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Ret5.5
Retatrutide Research
Mostly mechanism / observationalLimited safety
9 peer-reviewed studies
What the evidence says
Mostly mechanism / observational
Most Retatrutide studies are mechanism or observational rather than RCTs that measure a clinical effect — keep findings provisional.
Most evidence is from medium-quality randomised trials published 2022–2026 with a typical study size of 281 participants.
Based on 9 studies · 5 RCTs · 1,326 total participants
Confidence
High
By outcome
Glucose & glycemic control
Mostly mechanism / observational8 studies
Weight management
Mostly mechanism / observational7 studies
Safety profile
Mostly mechanism / observational6 studies
Liver fat & MASLD
Too few graded studies1 study
Active research area
9 studies in the last 5 years
20222026
1RCTn=537 · large study2026
the mean change from baseline in HbA1c concentration was -1·69%... with retatrutide 4 mg, -1·86%... with 9 mg, and -1·94%... with 12 mg, versus -0·81%... with placebo... The mean percentage change from baseline in bodyweight was -11·5%... with retatrutide 4 mg, -13·9%... with 9 mg, and -15·3%... with 12 mg, versus -2·6%... with placebo.
Bajaj HS, Welch M, Shah P, Luna E, Jaouimaa FZ, Liu B, Liu R, Chen Y, Patel H, Bartee A. · Lancet (2026)
First published phase-3 retatrutide trial (TRANSCEND-T2D-1, n=537): once-weekly subcutaneous retatrutide 4/9/12 mg vs placebo as monotherapy over 40 weeks in type 2 diabetes inadequately controlled by diet and exercise
HbA1c fell -1.94% at 12 mg vs -0.81% placebo (placebo-adjusted up to -1.12%; all p<0.0001); bodyweight fell -15.3% at 12 mg vs -2.6% placebo
GI events were the most frequent adverse events (mild-to-moderate, subsiding over time); AE discontinuation 2-5% vs 0% placebo; no severe hypoglycemia
At 48 weeks, the least-squares mean percentage change in the retatrutide groups was -8.7% in the 1-mg group, -17.1% in the combined 4-mg group, -22.8% in the combined 8-mg group, and -24.2% in the 12-mg group, as compared with -2.1% in the placebo group.
Jastreboff AM, Kaplan LM, Frías JP, Wu Q, Du Y, Gurbuz S, Coskun T, Haupt A, Milicevic Z, Hartman ML. · N Engl J Med (2023)
Phase-2, double-blind, randomized, placebo-controlled trial in 338 adults with obesity (or overweight + a weight-related condition), once-weekly subcutaneous retatrutide 1-12 mg vs placebo for 48 weeks
Mean weight loss at 48 weeks reached -24.2% at 12 mg vs -2.1% placebo — the largest reported for an incretin-class drug
At 48 weeks, ≥15% weight loss occurred in 83% of the 12 mg group; GI adverse events were dose-related and mostly mild-to-moderate, partially mitigated by a lower starting dose
In people with type 2 diabetes, retatrutide showed clinically meaningful improvements in glycaemic control and robust reductions in bodyweight, with a safety profile consistent with GLP-1 receptor agonists and GIP and GLP-1 receptor agonists.
Rosenstock J, Frias J, Jastreboff AM, Du Y, Lou J, Gurbuz S, Thomas MK, Hartman ML, Haupt A, Milicevic Z, Coskun T. · Lancet (2023)
Phase-2, double-blind, double-dummy, placebo- and active-comparator (1.5 mg dulaglutide)-controlled trial in 281 adults with type 2 diabetes, once-weekly retatrutide 0.5-12 mg over 36 weeks
HbA1c fell up to -2.02% at 24 weeks (12 mg) vs -0.01% placebo and -1.41% dulaglutide; reductions exceeded dulaglutide at the higher doses
Bodyweight fell dose-dependently up to -16.94% at 36 weeks vs -2.02% with dulaglutide
The mean relative change from baseline in LF at 24 weeks was -42.9% (1 mg), -57.0% (4 mg), -81.4% (8 mg), -82.4% (12 mg) and +0.3% (placebo) (all P < 0.001 versus placebo).
