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A Comparison of Safety and Efficacy of Semaglutide vs. Exenatide ER

Feb 10, 2018

GLP-1 agonists randomized showdown. Which agent is better?

Oral antidiabetic (OAD) agents are typically the primary starter agents for the treatment of type 2 diabetes (T2D). For those who are poorly controlled on these agents, injectable alternatives are considered for better control. Glucagon-like peptide (GLP)-1 agonists are commonly prescribed injectable agents. Their ability to help stimulate insulin secretion and glucagon suppression in the presence of glucose have resulted in lower hemoglobin A1c (HbA1c) levels and a lower risk for hypoglycemia. These agents also play a notable role on weight loss due to their ability to help patients feel full longer after eating. Adherence with these agents have been a concern in the past, which is why newer agents have been formulated to improve dosing from daily to once-weekly injections. The newest GLP-1 agonists on the market is Ozempic (Semaglutide). Its chemical structure is similar to liraglutide, but it has been formulated to be less susceptible to degradation by dipeptidyl peptidase-4 (DPP-IV) and has a higher affinity for albumin. Semaglutide has a 94% similarity to human GLP-1, while its comparator exenatide ER has only 53% homology. Both agents are once-weekly subcutaneous injections. The Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) 3 trial targeted both semaglutide and exenatide ER to compare their safety and efficacy to one another.

The SUSTAIN 3 was an open-label, randomized, phase 3a clinical trial. Semaglutide prefilled pen was dosed at 1mg subcutaneously/week vs. exenatide ER vial and syringe at 2 mg subcutaneously/week for glycemic control. The study was conducted over 56-weeks at 141 sites across the world. For inclusion, patients needed to be ³18 years of age, have T2D with an HbA1c of 7-10.5%, and have been adherent on one or two OADs (metformin, thiazolidinediones, and/or sulfonylureas) for 3 months or longer.  Patients with a glomerular filtration rate <60mL/min/1.73m2, previous antidiabetic therapy other than the above mentioned OADs in 90 days, idiopathic acute pancreatitis, and any history of cardiovascular or cerebrovascular event in 90 days were all excluded from this trial. There was a 1:1 randomization into either group of semaglutide or exenatide ER. Baseline characteristics were similar between both groups.  Semaglutide’s dosing schedule was fixed at 0.25mg for 4 weeks, then 0.5mg for 4 weeks, then a maintenance dose of 1mg for the remaining 48 weeks. Exenatide ER was a steady dose of 2mgs weekly for the entire 56 weeks. Patients on metformin and/or thiazolidinedione remained on that therapy throughout the trial, while sulfonylureas were titrated down as needed for hypoglycemia. If patients’ glycemia remained uncontrolled while on the tested agents, rescue agents were used. After the 56 weeks, a 5-week follow-up was conducted for all patients enrolled. To assess efficacy, the primary outcome was a change in baseline HbA1c and the secondary outcome was a change in baseline body weight. Safety was assessed through incidence of adverse events, hypoglycemia, pulse rate, and anti-trial drug antibodies. Several statistical analyses were conducted to evaluate the listed outcomes.

Results showed that efficacy of semaglutide was superior to exenatide for the improvement of glycemic control and reducing body weight. Semaglutide showed a decrease in HbA1c by 1.5% vs. 0.9% decrease with exenatide ER; (P<0.0001). More patients in the semaglutide group were able to achieve lower HbA1c targets without hypoglycemia or weight gain. Mean body weight, BMI, and waist circumference were reduced by 5.6kg in the semaglutide group vs. 1.9kg in the exenatide ER group (-3.78; -4.58-2.98; P<0.0001). Both drugs showed a comparable safety profile, 75% (semaglutide), 76.3% (exenatide ER). The most common reported adverse events were GI upset, nausea, vomiting, and diarrhea; which all diminished over time. A small amount of cholelithiasis and severe hypoglycemia cases were also reported.  Hypoglycemia was seen more often in patients on multiple medications other than the trial agents. Pulse rate increased both in the semaglutide group and exenatide ER group by 2.1bpm and 1.1bpm, respectively (P=0.0973). Anti-trial drug antibodies developed in both groups: 13 subjects in semaglutide group and 355 subjects in exenatide ER group. Rescue medication was given to 29 (7.2%) semaglutide patients vs. 48 (11.9%) exenatide ER patients for uncontrolled hyperglycemia.

In conclusion, for patients who are poorly controlled on oral antidiabetic agents, semaglutide would be the superior GLP-1 agonist choice for the treatment of T2D. A strength of this study was the 90% power it held in its participants. Another strength of this study was treatment duration, although longer studies still need to be conducted. A limitation of the study was unmatched tested products. Semaglutide prefilled pen injector was used while exenatide ER vial was used. This caused another limitation, which was the lack of trial blinding. Exenatide ER is available in a prefilled pen, which could affect future trials and results.

Practice Pearls:

  • Ozempic (Semaglutide) shows greater efficacy in reducing HbA1c and weight in comparison to exenatide ER.
  • Both drugs have a similar safety profile and are available in convenient prefilled pens.
  • Both drugs provide improved adherence for patients due to their once-weekly dosing.


Ahmann, Andrew J., et al. “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, vol. 41, no. 2, 15 Dec. 2017, pp. 258–266., doi:10.2337/dc17-0417.

Adrianna Jackson, Doctor of Pharmacy Candidate: Class of 2018; LECOM College of Pharmacy