— June 6, 2026 · Retatrutide: First Phase 3 Trial in Type 2 Diabetes

Table of Contents

1. At a Glance
2. What Was Done
3. What Was Found, Number by Number
4. Side Effects and Stopping Treatment
5. How a Triple Agonist Works
6. How It Fits With Earlier Research
7. What It Cannot Show
8. What the Researchers and the ADA Said
9. Since Then: Later Trials and Reports
10. Sources and Primary Documents
11. Key Research Papers
12. Connections

At a Glance

• Paper: Bajaj HS, Welch M, Shah P, et al. The Lancet 2026;407(10546):2402–2413, published online June 6, 2026 (PMID 42250575).
• Trial: TRANSCEND-T2D-1, ClinicalTrials.gov NCT06354660; 48 sites in the USA, Mexico and India.
• Design: phase 3, randomised 1:1:1:1, double-blind, placebo-controlled, 40 weeks.
• Who: 537 adults with type 2 diabetes on diet and exercise alone; average age 48.8 years, average diabetes duration 2.5 years, average HbA1c 7.9%, average BMI 35.8.
• Doses: retatrutide 4 mg, 9 mg or 12 mg, or placebo, injected under the skin once a week.
• Main result: HbA1c fell 1.69% to 1.94% on retatrutide versus 0.81% on placebo; compared with placebo, that is 0.88 to 1.12 percentage points more.
• Weight: fell 11.5% to 15.3% on retatrutide versus 2.6% on placebo.
• Safety: mostly mild-to-moderate digestive side effects; 2% to 5% stopped the drug because of side effects (0% on placebo); no severe hypoglycaemia.
• Funding: the drug’s maker.

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What Was Done

Between April 10, 2024 and April 21, 2025, researchers screened 930 people and randomly assigned 537 of them: 134 to retatrutide 4 mg, 133 to 9 mg, 136 to 12 mg and 134 to placebo. Neither the participants nor the investigators knew who was getting which injection. Everyone had type 2 diabetes with an HbA1c between 7.0% and 9.5% despite diet and exercise, and a body-mass index of at least 23. The registry adds that participants had not used insulin. They had also taken no other diabetes medicine, by mouth or by injection, for at least 90 days before screening. In other words, retatrutide was tested on its own (as monotherapy), early in the disease. Of the 537, 296 (55%) were women and 241 (45%) were men.

According to the meeting abstract, people on retatrutide started at 2 mg a week. The dose was raised in steps every four weeks until each person reached their assigned dose. The primary end point was the change in HbA1c from the start to week 40. HbA1c is a blood test that reflects average blood sugar over the previous few months (see what the HbA1c number measures). The key secondary end point was the percentage change in body weight. The registry also lists target HbA1c levels, fasting glucose, triglycerides, non-HDL cholesterol and systolic blood pressure as secondary end points.

The trial excluded people with type 1 diabetes, previous obesity surgery, a heart attack, stroke or heart-failure hospital stay in the previous 90 days, severe heart failure, past pancreatitis, a personal or family history of medullary thyroid cancer or MEN2 syndrome, or any past suicide attempt. In all, 490 people (91%) completed the treatment period on the study drug and 504 (94%) completed the study.

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What Was Found, Number by Number

The paper reports its main figures for the “treatment regimen estimand.” This analysis counts everyone who was randomised, including people who stopped their injections along the way. Numbers in brackets are standard errors (SE) or 95% confidence intervals (CI), as the abstract prints them.

HbA1c (the primary end point)

• Retatrutide 4 mg: −1.69% (SE 0.11); difference from placebo −0.88% (95% CI −1.18 to −0.59).
• Retatrutide 9 mg: −1.86% (SE 0.10); difference from placebo −1.04% (95% CI −1.32 to −0.76).
• Retatrutide 12 mg: −1.94% (SE 0.08); difference from placebo −1.12% (95% CI −1.39 to −0.85).
• Placebo: −0.81% (SE 0.12).
• All three doses beat placebo (p<0.0001 for each).

