On January 13, 2023, Novo Nordisk released a statement that its oral formulation of semaglutide (Rybelsus® 7mg and 14mg) had received the United States Food and Drug Association (FDA) approval as first-line treatment for Type 2 Diabetes Mellitus (T2DM).
This is a label update to its first indication back in 2019 which previously limited its use in patients naive to pharmacologic therapy, making it the first and only drug in its class to receive this indication. This article explores Semaglutide.
Semaglutide’s Mechanism of Action
Semaglutide, currently available in both oral and subcutaneous (Ozempic®) dosage forms, is a selective glucagon-like peptide-1 (GLP-1) receptor agonist (RA) with three main mechanisms of action. GLP-1 RAs reduce postprandial hyperglycemia by increasing glucose-dependent insulin secretion, decreasing inappropriate glucagon secretion, and slowing gastric emptying. Additionally, it has also appeared to act in areas of the brain involved in the regulation of appetite and caloric intake, where satiety remains an advantage in diabetics trying to control their dietary intake.
In vivo, proteins are expected to be degraded by gastric acid secretion, with GLP-1 further metabolised by the enzyme dipeptidyl peptidase-4. But this is where Rybelsus® stands out. Its unique co-formulation of semaglutide called SNAC (sodium N-(8-[2-hydroxybenzoyl] amino) caprylate), acts as a weak carboxylic acid and buffers the acidity in the stomach which limits enzymatic degradation of the semaglutide. SNAC also acts as an absorption enhancer, granting it properties to be developed as a pill which improves patient compliance and acceptance as compared to an injection.
GLP-1 RAs as the first line in diabetes mellitus?
The decision to move Rybelsus® up the treatment algorithm possibly stemmed from 10 different trials under the PIONEER group, powering the efficacy and safety of oral semaglutide against multiple comparators over a variety of trial populations.
PIONEER 1 was a 26-week placebo-controlled randomised study looking at 703 adults diagnosed with T2DM insufficiently controlled with diet and exercise. They were randomised to 3 doses of oral semaglutide 3 mg, 7 mg, 14 mg and placebo in equal proportions. By week 26, patients taking monotherapy oral semaglutide had statistically significant average placebo-adjusted HbA1c reductions ranging 0.6% – 1.1%. The highest dose of 14 mg also showed significant body weight reduction (of at least 5%) versus placebo.
The PIONEER 2 trial involved 821 patients with uncontrolled T2DM on metformin over 52 weeks, randomised to once daily open-label oral semaglutide 14 mg (n=412) or empagliflozin 25 mg (n=410), a sodium glucose cotransporter-2 inhibitors (SGLT2i). Oral semaglutide showed approximately 44% greater reduction in HbA1c versus empagliflozin at week 26 (treatment policy -1.3% vs. -0.9% P < 0.0001), with sustained effects through 52 weeks.
A larger study, PIONEER 3 with 1864 patients with T2DM on metformin, with or without a sulfonylurea, continued to show oral semaglutide’s efficacy over dipeptidyl peptidase 4-inhibitor, sitagliptin. At the 7 mg and 14 mg dose, on average, oral semaglutide reduced HbA1x further by 0.3% – 0.5% and bodyweight by 1.6 – 2.5 kg as compared to sitagliptin.
The other studies included patients with moderately impaired renal functions, high cardiovascular risk, those utilising flexible dosing regimens based on tolerability, those on insulin. More notably would be the studies done in the Asian population, Japanese in PIONEER 9 (against liraglutide or placebo) and 10 (against dulaglutide), and Chinese in PIONEER 11 (placebo-controlled) and 12 (against sitagliptin or placebo).
PIONEER 9 showed statistically significant dose-dependent HbA1c reductions ranging 1.1 – 1.7% at week 26 against placebo. Against liraglutide, there was also HbA1c reduction of 0.3% albeit at the highest dose, which was unfortunately not sustained by week 52.
PIONEER 11, involving 521 participants, continued to show efficacy in Chinese patients. Oral semaglutide at all doses showed superior reductions in HbA1c at week 26 (P<0.001). But only at the highest dose, did it show a significant reduction in body weight compared to placebo at week 26 (P<0.0001).
Overall, all results also showed a favourable benefit-risk profile, with gastrointestinal adverse events (AEs) being the most common, although they were mild and of short duration, consistent with the known AES of the class.
The updated indication for Rybelsus® could also have possibly been accelerated by the American Diabetes Association’s updates to the Standards of Care in Diabetes 2023. Of which, they’ve begun emphasising on exploring treatment options which support greater weight loss (notably 10% or more) which may have more significant disease-modifying effects and improve long-term cardiovascular outcomes.
However, it is imperative to note that the positioning of GLP1-RAs remains unfavourable when it comes to guidelines published by the National Institute for Health and Care Excellence (NICE). Some possible explanations include a lack of in-depth review of this class and its cardiovascular benefits (unlike SGLT2is). The variability of dosage forms, frequency of administration and efficacy within the same class also slow down the progress on reviews concerning cost-effectiveness which remain a cornerstone in guidance. However, considering that there has yet to be updates since 2015, it will be of little surprise that something is in the works, and there will be radical changes in the management of T2DM with all that has happened in the scene over the past 7 years.
And hopefully, with more established guidelines and treatment recommendations, accessibility to these disease-modifying options will be greatly improved for the better health of all in need.
Reference:
- UpToDate: Semaglutide. Accessed 1 February, 2023.
- ElSayed NA, Aleppo G, Aroda VR, et al. 9. Pharmacologic approaches to glycemic treatment: standards of care in diabetes—2023. Diabetes Care. 2023;46(Supplement_1):S140-S157.
