Retatrutide

Overview

Retatrutide is an investigational peptide that activates three hormone receptors at once: the GIP receptor, the GLP-1 receptor and the glucagon receptor. It is sometimes described as a "triple agonist" or "triple G" molecule. Like semaglutide and tirzepatide, it carries a fatty diacid chain that binds albumin and extends its half-life, which was about six days in an early human study (Urva 2022).

The rationale for adding glucagon receptor activity is energy balance. GLP-1 and GIP receptor agonism are associated mainly with reduced food intake, while glucagon receptor signaling is linked in animal research to increased energy expenditure and effects on liver fat. In the discovery paper, retatrutide showed balanced glucagon and GLP-1 receptor activity in cell assays, with stronger GIP receptor activity (Coskun 2022).

The human evidence so far comes from phase 1 and phase 2 trials involving a few hundred participants each, all funded by Eli Lilly. Those results are large in magnitude but short and relatively small compared with the phase 3 programs behind approved drugs in the class. For background on how this class evolved, see how GLP-1 receptor agonists reshaped metabolic research.

Research history

Retatrutide is the third step in a clear design lineage at Eli Lilly. After tirzepatide showed that adding GIP receptor activity to a GLP-1 receptor agonist produced larger effects on glucose and weight, researchers asked whether a third receptor could add more. Glucagon was an obvious candidate: earlier academic and industry work on GLP-1 and glucagon co-agonists had pointed to effects on energy expenditure and liver fat.

The 2022 discovery paper by Coskun and colleagues introduced the molecule as LY3437943. In obese mice it reduced body weight and improved glycemic control, and the authors attributed part of the effect to glucagon-driven increases in energy expenditure. A phase 1 single ascending dose study in the same paper reported a tolerability profile similar to other incretin drugs and pharmacokinetics compatible with once-weekly administration (Coskun 2022).

Phase 1b and phase 2 trials were run from late 2019 onward, with results published in 2022 and 2023. The phase 3 program began in 2023 with the TRIUMPH trials in obesity, followed in 2024 by the TRANSCEND trials in type 2 diabetes. For the molecule that preceded it, see the article on tirzepatide and semaglutide research head to head.

What published studies have examined

Cell and animal studies

Receptor assays and obese mouse models established the triple mechanism and suggested that glucagon receptor activity added energy expenditure to the appetite effects of GIP and GLP-1 receptor agonism (Coskun 2022). These data are preclinical and generated by the developer.

Phase 1b in type 2 diabetes

A 12-week multiple ascending dose trial enrolled 72 people with type 2 diabetes. Gastrointestinal events were the most frequently reported adverse events, and 29 participants discontinued early. In the higher dose groups, glucose and HbA1c fell significantly versus placebo, and body weight reductions appeared dose dependent (Urva 2022).

Phase 2 in obesity

A 48-week, double-blind trial randomized 338 adults with obesity, or overweight plus a weight-related condition, to one of several retatrutide dose groups or placebo. At 48 weeks, mean weight change ranged from minus 8.7 percent in the lowest dose group to minus 24.2 percent in the highest, versus minus 2.1 percent with placebo. Gastrointestinal events were dose related and mostly mild to moderate, and heart rate rose in a dose-dependent way, peaking at 24 weeks (Jastreboff 2023).

Phase 2 in type 2 diabetes

A separate phase 2 trial randomized 281 adults with type 2 diabetes to retatrutide, placebo or dulaglutide, an approved GLP-1 receptor agonist. At 24 weeks, HbA1c reductions were significantly greater than placebo in all but the lowest dose group, and body weight fell dose dependently through 36 weeks. No severe hypoglycemia or deaths were reported (Rosenstock 2023).

Liver fat substudy

In a substudy of 98 participants from the obesity trial who had metabolic dysfunction-associated steatotic liver disease, mean relative liver fat change at 24 weeks ranged from minus 42.9 percent to minus 82.4 percent across dose groups, versus plus 0.3 percent on placebo. Liver fat changes tracked closely with weight loss (Sanyal 2024).

Open questions

• Phase 3 confirmation. Phase 2 trials were smaller and shorter than registration trials. This profile cites only peer-reviewed publications and will be updated as full phase 3 results appear in journals.
• Heart rate and glucagon effects. The dose-dependent heart rate increase, and the long-term effects of chronic glucagon receptor stimulation on the heart, liver and amino acid metabolism, need longer study.
• Body composition. With weight reductions this large, how much of the loss is lean mass is an important unanswered question.
• Outcomes. A large cardiovascular and kidney outcome trial is registered but not expected to complete for several years.
• Funding. Every published human trial was sponsored by Eli Lilly.
• Unregulated products. Because retatrutide is not approved anywhere, any material sold as "retatrutide" is not a regulated medicine, and its identity and purity can only be established by independent testing.