The placebo group’s HbA1c also fell, by 0.81%. So the effect of the drug itself is the difference from placebo: 0.88 to 1.12 percentage points. The headline “up to 2%” figure is the total fall in the 12 mg group, which includes whatever happened in the placebo group too.

Body weight (key secondary end point)

• Retatrutide 4 mg: −11.5% (SE 0.7).
• Retatrutide 9 mg: −13.9% (SE 0.8).
• Retatrutide 12 mg: −15.3% (SE 0.8).
• Placebo: −2.6% (SE 0.5).

The abstract gives standard errors for these weight changes but prints no confidence interval for the difference from placebo, so none is given here. The American Diabetes Association’s release said that weight loss “did not reach its maximum magnitude by the end of 40 weeks.” In other words, people were still losing weight when the trial ended.

Other figures reported at the meeting

The following figures come from the meeting abstract as reported by the trade publication HCPLive on June 6. They are not in the Lancet abstract and could not be checked against the paper’s full text. 90% of people on retatrutide reached an HbA1c below 7%, and up to 85% reached 6.5% or lower. Triglycerides fell by up to 39.6%, non-HDL cholesterol by 19.8% and systolic blood pressure by 6.4 mmHg, and waist size shrank by 4.9 inches. Blood fats are explained on the site’s lipid panel page.

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Side Effects and Stopping Treatment

The Lancet abstract says the most frequent side effects were “generally mild to moderate gastrointestinal events, which subsided over time.” Treatment was stopped because of side effects by 2% to 5% of people on retatrutide and by 0% on placebo. There was no severe hypoglycaemia (dangerously low blood sugar). Two people died during the study, both in the 4 mg group, and the paper reports both deaths as unrelated to the study drug.

The meeting abstract, as reported by HCPLive, gave rates for each dose (4 mg, 9 mg and 12 mg, then placebo):

• Nausea: 16.4%, 19.5%, 26.5% vs 3.7%.
• Diarrhoea: 18.7%, 26.3%, 22.8% vs 4.5%.
• Vomiting: 15.7%, 15%, 17.6% vs 2.2%.
• Dysesthesia (abnormal or unpleasant skin sensations such as tingling or burning): 4.5%, 2.3%, 4.4% vs 0%.
• Urinary tract infections: 0.7%, 1.5%, 2.9% vs 0%.
• Stopped treatment because of side effects: 2.2%, 4.5%, 5.1% vs 0%.

HCPLive’s report described these effects as “generally mild to moderate and most resolved during treatment.” Dysesthesia is not unique to retatrutide. A French drug-safety analysis published in May 2026 linked it to several GLP-1 drugs. It reported that dysesthesia appears more often at higher doses, and that in many reported cases it got better after the drug was stopped. Heart rate is not reported in the Lancet abstract or in any meeting coverage this report found, so this trial’s heart-rate result is not known here. In the earlier phase 2 obesity trial, heart rate rose with dose, peaked at 24 weeks and then declined. The site’s page on side effects of GLP-1 drugs covers the side effects of the drug class.

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How a Triple Agonist Works

GLP-1 and GIP are “incretin” hormones that the gut releases after a meal. They help the pancreas release insulin when blood sugar is high, and they act on appetite. Semaglutide works on the GLP-1 receptor alone. Tirzepatide works on both GIP and GLP-1 receptors. Retatrutide adds a third target, the receptor for glucagon, the hormone the body uses to raise blood sugar and burn stored fuel between meals. The site’s animation GLP-1, incretins and how the new weight-loss drugs work shows the incretin system step by step.

Why add glucagon to a diabetes drug? The drug’s developers described the idea in a 2022 paper in Cell Metabolism. In obese mice, they reported that weight loss was “augmented by the addition of GCGR-mediated increases in energy expenditure to GIPR- and GLP-1R-driven calorie intake reduction.” Put simply, the GIP and GLP-1 parts mainly reduce how much is eaten, and the glucagon part adds extra energy use. In laboratory tests the molecule had about equal activity at the glucagon and GLP-1 receptors and more activity at the GIP receptor. In people its half-life is about six days, which allows weekly dosing. The American Diabetes Association’s release summed up the design as targeting three hormones “to help reduce appetite, improve insulin response, increase energy use, and promote fat metabolism.” The energy-use part of that idea comes mainly from animal work. This trial did not measure energy use. More on the class is on the site’s GLP-1 mechanism and insulin response page.

