Retatrutide (Eli Lilly's LY3437943) is a once-weekly injectable peptide that activates three receptors at once: GIP, GLP-1, and glucagon. The first two are the targets behind drugs like tirzepatide and semaglutide. The glucagon arm is the new piece, and it is what theoretically pushes the liver to burn fat and raise energy expenditure. As of mid-2026, retatrutide is investigational. It has not been approved by the FDA, the EMA, or any other regulator for any use. Everything below is published phase 2 trial data, reported here with attribution. None of it is medical advice, and material sold online as "retatrutide" is not an approved medicine.
Three phase 2 readouts are worth reading closely: an obesity trial in the New England Journal of Medicine, a type 2 diabetes trial in The Lancet, and a liver-fat substudy in Nature Medicine. All three came out of the same program (NCT04881760 for the obesity work) and were reported in 2023 and 2024.
Obesity: the NEJM phase 2 trial
Jastreboff and colleagues randomized 338 adults with obesity (BMI 30 or higher), or overweight with a weight-related condition, to weekly retatrutide at 1, 4, 8, or 12 mg, or placebo, for 48 weeks (NEJM 2023). Some dose groups used a slower 2 mg start to blunt nausea. The primary endpoint was percent change in body weight at 24 weeks.
The weight numbers were large. Least-squares mean change at 48 weeks:
| Dose | Body weight change, 24 wk | Body weight change, 48 wk |
|---|---|---|
| Placebo | -1.6% | -2.1% |
| 1 mg | -7.2% | -8.7% |
| 4 mg | -12.9% | -17.1% |
| 8 mg | -17.3% | -22.8% |
| 12 mg | -17.5% | -24.2% |
At 48 weeks, 93% of the 12 mg group lost at least 10% of body weight, and 83% lost at least 15%. The curves had not clearly flattened by week 48, which the authors flagged: weight was still trending down, so the true plateau is unknown from this trial.
Type 2 diabetes: the Lancet phase 2 trial
Rosenstock, Frías, Jastreboff and colleagues ran a separate phase 2 trial in 281 adults with type 2 diabetes inadequately controlled on diet, exercise, or metformin (Lancet 2023, 402:529-54401053-X/abstract)). This one had an active comparator, dulaglutide 1.5 mg, alongside placebo and retatrutide doses up to 12 mg. The primary endpoint was change in HbA1c at 24 weeks.
HbA1c fell by roughly 1.3% to 2.0% across the 4-12 mg retatrutide groups, against about 1.4% for dulaglutide and essentially no change for placebo. Body weight at the top dose dropped about 16.9% at 36 weeks. The trial reported no episodes of severe hypoglycemia, which fits the GLP-1/GIP mechanism (insulin release is glucose-dependent). It is a small, relatively short trial, so it speaks to glucose and weight signals, not to long-term diabetes outcomes.
Liver fat: the Nature Medicine phase 2a substudy
The glucagon receptor is why retatrutide drew interest for fatty liver disease. Sanyal and colleagues reported a prespecified substudy of the obesity trial: 98 of the 338 participants had 10% or more liver fat by MRI-PDFF and were analyzed for hepatic fat (Nature Medicine 2024). Relative reduction in liver fat at 24 weeks:
- 1 mg: -42.9%
- 4 mg: -57.0%
- 8 mg: -81.4%
- 12 mg: -82.4%
- placebo: +0.3%
At 24 weeks, 86% of the 12 mg group reached normal liver fat (under 5% PDFF), versus none on placebo.
One caveat matters more than the headline number. This substudy measured liver fat by imaging. It did not biopsy livers, so it cannot say anything about MASH resolution, inflammation, or fibrosis, which are what define the disease and what regulators want to see. A large relative drop in liver fat is associated with histologic improvement in MASH, but association is not the same as a biopsy-proven endpoint. Calling this a "MASH trial" overstates it; it is a steatosis (liver fat) signal that supports moving into dedicated MASH studies.
Safety and limitations
Across all three trials the dominant adverse events were gastrointestinal: nausea, vomiting, diarrhea, constipation. They were dose-related and mostly mild to moderate, and a slower dose escalation reduced them, the same pattern seen with other incretin drugs. The obesity trial also reported dose-dependent increases in heart rate that peaked around 24 weeks and then declined. The glucagon component can nudge glucose upward, so glycemic effects in people without diabetes deserve watching in larger studies.
The shared limitations are size and length. These are phase 2 trials of a few hundred people over roughly a year, designed to find effective doses and check safety signals, not to prove durable benefit or rare harms. Phase 3 (the TRIUMPH program) and dedicated MASH trials are the tests that matter for approval, and they are ongoing or reporting now.
What the phase 2 record shows is consistent, dose-dependent effects on weight, glucose, and liver fat in three populations. What it does not show is approval, long-term safety, or hard outcomes. Retatrutide remains an experimental compound under study.