By: Tanay Maddula PharmD Candidate c/o 2022
Rybelsus (oral semaglutide) was recently approved by the Food and Drug Administration (FDA) in September 2019 to help control blood sugar in adult patients with Type 2 Diabetes alongside diet and exercise. It is the first oral GLP-1 (glucagon like peptide-1) agonist as typical drugs of this class have only been subcutaneous injections.
How do GLP-1 agonists work in the body?
GLP-1 agonists work by acting as GLP-1 in the body. GLP-1 is a 30 to 31 amino acid long peptide secreted by intestinal enteroendocrine cells. GLP-1 binds to GLP receptors in the brain, stomach, cardiovascular system, pancreas, and liver, and exerts a different effect at each location (Table 1). The cumulation of all these effects results in the reduction of blood sugar in the body and better control of blood sugar for patients with type 2 diabetes.
Table 1: Semaglutide Mechanism of Action 1
Clinical Role of GLP-1 Agonists and Results of Semaglutide in Clinical Trials:
The American Diabetes Association (ADA) guidelines recommend GLP-1 agonists as second line therapy in the treatment of type 2 diabetes as an adjunct to maximum dose metformin in patients for whom atherosclerotic cardiovascular disease (ASCVD) predominates or in those who have a compelling need to lose weight and are not at their target A1C.2 Oral semaglutide received FDA approval from the results found from the PIONEER trials. The PIONEER clinical trials for oral semaglutide were a global developmental program that enrolled 8845 patients with Type 2 Diabetes across 10 clinical trials. The PIONEER 4 trial, a phase 3, randomized- controlled, double-blind, double-dummy clinical trial, compared oral semaglutide to subcutaneous liraglutide and placebo. The primary end point of the study was the change from baseline to week 26 in hemoglobin A1c (HbA1C). The non-inferiority margin or limit was set to be 0.4% difference of HbA1C. 3 It was found that oral semaglutide (14mg) was noninferior to subcutaneous liraglutide (dose escalated over 26 weeks to 1.8mg subcutaneously as that is the standard dosing regimen for liraglutide) with a treatment difference of HbA1C of -0.1% (95% CI of -0.3% to 0.0; p<0.0001). 3 Moreover, it was found in this trial that oral semaglutide was superior to placebo with a reduction of -1.1% (95% CI -1.2% to -0.9%; p<0.0001). 3 This study also had a secondary endpoint for weight reduction from baseline to week 26. Oral semaglutide was superior in weight reduction to both placebo and liraglutide after 26 weeks with a reduction of -1.5kg (95% CI: -2.2kg to -0.9kg; p<0.0001 ) compared to liraglutide and -4kg ( 95% CI: – 4.8kg to -3.2kg; p<0.0001) compared to placebo. 3
The PIONEER 6 trial, a randomized, double-blind, placebo controlled clinical trial, found the cardiovascular risk associated with oral semaglutide to be noninferior to placebo. The primary end-point of this study was the first occurrence of a major adverse cardiovascular event which included death from cardiovascular causes, nonfatal myocardial infarction, or non-fatal stroke.4 Secondary cardiovascular outcomes included the time from randomization to the first occurrence of the following: an expanded composite outcome consisting of the primary outcome plus unstable angina resulting in hospitalization or heart failure resulting in hospitalization, a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke, and the individual components of these composite outcomes. 4 The trial was designed to rule out an excess of 80% cardiovascular risk for oral semaglutide compared to placebo and therefore had a non-inferiority margin of 1.8 as the upper boundary for the 95% confidence interval of the hazard ratio used to analyze the data. 4 Primary endpoints results had a hazard ratio of 0.79 (95% CI: 0.57 to 1.11; p<0.001 for non-inferiority). 4
This non-inferior result is consistent with the noninferiority found in the SUSTAIN-6 randomized, double-blind, placebo-controlled, parallel-group trial of subcutaneous semaglutide. This trial compared subcutaneous semaglutide with placebo to rule out excess cardiovascular risks. It has the same primary composite endpoint that was the first occurrence of a major adverse cardiovascular event which included death from cardiovascular causes, nonfatal myocardial infarction, or non-fatal stroke. 5
The non-inferiority margin was designed to rule out an excess of 80% cardiovascular risk and thus the non-inferiority margin of 1.8 as the upper boundary for the 95% confidence interval of the hazard ratio was used. The primary outcome had a hazard ratio of 0.74 (95% CI: 0.58-0.95; p<0.001 for non-inferiority and p<0.02 for superiority) compared to placebo. 5 One should note that subcutaneous semaglutide based on these results from the SUSTAIN-6 trial is superior (though slightly) to placebo for cardiovascular outcomes, whereas, the oral semaglutide was only found to be non-inferior to placebo in the PIONEER 6 trial. Therefore, oral semaglutide could be considered slightly less efficacious in terms of cardiovascular benefit compared to subcutaneous semaglutide (though it still fulfilled the intent of the PIONEER-6 study to prove non-inferiority to placebo for cardiovascular outcomes).