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How It Fits With Earlier Research

The earlier retatrutide trials

A 12-week phase 1b trial in 72 people with type 2 diabetes, published in 2022, reported an “acceptable safety profile” and support for phase 2 development. Two phase 2 trials followed in June 2023. In the obesity trial (Jastreboff and colleagues, New England Journal of Medicine, 338 adults without diabetes), weight fell 24.2% at 48 weeks on 12 mg versus 2.1% on placebo. In the type 2 diabetes trial (Rosenstock and colleagues, The Lancet, 281 participants in the USA), HbA1c fell 2.02% at 24 weeks on 12 mg versus 0.01% on placebo and 1.41% on the GLP-1 drug dulaglutide. Weight fell 16.94% at 36 weeks on 12 mg versus 3.00% on placebo. That phase 2 diabetes trial allowed metformin and recruited people with an average diabetes duration of 8.1 years. Its authors wrote that it “informed dose selection for the phase 3 programme.” TRANSCEND-T2D-1 is the first test of those doses in a phase 3 trial.

Earlier monotherapy trials of other drugs

Two older trials used a similar design: weekly injections compared with placebo in people on diet and exercise alone. In SUSTAIN 1 (semaglutide, 30 weeks, 388 people), HbA1c fell 1.45% and 1.55% on the two doses versus 0.02% on placebo. In SURPASS-1 (tirzepatide, 40 weeks, 478 people), HbA1c fell 1.87% to 2.07% versus a rise of 0.04% on placebo, and weight fell by 7.0 to 9.5 kg. These are separate trials with different populations. SURPASS-1 participants, for example, had an average BMI of 31.9 against 35.8 here, and the placebo groups behaved very differently. Comparing numbers across them is not the same as a head-to-head trial. A direct comparison of retatrutide with semaglutide (TRANSCEND-T2D-2, 80 weeks) was listed as under way.

The muscle and lean-mass question

A recurring question about the GLP-1 drugs is how much of the weight lost is fat and how much is muscle and other lean tissue. The site’s January 2026 news report, fat or muscle on GLP-1 drugs, looked at a large records study of body composition after these drugs and after surgery. TRANSCEND-T2D-1’s abstract reports no body-composition data. The published evidence for retatrutide includes a DXA-scan substudy of the phase 2 diabetes trial, published in 2025. It was also maker-funded, and all of its authors were maker employees. Total fat mass fell 23.2% on 12 mg versus 4.5% on placebo. Only 103 people completed both scans. The authors concluded that “the proportion of lean mass loss to weight loss was similar to other obesity treatments.”

Heart and kidney outcomes in the class

For the older drugs, large outcome trials took years. In SELECT (2023), weekly semaglutide lowered major cardiovascular events in 17,604 adults with existing cardiovascular disease and overweight or obesity but no diabetes (hazard ratio 0.80, 95% CI 0.72 to 0.90). In SURPASS-CVOT (2025), tirzepatide was non-inferior, but not superior, to the GLP-1 drug dulaglutide in 13,299 people with type 2 diabetes and heart disease (hazard ratio 0.92, 95.3% CI 0.83 to 1.01). The site’s February 2026 report on oral semaglutide and heart failure covers another piece of that evidence. No such outcome result existed for retatrutide in June 2026.

