Removing the needle: the unmet need for oral GLP-1 drugs 


The hormone GLP-1 (glucagon-like peptide-1) and its receptor agonists (GLP-1RAs) have emerged as a compelling class of drugs to tackle diabetes, particularly due to their remarkable efficacy in lowering obesity levels, a fundamental contributing factor of type 2 diabetes. But there is much more to come from this drug class, argues Jeremy Skillington, CEO of Poolbeg Pharma. 

GLP-1RAs are a breakthrough class of drugs for the treatment of diabetes that have produced impressive results in a number of studies by mimicking GLP-1 in the body.  GLP-1 is a hormone that plays a crucial role in glucose metabolism and insulin secretion. Known for their ability to significantly lower blood glucose levels, GLP-1RAs offer a ray of hope for individuals seeking effective alternatives to insulin. In comparison to traditional treatments, GLP-1RAs have enabled less frequent administration/ injections, making them a preferred choice among patients and healthcare providers alike. 

In March 2024, Novo Nordisk’s anti-obesity GLP-1RA drug, Wegovy, received FDA approval for its potential to reduce cardiovascular risks in patients without diabetes. In October 2023 Novo celebrated positive clinical data for Semaglutide, the active ingredient of Wegovy, in chronic kidney disease showcasing the potential of this drug to have benefit in a range of metabolic diseases.  

A fundamental aspect of GLP-1RAs is their ability to mimic the actions of the naturally occurring hormone, GLP-1. GLP-1 is released by the body when we eat, and stimulates insulin secretion from the pancreas, which helps to manage glucose levels. Importantly, this stimulation occurs in such a way that insulin is released only when needed, such as after meals when blood glucose and lipids (fats) levels are elevated. This mechanism serves as a sophisticated regulatory system that aids in maintaining optimal glucose levels in the bloodstream. 

Advancements and challenges of oral GLP-1 formulations 

The GLP-1RA drug market is witnessing substantial growth, with a projection to exceed $150 billion by 20311. The market’s significance is further emphasised by the fact that the global health expenditure on diabetes is estimated to reach $825 billion by 20302, highlighting the urgency for effective and accessible solutions. 

While many injectable forms of GLP-1RAs are available, ongoing developments in oral formulations mark a significant stride in patient convenience and revolution of the treatment of diabetes. Efforts are underway to provide a more accessible oral option for individuals who may prefer it over injections. Oral formulations have an array of benefits over injections including their ease of administration, potential reduced manufacturing costs, ease of distribution, improved compliance by patients and potential to overcome needle-phobia.  

While the benefits of an oral GLP-1RA are obvious, getting this class of drug to work in oral form has proven a technical challenge. 

As a result there is currently only a single oral option for patients, Novo Nordisk’s Rybelsus, which is approved for patients with type 2 diabetes and is based on the same active ingredient used in Wegovy, semaglutide. 

As they are relatively large peptide molecules, GLP-1s like semaglutide are not readily absorbed by the gut. Novo Nordisk overcame this by adding a “carrier” to increase absorption and reduce the amount of active ingredient needed within the pill. 

Once this challenge was overcome, the oral formulation still required daily dosing, instead of weekly doses with some rival injected GLP-1s. 

This includes Novo Nordisk’s Ozempic (semaglutide), the formulation based around this active ingredient approved since 2017 for type 2 diabetes. 

Pfizer has been attempting to develop a weekly or fortnightly-dosed oral GLP-1, danuglipron, but announced at the end of 2023 that it would focus efforts on a daily formulation instead because of high discontinuation rates (more than 50%) because of gastrointestinal side-effects. 

Other issues experienced with GLP-1RAs are supply shortages as manufacturers have struggled to meet demand, which is increased by their off-label use in weight loss. 

Nonetheless, oral GLP-1RAs represent a multifaceted approach to the treatment of diabetes and related metabolic conditions. Their mechanisms of action, encompassing insulin secretion, glucagon suppression, gastric emptying regulation, and appetite control, highlight their potential for comprehensive glycaemic management. With advancements in oral formulations, these medications continue to evolve, offering patients more convenient options in their journey towards improved health. 

One solution for the oral delivery of metabolic peptide cargo is to target areas of the gut in a manner configured to increase the likelihood of effectiveness when administered. It aims to provide ready and safe absorption into systemic circulation as an effective treatment for patients with diabetes, obesity, and other metabolic diseases. 

With the diabetes epidemic reaching alarming proportions globally, the need for accessible, effective, and innovative treatments is more critical than ever. Such advances in developing an oral delivery system for GLP-1RAs could potentially transform the landscape of diabetes management and enhance patients’ lives. As we eagerly await further developments, the prospect of a scalable, safe, and oral GLP-1RA delivery system could mark a significant milestone in the ongoing battle against diabetes and related metabolic diseases. 


  1. The Economist, March 2023 
  2. Rhys Williams, Suvi Karuranga, Belma Malanda , Pouya Saeedi, Abdul Basit, Stéphane Besançon, Christian Bommer, Alireza Esteghamati, Katherine Ogurtsova, Ping Zhang, Stephen Colagiuri, Global and regional estimates and projections of diabetes-related health expenditure: Results from the International Diabetes Federation Diabetes Atlas, 9th edition, 13 Feb 2020 National Library of Medicine,annual%20health%20expenditures%20on%20diabetes 

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