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Oral Semaglutide vs Subcutaneous GLP-1RAs — ADA 2019

Jun 22, 2019
Editor: David L. Joffe, BSPharm, CDE, FACA

Author: Adam Chalela, B.S. Doctor of Pharmacy Candidate USF College of Pharmacy

New research findings on oral semaglutide vs subcutaneous liraglutide.

Many classes of medications exist for patients with type 2 diabetes to use to gain control of their blood sugars. Though lots of oral options exist, patients with more severe forms of the disease are usually required to inject themselves subcutaneously with medication in order to achieve adequate glycemic control. One class of medications, glucagon like peptide-1 receptor agonists (GLP-1RAs), are known for their ability to not only lower HbA1c levels but also significantly reduce patient weight. GLP-1RAs gained popularity after they were shown to preserve beta-cell mass and suppress the release of glucagon by the pancreas. Since the early 2000s, GLP-1RAs have been administered through subcutaneous injection only. Semaglutide, sold under the trade name Ozempic, is a GLP-1RA that was initially FDA approved for subcutaneous injection. Recently, a once daily oral tablet of semaglutide has been created and is currently in phase 3 study in hopes to gain FDA approval.


Previous studies have compared the relative safety and efficacy profile of oral semaglutide to sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor. Results showed that daily doses of 7mg and 14mg of semaglutide had significantly greater HbA1c lowering abilities as well as weight loss abilities compared to 100mg of sitagliptin daily at 26 and 52 weeks follow up; lower doses of semaglutide (3mg) failed to demonstrate superior outcomes. Safety profiles of the two medications were similar with highest incidences of gastrointestinal related events (nausea, vomiting, and abdominal pain).

A recently published study that was presented at the 2019 79th annual ADA Scientific Sessions conference compared the safety and efficacy of two GLP-1RAs to each other and placebo: oral semaglutide vs subcutaneous liraglutide. Patients with type 2 diabetes who were 18 years or older, had an HbA1c between 7.0% and 9.5% and were on a stable dose of metformin with or without SGLT-2 inhibitor therapy, were enrolled into this double blinded, double dummy phase 3 trial. A total of 711 patients randomized in a 2:2:1 fashion (semaglutide, liraglutide, and placebo, respectively) were enrolled and observed for a total of 52 weeks. The primary endpoint observed within this study was the net change in HbA1c percentage from baseline to week 26 and the secondary endpoint was net change in body weight from baseline to week 26.

A large majority of patients enrolled completed the entire study course of 52 weeks. Patients enrolled were split evenly between male and female and were an average age of 56 years old. Stratified analysis of study results demonstrated non-inferior HbA1c lowering capabilities of oral semaglutide to subcutaneous liraglutide (estimated difference -0.1%, 95% CI -0.3% to 0.0%) and superior HbA1c lowering capabilities to placebo (estimated difference -1.1%, 95% CI -1.2% to -0.9%) at 26 weeks. In the intent to treat analysis, oral semaglutide demonstrated superior HbA1c lowering capabilities to subcutaneous liraglutide (estimated difference -0.2%, 95% CI -0.3% to -0.1%) and placebo (estimated difference -1.2%, 95% CI -1.4kg to -1.0%) at 26 weeks. Stratified analysis of secondary endpoints shows that oral semaglutide demonstrated superior weight loss capabilities when compared to subcutaneous liraglutide (estimated difference -1.2kg, 95% CI -1.9kg to -0.6kg) and placebo (estimated difference -3.8kg, 95% CI -4.7kg to -3.0kg) at 26 weeks. Adverse events occurred significantly more in study groups than the placebo group (80% oral semaglutide, 74% subcutaneous liraglutide, and 67% placebo).

In conclusion, oral semaglutide is superior to subcutaneous liraglutide and placebo in ability to decrease body weight while maintaining significantly similar HbA1c lowering abilities to liraglutide in patients with type 2 diabetes over 26 weeks. Patients with type 2 diabetes requiring further HbA1c lowering with weight-loss treatment goals after initial treatment with metformin and/or an SGLT2 inhibitor should consider oral semaglutide if they wish to avoid injectable medications. The publication of these study results should pave the way towards an accelerated FDA approval for oral semaglutide.

Practice Pearls

  • Oral semaglutide showed superior weight reduction and non-inferior HbA1c lowering to subcutaneous liraglutide at week 26.
  • Currently, semaglutide is only available subcutaneously. The manufacturers are in the process of gaining FDA approval for an oral formulation.
  • Mechanistically, semaglutide causes gastrointestinal side effects such as nausea, vomiting, and abdominal pain significantly more than placebo.

Pratley R, Amod A, Hoff ST, et al. Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER4): a randomized, double-blind, phase 3a trial. 2019; [Epub ahead of print]. DOI: 10.1016/S0140-6736(19)31271-1.

Adam Chalela B.S., PharmD Candidate, USF College of Pharmacy Class of 2020

Reported at the American Diabetes Association 79th Scientific Sessions June, 2019