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What It Cannot Show

• Forty weeks only. The trial cannot show whether the HbA1c and weight results last, or what happens after the drug is stopped. Weight was still falling at week 40, according to the ADA release.
• Surrogate end points. HbA1c and weight are markers. The trial did not test whether retatrutide prevents heart attacks, strokes, kidney failure, eye or nerve damage, or deaths. Its lead author said at the meeting that long-term cardiovascular, kidney and liver benefits are “still unknown at this time.”
• Early, untreated diabetes. Participants had had diabetes for an average of 2.5 years and were taking no diabetes medicine. The results may not apply to people with long-standing diabetes, people already on several drugs, or people on insulin.
• Who was left out. People with recent heart attack or stroke, severe heart failure, past pancreatitis, certain thyroid cancers or a history of suicide attempt were excluded.
• Small groups for rare harms. With about 134 people per group, a 40-week trial cannot rule out uncommon side effects. Heart rate and body composition are not reported in the abstract.
• Industry funding. The drug’s maker funded the trial, six of the ten authors are its employees and shareholders, and the other four report payments or support from it.
• Full text not reviewed here. The authors’ own list of limitations is in the paywalled full text, which this report could not open, so it is not quoted.

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What the Researchers and the ADA Said

The paper’s own conclusion was that retatrutide “showed significant improvements in glycaemic control and bodyweight reduction as a monotherapy,” with “an adverse event profile consistent with molecules with GLP-1 agonist activity, supporting its potential as an effective treatment for type 2 diabetes.”

The American Diabetes Association’s press release of June 6 quoted the lead author, Harpreet Singh Bajaj of LMC Diabetes and Endocrinology in Canada: “The magnitude of weight loss observed with retatrutide has the potential to slow disease progression and reshape how we treat and manage type 2 diabetes.” He noted that weight loss with existing drugs “is often less for people living with type 2 diabetes compared to those without diabetes” and said that “no other trial has reported this magnitude of weight loss.” That is his assessment; this trial did not compare retatrutide with any other drug. The release itself said that adverse events “were low, similar to those of GLP-1 receptor agonists already in use, with no new reported safety concerns.” By the meeting abstract’s figures, nausea affected up to 26.5% of people on retatrutide versus 3.7% on placebo, while 2% to 5% stopped treatment because of side effects.

At the meeting’s press briefing, as reported by HCPLive, Bajaj said: “Of course, long-term outcomes – the question of whether this molecule, similarly to GLP-1s, will show long-term cardiovascular benefits, kidney benefits, or liver outcome benefits – is still unknown at this time.”

A number that differs from the paper. The ADA release and much of the coverage reported a 16.8% weight loss (36.6 pounds on average) on 12 mg. The Lancet abstract’s figure for 12 mg is 15.3%, from the analysis that counts everyone randomised. The releases did not say which analysis produced 16.8%. At the time, the drug was not approved for any use.

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Since Then: Later Trials and Reports

This section was added in October 2026 and covers events after June 6. Each item was checked against its own source.

• June 29, 2026 — pooled analysis. A meta-analysis of randomised retatrutide trials in High Blood Pressure & Cardiovascular Prevention found lower systolic blood pressure (weighted mean difference −6.79 mmHg, 95% CI −8.36 to −5.23). It also found lower triglycerides and LDL cholesterol, and no change in HDL cholesterol.
• September 29, 2026 — TRIUMPH-1 (obesity, no diabetes). The phase 3 obesity trial, also presented in symposium form at the June meeting, was published in the New England Journal of Medicine. It randomised 2,339 adults for 80 weeks. Weight fell 17.6% (4 mg), 23.7% (9 mg) and 25.0% (12 mg) versus 3.9% on placebo, counting everyone randomised. The June ADA release had given 28.3% for 12 mg; the release did not say which analysis that figure came from.
• September 29, 2026 — TRIUMPH-2 (obesity plus type 2 diabetes). Published in The Lancet: 1,152 adults, 80 weeks. Weight fell 11.9%, 16.8% and 18.8% versus 5.1% on placebo. The difference for 12 mg was −13.8 percentage points (95% CI −15.8 to −11.8). Dysesthesia (up to 7% vs 1%) and low blood pressure (up to 6% vs under 1%) were more frequent on retatrutide. Stopping treatment because of side effects or death reached 12% on 9 mg and 8% on 12 mg, versus 5% on placebo.
• Outcome trial still running. The registry record of TRIUMPH-Outcomes (NCT06383390) describes an event-driven trial of about 10,000 people with a BMI of 27 or more and heart or kidney disease, measuring heart attacks, strokes, heart failure and kidney events. As of its October 8, 2026 update it was active but no longer recruiting, with an estimated primary completion in February 2029.
• October 9, 2026 — unapproved sales. A JAMA medical news article described a “burgeoning black market” for retatrutide, which was still unapproved, and for another unapproved drug sold online, along with the risks of using them.

