Oral Semaglutide – A Phase 3 Trial in Patients with Type 2 Diabetes

Final results from this phase 3 study preceded FDA approval of oral semaglutide.

Editor’s Note: On September 20, 2019, The U.S. Food and Drug Administration approved Rybelsus (semaglutide) oral tablets to improve control of blood sugar in adult patients with type 2 diabetes, along with diet and exercise. The results of this phase 3 trial and others in the PIONEER series give more background on the safety and efficacy of this groundbreaking drug.

Glucagon-like peptide 1 agonists taken orally have low bioavailability resulting from the extensive degradation by proteolytic enzymes and the low absorption through the gastrointestinal mucosa. Oral semaglutide was formulated with an absorption enhancer called sodium caprylate (SNAC). SNAC helps semaglutide by increasing the pH around it as well as helping it pass transcellular through the mucosa. Pharmacokinetics of semaglutide have been established in a previous study to support once daily dosing. This phase 3 trial wanted to compare 3 doses of semaglutide vs. placebo to establish superiority in efficacy and safety in patients who have type 2 diabetes.

This trial was a 26-week, randomized, double-blinded, placebo-controlled, parallel-group trial that assessed a total of 703 patients with type 2 diabetes. Efficacy was addressed using 2 estimands, a treatment policy estimand and a trial product estimand. Treatment policy included all randomized patients regardless of discontinuation of semaglutide or the use of rescue medication. Trial product estimand included all randomized patients assuming they remained on semaglutide and did not use rescue medication to eliminate the confounding effect. Patient population were 50% females, had a mean age of 55 years, diabetes for about 3.5 years, a BMI of 31.8 kg/m2, and an HbA1c of 8.0%. Patients had to only be managed by diet and exercise solely and had to have not taken antidiabetic medications within 90 days before screening. Patients were randomized into 1:1:1:1 ratio being 3 mg:7mg:14mg of oral semaglutide: placebo. Patients who had to be on a dose higher than 3 mg were titrated up every 4 weeks until desired dose. Patients were followed up after 5 weeks from the 26-week mark. Rescue medication protocol was implemented in case of persistent hyperglycemia. Rescue medications excluded GLP-1 agonists, dipeptidyl peptidase -4 inhibitors, and amylin analogs.  Those patients who had to be rescued or discontinued semaglutide and were put on an alternative, continued the trial. Primary endpoint was change in HbA1c from baseline to week 26. Secondary endpoint was change in body weight from baseline to week 26. Supportive secondary endpoints included changes in fasting lipid levels from baseline to week 26. Safety endpoints included number of hypoglycemic episodes confirmed by and adverse events until week 31. Power of the study was 90% to confirm superiority of semaglutide vs placebo. Weighted Bonferroni closed-testing strategy was used to assess for efficacy endpoints. Treatment policy estimand was assessed by a pattern mixture model that used imputations to account for missing data from week 26 if product was discontinued. Ancova models was used for the analysis and imputation. Results were combined by Rubin’s rules. Trial product estimand was assessed by mixed model for repeated measurements to collect data prior to discontinuation or the use of rescue medication. 

For glycemic control, semaglutide reduced HbA1c compared to placebo regardless of rescue medication use or discontinuation (P<0.0001) with semaglutide 14mg being the most efficacious at 1.1% (treatment policy estimand) and 1.4% (Trial product estimand) reduction in HbA1c (P<0.0001). Reduction of HbA1c of less than 7% and less than or equal to 6.5% was achieved by semaglutide (P<0.001 for all doses). Fasting plasma glucose was also decreased (P<0.001, trial product estimand). Regarding body weight, only semaglutide 14 mg was superior to reduce body weight by 2.3 kg (P<0.001, treatment policy estimand) vs. placebo. Semaglutide 7 and 14 mg had significant weight loss in the trial product estimand. A weight loss of at least 5% was achieved by semaglutide 7 mg (P = 0.03) and 14 mg (P<0.001). Regarding safety, the most common adverse effects experienced by semaglutide were mainly gastrointestinal (nausea and diarrhea). No deaths occurred as a result of taking semaglutide. There was a low incidence of severe hypoglycemia and diabetic retinopathy across the groups. There were significant increases in mean levels of lipase (all doses) and mean pulse rate (14 mg) in the semaglutide groups. No acute pancreatitis had occurred.

In conclusion, oral semaglutide significantly reduced HbA1c and weight in a dose dependent manner.  Adverse events of oral semaglutide were similar to subcutaneous semaglutide with the most frequent being mild-to-moderate nausea. Limitations of generalizability of the study included patients who were only managed by diet and exercise and the use of oral semaglutide as first line therapy where metformin is usually first line. Future studies should be longer in duration and should assess the addition of oral semaglutide to other antidiabetic agents.

Benefits in patients with type 2 diabetes and high cardiovascular risk: Other aspects of oral semaglutide have been studied in various trials in the PIONEER program. Results of the PIONEER 6 trial announced in June 2019 indicated oral semaglutide is safe for patients with type 2 diabetes who are at high cardiovascular risk. PIONEER 6 found that oral semaglutide reduced cardiovascular death and all-cause mortality by nearly 50 percent, based on median follow up of 15.9 months. For more on PIONEER 6, see Cardiovascular Benefits of Oral GLP-1RA in High-Risk Patients with Type 2 Diabetes.

 Other trials in the series looked at oral semaglutide up to 14mg once daily as initial therapy of diabetes, in various combinations with oral or injected glucose-lowering agents, and compared to other medications (sitagliptin, empagliflozin and liraglutide) or placebo, and stratified to include populations with additional risk. The results have demonstrated that the efficacy, safety and tolerability of oral semaglutide is statistically significant. 

Practice Pearls:

• Oral Semaglutide achieved significant HbA1c reductions in all doses when used as monotherapy.
• Oral Semaglutide 7 mg and 14 mg achieved significant weight loss when used as monotherapy.
• The nausea associated with oral semaglutide can be mitigated by slowly titrating the dose to achieve the desired dose.
• Oral semaglutide does not increase the risk of adverse cardiovascular events in high risk patients with type 2 diabetes when compared to placebo.

Aroda, Vanita R., et al. “PIONEER 1: Randomized Clinical Trial of the Efficacy and Safety of Oral Semaglutide Monotherapy in Comparison With Placebo in Patients With Type 2 Diabetes.” Diabetes Care, July 2019

Press release, June 11, 2019: Oral Semaglutide Reduces Occurrence of Major Cardiac Events in People with Type 2 Diabetes With High Cardiovascular Risk, https://www.diabetes.org/newsroom/press-releases/2019/oral-semaglutide-reduces

Nour Salhab, Pharm.D. Candidate, USF College of Pharmacy

See more information on FDA approval of oral semaglutide here.