What are the most common retatrutide side effects reported in studies?

Gastrointestinal effects dominate. The Phase 2 obesity trial (NEJM 2023, Jastreboff et al., PMID 37366315, NCT04881760) reports that the most common adverse events in the retatrutide groups were gastrointestinal, that they were dose-related, mostly mild to moderate in severity, and were partially mitigated with a lower starting dose. The categories reported are nausea, diarrhoea, vomiting and constipation.

How large was the Phase 2 study behind the safety data?

It enrolled 338 adults and ran for 48 weeks, testing 1 mg, 4 mg, 8 mg and 12 mg against placebo, with the 4 mg and 8 mg arms each run with different starting doses. It is registered as NCT04881760 and published in the New England Journal of Medicine in 2023 (PMID 37366315). It was funded by Eli Lilly.

What is dysaesthesia and why does it come up with retatrutide?

Dysaesthesia is an altered skin sensation, in which ordinary touch is perceived as unusual or unpleasant. It surfaced as a notable sensory signal in the TRIUMPH-4 topline announcement, where it was reported at 0.7% under placebo, 8.8% at 9 mg and 20.9% at 12 mg. It is worth knowing about because it does not appear in the semaglutide or tirzepatide weight-management reporting and was not a headline of the earlier Phase 2 data. Those figures come from a sponsor topline, and without a head-to-head trial it is not established whether the difference is real or a reporting artefact.

Are the TRIUMPH-4 numbers peer-reviewed?

The results are not. The trial's rationale and design were published peer-reviewed (Diabetes Obes Metab 2026, PMID 41090431), but the outcomes themselves exist only as a sponsor topline announcement, so no independent reviewer has yet examined the reported event rates, the per-arm denominators or how events were adjudicated. Treat those figures as provisional. The Phase 2 outcome data (PMID 37366315) is peer-reviewed; the TRIUMPH-4 outcome figures are not.

How many participants stopped taking retatrutide because of side effects?

In the 48-week Phase 2 study, discontinuation ran roughly 6 to 16% depending on dose, against 0% on placebo. In the TRIUMPH-4 topline, discontinuation was 12.2% at 9 mg and 18.2% at 12 mg, against 4% on placebo. The sponsor noted that some TRIUMPH-4 discontinuations were attributed to weight loss perceived as too rapid rather than to classic intolerance, and that participants with higher BMI showed lower discontinuation. Without a full publication those attributions cannot be independently checked.

Does the dose affect how bad the side effects are?

Yes, and this is one of the most consistent findings in the data. The Phase 2 publication describes the gastrointestinal events as dose-related and states they were partially mitigated with a lower starting dose. The same pattern shows in the discontinuation and dysaesthesia figures, which both rise with dose. What the publication supports is narrower than the popular claim: a lower starting dose partially mitigated the gastrointestinal events. That is not the same as establishing that escalation speed causally drives tolerability, which the published data does not show.

What happens to heart rate?

Clinical studies observed a dose-dependent increase that peaked around week 24 and then declined. We deliberately do not restate a specific number of beats per minute, because the figure commonly quoted for retatrutide could not be traced to a source we can verify. Heart-rate increases are a known effect across incretin-based agonists and are monitored clinically in trials. This is a study observation, not a statement about any individual.

How does retatrutide compare with semaglutide and tirzepatide on side effects?

The broad categories overlap heavily, because all three act on incretin pathways and all three are dominated by gastrointestinal effects that scale with dose. The honest answer about head-to-head tolerability is that there is no completed head-to-head trial of retatrutide against either compound, so cross-trial comparison is the only option available and it is a weak one: different populations, durations, escalation schedules and reporting conventions. Dysaesthesia stands out because it appears in the retatrutide data and not in the semaglutide or tirzepatide weight-management reports, but that figure comes from a sponsor topline and, without a head-to-head trial, whether it is genuinely more specific to retatrutide is unestablished.

Which doses have been studied?

As a record of what trials administered, not as guidance: Phase 2 examined 1 mg, 4 mg, 8 mg and 12 mg once weekly over 48 weeks, with different starting doses in some arms. TRIUMPH-4 tested the two highest investigational doses, 9 mg and 12 mg, over 68 weeks. These are trial parameters in supervised clinical settings and are not a protocol to copy.

Is retatrutide approved as a medicine?

No. To our knowledge, as of July 2026, retatrutide holds no marketing authorisation in the EU or approval by the FDA for any indication. It is an investigational compound still in clinical development. It is sold here strictly as a research material, and nothing on this page is a therapeutic claim or a suggestion of human use.

Are the long-term safety questions settled?

No. The longest retatrutide data announced so far runs 80 weeks (TRIUMPH-1, n=2339, sponsor topline, May 2026); TRIUMPH-4 ran 68 weeks. Both are topline announcements rather than results publications. Questions that remain genuinely open include what happens to the dysaesthesia signal over longer exposure, what the durability and reversibility of the effects look like after stopping, and how the safety profile behaves in populations not represented in the trials so far.