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Sources and Primary Documents

Every trial figure above was taken from the paper’s abstract and declarations (read through PubMed), the trial registry, or, where labelled, the meeting abstract as reported on June 6, 2026. The full text of the Lancet paper is paywalled and was not read.

1. Bajaj HS, Welch M, Shah P, Luna E, Jaouimaa FZ, Liu B, Liu R, Chen Y, Patel H, Bartee A (2026). Efficacy and safety of retatrutide, a GIP, GLP-1, and glucagon receptor agonist, in people with type 2 diabetes and inadequate glycaemic control with diet and exercise (TRANSCEND-T2D-1): a double-blind, randomised, phase 3 trial. The Lancet 407(10546):2402-2413. — doi:10.1016/S0140-6736(26)00967-0 · PubMed PMID: 42250575
2. ClinicalTrials.gov record NCT06354660 (TRANSCEND-T2D-1): design, eligibility, end points and dates; completed February 20, 2026; no results posted on the registry. — NCT06354660
3. American Diabetes Association (June 6, 2026, New Orleans). Breakthrough Studies Demonstrate Effectiveness of the First Triple-Hormone Therapy for Type 2 Diabetes and Obesity. Press release. — diabetes.org press release
4. HCPLive (June 6, 2026). TRANSCEND-T2D-1: Retatrutide Demonstrates Superior Weight Loss and A1c Results Versus Placebo. Report of the ADA 2026 meeting abstract and press briefing; source of the per-dose side-effect figures. — HCPLive report
5. Jastreboff AM, Kaplan LM, Davies MJ, Wilding JPH, Ahmad NN, Murray M, et al. (2026). Retatrutide, a Triple Hormone Receptor Agonist, for Treatment of Obesity. New England Journal of Medicine, published online September 29, 2026. — doi:10.1056/NEJMoa2604169 · PubMed PMID: 42814954
6. Bellido V, le Roux CW, Ekinci EI, Bjornstad P, Frias JP, Giblin K, et al. (2026). Retatrutide in adults with obesity and type 2 diabetes (TRIUMPH-2): a double-blind, parallel-group, randomised, placebo-controlled, phase 3 trial. The Lancet 408(10563):1455-1472. — doi:10.1016/S0140-6736(26)01861-1 · PubMed PMID: 42810372
7. Simental-Mendía LE, Barragán-Zúñiga LJ, Reyes-Avitia V (2026). Effect of Retatrutide, a Novel Triple Receptor Agonist, on Blood Pressure and Lipid Levels: A Systematic Review and Meta-analysis of Randomized Controlled Trials. High Blood Pressure & Cardiovascular Prevention 33(5):503-516. — doi:10.1007/s40292-026-00812-6 · PubMed PMID: 42371360
8. ClinicalTrials.gov record NCT06383390 (TRIUMPH-Outcomes): cardiovascular and kidney outcomes of retatrutide; estimated primary completion February 2029. — NCT06383390
9. Rubin R (2026). Unapproved GLP-1 Drugs Retatrutide and Zenagamtide Sold Online Are No Bargain. JAMA, published online October 9, 2026 (Medical News). — doi:10.1001/jama.2026.20514 · PubMed PMID: 42853576

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Key Research Papers

Background papers on retatrutide’s development and on comparable trials of other drugs in the class. Each entry was checked against PubMed and Crossref before it was written down.

