What is retatrutide, and how much safety data exists?
Retatrutide (LY3437943) is described by its developer as an investigational once-weekly triple hormone receptor agonist — a single molecule activating the receptors for glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1) and glucagon. The glucagon arm is what separates it from the dual and single agonists, and it is also the reason its tolerability profile is worth reading separately rather than assumed from the wider incretin class.
The published safety record rests on two phase 2 trials — one in obesity, one in type 2 diabetes — a liver-fat substudy of the obesity trial, that obesity trial’s posted registry results, and topline announcements from four phase 3 trials. The phase 3 announcements are the largest part of that record by participant count and the weakest part by evidentiary standard: they are company press releases, not peer-reviewed papers, and the full adverse-event tables behind them have not been published.
What have the phase 3 trials reported?
Four phase 3 trials have reported topline safety data, across three announcements from Eli Lilly: TRIUMPH-4 in December 2025, TRIUMPH-1 in May 2026, and TRIUMPH-2 and TRIUMPH-3 together in July 2026. In the July release the company describes retatrutide as having "five positive Phase 3 studies". Each release states that detailed results will be presented at future medical meetings and published in peer-reviewed journals, so what follows is the summary the sponsor chose to publish, not a complete safety table.
TRIUMPH-1 (NCT05929066) carries the largest published tolerability dataset for the compound: an 80-week, randomised, double-blind, placebo-controlled trial that randomised 2,339 participants 1:1:1:1 to retatrutide 4 mg, 9 mg, 12 mg or placebo, with everyone assigned to retatrutide starting at 2 mg once weekly and escalating step-wise every four weeks.
| Event | Retatrutide 4 mg | Retatrutide 9 mg | Retatrutide 12 mg | Placebo |
|---|---|---|---|---|
| Nausea | 28.6% | 38.4% | 42.4% | 14.8% |
| Diarrhoea | 25.2% | 34.1% | 32.0% | 13.5% |
| Constipation | 23.8% | 25.9% | 26.1% | 10.9% |
| Vomiting | 10.6% | 22.8% | 25.3% | 4.8% |
| Upper respiratory tract infection | 14.2% | 12.2% | 13.1% | 11.6% |
| Dysesthesia | 5.1% | 12.3% | 12.5% | 0.9% |
| Urinary tract infection | 7.5% | 8.8% | 8.4% | 5.3% |
| Discontinued for an adverse event | 4.1% | 6.9% | 11.3% | 4.9% |
Two rows are worth reading against the rest. Upper respiratory tract infection runs 14.2%, 12.2% and 13.1% against 11.6% on placebo — almost no separation, which is a useful calibration for how much separation the gastrointestinal rows actually show. And discontinuation for an adverse event in the 4 mg group, reached in a single escalation step, was 4.1% against 4.9% on placebo; Lilly leads the announcement with that comparison.
Dysesthesia: the signal phase 3 added
Dysesthesia — altered or unpleasant sensation — is the adverse event with no counterpart in the phase 2 obesity trial’s posted table. It appears in all four phase 3 toplines, at rates that vary widely between them.
| Trial (randomised) | Dysesthesia, retatrutide | Dysesthesia, placebo | Discontinued for an adverse event | Placebo |
|---|---|---|---|---|
| TRIUMPH-1 (2,339) | 5.1%–12.5% | 0.9% | 4.1%–11.3% | 4.9% |
| TRIUMPH-2 (1,152) | 4.5%–7.3% | 0.7% | 3.8%–11.6% | 4.9% |
| TRIUMPH-3 (1,949) | 6.4% (both arms) | 1.3% | 9.8%–13.5% | 4.8% |
| TRIUMPH-4 (445) | 8.8%–20.9% | 0.7% | 12.2%–18.2% | 4.0% |
TRIUMPH-4 is the outlier on both measures, and it is also the smallest and most selected of the four: 445 participants, all with knee osteoarthritis, 84.0% of them at a baseline BMI of 35 kg/m² or above. Quoting its 20.9% as the phase 3 dysesthesia figure — as short summaries of this compound often do — takes the highest number from the smallest trial. Across the three larger trials the retatrutide-arm rates run 4.5% to 12.5%.
On severity the releases say much the same thing each time. TRIUMPH-1 states that events of dysesthesia and urinary tract infections were generally mild to moderate, that the majority resolved during treatment, and that most participants continued taking retatrutide. The TRIUMPH-2 and TRIUMPH-3 release repeats the first two of those clauses. TRIUMPH-4 states its dysesthesia events were generally mild and rarely led to treatment discontinuation. None of the releases publishes a severity breakdown behind those statements.
What the other three trials reported
TRIUMPH-2 (NCT05929079) randomised 1,152 participants with type 2 diabetes and obesity or overweight, 1:1:1:1 across the same three doses and placebo over 80 weeks. Diarrhoea led its adverse-event list at 27.4%, 33.5% and 33.6% against 13.2% on placebo, with nausea at 13.7%, 20.8% and 28.0% against 8.0%, decreased appetite at 5.8%, 12.3% and 17.1% against 4.5%, and vomiting at 5.5%, 10.2% and 15.7% against 4.2%. Nausea in this population ran well below the obesity trials at matching doses.
