An overview of new GLP-1 receptor agonists for type 2 diabetes

ABSTRACT

Introduction: The increasing prevalence of type 2 diabetes mellitus (T2DM) and the eventual need for multiple medications in most patients stimulated the development of new drug classes to reduce plasma glucose levels. The GLP-1 receptor agonists (GLP-1RAs) are established as an option for treatment of T2DM after metformin. They are also effective in reducing body weight but current GLP-1RAs have to be given by subcutaneous injection daily or once weekly.

Areas covered: This review focuses on the new GLP-1RAs currently undergoing development, some of which require less frequent subcutaneous administration and others that are being developed in oral formulations that may favor patient adherence.

Expert opinion: The new GLP-1RAs may have the benefit of requiring less frequent subcutaneous dosing or being active by oral administration. However, cardiovascular outcome trials have shown that DPP4 inhibitors are neutral for cardiovascular events and the first cardiovascular outcome trial with lixisenatide reported similar results, whereas the trial with the SGLT2 inhibitor empagliflozin showed a reduction in cardiovascular events. These findings in patients with high cardiovascular risk may favor the use of SGLT2 inhibitors as a second line treatment after metformin but there should still be an important role for novel GLP-1RAs, especially when weight reduction is required.

KEYWORDS:

• Efpeglenatide
• GLP-1
• GLP-1 receptor agonist
• glymera
• semaglutide
• type 2 diabetes mellitus

Declaration of interest

B Tomlinson has received research funding from Amgen Inc, AstraZeneca, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer Inc and Roche. They also act as a consultant/advisor for Amgen Inc, AstraZeneca, Merck Serono and are on speaker bureaus for Kowa Pharmaceuticals, Merck Serono and Servier. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Article highlights

• Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have a mode of action that has several potential advantages over other antidiabetic drugs, and they are associated with reduction of body weight. They are unlikely to cause hypoglycemia when used alone but may do so in combination with insulin or sulfonylureas.

• The currently available GLP-1RAs have the main disadvantage of requiring administration by subcutaneous injection at daily or weekly intervals, which may reduce patient adherence. They are also associated with nausea and vomiting in a substantial number of patients, but these adverse effects seem to decline with time.

• ITCA 650 is a miniature osmotic pump delivery system providing continuous subcutaneous delivery of exenatide for 28 days, which is in Phase III development.

• Semaglutide has entered Phase III trials both in once-weekly subcutaneous doses and in daily oral doses.

• Efpeglenatide seems effective in subcutaneous doses given once weekly, once every two weeks or once monthly for the treatment of T2DM or weight loss in obesity and is currently being evaluated in Phase III trials.

• Glymera is undergoing Phase II trials in once-weekly subcutaneous doses.

• Several orally available small molecules are currently in early stage development.

• Cardiovascular outcome studies have shown that DPP4 inhibitors and a GLP-1RA had neutral effects on cardiovascular events, whereas the study with empagliflozin showed a significant reduction in cardiovascular disease events and overall mortality.

• Improved patient adherence with less frequent injection therapy or oral administration should increase the use of GLP-1RAs, but this will be balanced by further results from cardiovascular outcome studies with this group of drugs and the SGLT2 inhibitors.

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