Glumitide Phase 1

What It Is

Glumitide (development code LY3537021) is an investigational long-acting selective glucose-dependent insulinotropic polypeptide receptor (GIPR) agonist developed by Eli Lilly and Company. The compound is a synthetic peptide engineered to engage the GIP receptor selectively, with no clinically relevant activity at the glucagon-like peptide-1 receptor (GLP-1R) or the glucagon receptor (GCGR). It is administered subcutaneously, has an estimated half-life of approximately 12 days at the highest Phase 1 dose tested, and is being developed to support once-weekly administration in metabolic indications. As of April 2026, "glumitide" is the proposed nonproprietary name in active circulation in the literature and patient community; the verified development code in published preclinical and Phase 1 papers remains LY3537021.

The scientific motivation for glumitide is unusually specific. Lilly's approved dual incretin agonist tirzepatide (Mounjaro / Zepbound) — a single-molecule combination of GIP and GLP-1 receptor agonism — has demonstrated greater weight loss and glycemic improvement than selective GLP-1R agonists in head-to-head trials such as SURPASS-2, SURPASS-CVOT, and SURMOUNT-5. The clinical question that has lingered for years is which receptor contribution is doing the work. GLP-1R agonism alone is a known weight-loss mechanism (semaglutide, liraglutide, dulaglutide). What does GIP agonism alone contribute? Glumitide was designed precisely to answer that question — it is a research probe as much as a drug candidate, isolating the GIP signal so that its independent contribution to body weight, glucose control, and gastrointestinal tolerability can be measured.

A second motivation is the so-called GIPR paradox. Two competing programs in late-stage industry development simultaneously claim that opposite manipulations of the GIP receptor reduce body weight in humans: Lilly's GIPR agonist (glumitide / LY3537021) and Amgen's GIPR antagonist-based combination drug maridebart cafraglutide (MariTide / AMG-133, an antagonist antibody fused to a GLP-1R agonist peptide). Both have shown weight reduction in clinical study, which is paradoxical and unresolved as a matter of GIP biology. Glumitide is one of the cleanest experimental tools the field has for probing the agonist side of that question, since it engages only the GIPR with no other receptor activity to confound the signal.

The published Phase 1 record consists of two studies. The first (NCT04586907; published as Pratt et al. and the corresponding ADA 2023 abstract 56-OR by Knop and colleagues) tested single ascending and multiple ascending doses in healthy volunteers and patients with type 2 diabetes in Singapore. The second (NCT05444569; published as Knop et al. 2024 in Diabetes, Obesity and Metabolism) tested a single 25 mg SC dose of LY3537021 in combination with daily-dose-escalating liraglutide in healthy volunteers, also in Singapore. Both Phase 1 trials are complete and peer-reviewed. As of April 2026, no Phase 2 obesity trial is publicly registered for LY3537021 as a monotherapy.

Mechanism of Action

Glumitide is mechanistically narrow by design. It is a single-receptor agonist with a long half-life — a short list of properties that the published preclinical and Phase 1 work characterizes carefully.

• Selective GIPR activation — In vitro cAMP accumulation assays at low-receptor-density clonal cell lines (the standard Lilly receptor-screening platform used for tirzepatide and retatrutide characterization) demonstrated that LY3537021 is a full agonist at the GIP receptor with potency greater than native human GIP, and shows minimal activation of GLP-1R or GCGR at clinically relevant concentrations. Selectivity holds across human, rat, and mouse GIPR orthologs (Pratt et al.).
• Glucose-dependent insulin secretion — GIP is one of the two endogenous incretin hormones (GIP and GLP-1) released from the gut after a nutrient load. GIPR agonism on pancreatic beta cells enhances glucose-dependent insulin secretion, contributing to post-meal glycemic control without the off-meal hypoglycemia risk of insulin itself. This is the classic incretin-effect arm of glumitide's pharmacology.
• Body-weight reduction (mechanism partially defined) — In rats, chronic dosing of LY3537021 reduced cumulative food intake and body weight. In Phase 1 humans with T2D, four weeks of weekly dosing produced weight reduction. The exact CNS pathway by which GIP agonism reduces appetite is less well characterized than the GLP-1R appetite-suppression pathway; current models implicate hypothalamic GIPR populations and a direct effect on energy expenditure / lipid handling distinct from gastric-emptying-mediated satiety. The 2025 MDPI review by Killion and colleagues (J Clin Med 14(11):3812) summarizes the candidate mechanisms in detail.
• No clinically meaningful gastric-emptying delay — Single SC doses of LY3537021 from 0.3 mg to 25 mg in healthy volunteers did not produce the gastric-emptying delay characteristic of GLP-1R agonists. This is mechanistically consistent with a GIPR-only signal (since GLP-1R is the receptor that drives gastric-emptying delay) and is part of the rationale for the GI-tolerability hypothesis.
• Anti-emetic component — Independent animal evidence in shrews (a tractable emetic-response model) shows GIPR agonism blunts chemotherapy-induced and GLP-1R-induced nausea and vomiting. The mechanism appears to involve area postrema GIPR populations modulating brainstem emetic circuits. The Knop 2024 DOM paper translates this signal into a human Phase 1 finding: a single 25 mg dose of LY3537021 reduced GI adverse-event burden during liraglutide dose-escalation. This is the most clinically interesting non-glucose mechanism in the glumitide dataset.
• Lipid clearance contribution — Endogenous GIP also facilitates dietary lipid clearance into adipose tissue. The GIPR agonist program assumes this peripheral lipid-handling effect contributes to long-term metabolic benefits, although it is not directly measured in the Phase 1 dataset.
• What this is not — Glumitide does not activate GLP-1R, GCGR, amylin, or any other receptor relevant to the modern obesity drug class at clinically tested doses. It is a pharmacologic probe of GIP biology in addition to a drug candidate. The narrowness is the point.

