Retatrutide

Efficacy and safety of retatrutide, a GIP, GLP-1, and glucagon receptor agonist, in people with type 2 diabetes and inadequate glycaemic control with diet and exercise (TRANSCEND-T2D-1): a double-blind, randomised, phase 3 trial.

Retatrutide is a GIP, GLP-1, and glucagon triple hormone receptor agonist, under clinical development for type 2 diabetes, obesity, and related complications. We aimed to assess the efficacy and safety of retatrutide as a monotherapy in people with type 2 diabetes that is inadequately controlled by diet and exercise alone. In this 40-week, phase 3, randomised, double-blind, placebo-controlled trial at 48 sites in the USA, Mexico, and India, we recruited adults (aged ≥18 years) with type 2 diabetes that is inadequately controlled by diet and exercise alone, glycated haemoglobin (HbA1c) between 7·0% and 9·5% (53-80 mmol/mol), and BMI of at least 23 kg/m2. Participants were randomly...

Authors

Harpreet S Bajaj, Michelle Welch, Parag Shah, Eduardo Luna, Fatima-Zahra Jaouimaa, Bing Liu, Rong Liu, Yanyun Chen

Source

peer_reviewed_research

DOI

10.1016/S0140-6736(26)00967-0

PubMed

42250575

Effect of retatrutide on liver fat content in adults with metabolic dysfunction-associated steatotic liver disease: a substudy of a randomised, double-blind, placebo-controlled, phase 2 trial

A 98-participant imaging substudy reported dose-related reductions in MRI-measured liver fat; imaging does not establish histologic or clinical liver outcomes.

Source

peer_reviewed_research

DOI

10.1038/s41591-024-03018-2

PubMed

38811598

Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA

A phase 2 trial in 281 adults found dose-related HbA1c and weight reductions; gastrointestinal events were most frequent during escalation.

Source

peer_reviewed_research

DOI

10.1016/S0140-6736(23)01053-X

PubMed

37385280

LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: From discovery to clinical proof of concept

Early translational and phase 1 work characterized triple-receptor pharmacology and dose-related metabolic effects; it is proof of concept, not approved clinical use.

Source

peer_reviewed_research

DOI

10.1016/j.cmet.2022.07.013

PubMed

36116484

Appetite, eating attitudes, and eating behaviours during treatment with retatrutide in adults with type 2 diabetes: Results of a phase 2 study.

To determine whether adults with type 2 diabetes (T2D) treated with retatrutide report greater changes in self-reported appetite, dietary restraint, and disinhibition compared to placebo or dulaglutide and to examine associations with weight change. These pre-specified exploratory analyses examined changes from baseline in Appetite Visual Analogue Scale (VAS) and Eating Inventory (EI) scores after 24 and 36 weeks of once-weekly treatment with placebo, dulaglutide 1.5 mg, or retatrutide 0.5, 4, 8, or 12 mg in 275 adults with T2D. Changes from baseline with retatrutide were compared to those with placebo and dulaglutide. Post-hoc correlations between changes in body weight and Appetite...

Decreases in circulating ANGPTL3/8 concentrations following retatrutide treatment parallel reductions in serum lipids.

The aim of this study was to determine if retatrutide, a triple agonist of glucose-dependent insulinotropic polypeptide (GIP) receptor, glucagon-like peptide 1 (GLP-1) receptor and glucagon (GCG) receptor, may lower serum triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C) levels in part by decreasing circulating concentrations of the angiopoietin-like protein 3/8 complex (ANGPTL3/8). In post-hoc analyses of two phase 2 retatrutide trials, concentrations of ANGPTL3/8, ANGPTL4/8 complex (ANGPTL4/8), ANGPTL3 and ANGPTL4 were measured using dedicated immunoassays to determine percent changes from baseline. Correlations of ANGPTL protein and complex levels with lipid and...

Effects of retatrutide on body composition in people with type 2 diabetes: a substudy of a phase 2, double-blind, parallel-group, placebo-controlled, randomised trial.

