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The First Oral Glucagon-like Peptide-1 Receptor Agonist - Rybelsus®

17 Jan 2020 12:43 PM | Anonymous

Author: Angelou Song, PharmD Candidate 2021-UMKC School of Pharmacy

Mentor: Barb Kasper, PharmD, BCACP; Clinical Assistant Professor-UMKC School of Pharmacy


The U.S. Food and Drug Administration (FDA) approved oral semaglutide tablets (Rybelsus®) in September 2019.1 Semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist analog and the first oral agent developed in the drug class. Oral semaglutide is indicated to lower A1C in patients with Type II Diabetes (T2DM).  According to the American Diabetes Association’s recommendations for pharmacological therapy, GLP-1 receptor agonists are used when A1c levels are over 1.5% above the glycemic target, as one of the agents for dual combination therapy. Also, GLP-1 receptor agonists are indicated when A1c levels are above target despite using two or three anti-hyperglycemic agents. Injectable GLP-1 receptor agonists with proven cardiovascular disease benefits (semaglutide, dulaglutide, liraglutide) are recommended to patients with established atherosclerotic cardiovascular disease (ASCVD), high ASCVD risk, chronic kidney disease or heart failure.2

Mechanism of Action

GLP-1 is an incretin peptide hormone that is released by enteroendocrine L cells in the gastrointestinal tract. GLP-1 is secreted in response to eating or an increase in glucose levels to stimulate insulin from pancreatic β-cells and lower glucagon secretion from pancreatic α-cells. GLP-1 receptor agonists lower postprandial blood glucose levels and delay postprandial gastric emptying. In addition to glucose lowering effects, GLP-1 receptor agonists also promote satiety, eventually leading to decreased body weight.3

Oral Drug Delivery System

Until oral semaglutide was developed, GLP-1 agents were only available as injectables, because the compounds undergo proteolytic degradation in the stomach. Oral semaglutide is formulated with sodium N-[8-(2-hydroxybenzoyl) aminocaprylate] (SNAC) to increase its absorption and efficacy in the stomach. SNAC is the intestinal permeation enhancer for oral delivery of macromolecules.4 SNAC allows semaglutide to accumulate in the cells and changes membrane permeability by interacting with the cell lipid membrane. SNAC converts oligomer forms of GLP-1 analogs into monomer forms, which increases absorption. Degradation of semaglutide occurs in an acidic environment and SNAC also works as a local buffer to protect from degradation and increase absorption.5

Dosage and Administration

The starting dose of oral semaglutide is 3 mg once daily for 30 days. The 3 mg dose is for initiation of therapy and minimization of gastrointestinal adverse effects, rather than glycemic control.  If tolerated, oral semaglutide is titrated up to 7 mg daily for at least 30 days. If additional glycemic control is needed, the dose may be titrated to a maximum of 14 mg daily.  Oral semaglutide is best absorbed on an empty stomach, at least 30 minutes before the first food, beverage, or other oral medication intake of the day. Additionally, the medication must be taken with less than 4 ounces of plain water only.   The manufacturer recommends eating 30 to 60 minutes after the dose.6

Literature reviews regarding efficacy and safety

A phase II, randomized, placebo-controlled trial was conducted to compare different dosages of oral semaglutide with placebo in 632 patients with T2DM and insufficient glycemic control. Oral semaglutide 2.5 mg, 5 mg, 10 mg, 20 mg, standard escalation of 40 mg, slow escalation of 40 mg, fast escalation of 40 mg, once weekly subcutaneous semaglutide 1 mg and oral placebo were compared with appropriate titration for 26 weeks. The primary endpoint was a change in A1c level from baseline to week 26. Oral semaglutide at 20 mg and standard escalation of 40 mg were not significantly different than subcutaneous semaglutide. More gastrointestinal adverse reactions were reported with oral semaglutide but fewer adverse reactions were reported when patients began on a low dose. The authors concluded that oral semaglutide is more effective at controlling glucose levels than a placebo over 26 weeks. Findings from this trial supported phase III trials.7

The Peptide Innovation for Early Diabetes Treatment (PIONEER) trials included a series of phase III trials conducted to establish the efficacy and safety of oral semaglutide.8 According to the PIONEER 1 trial, the average decrease in A1c was 0.9% for 7 mg and 1.1% for 14 mg. The mean weight loss was 0.9 kg and 2.3 kg for the 7 mg and 14 mg doses, respectively. 9


