Investigational glucagon-like peptide-1 agonists for the treatment of obesity

ABSTRACT

Introduction: Obesity is a worldwide problem predisposing to type 2 diabetes mellitus (T2DM), hypertension, cardiovascular disease, cancer and other comorbidities. Lifestyle modification is the first line intervention but adjunctive pharmacotherapy is often required. The GLP-1 receptor agonists (GLP-1RAs) were developed primarily for T2DM and they also reduce body weight. Liraglutide was approved for the treatment of obesity and other GLP-1RAs are likely to be suitable for this indication.

Areas covered: This review describes the GLP-1RAs that have been approved for the treatment of T2DM as potential candidates for the treatment of obesity and the new agents currently under development which may have advantages in patient adherence.

Expert opinion: The GLP-1RAs offer a welcome addition to obesity pharmacotherapy. They appear to be free of serious adverse effects although uncertainty remains about possible risks of pancreatitis and neoplasms. However, they have frequent gastrointestinal side effects, particularly nausea, which limits their tolerability. Cardiovascular outcome studies in T2DM support their use and this is likely to increase in both T2DM and obesity. Other GLP-1RAs which can be given by subcutaneous injection once weekly or less frequently or by oral administration would have advantages especially if nausea is less frequent than with liraglutide.

KEYWORDS:

• Efpeglenatide
• exenatide
• GLP-1 receptor agonist
• ITCA 650
• liraglutide
• obesity
• semaglutide

Article highlights

• The glucagon-like peptide-1 receptor agonists that have been approved for the treatment of T2DM result in varying degrees of body weight reduction and liraglutide has been approved for weight management in overweight or obese adults.

• Some of the other currently available GLP-1RAs have the advantage that they are given by weekly s.c. injection rather than by daily s.c. injection with liraglutide.

• All of the GLP-1RAs are associated with nausea and vomiting to a variable extent and these adverse effects tend to decline with time but do have a major influence on patient adherence and probably contribute to the weight loss.

• Exenatide, particularly in the long acting exenatide LAR formulation, may be a useful alternative to liraglutide for weight management.

• The miniature osmotic pump system for s.c. delivery of exenatide ITCA 650 is in late stage development and may have benefits depending on patient acceptability.

• GLP-1RAs in Phase II or III development for s.c. administration once weekly or less frequently include semaglutide, efpeglenatide and PB1023 for the indications of T2DM or obesity.

• Orally available GLP-1RAs including semaglutide and small molecules such as TTP273 are also being studied.

• CV outcome studies in T2DM patients have shown that lixisenatide had neutral effects on CV events, whereas liraglutide had benficial effects and results announced for semaglutide are reported to show a significant reduction in CVD events.

• Conclusions: GLP-1RAs provide an effective otion for obesity management and less frequent injection therapy or oral administration should improve patient adherence, especially if tolerability can be improved. The CV outcome studies in T2DM patients with GLP-1RAs support their use and further outcome studies in obesity are needed.

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Declaration of interest

B Tomlinson has received research funding from Amgen, AstraZeneca, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer Inc and Roche and has been a consultant, advisor or speaker for Amgen, AstraZeneca, Merck Serono and Sanofi. 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.

Additional information

Funding

This paper was not funded.