Retatrutide: a triple incretin receptor agonist for obesity management

ABSTRACT

Introduction

Obesity treatment is evolving rapidly with the emergence of agents targeting incretin receptors. Retatrutide, a triple agonist of these receptors, shows promise in obesity management.

Areas covered

Retatrutide, in phase-2 trials, exhibited significant reductions in glycated hemoglobin (HbA1c) and dose-dependent weight loss in individuals with type 2 diabetes mellitus (T2DM). In non-T2DM individuals, it produced substantial weight loss and improved glucose levels, albeit with gastrointestinal side effects. The role of glucagon receptor agonism in the management of heart failure and its potential impact on eating patterns have also been covered in this article.

Expert opinion

Although the reductions in HbA1c and dose-dependent weight loss among individuals with T2DM were significantly more for higher doses of retatrutide, it needs to be observed that the active comparator was dulaglutide, which is not approved for the treatment of obesity, at a dose of 1.5 mg, which is much lower than the highest approved dose of 4.5 mg. Dose-dependent increase in heart rate and incidents of mild to moderate cardiac arrythmias raise cardiovascular safety concerns and signify that carrying out long-term cardiovascular outcome trials (CVOTs) will be critical. In addition, retatrutide’s potential in heart failure management is intriguing given the series of positive findings of semaglutide on cardiovascular outcomes.

KEYWORDS:

• Retatrutide
• obesity
• diabetes mellitus
• glucagon
• heart failure

Article highlights

• The landscape of obesity treatment is rapidly changing with the development of incretin analogs targeting multiple receptors.

• Retatrutide, a triple agonist of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon (GCG) receptors, shows promise in obesity management albeit with concerns about delayed gastric emptying.

• Concerns about cardiac safety and a series of positive trial findings of semaglutide on heart failure outcomes makes long-term cardiovascular outcome trials (CVOTs) with retatrutide highly valuable.

Declaration of interest

The author has no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

A reviewer on this manuscript has disclosed they were a previous employee of Novo Nordisk. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.