Retatrutide, a glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1, and glucagon receptor agonist, has demonstrated robust glucose and bodyweight reductions in participants with type 2 diabetes. This substudy assessed percent change from baseline to week 36 in total body fat mass versus placebo and dulaglutide. This phase 2, double-blind, parallel-group, placebo-controlled, randomised controlled trial was done in 42 medical centres in the USA. Eligible participants were adults aged 18-75 years with type 2 diabetes, HbA1c of 7·0-10·5%, stable bodyweight, and BMI of 25-50 kg/m2. Eligible participants were randomly assigned in a 2:2:2:1:1:1:1:2 ratio to once-weekly...

Triple-Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial

A 48-week phase 2 trial in 338 adults without diabetes found dose-dependent weight reduction; gastrointestinal adverse events were common and dose related.

Source

peer_reviewed_research

DOI

10.1056/NEJMoa2301972

PubMed

37366315

Emerging pharmacotherapies for obesity: A systematic review.

A systematic review of phase 2 and phase 3 obesity-drug trials places retatrutide within the emerging triple-agonist pipeline and identifies the need for long-term safety, weight-maintenance, clinical-outcome, underrepresented-population, cost-effectiveness, and access data.

Authors

Michail Kokkorakis et al.

Source

systematic_review_or_meta_analysis

DOI

10.1124/pharmrev.123.001045

PubMed

39952695

Comparative Meta-Analysis of Retatrutide Versus Placebo and Dulaglutide for Weight Loss and Diabetes Management: Insights From Clinical Trials.

PubMed-indexed systematic review and meta-analysis addressing: Comparative Meta-Analysis of Retatrutide Versus Placebo and Dulaglutide for Weight Loss and Diabetes Management: Insights From Clinical Trials.

Authors

Hazem Ayesh, Suhail Ayesh, Kevin Niswender

Source

systematic_review_or_meta_analysis

DOI

10.1097/MJT.0000000000001743

PubMed

Efficacy and safety of triple hormone receptor agonist retatrutide for the management of obesity: a systematic review and meta-analysis.

Retatrutide is a novel triple hormone receptor agonist which has shown great promise in tackling obesity in preliminary trials. We did this systematic review and meta-analysis to pool the results of all available trials and ascertain its safety and efficacy in the treatment of obesity. A literature search was conducted in PubMed, Cochrane Central and Embase using appropriate search terms and randomized control trials (RCTs) were identified which reported the safety and efficacy of retatrutide. Data was pooled using mean differences for continuous variables and risk ratios for the safety profile in RStudio. After the initial search four RCTs were included in the analysis which compared...

Efficacy and safety of retatrutide for the treatment of obesity: a systematic review of clinical trials.

Obesity is a major public health issue linked to various health complications. Retatrutide, a triple agonist peptide targeting the glucagon receptor, GIP receptor, and GLP-1 receptor, shows promise in addressing this need. This systematic review assessed the safety and efficacy of retatrutide for obesity treatment using available clinical trial data. We conducted a comprehensive search of databases, including PubMed, Cochrane and ClinicalTrials.gov, from their inception until March 15, 2025 following PRISMA guidelines. Three articles were included in this systematic review, screening a total of 1,082 patients, with 691 randomly assigned to groups. The average age of participants was...

Efficacy and Safety of GLP-1 Receptor Agonists, Dual Agonists, and Retatrutide for Weight Loss in Adults With Overweight or Obesity: A Bayesian NMA.

To compare the efficacy and safety of GLP-1 receptor agonists (GLP-1RAs), dual agonists (GLP-1RAs/GIP or GCGR), and retatrutide (GLP-1/GIP/glucagon) for weight loss in adults with overweight or obesity. We conducted a systematic review and Bayesian network meta-analysis (NMA) of 19 randomized controlled trials (RCTs) including 29,506 adults (BMI ≥ 25 kg/m2), assessing liraglutide, semaglutide, survodutide, tirzepatide, retatrutide, and placebo. Outcomes included mean weight loss, achievement of ≥ 5%, ≥ 10%, and ≥ 15% weight loss, waist circumference (WC), BMI, and adverse events (AEs) at ≥ 36 weeks. Subgroup and meta-regression analyses evaluated the impact of diabetes status, sex, age,...

The power of three: Retatrutide's role in modern obesity and diabetes therapy.