TRIUMPH-3 (NCT05882045) randomised 1,949 participants with severe obesity and established cardiovascular disease, 1:1:2 to 9 mg, 12 mg or placebo over 80 weeks. Diarrhoea ran 30.1% and 24.4% against 8.7% on placebo, nausea 21.7% and 22.4% against 5.8%. It is the only one of the four to report cardiovascular outcomes: 44 MACE-5 events in participants randomised to pooled retatrutide against 52 on placebo (hazard ratio 0.82, 95.0% CI 0.55 to 1.22), and 27 MACE-3 events against 23 (hazard ratio 1.12, 95.0% CI 0.64 to 1.96), with Lilly noting that these events occurred less frequently than anticipated in both arms.
TRIUMPH-4 (NCT05931367) randomised 445 participants with obesity or overweight and knee osteoarthritis, 1:1:1 to 9 mg, 12 mg or placebo for 68 weeks. Nausea ran 38.1% and 43.2% against 10.7% on placebo, diarrhoea 34.7% and 33.1% against 13.4%, constipation 21.8% and 25.0% against 8.7%, vomiting 20.4% and 20.9% against 0.0%, and decreased appetite 19.0% and 18.2% against 9.4%.
As of the July 2026 announcement, Lilly states it is completing the manufacturing data package required for a Biologics License Application and plans to submit retatrutide in the first quarter of 2027 for US approval. Nothing has been submitted or approved yet, and the peer-reviewed phase 3 safety papers are still to come.
What did the phase 2 obesity trial report?
The phase 2 obesity trial (Jastreboff et al., NEJM 2023) enrolled 338 adults and ran 48 weeks, double-blind and placebo-controlled, across seven arms. Its abstract summarises the safety finding in one sentence: the most common adverse events were gastrointestinal, they were dose-related, mostly mild to moderate in severity, and were partially mitigated with a lower starting dose (2 mg vs. 4 mg).
The arm-level counts behind that sentence are posted on ClinicalTrials.gov under NCT04881760, covering baseline through end of safety follow-up (up to 52 weeks), with a reporting threshold of 5% in any treatment group. Two arms share each of the 4 mg and 8 mg maintenance levels, differing only in where escalation began.
| Arm | Nausea | Vomiting | Diarrhoea | Constipation | Any event* |
|---|---|---|---|---|---|
| Placebo (n=70) | 8 | 1 | 8 | 2 | 40 |
| 1 mg (n=69) | 10 | 2 | 6 | 5 | 46 |
| 4 mg, 2 mg start (n=33) | 6 | 4 | 4 | 5 | 22 |
| 4 mg, 4 mg start (n=33) | 12 | 4 | 4 | 2 | 24 |
| 8 mg, 2 mg start (n=35) | 6 | 2 | 7 | 4 | 26 |
| 8 mg, 4 mg start (n=35) | 21 | 9 | 7 | 4 | 31 |
| 12 mg, 2 mg start (n=62) | 28 | 12 | 9 | 10 | 52 |
*Any non-serious event reaching the 5% reporting threshold. Note the placebo column: 40 of 70 placebo participants reported at least one such event, and diarrhoea was reported by 8 of 70 on placebo against 9 of 62 on 12 mg. Reading a retatrutide column without reading the placebo column next to it overstates the compound’s contribution to almost every row.
A lower starting dose partially mitigated gastrointestinal events
That is the trial report’s own wording, and the posted table shows where it comes from. The two 8 mg arms reached the same maintenance level by different routes: one escalating from 2 mg, one starting at 4 mg. Nausea affected 6 of 35 in the first and 21 of 35 in the second; vomiting split 2 of 35 against 9 of 35. The trial does not rank the starting dose against the maintenance dose, and the same table shows the maintenance level moving nausea too — 6 of 35 at 8 mg against 28 of 62 at 12 mg among arms that all began at 2 mg.
Discontinuations, serious events and deaths
Withdrawal for an adverse event was rare in this trial: 0 of 70 on placebo, and 2 of 62 in the 12 mg arm, with one withdrawal in each of the 1 mg, 4 mg (2 mg start), 8 mg (2 mg start) and 8 mg (4 mg start) arms. Serious adverse events affected 3 of 70 placebo participants and 2 of 62 in the 12 mg arm. One death was recorded, in a 4 mg arm, posted under the term drowning.
Heart rate
The trial abstract reports that dose-dependent increases in heart rate peaked at 24 weeks and declined thereafter. No heart-rate outcome measure is included in the posted results for NCT04881760, so the published arm-level figure behind that sentence is not available from the registry — only the direction and the time course.
What did the diabetes and liver-fat trials add?
