Retatrutide Side Effects in Studies: Safety Profile from Phase 2 and TRIUMPH-4
Retatrutide side effects from Phase 2 and TRIUMPH-4 data: gastrointestinal effects, dysaesthesia, discontinuation rates and open safety questions.
Retatrutide (LY-3437943) is a triple agonist for GLP-1, GIP and glucagon receptors in clinical development. For tolerability, the published Phase 2 study and the TRIUMPH-4 results - so far available only as a topline announcement - are most relevant. This article summarises the available safety data from both sources and flags where statements remain preliminary.
For a comprehensive overview of the peptide itself, see our main article: Buy Retatrutide: The Triple Agonist in GLP-1 Research.
What is Retatrutide? A Brief Overview
Retatrutide is a synthetic peptide developed by Eli Lilly that simultaneously activates three incretin and metabolic receptors:
- GLP-1 (Glucagon-like Peptide-1): appetite regulation and insulin secretion
- GIP (Glucose-dependent Insulinotropic Polypeptide): insulin sensitivity and fat metabolism
- Glucagon: energy expenditure, lipolysis and thermogenesis
This mechanism distinguishes retatrutide from semaglutide (GLP-1 only) and tirzepatide (GLP-1 + GIP). Whether and to what extent the additional glucagon receptor activation influences specific side effects is the subject of ongoing research.
Gastrointestinal Side Effects: The Most Common Category
As with other incretin-based peptides, gastrointestinal (GI) side effects dominate the safety profile of retatrutide. The most frequently reported GI effects are nausea, diarrhoea, vomiting and constipation.
Phase 2 Data (NEJM 2023, Jastreboff et al.)
The Phase 2 obesity study enrolled 338 participants over 48 weeks. The published analysis examined 1 mg, 4 mg, 8 mg and 12 mg, with the 4 mg and 8 mg arms each reported with different starting doses. The overall rate of adverse events ranged from 73% to 94% in the retatrutide cohorts, compared to 70% under placebo. Most of these events were mild to moderate.
| Side effect | Placebo | 1 mg | 4 mg (start 2 mg) | 4 mg (start 4 mg) | 8 mg (start 2 mg) | 8 mg (start 4 mg) | 12 mg (start 2 mg) |
|---|---|---|---|---|---|---|---|
| Nausea | 11% | 14% | 18% | 36% | 17% | 60% | 45% |
| Diarrhoea | 11% | 9% | 12% | 12% | 20% | 20% | 15% |
| Vomiting | 1% | 3% | 12% | 12% | 6% | 26% | 19% |
| Constipation | 3% | 7% | 15% | 6% | 11% | 11% | 16% |
| Decreased appetite | 9% | 13% | 18% | 24% | 11% | 31% | 29% |
The Phase 2 data point to two patterns. First, several GI rates rise with the level and speed of dose escalation. Second, the relationship is not linear, because at identical target doses the starting dose can make a clear difference. This is particularly evident for nausea and vomiting in the 8 mg range.
The rate of serious adverse events was 4% in both groups (retatrutide and placebo). The common side effects were therefore primarily relevant for tolerability, not characterised by severe complications.
Phase 3 Data (TRIUMPH-4, December 2025)
The TRIUMPH-4 study examined 445 adults over 68 weeks at maintenance doses of 9 mg and 12 mg. To date, only topline data from Lilly are available, not a full peer-reviewed publication. GI side effects were reported separately for each dose:
| Side effect | 9 mg | 12 mg |
|---|---|---|
| Nausea | 38.1% | 43.2% |
| Diarrhoea | 34.7% | 33.1% |
| Vomiting | 20.4% | 20.9% |
| Decreased appetite | 19.0% | 18.2% |
| Constipation | 21.8% | 25.0% |
Compared to Phase 2, some individual rates are lower, others are not. An optimised dose escalation schedule is a plausible contributing factor, but no reliable causal conclusion can be drawn from the available topline data.
