Glucagon-like peptide-1 (GLP-1) receptor agonists, originally approved as treatment in type-2 diabetes, recently became a tremendous success in the obesity market. Currently, subcutaneous delivery – via needle-based syringes or pens – is the common route of administration for GLP-1 receptor agonists. However, this route is associated with several drawbacks. Sublingual delivery could be a more patient friendly alternative: it is easy, fast, reliable and may even reduce a number of side effects.
In 2009, EMA approved liraglutide for treatment of type 2 diabetes (T2D), followed by the approval of semaglutide for T2D treatment in 2018. Recently, these incretin drugs also became very popular as a treatment of obesity (combined with life style improvements).
Both liraglutide (brand names Saxenda® and Victoza®) and semaglutide (brand names Ozempic® and Wygovy®) mimic the physiological activity of so the called gut-derived insulinotropic peptide, or incretin, glucagon-like peptide-1 (GLP-1). GLP-1 emerged as a target for T2D treatment due to its unique mechanism of action. GLP-1 is an endogenous hormone produced by intestinal enteroendocrine L cells following nutrient ingestion.
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A brief retrospective on GLP-1
In 1932, La Barre and colleagues coined the incretin concept to describe as yet unknown humoral factors released from the intestine that lowered blood glucose in response to a meal.
The first actual incretin was described in 1973: glucose-dependent insulinotropic polypeptide, also known as gastric inhibitory polypeptide (GIP). GIP is known to stimulate insulin secretion in response to macronutrients. GLP-1, the second incretin, was discovered in 1987.GLP-1 stimulates insulin secretion in a glucose concentration-dependent manner at glucose level above 4.3 mmol/l. In addition, GLP-1 is a strong inhibitor of glucagon secretion.
GLP-1 analogues
Obviously, the discovery of the role of incretins in blood-glucose homeostasis sparked off the development of incretin analogues to be used in the treatment of T2D. In particular, GLP-1 receptor agonists proved to be safe and effective and are standard treatment-options for T2D now. Currently, six GLP-1 receptor agonists are marked approved; dulaglutide, exenatide, lixisenatide, liraglutide, tirzepatide and semaglutide.
Subcutaneous delivery
Because of their peptide-like nature, all GLP-1 receptor agonists are readily degraded in the gastrointestinal system. This is why subcutaneous delivery is at the moment the only feasible route for all GLP-1 receptor agonists. Only semaglutide is also available in an oral formulation. However, absorption of oral semaglutide is variable resulting is low biologic availability of a mere 1% to 2%, meaning 98% to 99% of the drug is lost.
Subcutaneous administration, however, is associated with several usual drawbacks such as injection pain, inconvenience, social distress and/or injection phobia. Furthermore, a major drawback of GLP-1 agonist drugs is a high incidence of gastrointestinal problems, like nausea, vomiting, diarrhoea, and constipation. Together these adversities might result in variable results or poor compliance hampering the effectiveness of these drugs in millions of patients depending on GLP-1 receptor agonists for the treatment of T2D and/or obesity.
Currently, there is much interest in delivering GLP-1 receptor agonists via alternate, non-invasive routes with high bioavailability and least side effects as possible.
Sublingual administration
Recently, a new sublingual modality for GLP-1 receptor agonists (and also for insulins) delivery has been developed by the Dutch company SUBLIN BV, established in 2018 as a spin-out of the healthcare branch of NanoServe BV. This modality is based on the use of nanoparticles, with various size ranging from nanometre to micrometre scale based on a patented technology process. These particles are able to encapsulate small as well as large drugs, and to release the loaded molecules in blood circulation after having passed the buccal sublingual mucosal barrier.
The process of synthesis is engineered to be easy to reproduce and enable a cost-effective scale up production. Furthermore, formulations for slow or rapid release profiles have been developed. Particles having a size ranging from 340 nm to 850 nm can be produced, scaled-up, characterized and tested.
a single dose per animal.
In vivo preclinical trials
Three different healthy pigs were exposed to either a low dose (sublingual 1) or an intermediate dose (sublingual 2) of an incretin or by subcutaneous administration of a standard dose (subcutaneous). Subsequent blood samples were extracted from these three pigs at different time points and analyzed for monitoring plasma incretin concentrations changes overtime. Clearly, sublingual applications appear to reach comparable plasma levels to the subcutaneous injections of this particular incretin, as depicted in figure 1. As was previously demonstrated for a sublingual insulin formulation (sublintherapeutics.com/sublin-bv-developing-a-first-in-class-sublingual-insulin-delivery-formulation/)), these in vivo incretin studies clearly show that the sublingual formulation technology can incorporate different drug classes and provide an effective alternative for patients to their daily injections.
As depicted in figure 2, Sublin has successfully encapsulated different incretins, with good in vivo safety and bioavailability after applying a single dose sublingually.
An important feature of the technology is that, depending on the physicochemical properties of the nanoparticles, the drug molecules can be taken up preferentially by the blood circulation (smaller molecules) or first via lymphatic absorption (larger molecules). The latter route has a large advantage of adding circulation time to the drug, allowing long-lasting effects of the drugs, potentially reducing the administration frequency and possibly also lowering gastrointestinal complications, as currently only subcutaneous and very few oral routes have been explored. This is yet to be confirmed by clinical studies. The lymphatic absorption has been illustrated in figure 3.
Future implications of sublingual formulations
As mentioned above, GLP-1 receptor agonists are approved for the treatment of T2D and (sometimes off label) used for the treatment of obesity. According to the International Diabetes Federation (IDF), about 537 million people worldwide have diabetes, with 90% being T2D. In addition, 1 in 8 people in the world are living with obesity, stated the World Health Organization (WHO). Moreover, both the number of cases and the prevalence of T2D and obesity have been steadily increasing worldwide over the past few decades. This means that, potentially, hundreds of millions of people worldwide will depend on regular use of insulins, GLP-1 receptor agonists, or both.
The current adopted subcutaneous administration of GLP-1 receptor agonists and insulins has several limitations. It is associated with drawbacks such as injection pain, injection site dystrophy, inconvenience, social distress and/or injection phobia. Therefore, there is an urge need for the development of alternative oral formulations for these drugs to overcome subcutaneous complications.
Sublingual formulation will make treatment much easier and much more patient friendly as exemplified in figure 4. This will increase compliance and therefore the effectiveness of the treatment for millions of patients. As a result, patients could live longer and with less complications which will decrease the burden of disease, increase quality of life, and relieve the health care system.
Towards a brighter future for millions of patients
Given the growing global prevalence of T2D and obesity, the implementation of sublingual formulations could have profound implications for public health. By simplifying administration and enhancing patient adherence, this modality may not only improve individual patient outcomes but also temper the broader healthcare burden associated with these chronic conditions. Future clinical studies are essential to validate these promising benefits and to optimize the formulations for widespread clinical use. As the development of a sublingual delivery of biological GLP-1 receptor agonists heralds a new era in chronic disease management, the technology is poised to significantly improve quality of life for millions of patients worldwide.
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Images Courtesy: Sublin Therapeutics