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

Authors Antza C, Nirantharakumar K, Doundoulakis I, Tahrani AA, Toulis KA

Received 31 October 2018

Accepted for publication 27 June 2019

Published 22 August 2019 Volume 2019:13 Pages 2985—2996


Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 3

Editor who approved publication: Dr Tuo Deng

Christina Antza,1,* Krishnarajah Nirantharakumar,2,* Ioannis Doundoulakis,3 Abd A Tahrani,4–6 Konstantinos A Toulis2,3

13rd Department of Internal Medicine, Papageorgiou Hospital, Aristotle University, Thessaloniki, Greece; 2Institute of Applied Health Research, University of Birmingham, Birmingham, UK; 3Department of Endocrinology and Diabetes, 424 General Military Hospital, Thessaloniki, Greece; 4Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK; 5Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK; 6Department of Diabetes and Endocrinology, Birmingham Heartlands Hospital, Birmingham, UK

Correspondence: Konstantinos A Toulis
Department of Endocrinology, Diabetes and Metabolism, 424 General Military Hospital, Thessaloniki, Greece
Tel +30 231 038 1902

*These authors contributed equally to this work

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

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