The most common side effects of oral semaglutide are nausea (20%), abdominal pain (11%), diarrhea (10%), decreased appetite (9%), vomiting (8%) and constipation (5%) for 14 mg. These adverse reactions are less severe with appropriate and slow dose titration. For severe adverse reactions, pancreatitis and diabetic retinopathy complications may happen. Oral semaglutide has a black box warning for risk of thyroid C-cell tumors. Oral semaglutide is contraindicated in patients with a personal or family history of medullary thyroid cancer or in patients with multiple endocrine neoplasia syndrome type 1.6

Comparison between oral and subcutaneous semaglutide

The two forms of semaglutide have not been studied against each other. Data were analyzed in Table 2 from individual studies to compare between oral and subcutaneous semaglutide by A1c level, amount of weight loss, side effects, cost and dosage.


Oral semaglutide is the first oral GLP-1 receptor agonist approved by the FDA.1 The PIONEER trials demonstrated the efficacy and safety of the agent versus placebo and active comparator agents.8 The oral formulation provides a more convenient dosage form and broadens options available within the GLP-1 drug class.


  1. FDA approves first oral GLP-1 treatment for type 2 diabetes. U.S. Food and Drug Administration. https://www.fda.gov/news-events/press-announcements/fda-approves-first-oral-glp-1-treatment-type-2-diabetes. Accessed January 5th, 2020.
  2. American Diabetes Association. Pharmacologic Approaches to Glycemic Treatment: Standard Medical Care in Diabetes - 2020. https://care.diabetesjournals.org/content/43/Supplement_1/S98 Published January 2020. Accessed January 12th, 2020.
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  4. 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 Feb 13;11(2). doi: 10.3390/pharmaceutics11020078.
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  6. Rybelsus (semaglutide tablets) [package insert]. Plainsboro, NJ; Novo Nodisk, Inc; Published September 2019. https://www.novo-pi.com/rybelsus.pdf. Accessed January 5th, 2020
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  8. A quick guide to the PIONEER trials. Medicine Matters website. https://diabetes.medicinematters.com/semaglutide/cardiovascular-outcomes/a-quick-guide-to-the-pioneer-trials/16877792. Accessed January 5th, 2020
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  10. 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 Dec; 42(12): 2272-2281. Doi:10.2337/dc19-0883
  11. 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. JAMA. 2019; 321(15):1466-1480. doi:10.1001/jama.2019.2942
  12. Pratley R, Amod A, Hoff ST, et al. Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomized, double-blind, phase 3a trial. Lancet Diabetes Endocrinol. 2019 July; 394(10192): 39-50. Doi: 10.1016/S0140-6736(19)31271-1
  13. 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 randomized phase 3a trial. Lancet Diabetes Endocrinol. 2019 June; 7(7): 515-527. doi: 10.1016/S2213-8587(19)30192-5
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  16. Zinman B, Aroda VR, Buse JB, et al. Efficacy, safety and tolerability of oral semaglutide versus placebo added to insulin with or without metformin in patients with type 2 diabetes: the PIONEER 8 trial. Diabetes Care. 2019 Dec; 42(12): 2262-2271. Doi:10.2337/dc19-0898
  17. Dose-response, safety and efficacy of oral semaglutide versus placebo and versus liraglutide, all as monotherapy in Japanese subjects with type 2 diabetes (PIONEER 9). ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03018028. Accessed January 5th, 2020
  18. Safety and efficacy and oral semaglutide versus dulaglutide both in combination with one OAD (oral antidiabetic drug) in Japanese subjects with type 2 diabetes (PIONEER 10). ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03015220. Accessed January 5th, 2020.
  19. Sorli C, Harashima SI, Tsoukas GM, et al. Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): a double-blind, randomized, placebo-controlled, parallel-group, multinational, multicenter phase 3a trial. Lancet Diabetes Endocrinol. 2017 Apr;5(4):251-260. doi: 10.1016/S2213-8587(17)30013-X
  20. Ozempic (semaglutide) [package insert]. Plainsboro, NJ: Novo Nordisk, Inc; Revised December 2019. https://www.novo-pi.com/ozempic.pdf. Accessed January 5th, 2020
  21. IBM Micromedex® RED BOOK®. IBM Micromedex®. https://www-micromedexsolutionscom.proxy.library.umkc.edu/micromedex2/librarian/PFDefaultActionId/redbook.ModifyRedBookSearch. Accessed January 12th, 2020

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