What the Research Shows

Glumitide's published evidence base is small but high-quality. It consists of two peer-reviewed Phase 1 trials and one ADA scientific-session abstract, plus the in vitro and rat preclinical work that supported the IND submission. Independent reviews have summarized the mechanistic context.

• Preclinical pharmacology (Pratt et al.) — In Long-Evans diet-induced obese (DIO) rats, daily LY3537021 over 14 days reduced body weight, cumulative food intake, and fat mass relative to vehicle control. In Wistar rats, LY3537021 improved glycemia during an intravenous glucose tolerance test (IVGTT). Receptor selectivity was confirmed across human, rat, and mouse GIPR.
• Phase 1 SAD/MAD (NCT04586907; Pratt et al.; Knop ADA 2023 abstract 56-OR) — Single ascending doses of 0.3 to 25 mg SC in healthy volunteers; multiple ascending doses (weekly × 4 weeks) at progressively higher cohorts in healthy volunteers and patients with T2D. Conducted in Singapore. Reported as well-tolerated. Phase 1 SAD/MAD reported weight loss and improved fasting glucose in the T2D cohort after four weeks of weekly dosing. The half-life at the 25 mg dose was approximately 12 days; Tmax was 8–96 h depending on cohort. No clinically meaningful delay in gastric emptying at any single dose tested.
• Phase 1 co-administration with liraglutide (NCT05444569; Knop FK et al., Diabetes Obes Metab 2024; DOI 10.1111/dom.15875) — Randomized, placebo-controlled, investigator- and participant-blinded, two-period crossover. Healthy male and female participants 21–60 years, BMI 23–40, body weight ≥55 kg. Single SC injection of 25 mg LY3537021 (or matching placebo) on day 1, followed by daily SC liraglutide dose-escalation from 0.6 mg (day 2) to 2.4 mg (day 5), then 2.4 mg through day 9. Primary readout: GI adverse events. Result: a single dose of LY3537021 reduced the number and proportion of participants experiencing GI adverse events during liraglutide initiation, primarily nausea and vomiting. Diarrhea was the exception — it was not reduced by LY3537021. The signal supports the GIPR-anti-emetic-component hypothesis from animal models.
• Independent contextual review (Killion et al., J Clin Med 2025;14(11):3812) — Reviewed the evidence motivating both GIPR agonist and GIPR antagonist drug-development programs. Cited LY3537021's Phase 1 weight-loss finding in healthy volunteers and patients with T2D as a proof point that GIPR agonism alone can reduce body weight in humans, distinct from the GLP-1R-driven weight-loss mechanism. Notes that this finding does not resolve the GIPR-paradox (since MariTide, a GIPR antagonist combination drug, also reduces body weight) — but it does establish that GIPR agonist monotherapy is mechanistically sufficient.
• Open scientific questions — Long-term efficacy and safety beyond 4 weeks; comparative magnitude of weight loss versus tirzepatide, semaglutide, MariTide; effect in obese non-T2D populations (the BMI >30, weight >100 kg subgroup the authors specifically called out); whether the GI-tolerability benefit persists across longer co-administration; cardiovascular outcome effects; lipid handling; bone-mineral metabolism; whether the anti-emetic mechanism is durable enough to support a glumitide + GLP-1R agonist combination as a tolerability strategy.

Human Data

As of April 2026, two completed and peer-reviewed Phase 1 clinical trials of LY3537021 exist on ClinicalTrials.gov.