Sanyal AJ, Kaplan LM, Frias JP, Brouwers B, Wu Q, Thomas MK, Harris C, Schloot NC, Du Y, Mather KJ, Haupt A, Hartman ML. · Nat Med (2024)
Phase-2a, randomized, double-blind, placebo-controlled MASLD substudy (n=98) of the obesity trial, in participants with ≥10% liver fat, once-weekly retatrutide 1-12 mg vs placebo
Liver fat fell ~81-82% at 8/12 mg by 24 weeks vs +0.3% placebo
Normal liver fat (<5%) was reached by 79% (8 mg) and 86% (12 mg) of participants vs 0% placebo
LY3437943 showed an acceptable safety profile, and its pharmacokinetics suggest suitability for once-weekly dosing... robust reductions in glucose and bodyweight, provides support for phase 2 development.
Urva S, Coskun T, Loh MT, Du Y, Thomas MK, Gurbuz S, Haupt A, Benson CT, Hernandez-Illas M, D'Alessio DA, Milicevic Z. · Lancet (2022)
Phase-1b, double-blind, placebo-controlled, multiple-ascending-dose trial in 72 adults with type 2 diabetes over 12 weeks, once-weekly subcutaneous LY3437943 vs placebo vs dulaglutide
Significant placebo-adjusted reductions in daily glucose and HbA1c at the higher doses; placebo-adjusted bodyweight reduction up to -8.96 kg in the 3/6/9/12 mg group
Retatrutide and survodutide enable simultaneous activation of the glucagon and GLP-1 receptors... focusing on muscle strength, bone density and fractures, exercise capacity, gastrointestinal motility, retained gastric contents and anesthesia, pancreatic and biliary tract disorders, and the risk of cancer.
Drucker DJ. · Diabetes Care (2024)
Authoritative review of GLP-1-based medicines, situating retatrutide among newer glucagon/GLP-1-activating agents
Catalogues class-level safety domains relevant to retatrutide: gastrointestinal motility/retained gastric contents (anesthesia), pancreatic and biliary disorders, muscle/bone effects, and cancer-risk questions
Frames the GLP-1 class's established cardiorenal benefits as not yet demonstrated for investigational triple agonists
In obese mice, administration of LY3437943 decreased body weight and improved glycemic control. Body weight loss was augmented by the addition of GCGR-mediated increases in energy expenditure to GIPR- and GLP-1R-driven calorie intake reduction.
Coskun T, Urva S, Roell WC, Qu H, Loghin C, Moyers JS, O'Farrell LS, Briere DA, Sloop KW, Thomas MK, Pirro V, Wainscott DB, Willard FS, Abernathy M, Morford L, Du Y, Benson C, Gimeno RE, Haupt A, Milicevic Z. · Cell Metab (2022)
Discovery-to-proof-of-concept report: LY3437943 is a balanced GCGR/GLP-1R agonist with relatively more GIPR activity in vitro
In obese mice, weight loss combined glucagon-driven energy expenditure with GIP/GLP-1-driven calorie-intake reduction — the mechanistic basis for the triple-agonist approach
A phase-1 single-ascending-dose study showed incretin-like safety/tolerability and pharmacokinetics supporting once-weekly dosing, with weight reduction persisting to day 43 after a single dose
The role of stimulating glucagon receptors in the treatment of type 2 diabetes and/or obesity is poorly defined and needs to be clarified... The safety of retatrutide needs to be determined in larger and longer trials.
Doggrell SA. · Expert Opin Investig Drugs (2023)
Critical commentary on the early retatrutide evidence, providing a skeptical counterweight to the striking efficacy headlines
Notes the role of glucagon-receptor agonism is poorly defined and that the dulaglutide comparison is not a strong benchmark (semaglutide/tirzepatide are more relevant comparators)
Stresses that safety must be established in larger and longer trials before conclusions about benefit-risk
Optimized triagonists normalize body weight in DIO mice and enhance energy expenditure in a manner superior to that of GLP-1R mono-agonists and GLP-1R/GIPR co-agonists.
Knerr PJ, Mowery SA, Douros JD, Premdjee B, Hjøllund KR, He Y, Kruse Hansen AM, Olsen AK, Perez-Tilve D, DiMarchi RD, Finan B. · Mol Metab (2022)
Preclinical (mouse) study of optimised once-weekly GLP-1/GIP/glucagon triple agonists in a diet-induced-obesity model
Triagonists normalised body weight and enhanced energy expenditure beyond GLP-1 mono-agonists (e.g. semaglutide) and GLP-1/GIP co-agonists (e.g. tirzepatide)
Implicated glucagon-receptor activation as the differentiating factor for the added weight/energy-expenditure effect