Retatrutide: what the phase 2 and phase 3 trials have shown so far, and what is still missing

Retatrutide has moved from "the next weight-loss drug" headlines into published phase 3 trials. If you are weighing questions like "how much weight did people actually lose", "is it better than what is already prescribed" or "can I get it", the answers depend on who was in each trial and on what has not yet been measured. Here is what the peer-reviewed results show so far, and where they stop.

This material is for information only and does not replace a consultation with a doctor.

What kind of drug is retatrutide?

Retatrutide is a once-weekly injection that acts on three hormone receptors at once: GLP-1 (the target of semaglutide), GIP (which tirzepatide adds) and glucagon. The idea behind adding the third receptor is a larger effect on body weight and liver fat than two-receptor drugs; the published trials have not tested retatrutide directly against them. Whether that idea translates into better health outcomes is exactly what the trials below have, and have not yet, tested.

What did the first human trials show?

The phase 2 obesity trial, published in 2023, enrolled 338 adults with a body-mass index (BMI) of 30 to 50, or of 27 to less than 30 plus high blood pressure, abnormal blood lipids or cardiovascular disease, and without type 1 or type 2 diabetes. After 48 weeks, average weight change was −24.2% on the highest dose (12 mg) and −2.1% on placebo. The most common side effects were gastrointestinal, dose-related and mostly mild to moderate; heart rate rose with dose, peaked at 24 weeks and declined afterwards.

A substudy of that trial looked at 98 participants from that trial with metabolic dysfunction-associated steatotic liver disease (fatty liver) and at least 10% liver fat. At 24 weeks, liver fat fell by 82.4% on average on 12 mg versus essentially no change on placebo, and 86% of people on that dose reached the normal range (below 5% liver fat). Liver fat is an imaging measurement, not a clinical outcome: the substudy did not test liver scarring, cirrhosis or survival.

A parallel phase 2 trial in 281 adults with type 2 diabetes, run in the United States, compared retatrutide with placebo and with dulaglutide, an older GLP-1 drug. At 24 weeks, HbA1c fell by 2.02 percentage points on 12 mg, versus 1.41 on dulaglutide 1.5 mg and essentially none on placebo.

What did the phase 3 trials show?

Three phase 3 trials have now been published.

• TRIUMPH-1 (2026) randomised 2,339 adults with obesity and without diabetes for 80 weeks. Average weight change was −17.6% on 4 mg, −23.7% on 9 mg and −25.0% on 12 mg, versus −3.9% on placebo. The trial was built as a "basket": within it, 574 participants with knee osteoarthritis and 243 with obstructive sleep apnoea had their own primary outcomes. On the main analysis, knee pain on a 1–10 WOMAC pain score was 1.6 points (9 mg) and 1.8 points (12 mg) lower than with placebo. The apnoea-hypopnoea index was 24.4 (9 mg) and 21.9 (12 mg) events per hour lower than with placebo. These are differences against placebo, not the total fall from the start.

• TRIUMPH-2 (2026) randomised 1,152 adults with a BMI of 27 or higher and type 2 diabetes, run across eight countries. At 80 weeks, weight change was −11.9% on 4 mg, −16.8% on 9 mg and −18.8% on 12 mg, versus −5.1% on placebo. Diarrhoea occurred in about a third of people on the two higher doses versus 13% on placebo, and nausea in up to 28% versus 8%. Low blood pressure and dysaesthesia (unusual skin sensations) were also more common than on placebo. Permanent discontinuation because of an adverse event or death was more frequent on 9 mg (12%) and 12 mg (8%) than on placebo (5%). The investigators judged the deaths unrelated to the study drug.

• TRANSCEND-T2D-1 (2026) tested retatrutide on its own in 537 adults with type 2 diabetes not controlled by diet and exercise, at sites in the USA, Mexico and India, for 40 weeks. HbA1c fell by 1.69–1.94 percentage points across doses versus 0.81 on placebo, and weight changed by −11.5% to −15.3% versus −2.6%. No severe hypoglycaemia was reported.

