By William Elliott, MD, FACP, and James Chan, PharmD, PhD

Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.

Drs. Elliott and Chan report no financial relationships relevant to this field of study.

The FDA has approved the first oral glucagon-like peptide-1 (GLP-1) receptor agonist for the treatment of type 2 diabetes mellitus (T2D). Semaglutide is a GLP-1 analog that has been marketed as an injectable since December 2017 (Ozempic). In the oral form, semaglutide is coformulated with an absorption enhancer, salcaprozate sodium (SNAC), to permit once-daily oral dosing. The FDA granted priority review. The drug will be marketed as Rybelsus.


Semaglutide is indicated as adjunct to diet and exercise to improve glycemic control in adults with T2D.1


The starting dose is 3 mg once daily for 30 days.1 After 30 days, increase the dose to 7 mg once daily. The dose may be increased to 14 mg once daily after 30 days (if additional glycemic control is needed). The dose should be taken (with no more than 4 oz of plain water) at least 30 minutes before the first food, beverage, or other oral medications of the day. Semaglutide is available as 3 mg, 7 mg, and 14 mg tablets.


Oral semaglutide is the first oral GLP-1 receptor agonist to be approved. It can be transitioned to subcutaneous injection easily (7 mg or 14 mg to 0.5 mg).1


Oral semaglutide has low bioavailability (0.4%-1%), and requires optimal conditions for absorption. The oral form is dosed 7 to 14 times the subcutaneous dose on a mg basis and given daily instead of weekly. The drug should be taken on an empty stomach upon awakening with a sip of water (no more than 4 oz). Food should be eaten 30-60 minutes after taking oral semaglutide. The exposure of oral semaglutide decreases with increase in body weight (e.g., 129 kg vs. 56 kg).1 A higher dose (e.g., 14 mg) may be required for this population. The drug carries the same warnings and precautions as parenteral GLP-1 receptor agonists (e.g., risks of thyroid C-cell tumors, pancreatitis). Diabetic retinopathy was reported at a significantly higher rate than placebo (3% vs. 1.8%) in the cardiovascular trial for the injectable form.1 The most frequently reported adverse reactions (vs. placebo) were nausea (11-20% vs. 6%), abdominal pain (10-11% vs. 4%), diarrhea (9-10% vs. 4%), increase in amylase (10-13% vs. 0%), and increase in lipase (30-34% vs. 0%).1


SNAC coformulated with semaglutide results in absorption of semaglutide across the gastric mucosa.2,3 The oral formulation (20-40 mg) produces nonsignificant difference reductions in HbA1c and weight loss as the 1 mg subcutaneous dose.4 Its efficacy was evaluated in numerous studies as monotherapy and in combination with metformin, sulfonylureas, insulins, and thiazolidinediones. Rybelsus has been compared to the sodium-glucose cotransporter-2 (SGLT-2) inhibitors (empagliflozin and sitagliptin) as well as the GLP-1 receptor agonist liraglutide. As monotherapy, semaglutide reduces HbA1c vs. placebo about 1% from a baseline of 8.0%.1,5 Semaglutide 14 mg daily plus metformin produced a greater reduction in HbA1c compared to empagliflozin 25 mg plus metformin (1.3 vs. 0.9 from a baseline of 8.1%).1,6 Both 7 mg and 14 mg of semaglutide with metformin (and with or without a sulfonylurea) were more effective than sitagliptin 100 mg with the same combination (-1.0%, -1.3% vs. -0.8%).1,7 When combined with metformin or metformin plus SGLT-2 inhibitor, semaglutide was noninferior to liraglutide.1,8 Semaglutide was effective in patients with moderate renal impairment.1,9 In subjects with cardiovascular, chronic kidney disease, or both, semaglutide did not increase the risk of major adverse cardiovascular outcomes compared to placebo (3.8% vs. 4.8%; i.e., noninferior to placebo).1,10


Oral semaglutide is the first oral formulation of a GLP-1 receptor agonist. As with other GLP-1 receptor agonists, it is not recommended as first-line therapy for patients not adequately controlled on diet and exercise. The subcutaneous formulation has been shown to reduce major adverse cardiovascular events compared to placebo in subjects with established cardiovascular disease, chronic disease kidney disease, or both.11 The oral formulation did not reach this threshold, possibly due to a shorter follow-up time (15.9 months vs. 25.2 months), lower rates of cardiovascular events in the placebo group (4.8% vs. 8.9%), and underpowered for superiority. Diabetic retinopathy-related adverse events were 7.1% for oral semaglutide vs. 6.3% for placebo (not statistically significant). The cost for oral semaglutide is $772.43 for a 30-day supply, similar to a four-week supply of the subcutaneous form.


  1. Novo Nordisk Inc. Rybelsus Prescribing Information, September 2019. Available at: Accessed Oct. 9, 2019.
  2. Twarog C, Fattah S, Heade J, et al. Intestinal permeation enhancers for oral delivery of macromolecules: A comparison between salcaprozate sodium (SNAC) and sodium caprate (C10). Pharmaceutics 2019;11(2). pii: E78. doi: 10.3390/pharmaceutics11020078.
  3. Granhall C, Donsmark M, Blicher TM, et al. Safety and pharmacokinetics of single and multiple ascending doses of the novel oral human GLP-1 analogue, oral semaglutide, in healthy subjects and subjects with type 2 diabetes. Clin Pharmacokinet 2019;58:781-791.
  4. Davies M, Pieber TR, Hartoft-Nielsen ML, et al. Effect of oral semaglutide compared with placebo and subcutaneous semaglutide on glycemic control in patients with type 2 diabetes: A randomized clinical trial. JAMA 2017;318:1460-1470.
  5. Aroda VR, Rosenstock J, Terauchi Y, 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 2019;42:1724-1732.
  6. 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; Sep 17. pii: dc190883. doi: 10.2337/dc19-0883. [Epub ahead of print].
  7. Rosenstock J, Allison D, Birkenfeld AL, et al. Effect of additional oral semaglutide vs sitagliptin on glycated hemoglobin in adults with type 2 diabetes uncontrolled with metformin alone or with sulfonylurea: The PIONEER 3 Randomized Clinical Trial. JAMA 2019;321:1466-1480.
  8. 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;394:39-50.
  9. Mosenzon O, Blicher TM, Rosenlund S, et al. Efficacy and safety of oral semaglutide in patients with type 2 diabetes and moderate renal impairment (PIONEER 5): A placebo-controlled, randomised, phase 3a trial. Lancet Diabetes Endocrinol 2019;7:515-527.
  10. Husain M, Birkenfeld AL, Donsmark M, et al. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2019;381:841-851.
  11. Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2016;375:1834-1844.