Investigational — not available anywhere
This compound is not approved for any use and is not currently sold by any vendor, including research-chemical and RUO (“research use only”) sellers. Everything on this page comes from the developer’s own registered trials or from published research; there is no legitimate product to buy under this name, and any listing claiming otherwise should be treated with suspicion. See the full Obesity Pipeline for other compounds at this same stage.
Nisotirostide (LY3457263) is an investigational peptide from Eli Lilly that activates the NPY2 receptor, the same receptor targeted by the natural gut hormone peptide YY (PYY), which signals fullness after eating. Unlike most peptides in the obesity pipeline, it is not being developed as a standalone weight-loss drug: Lilly’s trials have tested it specifically as an add-on given alongside tirzepatide or semaglutide, on the idea that combining a PYY-pathway drug with a GLP-1-pathway drug might improve results beyond either alone. It completed one phase 1 trial in people with obesity and is now in a phase 2 trial in type 2 diabetes measuring blood sugar control, not weight loss, as its main outcome. It has never been approved and has never been sold anywhere.
Research snapshot
| Peptide category | NPY2 receptor agonist (PYY analog) |
| Primary research interest | Add-on therapy alongside GLP-1/GIP drugs (tirzepatide, semaglutide), for both glycemic control and potential weight benefit |
| Highest available evidence | Completed Phase 1 trial (obesity, add-on to tirzepatide); Phase 2 trial ongoing (type 2 diabetes, add-on to semaglutide or tirzepatide) |
| Human research available | Yes — one completed Phase 1 trial, one active Phase 2 trial |
| Development status | Phase 2 (active, recruiting) |
| Regulatory status | Not approved anywhere. Not sold under any legitimate or grey-market channel. |
| Last reviewed | September 27, 2026 |
Technical identity
| Primary name | Nisotirostide |
| Alternative names | LY3457263 |
| Peptide sequence | Not published in a primary source identified for this page |
| Amino-acid length | Not reliably established, though the molecular formula below is consistent with a large, modified peptide |
| Molecular formula | C230H343N59O65 (per PubChem, CID 171118544) |
| Molecular weight | Not independently calculated or confirmed here; the PubChem CID record can be consulted directly for the current computed value |
| CAS Registry Number | 2663844-45-7, per multiple commercial vendor listings; not independently cross-confirmed against a regulatory database |
| PubChem CID | 171118544 |
| UNII | Not reliably established |
| DrugBank ID | Not listed |
| Chemical modifications | Not disclosed in sources reviewed; commercial vendors describe it simply as a “synthetic peptide” |
| Peptide class | Peptide YY (PYY) pathway analog / NPY2 receptor agonist |
| Primary biological target | NPY2 receptor (Y2 receptor), the receptor PYY3-36 acts on |
| Developer or originator | Eli Lilly and Company |
| Development status | Phase 2 |
What is nisotirostide?
Nisotirostide, known in Lilly’s own trial records by its code LY3457263, is an investigational synthetic peptide that activates the NPY2 receptor. That receptor’s natural ligand is peptide YY, specifically a shortened, active form called PYY3-36, a hormone released by cells in the gut after eating that helps signal fullness to the brain. PYY has been studied as an obesity target for decades, short-term intravenous PYY3-36 infusion studies go back to the early 2000s, but turning it into a practical, long-acting drug has been a persistent challenge, partly because PYY-pathway effects on their own tend to be modest compared to the GLP-1 pathway that drugs like semaglutide and tirzepatide target.
That history is likely why Lilly is not developing nisotirostide as a standalone weight-loss drug the way it developed tirzepatide or retatrutide. Instead, every trial identified for this page tests nisotirostide specifically as an add-on, given alongside an already-approved GLP-1 or GLP-1/GIP drug, rather than by itself. The first, a completed phase 1 trial (NCT05582096), enrolled 38 adults with overweight or obesity and tested nisotirostide added to tirzepatide against tirzepatide plus placebo, evaluating safety, tolerability, and pharmacokinetics over roughly 11 weeks. The current, larger trial (NCT06897475, phase 2, actively recruiting as of this review) tests nisotirostide as an add-on in 200 people with type 2 diabetes who are already on a stable dose of semaglutide or tirzepatide but have not reached their blood sugar targets, with the primary outcome being change in HbA1c, a measure of average blood sugar, rather than weight loss.
That shift, from an obesity-focused phase 1 add-on trial to a diabetes-focused phase 2 add-on trial with a glycemic, not weight, primary endpoint, is worth being upfront about: as of this review, nisotirostide’s most advanced, currently active program is not primarily a weight-loss study.
