How Does Retatrutide Work?

One peptide, three receptors

Retatrutide, first described under the code LY3437943, is a single peptide with agonist activity at the glucagon receptor (GCGR), the glucose-dependent insulinotropic polypeptide receptor (GIPR) and the glucagon-like peptide-1 receptor (GLP-1R). The discovery paper presented it as a novel triple agonist, carried from discovery to clinical proof of concept in a single report.Animal study · PMID 35985340

The receptor balance is not equal. In cell-based assays, the discovery team measured balanced activity at the glucagon and GLP-1 receptors but more activity at the GIP receptor. That profile is the starting point for every mechanistic explanation in the later literature, because each receptor is linked to a different part of energy and glucose regulation.Animal study · PMID 35985340

Later trial reports describe the molecule in the same terms: a GIP, GLP-1 and glucagon triple hormone receptor agonist under clinical development for type 2 diabetes, obesity and related conditions. The published human data therefore come from investigational trials, not from approved clinical use.Human RCT · PMID 42250575Human RCT · PMID 42810372

What the animal studies attributed to each receptor

In obese mice, the discovery paper reported lower body weight and changes in glycemic measures. The authors split the mechanism into two parts. Signaling through the GIP and GLP-1 receptors was linked to lower calorie intake. Signaling through the glucagon receptor was linked to energy expenditure, measured as an added component on top of that.Animal study · PMID 35985340

In the mouse data, the change in body weight was described as augmented when the glucagon receptor contribution was added to the other two.Animal study · PMID 35985340

The same paper included a phase 1 single ascending study in people. It reported a safety and tolerability profile similar to other incretins and a pharmacokinetic profile the authors judged compatible with weekly scheduling, and it recorded that a change in body weight persisted up to day 43 after a single exposure.Animal study · PMID 35985340

The first trials in type 2 diabetes

The phase 1b trial enrolled 72 adults with type 2 diabetes at four centres in the USA for 12 weeks, comparing several ascending cohorts with placebo and dulaglutide. Its primary purpose was safety and tolerability. Adverse events emerging during the study were reported by 33 (63%) participants on the study peptide, 3 (60%) on dulaglutide and 8 (54%) on placebo, with gastrointestinal disorders the most frequent. 29 participants discontinued the study early. The measured half-life was approximately 6 days.Human RCT · PMID 36354040

At week 12 in that trial, placebo-adjusted mean daily plasma glucose and HbA1c differed significantly from baseline in the three highest cohorts, and placebo-adjusted body weight change appeared to follow the cohort level, reaching up to -8.96 kg in the highest cohort.Human RCT · PMID 36354040

A phase 2 trial at 42 centres in the USA then randomly assigned 281 adults with type 2 diabetes to placebo, dulaglutide or one of several retatrutide arms. At 24 weeks, the least-squares mean change in HbA1c ranged from -0.43% in the lowest arm to -2.02% in the highest, against -0.01% with placebo and -1.41% with dulaglutide. At 36 weeks, body weight changed by 3.19% in the lowest arm and 16.94% in the highest, against 3.00% with placebo. Gastrointestinal adverse events were reported by 67 (35%) of 190 participants across the retatrutide arms and 6 (13%) of 45 on placebo.Human RCT · PMID 37385280

The phase 2 obesity trial and its substudies

The phase 2 obesity trial enrolled 338 adults, 51.8% of them men, with a BMI of 30 or higher, or 27 or higher with at least one weight-related condition. At 48 weeks, the least-squares mean change in body weight ranged from -8.7% in the lowest arm to -24.2% in the highest, against -2.1% with placebo. The most common adverse events were gastrointestinal, mostly mild to moderate, and heart rate rose in a pattern that tracked the arm level and peaked at 24 weeks and declined afterwards.Human RCT · PMID 37366315

A liver substudy of that trial included 98 participants with metabolic dysfunction-associated steatotic liver disease and at least 10% liver fat at baseline. The primary measure was relative change in liver fat at 24 weeks. By that point, liver fat below 5% was recorded in 27% to 86% of participants across the active arms and in 0% on placebo. The authors reported that liver fat changes tracked changes in body weight, abdominal fat and metabolic measures.Human RCT · PMID 38858523

A body-composition substudy of the type 2 diabetes phase 2 trial enrolled 189 participants and measured fat mass by dual-energy X-ray absorptiometry; 103 completed both baseline and week 36 scans. Total fat mass changed by 4.9% in the lowest retatrutide arm and by up to 26.1% in the pooled middle arms, against 4.5% with placebo and 2.6% with dulaglutide. The authors reported that the share of lean mass in total weight change was similar to other agents studied for obesity.Human RCT · PMID 40609566

Phase 3 results so far

TRANSCEND-T2D-1 was a 40-week phase 3 trial at 48 sites in the USA, Mexico and India. It randomly assigned 537 adults with type 2 diabetes managed by diet and exercise alone. Mean HbA1c change was -1.69% to -1.94% across the three retatrutide arms, against -0.81% with placebo, and mean body weight change was -11.5% to -15.3%, against -2.6% with placebo. Discontinuation for adverse events was 2-5% in the retatrutide arms and 0% on placebo.Human RCT · PMID 42250575

TRIUMPH-2 was an 80-week phase 3 trial at 92 centres in eight countries. It randomly assigned 1152 adults with obesity and type 2 diabetes. Mean body weight change at week 80 was -11.9%, -16.8% and -18.8% in the three active arms, against -5.1% with placebo. Diarrhoea was recorded in 27% to 34% of participants across the active arms versus 13% on placebo, and nausea in 14% to 28% versus 8%. Hypotension and dysesthesia were also more frequent than on placebo.Human RCT · PMID 42810372

What these studies do not settle

The split between calorie intake and energy expenditure comes from obese mice. The human trials measured body weight, HbA1c, liver fat and fat mass, but those endpoints do not by themselves separate how much each receptor contributes in people. All of the trials summarised here were funded by the developer, Eli Lilly and Company.Animal study · PMID 35985340Human RCT · PMID 37366315Human RCT · PMID 42810372

Safety signals also need longer follow-up. The trials consistently recorded gastrointestinal events as the most frequent adverse events. The phase 2 obesity trial recorded a rise in heart rate that peaked at 24 weeks, and TRIUMPH-2 recorded more hypotension and dysesthesia than placebo. Discontinuation for adverse events in TRIUMPH-2 was 12% and 8% in two of the active arms, against 5% on placebo.Human RCT · PMID 37366315Human RCT · PMID 42810372

The studies at a glance

Key retatrutide studies. Figures are mean changes from baseline as reported in each abstract; ranges span the lowest to highest active arm.

Frequently asked questions