Is There a Role for Short-Acting Exenatide in Type 1 Diabetes?

Short-acting exenatide administered 3 times daily with meals as an add-on to insulin treatment in patients with type 1 diabetes had no clinically relevant effects on glycemic control, postprandial glycemic excursions, or glycemic variability, according to study results published in The Lancet Diabetes & Endocrinology.

As short-acting glucagon-like peptide-1 receptor agonists can slow gastric emptying rate and lower postprandial glucose excursions in patients with type 2 diabetes, it has been suggested that these effects may also be beneficial in patients with type 1 diabetes.

MAG1C (Meal-time Administration of Exenatide for Glycaemic Control in Type 1 Diabetic Cases; ClinicalTrials.gov Identifier: NCT03017352) was a single-center, 26-week, phase 2a, double-group, parallel-group, randomized, double-blind, placebo-controlled clinical trial performed at Steno Diabetes Center Copenhagen in Gentofte, Denmark. Adult patients with hemoglobin A1c (HbA1c) levels between 7.5% and 10.0% and a body mass index >22.0 kg/m² were randomly assigned to preprandial subcutaneous injection of 10 µg exenatide or placebo 3 times daily for 26 weeks as an add-on treatment to insulin therapy. The primary outcome was the between-group difference in HbA1c at end of treatment at 26 weeks.

Of 654 patients assessed for eligibility, 108 patients were randomly assigned to exenatide (54 patients; 52 patients included in intention-to-treat analysis; mean age, 50.1 years; 75% men) or placebo (54 patients; 53 patients included in intention-to-treat analysis; mean age, 50.4 years; 70% men). With respect to baseline characteristics, the 2 groups were similar apart from small differences in body weight and body mass index. During the trial, 17 participants in the exenatide group and 6 in the placebo group discontinued treatment.

Exenatide did not improve glycemic control: assessment of the primary outcome revealed that from a baseline-adjusted mean of 8.2%, HbA1c changed by -0.3% (95% CI, -0.5 to -0.1) with exenatide and by -0.2% (95% CI, -0.3 to -0.1) with placebo after 26 weeks (estimated treatment difference, -0.1%; 95% CI, -0.3 to 0.1; P =.36). Exenatide resulted in the greatest HbA1c reductions vs placebo at week 12, with deterioration in this effect thereafter.

Exenatide lowered glycemic excursions after 4 weeks, but this effect also deteriorated over time, and no considerable effect was noted after 26 weeks. Exenatide did not affect measures of glycemic variability.

After 26 weeks, exenatide did not carry an increased risk for hypoglycemia. However, 4 weeks into the trial, exenatide caused a worsening in some hypoglycemic endpoints, but subsequent improvements were noted. There were 4 confirmed severe hypoglycemic episodes that required third-party assistance with exenatide treatment and 2 such events with placebo.

Exenatide reduced prandial insulin requirements equally for all main meals, resulting in reduced total insulin dose. Furthermore, exenatide lowered body weight, with mean body weight decreasing from 87.9 kg at baseline to 83.6 kg at 26 weeks for exenatide users vs no change in the body weight in the placebo group (estimated treatment difference, -4.4 kg; 95% CI, -5.4 to -3.3; P <.0001).

Gastrointestinal adverse events were more common in the exenatide group; the most common symptoms included nausea, decreased appetite, vomiting, and acid reflux or heartburn. In the exenatide group, there were 2 serious adverse events compared with 6 events in the placebo group; none was considered to be related to the study treatment.

The researchers noted that the study had several limitations, including limitations related to the study design and the eligibility criteria, large dropout rate with a small sample size, and possible selection bias.

“On the basis of these results, short-acting exenatide does not seem to have a future as a standard add-on treatment to insulin therapy in type 1 diabetes, but we cannot exclude the possibility that subgroups of patients with type 1 diabetes…might benefit from exenatide therapy—further studies are needed to investigate this possibility,” stated the researchers.

Disclosure: This clinical trial was supported by AstraZeneca, the producer of short-acting exenatide. Please see the original reference for a full list of authors’ disclosures.

Reference

Johansen NJ, Dejgaard TF, Lund A, et al. Efficacy and safety of meal-time administration of short-acting exenatide for glycaemic control in type 1 diabetes (MAG1C): a randomised, double-blind, placebo-controlled trial [published online March 2, 2020]. Lancet Diabetes Endocrinol. doi:10.1016/S2213-8587(20)30043-7