Retatrutide: a triple incretin receptor agonist for obesity management

ABSTRACTIntroduction 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 management of heart failure and its potential impact on eating patterns have also been covered in this paper.Expert opinion Although the reductions in HbA1c and dose-dependent weight loss amongst 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 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. Additionally, retatrutide's potential in heart failure management is intriguing given the series of positive findings of semaglutide on cardiovascular outcomes.KEYWORDS: RetatrutideobesityDiabetes mellitusGlucagonheart failureDisclaimerAs a service to authors and researchers we are providing this version of an accepted manuscript (AM). Copyediting, typesetting, and review of the resulting proofs will be undertaken on this manuscript before final publication of the Version of Record (VoR). During production and pre-press, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal relate to these versions also. Article highlightsThe landscape of obesity treatment is rapidly changing with the development of incretin analogues 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 interestThe 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 disclosuresA 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.Figure 1. The role of glucagon in maintaining glucose homeostasis and regulation of its secretion from the pancreas. GLP-1: glucagon-like peptide 1Display full sizeAdditional informationFundingThis study did not receive funding from any source.