Do the side effects go away over time?

The data offers only partial answers. The heart-rate increase was reported to peak around week 24 and then decline; whether that reflects adaptation is not established. Gastrointestinal effects were described as mostly mild to moderate and partially mitigated with a lower starting dose, which points to the escalation phase mattering, though duration effects are not separable from the published data. For dysaesthesia the sponsor topline described events as mild and rarely leading to discontinuation, but without a results publication the time course cannot be assessed.

Why does the article rely partly on a press release?

Because for the TRIUMPH-4 outcomes it is currently the only source. The trial design was published peer-reviewed (PMID 41090431), but the results were not, so a sponsor announcement is all there is. We would rather say that plainly than present topline figures as if they carried the weight of a peer-reviewed publication. Where you see a TRIUMPH-4 number on this page, read it as sponsor topline.

What is retatrutide and how does it differ from the others?

It is an investigational synthetic peptide from Eli Lilly that activates three receptors at once: the glucagon receptor (GCGR), the glucose-dependent insulinotropic polypeptide receptor (GIPR) and the glucagon-like peptide-1 receptor (GLP-1R). Semaglutide targets one of those pathways and tirzepatide two. The added glucagon-receptor activity is the pharmacological difference, and it is a plausible reason its side-effect profile is not simply a scaled version of the others.

Where can I read the primary studies myself?

The Phase 2 obesity trial is Jastreboff AM et al., New England Journal of Medicine 2023, PMID 37366315, registered as NCT04881760. A 2025 systematic review and meta-analysis by Abouelmagd et al. in Baylor University Medical Center Proceedings (38(3):291-303) aggregates the randomised evidence. For TRIUMPH-4 the rationale and design are published (PMID 41090431) but the results are not; only the sponsor's topline announcement exists. Reading the primary sources is worth the effort, because most secondary coverage of this compound summarises a press release.

Is any of this medical advice?

No. Everything on this page is a summary of published and announced clinical research, reported for a research audience. It is not medical advice, not a treatment recommendation and not a dosing protocol. The products sold on this site are research materials, not for human consumption.

Where can I see your certificates of analysis?

They are published on our lab reports page, organised by product and batch, with the testing lab named and a verification link where the lab provides one. Most of those reports were commissioned by the manufacturer rather than by us, and we say so rather than describing them as independent. A certificate reports on the material in the vial; it says nothing about the clinical safety data discussed on this page.

Retatrutide Side Effects in Studies: Safety Profile from Phase 2 and TRIUMPH-4

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., PMID 37366315, NCT04881760)

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%

Nausea

Placebo: 11%
1 mg: 14%
4 mg (start 2 mg): 18%
4 mg (start 4 mg): 36%
8 mg (start 2 mg): 17%
8 mg (start 4 mg): 60%
12 mg (start 2 mg): 45%

Diarrhoea

Placebo: 11%
1 mg: 9%
4 mg (start 2 mg): 12%
4 mg (start 4 mg): 12%
8 mg (start 2 mg): 20%
8 mg (start 4 mg): 20%
12 mg (start 2 mg): 15%

Vomiting

Placebo: 1%
1 mg: 3%
4 mg (start 2 mg): 12%
4 mg (start 4 mg): 12%
8 mg (start 2 mg): 6%
8 mg (start 4 mg): 26%
12 mg (start 2 mg): 19%

Constipation

Placebo: 3%
1 mg: 7%
4 mg (start 2 mg): 15%
4 mg (start 4 mg): 6%
8 mg (start 2 mg): 11%
8 mg (start 4 mg): 11%
12 mg (start 2 mg): 16%

Decreased appetite

Placebo: 9%
1 mg: 13%
4 mg (start 2 mg): 18%
4 mg (start 4 mg): 24%
8 mg (start 2 mg): 11%
8 mg (start 4 mg): 31%
12 mg (start 2 mg): 29%

The Phase 2 data point to two patterns. First, the gastrointestinal events were dose-related. Second, the relationship is not driven by the target dose alone: the publication states the events "were partially mitigated with a lower starting dose", so at the same target dose the starting point mattered. Note the limit of that claim: it establishes that the starting dose made a difference, not that escalation speed as such drives tolerability.

The rate of serious adverse events was reported at 4% in both groups (retatrutide and placebo). Read that similarity carefully: the trial was sized to detect weight outcomes, not uncommon harms, so equal serious-event rates at this sample size are not evidence that severe complications do not occur.

