October 24, 2026 · 3 min read

Retatrutide: what the published phase 2 research shows about a triple-agonist peptide

A research overview of retatrutide, an investigational GIP, GLP-1 and glucagon receptor agonist, and what its published phase 2 trials reported.

Retatrutide (LY3437943) is an investigational peptide from Eli Lilly that activates three receptors with one molecule: GIP, GLP-1 and glucagon. It is not an approved medicine. What follows is a plain summary of what the peer-reviewed papers report.

Why three receptors

GLP-1 agonists cut appetite and slow gastric emptying. GIP affects insulin secretion and how fat tissue behaves. Glucagon is better known for raising blood glucose, but it also increases energy expenditure and changes how the liver handles fat. Putting all three into one peptide is an attempt to work on both sides of the energy balance: how much is taken in and how much is burned.

One molecule, three receptors

1
GLP-1 receptor
Reduces appetite and slows gastric emptying.
2
GIP receptor
Affects insulin secretion and fat tissue biology.
3
Glucagon receptor
Increases energy expenditure and changes liver fat handling.
4
Retatrutide
Activates all three with a single peptide.

How the three receptor targets are described in the published literature. Illustrative summary, not a pharmacology diagram.

The phase 2 obesity trial

The main phase 2 results appeared in the New England Journal of Medicine in 2023. The trial was double-blind, randomized and placebo-controlled, with 338 adults who had obesity, or overweight plus a weight-related condition. They got subcutaneous retatrutide or placebo once a week for 48 weeks.

At 24 weeks the mean change in body weight ran from -7.2% on the lowest dose to -17.5% on the highest, against -1.6% on placebo. At 48 weeks the 12 mg group was down 24.2% and the placebo group 2.1%. Most adverse events were gastrointestinal, scaled with dose, and were mostly mild to moderate. Starting at a lower dose reduced them. Heart rate went up in a dose-dependent way, peaked at 24 weeks, then came back down.

Mean body-weight change by dose, at 24 and 48 weeks

24 weeks
48 weeks

Placebo

-1.6% 24 weeks
-2.1% 48 weeks

1 mg

-7.2% 24 weeks
-8.7% 48 weeks

4 mg

-12.9% 24 weeks
-17.1% 48 weeks

8 mg

-17.3% 24 weeks
-22.8% 48 weeks

12 mg

-17.5% 24 weeks
-24.2% 48 weeks

Least-squares mean percentage change from baseline in the phase 2 trial of 338 adults (Jastreboff et al., N Engl J Med 2023). The 4 mg and 8 mg rows are combined dose groups.

How many reached each target

The same trial reports responder rates. At 48 weeks, 60% of people on the combined 4 mg groups, 75% on 8 mg and 83% on 12 mg had lost 15% or more of their body weight, against 2% on placebo. Every participant on 8 mg or 12 mg lost at least 5%.

Participants reaching each weight-loss target at 48 weeks

Placebo
4 mg
8 mg
12 mg

5% or more

27% Placebo
92% 4 mg
100% 8 mg
100% 12 mg

10% or more

9% Placebo
75% 4 mg
91% 8 mg
93% 12 mg

15% or more

2% Placebo
60% 4 mg
75% 8 mg
83% 12 mg

Share of participants with a weight reduction of at least the stated percentage at 48 weeks (Jastreboff et al., N Engl J Med 2023). The 4 mg and 8 mg groups are combined.

Liver fat

A separate phase 2a trial in Nature Medicine looked at retatrutide in people with metabolic dysfunction-associated steatotic liver disease, which means fat building up in the liver. If you care about what the glucagon arm adds beyond weight loss, that paper is the one to read, mainly for its imaging methods and endpoints.

Limits of phase 2 data

Phase 2 exists to find a dose range and spot safety signals. The trials are small by drug-development standards, so they can't establish long-term benefit or safety. Later results have started to appear, including the 2026 NEJM paper listed below, and those are the better place to look for longer follow-up and broader populations.

Participants were screened tightly and don't represent everyone.
Weight loss on treatment says little about what happens after it stops.
Trial results belong to the trial material. Another product sold under the same name may have been made differently and never characterized.

That last point is why we publish a certificate of analysis for each batch. If you work with retatrutide in the lab, HPLC purity plus a mass spec match to the expected molecular weight is the minimum before you interpret an experiment. Our guide to reading a certificate of analysis covers what to look for.