Posted on December 03, 2019 in: Professional Practice
By Makenzie Thelen, Pharm.D. Candidate 2020, University of Michigan, Ann Arbor
Oral semaglutide (Rybelsus) was approved Sept. 20, 2019, for the treatment of type 2 diabetes along with diet and exercise.1,2 Semaglutide is the first oral GLP-1 agonist to be approved in the USA, the remaining options being injectable formulations.1 GLP-1 is a hormone that is often deficient in patients with type 2 diabetes.1 GLP-1 enhances insulin secretion from the pancreas in a glucose-dependent manner, suppresses liver glucose production, and slows gastric motility.1 In addition to lowering blood glucose and A1C, GLP-1 agonists promote weight loss. The basis of oral semaglutide’s Food and Drug Administration (FDA) approval are the PIONEER clinical trials which included 9,543 adult participants over 10 trials.3
PIONEER 2 compared oral semaglutide 14 mg once daily to empagliflozin 25 mg once daily in adults with type 2 diabetes also taking metformin. At week 26, participants taking semaglutide had an A1C decrease of 1.3% compared to empagliflozin participants who had an A1C decrease of 0.9% (p<0.001). Both groups experienced weight loss, with the oral semaglutide 14 mg group having a mean change of -3.8kg and the empagliflozin 25 mg having -3.7 kg.2 In PIONEER 3, oral semaglutide also demonstrated statistically superior A1C lowering effects when compared to sitagliptin 100 mg. Oral semaglutide 14 mg lowered A1C by 1.3% compared to sitagliptin 100 mg that lowered A1C by 0.8% (p<0.001) at week 26.2
Oral semaglutide 14 mg was also compared to liraglutide 1.8 mg, a subcutaneous GLP-1 agonist as part of PIONEER 4 in combination with metformin with or without an SLGT2 inhibitor. The two GLP-1 agents were found to be non-inferior to each other in their A1C reduction. The liraglutide 1.8 mg group had an A1C decrease of 1.1% while the oral semaglutide group had a decrease of 1.2% at week 26.2,4 The oral semaglutide group experienced significantly more weight loss (4.4 kg) when compared to liraglutide (3.1 kg, p<0.001) and had a similar adverse event profile.4
Overall, the PIONEER trials have demonstrated that oral semaglutide is superior in lowering A1C compared to other once daily oral agents empagliflozin and sitagliptin. Oral semaglutide also had a similar efficacy and side effect profile when compared to the injectable GLP-1 agonist liraglutide. However, not all patients able to take oral medications may be good candidates for oral semaglutide.
Semaglutide as a once daily oral option may be attractive to patients who are hesitant to begin or continue injection therapy and may increase adherence. However, there are some special instructions that need to be followed with semaglutide therapy. Oral semaglutide must be taken 30 minutes with four ounces of water before the first food or beverage of the day. If the patient waits less than 30 minutes, efficacy will be reduced.2 By waiting more than 30 minutes, absorption of oral semaglutide may be increased.2 This differs significantly from injectable semaglutide, which may be given at any time of day without regards to meals.5 Patients with type 2 diabetes may have other comorbid conditions or therapies that would prohibit following the instructions of oral semaglutide.
Health system pharmacists should consider cost balanced with convenience when debating adding oral semaglutide to their institution’s formulary. Oral semaglutide costs $772 for 30 tablets, putting it in the same price category as GLP-1 agonist injectables. However, ease of storage may mitigate some amount of operating costs and loss of drug due to refrigeration malfunctions.
Overall, oral semaglutide is the first oral GLP-1 agonist within a historical class of only injectable agents. It has a similar side effect and efficacy profile as other GLP-1 agonist injectables while having a similar cost. Its administration instructions may complicate medication regimens and lead to ineffective use or drug discontinuation. For patients with type 2 diabetes who are hesitant to begin injection therapy, oral semaglutide provides an effective treatment option in a drug class previously closed to them. In the future, look for more oral options in the GLP-1 agonist class and further studies evaluating the long-term effects of oral GLP-1 agonists.
1. Food and Drug Administration. FDA approves first oral GLP-1 treatment for type 2 diabetes. (Sept. 20 2019). www.fda.gov/news-events/press-announcements/fda-approves-first-oral-glp-1-treatment-type-2-diabetes (accessed Nov. 14 2019).
2. Rybelsus (semaglutide tablets) prescribing information. Novo Nordisk Inc. 2019 September.
3. Center Watch. Rybelsus (oral semaglutide). www.centerwatch.com/drug-information/fda-approved-drugs/drug/100431/rybelsus-oral-semaglutide- (accessed Nov. 14 2019).
4. Pratley R, Amod A, Hoff, ST, et al. Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomised, double-blind, phase 3a trial. Lancet 2019 Jul;394(10192):39-50.
5. Ozempic (semaglutide injection) prescribing information. Novo Nordisk Inc. 2019 April.