How does it work?
Plain-English explanation
After you eat, your gut releases a hormone called PYY that travels to the brain and helps create the feeling of being full. Nisotirostide is a lab-made peptide designed to activate the same receptor that natural PYY uses, called the NPY2 or Y2 receptor, essentially delivering an artificial, longer-lasting version of that “you’re full” signal. Because it works on a completely different pathway from GLP-1 drugs like semaglutide, the idea Lilly is testing is that adding it on top of an existing GLP-1 drug might improve blood sugar control or weight results beyond what the GLP-1 drug achieves on its own.
Technical explanation
Nisotirostide is an NPY2 receptor agonist engineered as a synthetic analog in the peptide YY signaling pathway. PYY, released from L-cells in the distal gut postprandially, and its active fragment PYY3-36 act at NPY2 receptors in the hypothalamic arcuate nucleus, among other central and peripheral sites, to reduce food intake, a mechanism distinct from and potentially complementary to GLP-1 receptor agonism. No detailed pharmacokinetic parameters or receptor-binding potency data were identified in the public sources reviewed for this page; the molecular formula (C230H343N59O65) indicates a large, chemically modified peptide consistent with a design intended for extended duration of action, though this inference is not independently confirmed by a published structural paper.
Potential benefits and research applications
Add-on to tirzepatide in people with obesity
The completed phase 1 trial (NCT05582096) tested nisotirostide added to tirzepatide, versus tirzepatide plus placebo, in 38 adults with a BMI of 27 to 45. The trial’s stated primary objectives were safety, tolerability, and pharmacokinetics, not efficacy; no weight-loss results from this trial were identified in the sources reviewed for this page. Evidence: is being investigated for (completed but not identified as published in a peer-reviewed journal as of this review; safety/PK data only, no disclosed efficacy outcome).
Add-on to semaglutide or tirzepatide for glycemic control in type 2 diabetes
The active phase 2 trial (NCT06897475) is testing nisotirostide, versus placebo, in 200 people with type 2 diabetes who remain above their HbA1c target despite a stable dose of semaglutide or tirzepatide. The primary endpoint is change in HbA1c. This is Lilly’s most advanced and largest disclosed nisotirostide program as of this review. Evidence: is being investigated for (registered, actively recruiting trial with an estimated completion date of June 30, 2027; no results reported yet).
Weight loss as a standalone effect
No trial identified for this page tests nisotirostide as a standalone (monotherapy) weight-loss drug; every disclosed program pairs it with an existing GLP-1 or GLP-1/GIP drug. Evidence: has not been established, since the question has not been tested in the trials disclosed publicly.
What dosage information circulates?
Figures in this section summarize amounts and schedules reported in published research or circulating online. Their inclusion documents what is reported and does not establish that a regimen is verified, safe, effective, or appropriate. Nisotirostide has never been sold anywhere, legitimately or otherwise. Every dose used in human testing so far has been inside a Lilly-sponsored trial, and specific milligram amounts have not been publicly disclosed in the sources reviewed for this page.
The completed phase 1 trial, add-on to tirzepatide in obesity/overweight, dosed nisotirostide by subcutaneous injection over approximately 11 weeks; specific amounts were not disclosed. The active phase 2 trial, add-on to semaglutide or tirzepatide in type 2 diabetes, doses nisotirostide by injection over approximately 9 months total participation; specific amounts also have not been disclosed. Both trials are sponsor-run, and neither has published the specific milligram doses tested in a source this page could independently verify; that detail typically surfaces later, either in a peer-reviewed publication of the completed phase 1 trial or in the eventual phase 2 results. There is no community or vendor dosage to reconcile against, since nisotirostide has no presence outside these two Lilly trials.
| Reported use or research objective | Route reported | Amount reported | Frequency reported | Reported duration | Evidence or source category |
|---|---|---|---|---|---|
| Phase 1, add-on to tirzepatide, obesity/overweight | Subcutaneous injection | Not disclosed in sources reviewed | Not disclosed | Approximately 11 weeks | Registered, completed human trial; results not identified as published |
| Phase 2, add-on to semaglutide or tirzepatide, type 2 diabetes | Injectable (route per trial registration) | Not disclosed | Not disclosed | Approximately 9 months total participation | Registered, ongoing human trial |
| Any community, forum, or vendor protocol | — | — | — | — | Not consistently reported — no established or reliably sourced dosing information exists |
What circulates E5
| Reported use | Route | Amount reported | Frequency | Reported length |
|---|---|---|---|---|
| Phase 1, add-on to tirzepatide, obesity/overweight | Subcutaneous injection | Not disclosed in sources reviewed | Not disclosed | Approximately 11 weeks |
| Phase 2, add-on to semaglutide or tirzepatide, type 2 diabetes | Injectable (route as specified in trial registration) | Not disclosed | Not disclosed | Approximately 9 months total participation |
| Community, forum, or vendor protocol | Not applicable | Not applicable; no established or reliably sourced dosing information exists | Not applicable | Not applicable |
No established or reliably sourced consumer dosing information was identified. Nisotirostide has never been sold anywhere, legitimately or otherwise. Every dose used in human testing so far has been inside a Lilly-sponsored trial, and specific milligram amounts have not been publicly disclosed.