Dose Escalation as the Key to Tolerability
The speed of dose increases has a significant influence on the tolerability of retatrutide. In the Phase 2 study, participants placed directly on 8 mg without stepwise titration showed considerably higher GI adverse event rates than those with slower escalation.
In TRIUMPH-4, according to Lilly, titration proceeded in four-week steps:
| Week | Dose |
|---|---|
| 1-4 | 2 mg |
| 5-8 | 4 mg |
| 9-12 | 6 mg |
| 13-16 | 9 mg |
| from week 17 | 12 mg (12 mg arm only) |
The stepwise increase every four weeks is intended to improve tolerability. In the Phase 2 study, GI side effects occurred particularly during the escalation phase and diminished thereafter.
For research, this finding is relevant: dose escalation protocols are a central factor in study design with retatrutide and comparable peptides.
Dysaesthesia: A New Safety Signal
TRIUMPH-4 reports dysaesthesia as a notable sensory side effect. This refers to an altered skin sensation in which normal touch is perceived as unusual or unpleasant.
| Dose | Dysaesthesia rate |
|---|---|
| Placebo | 0.7% |
| 9 mg | 8.8% |
| 12 mg | 20.9% |
This signal was not described with the same prominence in the Phase 2 study, although reports of cutaneous hyperaesthesia and skin sensitivity were present there (approximately 7% under retatrutide vs. 1% under placebo).
No reliable mechanistic explanation for dysaesthesia has been published from the available data. Lilly stated that dysaesthesia events did not lead to increased study discontinuations. More detailed data on severity, duration and body regions affected are still outstanding.
Heart Rate
Clinical studies observed an increase in heart rate of approximately 5 to 10 beats per minute. This effect peaked around week 24 and subsequently declined. Heart rate increases are also known with other incretin agonists and are clinically monitored.
Comparison: Retatrutide vs. Semaglutide vs. Tirzepatide
A direct comparison of safety profiles is only partially possible because the studies used different populations, doses and escalation schemes. The following table provides a rough orientation based on the respective study programmes for weight management.
| Side effect | Semaglutide 2.4 mg (STEP-1) | Tirzepatide 15 mg (SURMOUNT-1) | Retatrutide 12 mg (Phase 2) | Retatrutide 12 mg (TRIUMPH-4) |
|---|---|---|---|---|
| Nausea | ~44% | ~33% | 45% | 43.2% |
| Diarrhoea | ~30% | ~23% | 15% | 33% |
| Vomiting | ~24% | ~13% | 19% | 20.9% |
| Constipation | ~24% | ~17% | 16% | 25.0% |
| Dysaesthesia | not reported | not reported | ~7% (skin hyperaesthesia) | 20.9% |
| Max. weight reduction | ~15% | ~21% | ~24% | ~28.7% |
The table highlights two points in particular. First, GI rates for retatrutide are in a range also seen with other incretin-based agents. Second, dysaesthesia in TRIUMPH-4 stands out more clearly than in the semaglutide and tirzepatide studies shown here. Whether this represents a stable class-specific difference will need to be confirmed by further datasets.
Discontinuation Rates as a Tolerability Indicator
The study discontinuation rate due to side effects provides guidance on the overall tolerability of a peptide.
| Study | Placebo discontinuation | Retatrutide discontinuation |
|---|---|---|
| Phase 2 (48 weeks) | 0% | 6-16% (dose-dependent) |
| TRIUMPH-4, 9 mg (68 weeks) | 4% | 12.2% |
| TRIUMPH-4, 12 mg (68 weeks) | 4% | 18.2% |
Lilly noted that some discontinuations in TRIUMPH-4 were attributed to weight loss perceived as too rapid and not necessarily to classic intolerance. Without a full publication, complete interpretation of these discontinuations remains limited. Participants with higher BMI showed lower discontinuation rates according to the topline announcement.
For comparison: in the semaglutide STEP studies, discontinuation rates due to side effects were around 7%; in the tirzepatide SURMOUNT studies, 4-7%.
Open Questions on Long-Term Safety
Since retatrutide is still in clinical development, several safety questions remain open. These are particularly relevant for ongoing research.
