Editor: David L. Joffe, BSPharm, CDE, FACA
Author: Mit Suthar, PharmD. Candidate, LECOM School of Pharmacy
The MAG1C interventional study was a single-center, 26-week, phase 2a, to look at how Exenatide might benefit patients with type 1 diabetes.
A study called MAG1C (Meal-time Administration of Exenatide for Glycaemic Control in Type 1 Diabetic Cases; ClinicalTrials.gov Identifier: NCT03017352) which recently published results in The Lancet Diabetes & Endocrinology found that short-acting Exenatide administered three times a day along with meals as an add-on to insulin is not a viable addition to therapy for patients with type 1 diabetes.
Exenatide, a short-acting glucagon-like peptide-1 receptor agonist, can slow the gastric emptying rate and lower glucose excursions in patients with type 2 diabetes. It was postulated that perhaps these effects could also be beneficial in patients with type 1 diabetes.
The MAG1C interventional study 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. The investigators hypothesized that the add-on of Exenatide to insulin therapy in patients with type 1 diabetes would reduce insulin requirements, reduce glycemic excursions, reduce body weight, and improve glycemic control without increasing the risk of hypoglycemia. The study’s primary outcome was the between-group difference in HbA1c at the end of the 26-week treatment.
The patients included in the trial had to meet the following eligibility criteria:
T1D according to WHO criteria with a duration of ≥1 year, Age ≥18 years, BMI >22.0 kg/m2, HbA1c >7.5%, and <10.0% at visit 0 (screening), and Able to count carbohydrates. These patients were randomly assigned to a preprandial subcutaneous injection of 10 µg Exenatide or placebo three times daily for 26 weeks as an add-on treatment to insulin therapy.
Six hundred fifty-four patients were assessed for eligibility, but only 108 patients were enrolled. These 108 patients were randomly assigned to Exenatide (54 patients; 52 patients included in the intention-to-treat analysis; mean age, 50.1 years; 75% men) or placebo (54 patients; 53 patients included in the intention-to-treat analysis; mean age, 50.4 years; 70% men). The two groups had very similar baseline characteristics, with only minor differences in body weight and body mass index. During the trial, 17 participants in the Exenatide group discontinued treatment, and six patients in the placebo group discontinued treatment.
The treatment with Exenatide was not shown to improve glycemic control. The primary outcome assessed uncovered a reduction in HbA1c of -0.3% (95% CI, -0.5 to -0.1) from a baseline-adjusted mean of 8.2% with Exenatide. A reduction in HbA1c of -0.2% (95% CI, -0.3 to -0.1) was seen with the placebo, however; thus the estimated treatment difference was merely -0.1% (95% CI, -0.3 to 0.1; P =0.36).
Exenatide displayed the most significant HbA1c reductions vs. placebo during week 12. However, this beneficial effect was seen to decline during subsequent weeks.
Exenatide lowered glycemic excursions after four weeks, but this benefit also declined over time, and no significant effects were recorded after the completion of the 26-week trial. Exenatide also did not affect measures of glycemic variability.
Previously analyses involving Liraglutide found modest reductions in HbA1c at around -0.29% when compared to placebo, though these results were statistically significant. It was also theorized that hypoglycemic risk would be minimized in T1DM with the use of GLP-1 agonists. Unfortunately, we should note that the adverse effect of nausea associated with Liraglutide also made it an unpopular option for such a small reduction of A1c.
It was found that Exenatide, however, at four weeks into the trial, did increase the risk for hypoglycemia, though subsequent improvements were noted, and ultimately after 26 weeks, Exenatide was not shown to carry an increased risk for hypoglycemia. During the trial, four significant hypoglycemic episodes occurred that required third-party assistance, in the group that was treated with Exenatide. 2 hypoglycemic events occurred in the group treated with placebo.
As with the other study involving Liraglutide, gastrointestinal events were frequent in the Exenatide group. The most common symptoms experienced were nausea, decreased appetite, vomiting, and acid reflux, or heartburn.
Exenatide decreased the prandial insulin requirements equally for all main meals, which resulted in a reduced total insulin dose. Additionally, Exenatide reduced the bodyweight of participants, 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).
There was a total of 8 serious adverse events, with two events from the Exenatide group and six from the placebo group, which suggested that these events were not related to the study treatment.
There were numerous limitations to the study noted by the researchers themselves: limitations related to the study design and the eligibility criteria, tremendous dropout rate with small sample size, and possible selection bias.
The researchers found that short-acting Exenatide had no clinically relevant effects on glycemic control, postprandial glycemic excursions, or glycemic variability. The researchers admitted that Exenatide is an unlikely future add-on therapy:
“Based on 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.“
Practice Pearls:
- In the MAG1C interventional study, researchers investigated whether the benefits that GLP-1 agonists provided to patients with T2DM could be useful to patients with T1DM.
- Exenatide did not carry an increased risk for hypoglycemia after 26 weeks.
- Exenatide as an add-on to insulin therapy in patients with T1DM is an unlikely prospect as the study found no clinically relevant effects on glycemic control, postprandial glycemic excursions, or glycemic variability.
Akirov, Amit. “Is There a Role for Short-Acting Exenatide in Type 1 Diabetes?” Endocrinology Advisor, The Lancet Diabetes & Endocrinology, 11 Mar. 2020, www.endocrinologyadvisor.com/home/topics/diabetes/type-1-diabetes/short-acting-exenatide-unlikely-to-be-useful-in-type-1-diabetes/.
Mit Suthar, PharmD. Candidate, LECOM School of Pharmacy
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