Recorded as an observation about what is published elsewhere. No figure here is a dose, a protocol, or a recommendation, and nothing in this section is evidence that any amount is safe or effective.
Side effects, risks, and limitations
No detailed adverse-event data was identified in the public sources reviewed for either the completed phase 1 trial or the ongoing phase 2 trial. Based on the drug class, a gut-hormone-pathway peptide related to PYY, gastrointestinal side effects, nausea, and PYY-pathway drugs have historically also been associated with effects like vomiting in some earlier PYY3-36 infusion research, are a plausible mechanism-based concern, but this is a general class expectation, not a confirmed finding for nisotirostide specifically, and should not be read as a reported result. Because nisotirostide has never been sold outside these two sponsor-controlled trials, there is no purity, contamination, or counterfeit-product concern to report.
What is not established: any efficacy result, in either weight loss or glycemic control; the specific doses tested; long-term safety; and whether the add-on strategy actually outperforms GLP-1/GIP monotherapy, which is precisely the question both trials exist to answer and neither has reported yet.
Regulatory and developmental status
Nisotirostide is not approved anywhere and has no regulatory filing. It is in phase 2 development, its most advanced active program, in type 2 diabetes as an add-on to semaglutide or tirzepatide, sponsored by Eli Lilly and Company. Its earlier phase 1 obesity add-on trial is completed, but its results have not been identified as published in this review. No regulatory filing timeline has been disclosed.
Frequently asked questions
What is nisotirostide?
Nisotirostide (LY3457263) is an investigational Eli Lilly peptide that activates the NPY2 receptor, the same receptor the natural fullness hormone PYY uses, being developed specifically as an add-on to GLP-1 drugs rather than a standalone treatment.
How does nisotirostide work?
It mimics peptide YY, a gut hormone that signals fullness after eating, working through a different biological pathway than GLP-1 drugs like semaglutide, which is why Lilly is testing it as a complement to those drugs rather than a replacement.
What dosage has been studied?
Specific milligram doses have not been publicly disclosed. It has been tested as an injectable add-on in a completed phase 1 trial with tirzepatide and an ongoing phase 2 trial with semaglutide or tirzepatide.
What dosage commonly circulates online?
None. Nisotirostide has never been available for purchase anywhere; it exists only inside Lilly’s own clinical trials.
Is nisotirostide meant to be used alone?
No trial disclosed for this page has tested it as a standalone drug; every study pairs it with an already-approved GLP-1 or GLP-1/GIP drug.
Has nisotirostide been studied in humans?
Yes. A phase 1 add-on trial in people with obesity has completed, and a phase 2 add-on trial in people with type 2 diabetes is actively recruiting.
Is nisotirostide approved?
No. It remains in phase 2 clinical development with no announced regulatory filing.
What is nisotirostide’s current primary goal, weight loss or blood sugar control?
As of this review, its most advanced active trial (phase 2, NCT06897475) is measuring blood sugar control, HbA1c, as its primary endpoint, not weight loss, even though its earlier phase 1 trial was conducted in a population with obesity.
What remains unknown?
Whether the PYY/NPY2 add-on strategy actually improves outcomes over GLP-1 monotherapy, what doses were tested, any efficacy result at all, and long-term safety.
Bottom line
Nisotirostide is a genuinely different kind of pipeline entry: rather than competing with drugs like semaglutide or tirzepatide, Lilly is testing it specifically as something to add on top of them, targeting the peptide YY/NPY2 pathway instead of the GLP-1 pathway those drugs already use. Its evidence so far is thin and does not yet answer the question its own development strategy raises, does adding a PYY-pathway drug to a GLP-1 drug actually help, since neither its completed phase 1 trial nor its ongoing phase 2 trial has reported an efficacy result. Worth flagging plainly: its most advanced current program is measuring blood sugar control in type 2 diabetes, not weight loss, even though it started life as an obesity-population trial. It has never been approved and has never been sold anywhere.