Retatrutide and Triple GLP-1, GIP, and Glucagon Receptor Agonism: What the Published Studies Report

Retatrutide (LY3437943) is described in the literature as a single peptide with agonist activity at the glucose-dependent insulinotropic polypeptide (GIP) receptor, the glucagon-like peptide-1 (GLP-1) receptor, and the glucagon receptor [1]. Reviews of the incretin field place it among a group of multi-receptor agonists in which GLP-1 receptor agonism is combined with additional gastro-entero-pancreatic hormone receptor activity, alongside molecules such as tirzepatide (GLP-1/GIP), survodutide and mazdutide (glucagon co-agonists), and amylin-based combinations [2][3]. One perspective review characterises retatrutide as an example of rational multi-agonist peptide engineering within systems pharmacology [4]. In a randomised, double-blind, placebo- and active-controlled phase 2 trial in 281 adults with type 2 diabetes conducted at 42 sites in the USA, least-squares mean change in HbA1c at 24 weeks ranged from -0.43% in the lowest retatrutide group to -2.02% in the highest, compared with -0.01% for placebo and -1.41% for 1.5 mg dulaglutide, and bodyweight decreased in a dose-dependent manner at 36 weeks by 3.19% to 16.94% versus 3.00% with placebo [1]. Mild-to-moderate gastrointestinal adverse events, including nausea, diarrhoea, vomiting, and constipation, were reported in 35% of participants across the retatrutide groups, with no reports of severe hypoglycaemia and no deaths during that human study [1]. A subsequent 40-week phase 3 randomised, double-blind, placebo-controlled trial (TRANSCEND-T2D-1) enrolled 537 adults with type 2 diabetes inadequately controlled by diet and exercise at 48 sites in the USA, Mexico, and India [5]. Mean change from baseline in HbA1c at week 40 was -1.69%, -1.86%, and -1.94% across the three retatrutide groups versus -0.81% with placebo, and mean percentage change in bodyweight was -11.5%, -13.9%, and -15.3% versus -2.6% with placebo [5]. The investigators reported that the most frequent adverse events were generally mild to moderate gastrointestinal events that subsided over time, discontinuations due to adverse events were 2-5% with retatrutide and 0% with placebo, and no severe hypoglycaemia was reported [5]. Evidence syntheses of the human trial data have been published. A systematic review and meta-analysis of three randomised controlled trials totalling 878 patients with obesity, with or without diabetes, reported pooled mean differences versus placebo of -14.33% for body weight, -5.38 for body mass index, -10.51 cm for waist circumference, -23.51 mg/dL for fasting plasma glucose, and -0.91% for HbA1c, with no significant difference in adverse events between groups (relative risk 1.11) [6]. A separate systematic review of clinical trials screening 1,082 patients, of whom 691 were randomly assigned, reported that the highest dose group showed the largest reductions in body weight, body mass index, and waist circumference, and that gastrointestinal adverse effects were the most commonly reported events [7]. A Bayesian network meta-analysis of 19 randomised controlled trials including 29,506 adults with overweight or obesity reported that retatrutide and dual agonists achieved equivalent mean weight loss (-11.0 kg) compared with -9.0 kg for GLP-1 receptor agonists, that retatrutide had the highest odds ratio for achieving at least 15% weight loss, and that retatrutide carried the highest adverse event risk in that analysis [8]. A narrative review summarising phase 2 findings reports mean weight loss of up to 24.2% after 48 weeks in people with obesity and 16.9% after 36 weeks in people with type 2 diabetes, HbA1c improvement of 2.2% in the type 2 diabetes study with 82% of participants reaching HbA1c of 6.5% or below, and changes in blood pressure, lipids, waist circumference, and liver fat, with gastrointestinal symptoms the most common side effects [9]. A separate review of preclinical and clinical work notes that animal studies of retatrutide examined gastric emptying, food intake, and bodyweight, while phase 1 and phase 2 human trials examined dose-dependent bodyweight change, HbA1c, liver steatosis, and diabetic kidney disease endpoints [10]. Mechanistic work has addressed the glucagon receptor component specifically. In post-hoc analyses of two phase 2 retatrutide trials, circulating concentrations of the angiopoietin-like protein 3/8 complex (ANGPTL3/8) decreased in participants with type 2 diabetes and in participants with obesity or overweight without diabetes, and these decreases paralleled reductions in triglycerides and LDL cholesterol [11]. In the same report, in vitro experiments in primary human hepatocytes showed that both glucagon and retatrutide decreased ANGPTL3/8 secretion and that these reductions were blocked by a glucagon receptor antagonist antibody, which the authors interpreted as evidence that glucagon receptor agonism contributes to the observed lipid changes [11]. Outside metabolic endpoints, an operant drug discrimination study in male and female rats reported that acute administration of semaglutide, tirzepatide, and retatrutide each attenuated alcohol discrimination, which the authors described as modulation of alcohol's interoceptive effects; repeated semaglutide maintained this effect across a 15-day treatment period, with discrimination returning to control levels three days after cessation [12]. That work is an animal model and was not conducted in humans [12]. A narrative review of binge eating disorder pharmacology states that it is currently unclear whether GIP/GLP-1/glucagon receptor agonists such as retatrutide affect binge eating disorder and its comorbidities, while noting reports of reduced binge eating in individuals with obesity or overweight [13]. Another review of GLP-1 receptor agonists in psychiatry describes retatrutide as a triple GLP-1, GIP, and glucagon receptor agonist within a class whose members reduce appetite and food intake and slow gastric emptying, and notes gastrointestinal adverse reactions as typical for the class [14]. Reviews also flag open questions. A narrative review of incretin-based pharmacotherapy notes that agents in this class, including retatrutide, have been associated with loss of lean mass of roughly 10% or about 6 kg in trial populations, and discusses resistance exercise as a research question for body composition during incretin therapy [15]. A review of GLP-1 medicine efficacy and safety situates retatrutide among molecules enabling simultaneous activation of glucagon and GLP-1 receptors and discusses safety domains under investigation, including muscle strength, bone density, gastrointestinal motility, pancreatic and biliary disorders, and cancer risk [2]. Reviews of the obesity pharmacotherapy pipeline note that retatrutide has progressed to phase 3 trials and that early data suggested weight change greater than that seen with tirzepatide [16][17], while another review notes beneficial effects reported on both body weight and steatotic liver disease for triple agonism [18]. A review of gut hormones and appetite regulation lists retatrutide among agents reported effective for weight loss and metabolic parameters in humans, and calls for integrated long-term studies [19]. A review of newer type 2 diabetes drug therapies places GIP/GLP-1 dual agonism and subsequent novel agents within the broader development pipeline [20].