Head-to-Head Comparison: Oral Semaglutide vs. Empagliflozin

Oral semaglutide vs. empagliflozin : the first oral glucagon-like peptide receptor agonist recently gained FDA approval, but how does it compare to oral agents already on the market?

With the recent approval of the first oral glucagon-like peptide agonist, Rybelsus (semaglutide), many clinicians are wondering how it stacks up to oral agents that they may already be utilizing in practice. The PIONEER-2 trial conducted by the manufacturer of Rybelsus, Novo Nordisk, evaluated several outcomes associated with its new drug versus Jardiance (empagliflozin) in an open-label, head-to-head comparison. Empagliflozin is an oral sodium-glucose cotransporter-2 inhibitor and has been on the market for about four years. It was chosen for the study due to its classification as a generally well-tolerated agent, as well as its positive cardiovascular benefits and positive weight profile. The general goal was to compare the new oral semaglutide to the “best” in another class of diabetes medications to help refine how clinicians choose which agent is most appropriate for their patient populations. While studies have already confirmed the safety of the new oral semaglutide, this is the first which directly compares the agent to another concerning change in baseline hemoglobin A1c and patient body weight.

The documented objective of PIONEER-2 was to evaluate the efficacy and safety of  oral semaglutide and empagliflozin in patients with type 2 diabetes who were uncontrolled on titrated doses of metformin. The trial was conducted as an open-label trial, which consisted of 822 patients at randomization and 787 patients remaining when final patient data was obtained. Patients were randomized into two treatment groups with one group receiving oral semaglutide 14mg once daily and the other receiving empagliflozin 25mg once daily. These doses represent the maximum dose of each agent. The primary endpoint evaluated was the patient’s change from baseline A1c which was measured at weeks 26 and 52. The secondary endpoint assessed was change in body weight which was measured at the same time intervals. Efficacy related questions were addressed using two estimands, treatment policy, and the trial product. The treatment policy estimand included, patients who stopped the trial product and those who required rescue medication, while the trial product estimand included those concerning who did not require any rescue medications and remained on the trial product.

At week 5, four hundred patients remained in the oral semaglutide group, and 387 remained in the empagliflozin group. At week 26 oral semaglutide proved to be superior concerning reductions in baseline A1c  for the treatment policy estimand. Oral semaglutide was also superior at week 52 concerning baseline A1c reductions for both identified estimands. Final measured reductions for oral semaglutide were calculated to be -1.4% while empagliflozin’s reductions were calculated at -0.9%. The confidence interval was reported to be 95%, and the p-value was <0.0001

With regard to the secondary endpoint, at week 26, oral semaglutide was not proven to cause more weight loss over empagliflozin. However, at week 52 oral semaglutide did show superior weight loss benefit. Patients in the oral semaglutide group lost an average of 4.7 kilograms, while the empagliflozin group averaged a loss of 3.8 kilograms. The P-value for this endpoint was 0.0114. Gastrointestinal adverse effects (nausea) were the most commonly reported in both groups but occurred more often with oral semaglutide. The adverse effect was considered to be transient as it improved with continued therapy, but in the first 16 weeks of the trial, discontinuation due to this effect was the highest in the oral semaglutide group. In summary, at week 26 oral semaglutide was superior to empagliflozin in reducing A1c but this was not the case for reductions in body weight. At week 52, oral semaglutide proved superior in both reductions in A1c and body weight.

One identifiable weakness in the study was the fact that concerning the cardiovascular profile, there is no evidence that supports the use of oral semaglutide over empagliflozin. PIONEER-6 showed that oral semaglutide does not increase a patient’s cardiac risk or cause harm, but in patients with established cardiovascular disease or high cardiovascular risk, empagliflozin would remain the agent of choice until further studies are completed. As many patients with diabetes do not wish to inject themselves if it is not necessary, the results of the trial facilitate clinicians being able to prescribe a new oral agent with data to back up that it is just as or even more effective than the “best” oral agents they were already prescribing. 

Practice Pearls:

• Oral semaglutide showed superiority for both A1c reductions and weight loss over 52 weeks in uncontrolled type 2 diabetes patients on metformin.
• Patients started on oral semaglutide should be counseled on transient gastrointestinal adverse effects to facilitate the continuation of therapy.
• All of the patients in the study were on maximum tolerated doses of metformin; therefore, before initiating oral semaglutide or empagliflozin metformin should be started and maximized.

References for “Head to- Head Comparison: Oral Semaglutide vs. Empagliflozin”:
Rodbard HW, Rosenstock J, Canani LH, et al. Oral Semaglutide Versus Empagliflozin in Patients With Type 2 Diabetes Uncontrolled on Metformin: The PIONEER 2 Trial. Diabetes Care. 2019:dc190883. doi:10.2337/dc19-0883

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. New England Journal of Medicine. 2017;376(9):890-892. doi:10.1056/nejmc1615712.

‘Best in Class’ Diabetes Drugs Compared in Head-to-Head Trial. Medscape. https://www.medscape.com/viewarticle/921053#vp_2. Published November 11, 2019. Accessed November 12, 2019.

Jordan Boyd, PharmD. Candidate Florida Agricultural & Mechanical University School of Pharmacy

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