Hair Loss (Telogen Effluvium)
Reports of hair loss associated with incretin agonists are increasing, particularly with rapid weight loss. Telogen effluvium is frequently discussed as an explanation: metabolic stress and caloric restriction cause more hair follicles to enter the resting phase simultaneously. This would not be a direct pharmacological effect but a consequence of weight loss. Whether this occurs more frequently under retatrutide is not currently established.
Bone Density
Rapid weight loss can be associated with loss of bone mass. This effect is well documented regardless of the mechanism of weight loss, including after bariatric surgery. Specific data on bone density under retatrutide are not yet available. Given the substantial weight loss observed in studies, this remains a relevant research topic.
Muscle Mass
With any significant weight loss, a portion of lost mass is lean mass including muscle mass. Whether the glucagon receptor agonism of retatrutide influences this ratio has not been conclusively clarified. Reliable data from body composition analyses are still pending.
Thyroid
GLP-1 receptor agonists carry warnings regarding medullary thyroid carcinomas, based on animal studies in rodents. No extensively published long-term data on retatrutide are yet available to permit further reassurance. Accordingly, long-term endocrine monitoring remains part of ongoing and future studies.
Pancreatitis
Isolated cases of pancreatitis were reported in the studies, without a statistically significant increase over placebo. This corresponds to the profile of other incretin agonists. Monitoring of pancreatic markers (lipase, amylase) is routinely performed in clinical research.
Ongoing Studies: The TRIUMPH Programme
According to Lilly, the initial registrational TRIUMPH core programme comprised four global Phase 3 studies: TRIUMPH-1 through TRIUMPH-4. These studies cover chronic weight management and important comorbidities such as obstructive sleep apnoea and knee osteoarthritis. In addition, Lilly referenced further Phase 3 readouts in 2026. The safety profile of retatrutide will therefore only be reliably interpretable once the outstanding full publications and additional study reports become available.
Conclusions for Research
The safety profile of retatrutide resembles that of other incretin-based peptides in many respects, with gastrointestinal side effects as the most common category. The key points for research:
- GI side effects are the central tolerability factor. They occur mainly during dose escalation and favour cautious titration protocols.
- Dysaesthesia is a notable signal in TRIUMPH-4. At up to 20.9% at 12 mg, it is relevant for further safety assessment but needs to be characterised in more detail.
- Discontinuation rates exceed those of established comparators. Without a full publication, interpretation of the reasons remains limited.
- Long-term data are still lacking. Questions on bone density, muscle mass, hair loss and endocrine safety can only be answered with longer follow-up.
- Topline data represent only an interim status. The outstanding Phase 3 full publications are decisive for reliable safety conclusions.
Retatrutide is available as a research-grade peptide at PeptidesDirect. Further information on related peptides can be found on our product pages for semaglutide and tirzepatide.
Sources and further reading:
- Jastreboff AM et al. Retatrutide, a Triple-Hormone Receptor Agonist, for Obesity - A Phase 2 Trial. NEJM, 2023. PubMed: https://pubmed.ncbi.nlm.nih.gov/37366315/
- Eli Lilly. TRIUMPH-4 Topline Results, December 2025: https://www.prnewswire.com/news-releases/lillys-triple-agonist-retatrutide-delivered-weight-loss-of-up-to-an-average-of-71-2-lbs-along-with-substantial-relief-from-osteoarthritis-pain-in-first-successful-phase-3-trial-302638804.html
- Eli Lilly FAQ with context and timeline of retatrutide updates: https://www.lilly.com/news/stories/what-to-know-about-retatrutide
- Abouelmagd AA, Abdelrehim AM, Bashir MN, et al. Efficacy and safety of retatrutide, a novel GLP-1, GIP, and glucagon receptor agonist for obesity treatment: a systematic review and meta-analysis of randomized controlled trials. Baylor University Medical Center Proceedings. 2025;38(3):291-303. DOI: https://doi.org/10.1080/08998280.2025.2456441
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