Novel approaches to anti-obesity drug discovery with gut hormones over the past 10 years

ABSTRACT

Introduction: Obesity is a global pandemic and new pharmacotherapies which combine weight loss efficacy, long-term safety, and reversal of metabolic co-morbidities are sorely needed. Gut hormones play key roles in regulating satiety and metabolism, and are natural candidates for therapeutic development.

Areas covered: The authors discuss recent drug developments for the treatment of obesity using gut hormones. The review was based on a search of PubMed using keywords ‘obesity’ AND (‘therapy’ OR ‘pharmacotherapy’ OR ‘gut hormones’ OR ‘analogues’), limited to the last 10 years.

Expert opinion: Analogues of glucagon-like peptide (GLP-1) have been developed for obesity but so far do not provide enough weight loss. Bariatric surgery increases the post-prandial secretion of multiple gut hormones, leading to beneficial effects on weight loss and metabolism. This recognition has led to poly-agonist strategies: GLP-1/glucagon or GLP-1/glucose-dependent insulinotropic peptide (GIP) dual agonism, or even GLP-1/glucagon/GIP triple agonism. New delivery approaches include peptide-conjugate therapies that target key metabolic tissues. Practicable methods for oral delivery of peptide gut hormones are also close to market, expanding the potential market for these treatments. Anti-obesity therapy is therefore poised for an exciting phase, and it will be interesting to see which of these will eventually prevail.

KEYWORDS:

• Combination therapies
• drug development
• gut hormones
• obesity
• weight loss

Article Highlights

• Obesity is a continually growing global public health challenge. Past and current treatment options have been dogged by inadequate efficacy and/or unacceptable side effects and improved drug options are urgently required.

• Gut hormones are known to regulate food intake and metabolism through natural pathways and it is known that bariatric surgery effectuates its benefits through enhanced secretion of these hormones. Hence gut hormone-based therapies represent a potential class of "druggable" targets.

• GLP-1 agonists have been a successful forerunner for gut hormone therapies. Liraglutide is now licensed for use in obesity, and other GLP-1 agonists such as semaglutide are being actively investigated for this indication. However, this single agonist approach is not efficacious enough for many obese patients and carries significant side effects.

• The use of gut hormone combinations that simultaneously target different signalling pathways can produce synergistic effects whilst minimizing side effects. There are ongoing pre-clinical and clinical studies into dual and triple agonism for GLP-1/glucagon, GLP-1/GIP, and even GLP-1/GIP/glucagon.

• There is also growing interest in peptide-directed targeting of hormonal therapies using long acting conjugates, with promising pre-clinical results, but their safety is still being definitively established.

This box summarizes key points contained in the article.

Declaration of interest

T Tan has received grants from the UK Medical Research Council and the National Institute of Health Research as well as from the Moulton Charitable Foundation. Meanwhile, S Bloom has received grants from the UK Medical Research Council and the National Institute of Health Research. 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.

Reviewer Disclosures

One referee is involved in the drug development of fixed dose combination products with low molecular drugs with a focus on obesity as a main indication. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

The authors are funded by grants from the Medical Research Council and the Biotechnology and Biological Sciences Research Council. They are also supported by the NIHR Imperial Biomedical Research Centre Funding Scheme through their department.