The increasing prevalence of obesity and type 2 diabetes mellitus has resulted in a significant challenge to public health throughout the globe. It required the development of novel therapeutic approaches. Retatrutide is a groundbreaking triple agonist that targets glucagon receptors, gastric inhibitory polypeptide, and glucagon-like peptide-1. Retatrutide's complex mechanism of action involves a synergistic interaction among these receptors, resulting in increased insulin secretion, improved glucose homeostasis, and refined appetite modulation. Clinical trials in phases 1 to 3 have demonstrated significant efficacy, highlighted by significant reductions in body weight and favorable...

Effects of once-weekly subcutaneous retatrutide on weight and metabolic markers: A systematic review and meta-analysis of randomized controlled trials.

To assess the effects of once-weekly subcutaneous retatrutide on weight and metabolic markers and the occurrence of side effects in patients with overweight, obesity and/or type 2 diabetes (T2D). PubMed, Embase, Cochrane Library, and ClinicalTrials.gov databases were systematically searched for placebo-controlled, randomized clinical trials (RCTs) published up until February 23, 2024. Weighted mean differences (WMDs) for continuous outcomes and risk ratios (RRs) for binary endpoints were computed, with 95 % confidence intervals (CIs). A total of three studies were included, comprising 640 patients, of whom 510 were prescribed retatrutide. Compared with placebo, retatrutide significantly...

Efficacy and Safety of GLP-1 Medicines for Type 2 Diabetes and Obesity.

The development of glucagon-like peptide 1 receptor agonists (GLP-1RA) for type 2 diabetes and obesity was followed by data establishing the cardiorenal benefits of GLP-1RA in select patient populations. In ongoing trials investigators are interrogating the efficacy of these agents for new indications, including metabolic liver disease, peripheral artery disease, Parkinson disease, and Alzheimer disease. The success of GLP-1-based medicines has spurred the development of new molecular entities and combinations with unique pharmacokinetic and pharmacodynamic profiles, exemplified by tirzepatide, a GIP-GLP-1 receptor coagonist. Simultaneously, investigational molecules such as maritide...

Retatrutide showing promise in obesity (and type 2 diabetes).

Obesity is a major risk factor for cardiovascular disease, diabetes, osteoarthritis, and some cancers. Retatrutide stimulates Glucagon-like peptide 1 (GLP-1), Glucose-dependent insulinotropic polypeptide (GIP) receptors, and glucagon receptors, and is being developed for the treatment of obesity and type 2 diabetes. A phase 2 clinical trial of retatrutide (LY3437943) in the treatment of obesity. The primary end point was percentage change in weight from baseline to 24 weeks, which ranged from -7.2% to -~18% as the dose of retatrutide increased from 1 mg to 12 mg. The most frequent adverse events were gastrointestinal (nausea, diarrhea, vomiting). The results for retatrutide in phase 2...

Efficacy and safety of retatrutide, a novel GLP-1, GIP, and glucagon receptor agonist for obesity treatment: a systematic review and meta-analysis of randomized controlled trials.

Retatrutide is a novel triple agonist targeting the receptors of glucagon-like peptide 1 (GLP-1), gastric inhibitory polypeptide (GIP), and glucagon. We sought to assess the efficacy and safety of retatrutide in obese patients with or without diabetes. PubMed, Scopus, Web of Science, and Cochrane databases were searched from inception until May 2024. Eligible studies comprised randomized controlled trials that compared retatrutide with placebo in obese patients. We excluded studies on healthy populations, non-English texts, single-arm studies, animal studies, and abstracts. RevMan software (version 5.4) was used for analysis, with subgroup evaluation by dose (4 mg, 8 mg, 12 mg). Three...

Retatrutide in type 2 diabetes mellitus and obesity: an overview.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are increasingly used for T2DM and obesity. An electronic search was conducted in Scopus, PubMed/MEDLINE, and Google Scholar databases. Retatrutide (LY3437943) is a novel triple agonist targeting glucagon receptor (GCGR), glucose-dependent insulinotropic polypeptide receptor (GIPR), and glucagon-like peptide-1 receptor (GLP-1 R). In subjects with type 2 diabetes mellitus (T2DM), decreased glycated hemoglobin (HbA1c) by up to 2.16% and decreased fasting glucose by up to 69.1 mg/dL have been seen. Weight loss up to 16.94% was observed in subjects with T2DM. Subjects with overweight or obesity experienced a greater weight loss by up to...

Retatrutide-A Game Changer in Obesity Pharmacotherapy.