In summary, oral semaglutide is equally efficacious to subcutaneous GLP-1 agonists on the market with the benefit of being an oral formulation opposed to an injectable formulation.
Significance of Peptide in Oral Dosage Forms and how Oral Semaglutide was made
The significance of oral semaglutide can be explained through the Biopharmaceutical Classification System (BCS). The BCS is divided into 4 categories; Class 1 is both high solubility and high permeability, Class 2 has low solubility but high permeability, Class 3 has high solubility but low permeability, and Class 4 has low solubility and low permeability. Hydrophilic peptides such as GLP-1 agonists would fit into the category of Class 3, due to their low permeability through the stomach because of the lack of passive or carrier-mediated transport or transcellular transport of such macromolecules. 6 This is coupled with the problem of being susceptible to degradation from the high pH and enzymes of the digestive tract. This results in class of macromolecules, peptides and proteins, not being suited for the oral dosage form. Since the 1980’s, over 90% of all protein or peptide-based drugs have only injectables. Oral semaglutide is a step forward in the innovation of oral peptides as this drug class requires frequent chronic dosing, which typically makes them quite hard to be oral due to the previously described limiting factors. 6
The oral dosage form was made possible due to the use of an intestinal permeation enhancer called salcaprozate sodium (SNAC) which is a synthetic N-acetylated amino-acid derivative of salicylic acid. SNAC works by many mechanisms to increase permeability including, opening tight junctions to increase paracellular permeability, decreasing mucus viscosity, inhibition of epithelial efflux pumps, complexation of payload, increasing membrane fluidity, and (indirectly) via peptidase inhibition. 6 It should be noted that semaglutide itself has a very long half-life of 7 days, is highly potent, and stable. 7 This makes it easier to predict levels from the oral dosage formulation compared to less stable peptides. SNAC in pre-clinical trials has shown promise for increasing insulin bioavailability in an oral dosage form as well. Overall, with the introduction of Rybelsus, the first oral GLP-1 agonist on the market, there is hope for other peptide or protein-based injections to be introduced in oral forms in the future such as insulin.
- Koliaki C, Doupis J. Incretin-based therapy: a powerful and promising weapon in the treatment of type 2 diabetes mellitus. Diabetes Ther. 2011 May;2(2):101-21.
- American Diabetes Association. Standards of Medical Care in Diabetes-2020 Abridged for Primary Care Providers. Clin Diabetes. 2020 Jan;38(1):10-38
- Pratley R, Amod A, Hoff ST, Kadowaki T, Lingvay I, Nauck M, Pedersen KB, Saugstrup T, Meier JJ; PIONEER 4 investigators. Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomised, double-blind, phase 3a trial. Lancet. 2019 Jul 6;394(10192):39-50.
- Husain M, Birkenfeld AL, Donsmark M, Dungan K, Eliaschewitz FG, Franco DR, Jeppesen OK, Lingvay I, Mosenzon O, Pedersen SD, Tack CJ, Thomsen M, Vilsbøll T, Warren ML, Bain SC; PIONEER 6 Investigators. Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2019 Aug 29;381(9):841-851
- Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA, Lingvay I, Rosenstock J, Seufert J, Warren ML, Woo V, Hansen O, Holst AG, Pettersson J, Vilsbøll T; SUSTAIN-6 Investigators. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2016 Nov 10;375(19):1834-1844.
- Twarog C, Fattah S, Heade J, Maher S, Fattal E, Brayden DJ. Intestinal Permeation Enhancers for Oral Delivery of Macromolecules: A Comparison between Salcaprozate Sodium (SNAC) and Sodium Caprate (C 10 ). Pharmaceutics. 2019 Feb 13;11(2):78.
- Hall S, Isaacs D, Clements JN. Pharmacokinetics and Clinical Implications of Semaglutide: A New Glucagon-Like Peptide (GLP)-1 Receptor Agonist. Clin Pharmacokinet. 2018 Dec;57(12):1529-1538. doi: 10.1007/s40262-018-0668-z. PMID: 29915923.