Note the pattern: in people with type 2 diabetes, average weight loss was smaller than in people without diabetes. That is what these retatrutide trials show when they are set side by side, and it is one reason why a single "headline percentage" says little about what to expect in a particular person.

Is it "better" than semaglutide or tirzepatide?

The published trials do not answer that. Each compared retatrutide with placebo (and, in the phase 2 diabetes trial, with dulaglutide), not with semaglutide or tirzepatide. Placing numbers from different trials side by side is tempting: in STEP 1, average weight change among adults with overweight or obesity was −14.9% on semaglutide 2.4 mg at 68 weeks; in SURMOUNT-1, it was −20.9% among adults with obesity on tirzepatide 15 mg at 72 weeks. But the trials differed in duration, populations and methods, so such a comparison shows a direction of interest, not a ranking.

What is still missing?

• Hard outcomes. None of the published retatrutide trials was designed to show fewer heart attacks, strokes or deaths. For comparison, semaglutide has such a trial: in SELECT, 17,604 people with established cardiovascular disease and overweight or obesity, without diabetes, had fewer major cardiovascular events than on placebo. For retatrutide this has not been shown yet.

• Duration. The primary results reported in these trials are at up to 80 weeks of treatment. The trials summarised here do not describe what happens to weight after the drug is stopped.

• Who was studied. The trials enrolled adults with obesity or overweight, and with or without type 2 diabetes. Results do not automatically apply to people without excess weight, to adolescents or to people with conditions the trials excluded.

• Regulatory status. At the time of writing, retatrutide is an investigational drug: its trials are published, but this alone is not an approval for prescription.

What to do with this information

• If weight, blood sugar, knee pain or sleep apnoea are your questions, the options that are already available are a conversation for your doctor now; the retatrutide data are a reason to follow the field, not a reason to postpone that conversation.

• If you see retatrutide offered for sale before it is approved, treat it with caution: an unregistered product bought outside a pharmacy is not the substance tested in these trials.

• Numbers worth tracking with your doctor whatever the treatment: weight and waist, HbA1c, blood pressure and liver tests. For one of these, see our article on waist-to-height ratio.

This material is for information only and does not replace a consultation with a doctor.

References

• Jastreboff AM, et al. Triple-hormone-receptor agonist retatrutide for obesity — a phase 2 trial. N Engl J Med. 2023. PMID 37366315

• Sanyal AJ, et al. Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial. Nat Med. 2024. PMID 38858523

• Rosenstock J, et al. Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a phase 2 trial. Lancet. 2023. PMID 37385280

• Jastreboff AM, et al. Retatrutide, a triple hormone receptor agonist, for treatment of obesity (TRIUMPH-1). N Engl J Med. 2026. PMID 42814954

• Bellido V, et al. Retatrutide in adults with obesity and type 2 diabetes (TRIUMPH-2): a phase 3 trial. Lancet. 2026. PMID 42810372

• Bajaj HS, et al. Efficacy and safety of retatrutide in people with type 2 diabetes and inadequate glycaemic control with diet and exercise (TRANSCEND-T2D-1): a phase 3 trial. Lancet. 2026. PMID 42250575

• Giblin K, et al. Retatrutide for the treatment of obesity, obstructive sleep apnea and knee osteoarthritis: rationale and design of the TRIUMPH registrational clinical trials. Diabetes Obes Metab. 2026. PMID 41090431

• Wilding JPH, et al. Once-weekly semaglutide in adults with overweight or obesity (STEP 1). N Engl J Med. 2021. PMID 33567185

• Jastreboff AM, et al. Tirzepatide once weekly for the treatment of obesity (SURMOUNT-1). N Engl J Med. 2022. PMID 35658024

• Lincoff AM, et al. Semaglutide and cardiovascular outcomes in obesity without diabetes (SELECT). N Engl J Med. 2023. PMID 37952131