Obesity and type 2 diabetes mellitus (T2DM) are global health crises with significant morbidity and mortality. Retatrutide, a novel triple receptor agonist targeting glucagon-like peptide-1 (GLP-1), Glucose-Dependent Insulinotropic Polypeptide (GIP), and glucagon receptors, represents a groundbreaking advancement in obesity and T2DM pharmacotherapy. This review synthesizes findings from preclinical and clinical studies, highlighting retatrutide's mechanisms, efficacy, and safety profile. Retatrutide's unique molecular structure enables potent activation of GLP-1, GIP, and glucagon receptors, leading to significant weight reduction, improved glycemic control, and favorable metabolic...

A review of an investigational drug retatrutide, a novel triple agonist agent for the treatment of obesity.

Obesity is one of the critical public health problems in our society. It leads to various health conditions, such as type 2 diabetes mellitus, cardiovascular disease, hypertension, dyslipidaemia, and non-alcoholic fatty liver disease. With the rising incidence of obesity, there is a growing demand for new therapies which can effectively manage body weight and improve health. Currently under development, multi-receptor agonist drugs may offer a promising solution to meet this unmet medical need. Retatrutide is a novel triple receptor agonist peptide that targets the glucagon receptor (GCGR), glucose-dependent insulinotropic polypeptide receptor (GIPR), and glucagon-like peptide-1 receptor...

The Triple-Agonist Revolution: Retatrutide and the Paradigm Shift in Multi-Hormonal Pharmacotherapy for Obesity and Cardiometabolic Comorbidities.

Obesity has emerged as a global health crisis requiring innovative therapeutic strategies beyond conventional approaches. While glucagon-like peptide-1 (GLP-1) and dual GIP/GLP-1 receptor agonists have redefined pharmacological management, their limitations necessitate further innovation. Retatrutide (LY3437943), a novel triple agonist targeting GLP-1, glucose-dependent insulinotropic polypeptide (GIP), and glucagon receptors, represents a transformative advance in obesity pharmacotherapy. Phase 2 trials report unprecedented weight reductions, comparable to bariatric surgery, with additional benefits for metabolic comorbidities such as NASH and cardiovascular disease. Retatrutide...

Efficacy and Safety of Retatrutide in the Treatment of Diabetes and/or Obesity Comorbid with Chronic Kidney disease: a Systematic Review and Meta-Analysis.

There are still substantial clinical challenges in treating patients who come with type 2 diabetes and/or obesity in addition to chronic kidney disease (CKD). Retatrutide, an innovative agent, represents a potential advancement in therapy; however, its performance and safety profile specifically in a CKD population are not fully determined yet. This meta-analysis and systematic review sought to consolidate existing research on the use of retatrutide in this comorbid patient group. A comprehensive literature search identified relevant randomized controlled trials for inclusion. Reductions in glycated hemoglobin (HbA1c) and body weight were the primary goals for evaluating effectiveness,...

Efficacy of Tirzepatide, Retatrutide, and Semaglutide for Weight Loss in Obese Individuals Without Diabetes.

PubMed-indexed narrative or scoped review addressing: Efficacy of Tirzepatide, Retatrutide, and Semaglutide for Weight Loss in Obese Individuals Without Diabetes.

Authors

Bastu Adebayo Olowo-Oribi, Richard James Salway

Source

systematic_review_or_meta_analysis

DOI

10.1111/acem.70088

PubMed

40583149

The promise of glucagon-like peptide 1 receptor agonists (GLP-1RA) for the treatment of obesity: a look at phase 2 and 3 pipelines.

GLP-1-based therapies have changed the treatment of overweight/obesity. Liraglutide 3.0 mg daily, the first GLP-1 RA approved for treatment of overweight, induced a weight loss of 6-8%, Semaglutide 2.4 mg once weekly improved weight loss to about 12-15%, while the dual GIP/GLP-1 receptor agonist tirzepatide once weekly has induced a weight loss of about 20% in obese people without diabetes. This review describes results obtained with GLP-1 mono-agonists, GLP-1/GIP dual agonists, GLP-1/glucagon co-agonists, and the triple agonist retatrutide (GIP/GLP-1/glucagon), which have shown beneficial effect both on body weight and steatotic liver disease. A combination of semaglutide (a GLP-1...