The phase 2 type 2 diabetes trial (Rosenstock et al., Lancet 2023) recruited 281 participants at 42 centres in the USA and, unusually for this compound, included an active comparator rather than placebo alone.
It reported mild-to-moderate gastrointestinal adverse events — nausea, diarrhoea, vomiting and constipation — in 67 (35%) of 190 participants across the retatrutide groups, ranging from six (13%) of 47 in the 0.5 mg group to 12 (50%) of 24 in the 8 mg fast escalation group. Placebo was six (13%) of 45. The dulaglutide comparator was 16 (35%) of 46 — identical, at the pooled level, to retatrutide.
That trial also reported no severe hypoglycaemia and no deaths, with 237 (84%) of participants completing the study and 222 (79%) completing study treatment.
The liver-fat substudy (Sanyal et al., Nature Medicine 2024) drew 98 participants with metabolic dysfunction-associated steatotic liver disease from the same obesity trial. Its safety section reports that transient, generally mild-to-moderate gastrointestinal events were the most frequently reported adverse events, more frequent in the 8 mg and 12 mg groups; that two participants treated with retatrutide (2.5%) experienced a total of three serious adverse events; and that there were no hepatotoxicity signals in either the overall obesity population or the liver-disease subset through 48 weeks.
What does the pooled analysis say?
A 2025 systematic review and meta-analysis in Baylor University Medical Center Proceedings pooled three randomised controlled trials covering 878 patients, with subgroup evaluation by dose. On safety its conclusion is a single line: no significant difference in adverse events was observed between the groups, relative risk 1.11, P = 0.24. Its evidence base is the phase 2 record — it predates every phase 3 readout above.
How does this compare with semaglutide and tirzepatide?
Not directly, because none of the trials cited here used either compound as a comparator. The phase 2 obesity trial and all four phase 3 trials were placebo-controlled; the phase 2 diabetes trial’s active comparator was dulaglutide. Any ranking of retatrutide’s tolerability against semaglutide or tirzepatide is therefore a cross-trial comparison between different protocols, populations and durations.
The nearest thing to a class anchor in this evidence is Lilly’s own framing: TRIUMPH-1 states that the types of adverse events seen were generally consistent with trials of other incretin-based therapies. That is a qualitative statement about event types, not a quantitative comparison of rates. The same caution applies to the weight-change figures, and the three-way comparison post sets out which of those numbers can be placed on one scale and which cannot.
What does "research-grade retatrutide in India" mean?
It means an investigational compound supplied for laboratory work, not a medicine. Lilly’s July 2026 release states that retatrutide "is an investigational molecule that cannot be legally sold or marketed for human use", and its May 2026 release states that it "is legally available only to participants in Lilly’s clinical trials". No regulator has licensed it, in India or anywhere else; the company’s stated plan is to file for US approval in the first quarter of 2027.
- Research use only — it is supplied as lyophilised powder for laboratory research, and is not for human or veterinary use.
- Identity and purity belong to the batch, not the label. Each batch has its own certificate of analysis published online, so a vial can be matched to the lab result for the material it actually contains.
- The trial figures on this page describe what happened to participants in supervised clinical trials under a protocol. They are not a prediction about anything else.
Batch certificates for stocked compounds are published on the batch lab results page linked below, and the retatrutide product page carries the current batch reference.
What does this evidence not tell you?
- Duration. The longest reported follow-up is 80 weeks, in TRIUMPH-1, TRIUMPH-2 and TRIUMPH-3, with a pre-specified extension to 104 weeks in the 532 TRIUMPH-1 participants who had a baseline BMI of 35 or above and tolerated their assigned dose. Nothing longer has been reported.
- Peer review. All four phase 3 readouts are company topline announcements, and each states that detailed results are still to be presented at medical meetings and published in peer-reviewed journals. The full adverse-event tables behind the percentages on this page are not public.
- Populations. The phase 2 diabetes trial recruited only in the USA, at 42 centres. TRIUMPH-3 enrolled only participants with severe obesity and established cardiovascular disease; TRIUMPH-4 only participants with knee osteoarthritis, 84.0% of them at a baseline BMI of 35 or above. None of these is a general population, and the trials differ enough that comparing their rates directly is itself a cross-trial comparison.
- Reporting thresholds. The posted phase 2 results list only non-serious events reaching 5% in at least one arm, so anything rarer is absent by design rather than by absence. That is why dysesthesia has no phase 2 row to compare against: the nearest posted nervous-system term is allodynia, in 4 of 62 participants in the 12 mg arm and none elsewhere.
- Comparators. None of the trials cited here used semaglutide or tirzepatide as a comparator, so no head-to-head tolerability comparison appears in this evidence.
What the record does support is narrow and consistent: gastrointestinal events are the dominant reported side effect, they rise with dose, the phase 2 trial reports that a lower starting dose partially mitigated them, and phase 3 has added a dysesthesia signal that the phase 2 posted table did not show.