1. Coskun T, Urva S, Roell WC, Qu H, Loghin C, Moyers JS, et al. (2022). LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: From discovery to clinical proof of concept. Cell Metabolism 34(9):1234-1247.e9. — PubMed PMID: 35985340
2. Urva S, Coskun T, Loh MT, Du Y, Thomas MK, Gurbuz S, et al. (2022). LY3437943, a novel triple GIP, GLP-1, and glucagon receptor agonist in people with type 2 diabetes: a phase 1b, multicentre, double-blind, placebo-controlled, randomised, multiple-ascending dose trial. The Lancet 400(10366):1869-1881. — PubMed PMID: 36354040
3. Jastreboff AM, Kaplan LM, Frías JP, Wu Q, Du Y, Gurbuz S, et al. (2023). Triple-Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial. New England Journal of Medicine 389(6):514-526. — PubMed PMID: 37366315
4. Rosenstock J, Frias J, Jastreboff AM, Du Y, Lou J, Gurbuz S, et al. (2023). Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA. The Lancet 402(10401):529-544. — PubMed PMID: 37385280
5. Coskun T, Wu Q, Schloot NC, Haupt A, Milicevic Z, Khouli C, Harris C (2025). Effects of retatrutide on body composition in people with type 2 diabetes: a substudy of a phase 2, double-blind, parallel-group, placebo-controlled, randomised trial. The Lancet Diabetes & Endocrinology 13(8):674-684. — PubMed PMID: 40609566
6. Rosenstock J, Wysham C, Frías JP, Kaneko S, Lee CJ, Fernández Landó L, et al. (2021). Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomised, phase 3 trial. The Lancet 398(10295):143-155. — PubMed PMID: 34186022
7. Sorli C, Harashima SI, Tsoukas GM, Unger J, Karsbøl JD, Hansen T, Bain SC (2017). Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): a double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial. The Lancet Diabetes & Endocrinology 5(4):251-260. — PubMed PMID: 28110911
8. Lincoff AM, Brown-Frandsen K, Colhoun HM, Deanfield J, Emerson SS, Esbjerg S, et al. (2023). Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. New England Journal of Medicine 389(24):2221-2232. — PubMed PMID: 37952131
9. Nicholls SJ, Pavo I, Bhatt DL, Buse JB, Del Prato S, Kahn SE, et al. (2025). Cardiovascular Outcomes with Tirzepatide versus Dulaglutide in Type 2 Diabetes. New England Journal of Medicine 393(24):2409-2420. — PubMed PMID: 41406444
10. Laroche ML, Géniaux H, Jardou M (2026). Dysesthesia associated with GLP-1 agonist therapies: data-mining analysis and literature review. European Journal of Clinical Pharmacology 82(6):154. — PubMed PMID: 42168638

PubMed Topic Searches

1. PubMed: Retatrutide
2. PubMed: Retatrutide trials in type 2 diabetes
3. PubMed: GIP, GLP-1 and glucagon triple agonists
4. PubMed: Incretin drugs and lean mass
5. PubMed: GLP-1 drugs and heart rate

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Connections

• News Archive
• Type 2 Diabetes — causes, course and treatment research
• Obesity — the condition the TRIUMPH trials address
• Diabetes — the site’s diabetes hub
• Hemoglobin A1C — the blood test behind the trial’s primary end point
• Glycation and HbA1c — what the HbA1c number measures
• GLP-1 Receptor Agonists — the drug class retatrutide builds on
• GLP-1 Mechanism and Insulin Response — how the incretin drugs act
• GLP-1 Side Effects and Cautions — the class’s known adverse effects
• GLP-1 Weight Loss Studies — the weight-loss trials of the class
• GLP-1 and Incretins — interactive animation of the hormone system
• Cardio-Renal Protection — heart and kidney outcome trials of diabetes drugs
• Lipid Panel — triglycerides and cholesterol explained
• Fat or Muscle on GLP-1 Drugs — January 2026 report on body composition
• Oral Semaglutide and Heart Risk — February 2026 report on heart failure in type 2 diabetes

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