The development of an oral GLP-1 receptor agonist for the management of type 2 diabetes: evidence to date

Abstract

Glucagon-like peptide 1 receptor agonists (GLP1-RA) are prominent agents in the therapeutics of type 2 diabetes mellitus due to their exemplary efficacy in both preprandial and postprandial glycemia, their safety, low risk of hypoglycemia, their multilevel pathophysiological superiority, weight loss and importantly the observed benefits in cardiovascular disease reduction. Their major drawback is the subcutaneous route of administration, constituting a barrier to adoption and reason for treatment discontinuation. Thus, the development of an oral GLP1-RA agent would promote medication adherence and quality of life, further consolidating its beneficial effects in real-life clinical practice. However, this task is hampered by suboptimal gastrointestinal protein absorption. Yet, the introduction of oral semaglutide, a modified form of semaglutide with the addition of a carrier sodium N-(8-[2-hydroxybenzoyl] amino) caprylate, may have provided a safe and effective way to reach systemic circulation while other molecules are in development. Whether this molecule still has the impressive cardiovascular effects demonstrated with the use of its precursor remains to be explored. However, to date, its efficacy and safety have already been showcased in a randomized trial. More research is warranted in order to further consolidate these findings across different type 2 diabetes mellitus (T2DM) subpopulations, and adequately powered studies with a longer follow-up that would allow the exploration of microvascular and macrovascular complications are needed. Finally, studies comparing oral semaglutide and similar molecules with other currently established antidiabetic agents to evaluate the relative efficacy, the cost-effectiveness and further understand its place in T2DM therapeutic algorithm are needed. This review focuses on the development of oral GLP1-RA agents and summarizes the challenges, milestones and expected benefits associated with a successful introduction.

Keywords:

• glucagon-like peptide
• pharmacokinetics
• therapeutics

Acknowledgments

AAT is a clinician scientist supported by the National Institute for Health Research in the UK. The views expressed in this publication are those of the authors and not necessarily those of the National Health Service, the National Institute for Health Research, or the Department of Health (UK).

Abbreviations list

GLP1-RA, Glucagon-like peptide 1 receptor agonist; HbA1c, hemoglobin A1c; T2DM, type 2 diabetes mellitus; CV, cardiovascular; FDA, food and drug administration; EMA, European Medicines Agency; SNAC, sodium N-(8-[2-hydroxybenzoyl] amino) caprylate; GIP, gastric inhibitory polypeptide.

Author contributions

All authors contributed towards data analysis, drafting and critically revising the paper, gave final approval of the version to be published, and agreed to be accountable for all aspects of the work.

Disclosure

Dr Doundoulakis, Dr Antza, and Dr Toulis report no conflicts of interest in this work. Dr Nirantharakumar reports grants from National Institute for Health Research, MRC Medical Research Council, Diabetes UK, Vifor, and AstraZeneca, and personal fees from Merck Sharp & Dohme, Sanofi, and Boehringer Ingelheim, outside of and unrelated to the submitted work. Dr Tahrani reports grants, personal fees, and non-financial support from NovoNordisk, personal fees and non-financial support from Eli Lilly, Boehringer Ingelheim and AstraZeneca, and personal fees from Janssen, during the conduct of the study. The authors report no other conflicts of interest in this work.