clinical Metabolic Research at Gentofte Hospital, University of Copenhagen, Hellerup, Denmark, told Healio. “In order to unravel the potential of short-acting exenatide in the management of type 1 diabetes, investigations encompassing a primary endpoint not only focusing on HbA1c are needed.”
In the MAG1C study, Knop and colleagues analyzed data from 108 white adults with type 1 diabetes, an HbA1c of at least 7.5% and a BMI of at least 22 kg/m² who were using multiple injection therapy (mean age, 50 years; mean baseline HbA1c, 8.2%). Between January 2017 and January 2019, researchers assigned participants a preprandial short-acting injection of 10 µg exenatide (Byetta, AstraZeneca; n = 52; 25% women) or placebo (n = 53; 30% women) three times daily for 26 weeks as an add-on to insulin therapy, with titration assessed by clinic staff. Primary endpoint was between-group difference in HbA1c after 26 weeks, analyzed with a linear mixed model in the intention-to-treat population.
No benefit observed
Within the cohort, 17 participants in the exenatide arm and six participants in the placebo arm discontinued treatment.
Researchers found that participants in the short-acting exenatide group experienced a mean –0.3% decrease in HbA1c during 26 weeks of treatment compared with a mean –0.2% HbA1c decrease among those assigned placebo, for an estimated treatment difference of –0.1% (95% CI, –0.3 to 0.1).
“Exenatide resulted in the greatest HbA1c reductions vs. placebo at week 12 with following deterioration,” the researchers wrote.
In an analysis of self-monitored blood glucose profiles, researchers found that exenatide “substantially reduced” all measures of postprandial glycemic excursions after 4 weeks compared with placebo; however, the between-group differences waned over time, with no relevant difference at 26 weeks. Time-in-range glycemia and time in hyperglycemia were unchanged from baseline levels at 26 weeks, and researchers observed no differences for glycemic variability measures.
More participants in the exenatide group reported gastrointestinal adverse events compared with placebo, with the most common being nausea (37 vs. 9). The researchers observed two serious adverse events in the exenatide group and six in the placebo group; none were considered to be related to the study drug.
“Despite the fact that our findings do not support the use of short-acting exenatide as a standard add-on treatment to insulin therapy in type 1 diabetes, they clearly show that short-acting GLP-1 receptor agonist treatment — most likely via its decelerating effect on gastric emptying — reduces insulin requirements in these patients,” Knop said. “Furthermore, short-acting exenatide exerts a body weight-lowering effect, which is helpful for the majority of patients with type 1 diabetes. Thus, we cannot exclude the possibility that subgroups of patients with type 1 diabetes, such as those with overweight or obesity and severe postprandial hyperglycemia requiring high prandial insulin doses, might benefit from short-acting exenatide. Further studies are needed to investigate this possibility.”
A ‘delicate balance’
In commentary accompanying the study, Michael A. Nauck, MD, head of clinical research at Diabetes Center Bochum-Hattingen at St. Josef-Hospital of the Ruhr-University of Bochum (RUB), Germany, and Juris J. Meier, MD, professor of medicine and head of the division of diabetology and GI endocrinology at St. Josef-Hospital of the Ruhr-University of Bochum, wrote that the findings contrast with the effects of adding GLP-1 receptor agonists to basal insulin therapy for people with type 2 diabetes.
“Overall, all added medications (in the case of MAG1C, a GLP-1 receptor agonist) will reduce glycemia, whereas the compensatory dose reduction in (prandial) insulin will rather support (transient) rises in plasma glucose concentrations,” Nauck and Meier wrote. “The delicate balance between both effects might explain the overall minor effects on glycemia (HbA1c) seen with adjunct glucose-lowering medications, including GLP-1 receptor agonists, added to insulin regimens in patients with type 1 diabetes.” – by Regina Schaffer
For more information:
Filip K. Knop, MD, PhD, can be reached at the Center for Clinical Metabolic Research, Gentofte Hospital, Svei 7, Third Floor, DK-2900, Hellerup, Denmark; email: filip.krag.knop.01@region.dk; Twitter: @KnopFilip.
Disclosures: AstraZeneca funded this study and representatives were allowed to read and comment on the draft report before submission. Knop reports he has received research support, speaking and consultant fees and served on scientific advisory panels for AstraZeneca. Meier reports he has received research support, consultant and speaking fees from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Merck, Novartis, Novo Nordisk and Sanofi. Nauck reports he has researched grant support, speaking fees and served on advisory boards for AstraZeneca, Boehringer Ingelheim, Eli Lilly, Fractyl, GlaxoSmithKline, Menarini-Berlin Chemie, Merck, Novartis and Novo Nordisk. Please see the study for all other authors’ relevant financial disclosures.
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