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%

Nausea

9 mg: 38.1%
12 mg: 43.2%

Diarrhoea

9 mg: 34.7%
12 mg: 33.1%

Vomiting

9 mg: 20.4%
12 mg: 20.9%

Decreased appetite

9 mg: 19.0%
12 mg: 18.2%

Constipation

9 mg: 21.8%
12 mg: 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 and Starting Dose

The starting dose influences the tolerability of retatrutide. The Phase 2 study ran the 4 mg and 8 mg targets with different starting doses, and the publication states that the gastrointestinal events "were partially mitigated with a lower starting dose" (PMID 37366315). Participants who reached 8 mg starting from 4 mg showed higher GI event rates than those escalating from a lower start. What the publication supports is the effect of the starting dose; it does not isolate escalation speed as a separate causal factor.

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)

1-4

Dose: 2 mg

5-8

Dose: 4 mg

9-12

Dose: 6 mg

13-16

Dose: 9 mg

from week 17

Dose: 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%

Placebo

Dysaesthesia rate: 0.7%

9 mg

Dysaesthesia rate: 8.8%

12 mg

Dysaesthesia rate: 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 were mild and rarely led to discontinuation, which is not the same as saying they did not affect discontinuation at all. More detailed data on severity, duration and body regions affected are still outstanding.

Heart Rate

Clinical studies observed a dose-dependent increase in heart rate that peaked around week 24 and subsequently declined. We are not restating a specific magnitude here, because the figure we previously carried could not be traced to a source we can verify. Heart-rate increases are a known effect across incretin agonists and are monitored clinically.

Comparison: Retatrutide vs. Semaglutide vs. Tirzepatide

This article previously carried a table of side-by-side adverse-event percentages for semaglutide (STEP-1), tirzepatide (SURMOUNT-1) and retatrutide. We have removed it, and the reason is worth stating plainly.

No head-to-head trial of retatrutide against semaglutide or tirzepatide exists. Every number in such a table therefore comes from a different trial, in a different population, with a different escalation schedule, a different duration and different reporting conventions. Lining those columns up implies a comparison the underlying data cannot support.

Worse, when we went back to re-verify the individual percentages against the primary publications, we could not confirm several of them from the sources we can actually read: the per-dose adverse-event rates for the comparator trials sit in full-text supplements rather than in the abstracts, and at least one figure we had published appears to have been materially off. Rather than keep numbers we cannot stand behind and label them "indicative", we took them out.

What can be said honestly is narrower:

All three compounds are dominated by gastrointestinal adverse events, and in all three those events scale with dose. This is the consistent finding across the programmes.
Retatrutide adds glucagon-receptor activity that the other two do not have (tirzepatide has two targets, semaglutide one), which is a plausible reason to expect its profile is not simply a scaled version of theirs, but that is a mechanistic expectation and not a measured comparison.
Dysaesthesia appears in the retatrutide reporting and does not appear in the semaglutide or tirzepatide weight-management reports. Whether that reflects a real difference between the compounds, or a difference in how and what these trials reported, is not established by the data available.

Anyone who shows you a clean cross-trial safety ranking of these three is showing you an artefact of trial design, not a finding.

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%

Phase 2 (48 weeks)

Placebo discontinuation: 0%
Retatrutide discontinuation: 6-16% (dose-dependent)

TRIUMPH-4, 9 mg (68 weeks)

Placebo discontinuation: 4%
Retatrutide discontinuation: 12.2%

TRIUMPH-4, 12 mg (68 weeks)

Placebo discontinuation: 4%
Retatrutide discontinuation: 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.

We previously placed comparator discontinuation rates from the semaglutide and tirzepatide programmes next to these figures. We have removed them for the same reason we removed the comparison table: no head-to-head trial exists, the trials differ in population, duration and escalation, and we could not re-verify those comparator percentages against a primary source.

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. In the trials they occurred mainly during the escalation phase, and the Phase 2 publication reports they were partially mitigated with a lower starting dose. That is an observation from supervised clinical trials, not a protocol suggestion.
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 in the retatrutide trials was dose-related. It ran roughly 6 to 16% in Phase 2 against 0% on placebo, and 12.2% (9 mg) and 18.2% (12 mg) against 4% on placebo in the TRIUMPH-4 topline. We do not rank this against other compounds, because no head-to-head trial exists. Without a results publication, the reasons behind the TRIUMPH-4 discontinuations cannot be independently interpreted.
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

This article is for informational purposes only for scientific research.

Disclaimer: FOR RESEARCH USE ONLY. All products from PeptidesDirect are intended exclusively for in vitro research and laboratory use. Not for human consumption. Not for in vivo applications. By purchasing you confirm that the products are not intended for ingestion or other application in humans.

Frequently Asked Questions

Related Products

Retatrutidemetabolic

First-ever triple-action weight management peptide targeting three receptors at once: GLP-1, GIP, and glucagon. Shown exceptional results in Phase 2 trials - up to 24% weight reduction. The most advanced metabolic peptide available.

Tirzepatidemetabolic

A first-in-class dual GIP and GLP-1 receptor agonist, and one of the most extensively studied compounds in modern metabolic and weight-regulation research. Supplied as a lyophilised research peptide with a per-batch certificate of analysis, for laboratory and in-vitro use only.