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Semaglutide Shows Superiority Over Exenatide ER in Head-to-Head Trial

Jan 20, 2018

Battle between two GLP-1 receptor agonists proves semaglutide achieves favorable HbA1c levels, decreased mean body weight.

Recently FDA approved Novo Nordisk’s New Drug Application for semaglutide based on results from two phase 3 trials. One of those trials, SUSTAIN-3 trial, compared the efficacy and safety of two GLP-1 agonists semaglutide (Ozempic) and exenatide ER (Bydureon). GLP-1 receptor agonists, well-established second-line treatment option for patients with type 2 diabetes, work by enhancing the glucose-dependent secretion of insulin while reducing improper glucagon secretion. In addition, GLP-1 agonists slow gastric emptying, enticing the feeling of fullness longer and, therefore, lead to weight loss. Due to increased albumin binding and decreased potential to be degraded by dipeptidyl peptidase-4, a novel GLP-1 agonist semaglutide has a half-life of approximately one week. Similarly, exenatide ER has a half-life of about 2 weeks owing to microsphere capsules, which allow for a sustained release of the drug.

SUSTAIN-3 trial is a phase 3a active-comparator, open-label, parallel-group randomized study. The trial lasted 56 weeks and was conducted in the United States, Europe, and South America across 141 sites. Study participants underwent a 1:1 randomization to either 1 mg semaglutide SubQ once-weekly injection, or 2 mg exenatide ER SubQ once-weekly injection. Subjects in semaglutide arm received 0.25 mg of drug for 4 weeks, followed by a titration to 0.5 mg for 4 weeks, then were transitioned to maintenance dose of 1 mg for 48 weeks. Subjects in exenatide ER arm received 2 mg of the drug for the duration of 56 weeks. Enrolled patients included those over 18 years of age who were diagnosed with diabetes type 2, and who were receiving either one or two oral anti-diabetic medications such as metformin, sulfonylureas, or thiazolidinediones.  Patients who had a renal function below 60 mL/min GFR, heart failure NYHA class IV, or patients who were receiving oral anti-diabetic medications other than the ones mentioned above were excluded from the study. The primary and confirmatory secondary outcome included HbA1c change from baseline and weight change from baseline, respectively.

Hypoglycemic episodes, incidence of adverse events, and anti-trial drug antibodies were safety outcomes included in the trial.

At the conclusion of 56 weeks, semaglutide treated subjects had a 1.5% HbA1c decrease from baseline compared to 0.9% HbA1c  decrease in exenatide ER subjects.  The difference of HbA1c decrease between the patients was 0.62% (p value < 0.0001) favoring the semaglutide arm. More patients in the semaglutide arm achieved target HbA1c levels of <7% per the ADA criteria, and <6.5% per the AACE criteria. The ADA and AACE criteria goals were met by 67% and 47% of patients in the semaglutide arm, and 47% and 22% of patients in exenatide ER arm, respectively. When it comes to weight loss, semaglutide proved to be superior once again. Mean body weight difference of 5.6 kg was seen in semaglutide-treated patients, while 1.9 kg weight difference was seen in patients treated with exenatide ER, p value <0.0001. However, safety outcomes between these two agents were proven to be comparable. Adverse events were reported in 75% of patients in semaglutide arm, and in 76.3% of patients in the exenatide ER arm. Patients were more likely to prematurely discontinue semaglutide than exenatide ER (9.4% versus 5.9%). While more patients experienced gastrointestinal side-effects in the semaglutide arm, there were more patients who experienced injection-site nodules in the exenatide ER arm.

For patients who are not adequately controlled with oral anti-diabetic medications, semaglutide was proven to be superior in achieving the favorable HbA1c levels and decreased mean body weight when compared to exenatide ER. While the study shows a clear advantage to using semaglutide, there were several drawbacks to this study.  One was the design of the study — the open label trial -— which could have potentially led to bias. Second, the exenatide ER formulation was administered via a vial and syringe, while pre-filled injections of semaglutide were used. In October of 2017, FDA approved a new exenatide ER formulation, Bydureon BCise single-dose autoinjector device. This formulation has a more sustained HBA1c decrease with added weight loss improvement. It will be interesting to see if the results of this study will be replicated when semaglutide is compared to the new and improved exenatide ER formulation.

Practice Pearls:

  • Semaglutide decreased baseline HbA1c by 0.62% more than exenatide ER (p< 0.0001).
  • Semaglutide is superior to exenatide ER in mean body weight loss (5.6 kg and 1.9 kg, respectively).
  • Semaglutide and exenatide ER show a comparable safety profile.


Ahmann Andrew. “Efficacy and Safety of Once-Weekly Semaglutide Versus Exenatide ER in Subjects With Type 2 Diabetes (SUSTAIN 3): A 56-Week, Open-Label, Randomized Clinical Trial.” Diabetes Care, American Diabetes Association, 22 Dec. 2017. Accessed Jan. 2018.

Thomas Kudsk Larsen. “US FDA approves new easy-to-use, once-weekly Bydureon BCise injectable medicine for patients with type-2 diabetes.” AstraZeneca, 23 Oct. 2017. Accessed Jan. 2018.

Lamija Zimic PharmD(c), University of South Florida College of Pharmacy