• NCT04586907 — A Study of LY3537021 in Healthy Participants and Participants With Type 2 Diabetes Mellitus — Phase 1, randomized, placebo-controlled, single ascending dose / multiple ascending dose. Sponsor: Eli Lilly and Company. Conducted in Singapore. Doses: 0.3 mg to 25 mg SC. Endpoints: safety, tolerability, pharmacokinetics, pharmacodynamics (glucose, insulin, body weight). Published: Pratt et al., long-acting GIPR agonist LY3537021 reduces body weight and fasting blood glucose in patients with T2D — preclinical development and Phase 1 randomized ascending dose studies.
• NCT05444569 — A Study of LY3537021 With Liraglutide in Healthy Participants — Phase 1, randomized, placebo-controlled, crossover. Sponsor: Eli Lilly and Company. Conducted in Singapore. Single 25 mg SC LY3537021 (or placebo) followed by daily liraglutide 0.6 → 2.4 mg dose-escalation through day 9. Endpoints: GI adverse events (primary), pharmacokinetics, immunogenicity. Published: Knop FK, Pratt EJ, Roell W, et al. Diabetes Obes Metab 2024; DOI 10.1111/dom.15875.
• Conference disclosure: ADA 2023 abstract 56-OR (Knop, Urva, Rettiganti, Benson, Roell, Mather, Haupt, Pratt) — "A Long-Acting Glucose-Dependent Insulinotropic Polypeptide Receptor Agonist Shows Weight Loss without Nausea or Vomiting." Diabetes 20 June 2023; 72 (Supplement_1): 56-OR. The Phase 1 SAD/MAD weight-loss-without-emesis signal first publicly disclosed at ADA, prior to full publication.
• What is not yet registered — As of April 2026, ClinicalTrials.gov does not list a Phase 2 monotherapy trial of LY3537021 in obesity, T2D, or any other indication. There is no registered head-to-head trial against tirzepatide or semaglutide. There is no registered cardiovascular outcomes trial.
• What this means in practice — Glumitide is a Phase 1 compound with promising mechanistic findings in small numbers of well-selected participants over short durations. It is not a clinical drug. Anyone presenting it as a usable obesity therapy is misrepresenting its development status.

Dosing from the Literature

The following dosing information is provided as a research-context reference only and reflects the doses studied in published Phase 1 trials. There is no FDA-approved dose, no clinical-practice guidance, and no compounding-pharmacy formulary for glumitide. This is not a usage protocol.

Pharmacokinetics

Pharmacokinetic data is drawn from the Phase 1 Singapore SAD/MAD program (Pratt et al.; NCT04586907) and the co-administration study (Knop et al. 2024; NCT05444569).

• Half-life — Approximately 12 days at the 25 mg subcutaneous dose in non-T2D and T2D cohorts; reported range 11–14 days across the published Phase 1 dataset. Supports once-weekly administration.
• Time to maximum concentration (Tmax) — 8 to 96 hours, varying across cohorts and dose levels. Slow absorption from SC depot is consistent with a long-acting peptide format.
• Route — Subcutaneous injection only. No oral, IM, IV, or intranasal administration is reported in the published dataset.
• Dose-proportionality — Across the 0.3 to 25 mg range tested, exposure scaled approximately dose-proportionally without unexpected nonlinearity.
• Gastric emptying — Single SC doses 0.3 to 25 mg did not produce a clinically meaningful gastric-emptying delay (a contrast with the GLP-1R agonist class).
• Drug-drug interaction signal — When co-administered with liraglutide, no PK interaction signal of clinical concern was reported. The reduction in liraglutide-associated GI adverse events appears to be a pharmacodynamic interaction (anti-emetic GIPR signal) rather than a PK interaction.

Reconstitution & Storage

Side Effects & Risks

The Phase 1 safety profile is favorable but limited in scope. The dataset covers small numbers of carefully selected participants (no serious comorbidities; healthy volunteers and well-managed T2D) over short durations (single dose to 4 weeks of weekly dosing). Long-term safety is undefined.

• Reported tolerability (Phase 1) — Generally well-tolerated across the 0.3 to 25 mg dose range. No serious adverse events reported in the published SAD/MAD or co-administration trial. The signature finding is the absence of the classic GLP-1R-class GI adverse-event profile (no marked nausea, no vomiting at the doses tested).
• Diarrhea exception — In the liraglutide co-administration study (NCT05444569), diarrhea was the one GI event NOT reduced by glumitide. The mechanism of this dissociation is not fully explained and may reflect a non-emetic GI pathway (intestinal motility / secretion) that GIPR agonism does not engage.
• Hypoglycemia signal — GIP-driven insulin secretion is glucose-dependent, so monotherapy hypoglycemia risk is theoretically low. Co-administration with insulin secretagogues (sulfonylureas) or insulin itself has not been studied and would warrant attention in any future Phase 2 design.
• Cardiovascular safety — Not assessed in Phase 1. No cardiovascular outcomes trial is registered. Long-term cardiovascular effects of GIPR-only agonism are unknown.
• Bone mineral density and fat distribution — Endogenous GIP has known roles in bone metabolism and lipid handling. Any long-duration glumitide program would need bone-density and body-composition monitoring in Phase 2 / Phase 3.
• Immunogenicity — Long peptides administered chronically can induce anti-drug antibodies. Not yet characterized for glumitide in published material; would be a standard Phase 2 readout.
• Counterfeit / adulterated product risk — Because glumitide is a high-interest Phase 1 compound for a major Western indication (obesity), there is documented research-chemical-channel marketing of products labeled "glumitide" or "LY3537021." These products have no Lilly chain of custody, no IND-quality analytical pedigree, and no published method to verify identity. Use of such products carries unknown impurity risks.

Bloodwork & Monitoring

There is no clinical-practice monitoring guideline for glumitide because it is investigational. The following is a list of measurements that any responsible Phase 2 obesity protocol would track, derived from the broader incretin-class monitoring literature. This is not a self-monitoring protocol.

• Fasting glucose and HbA1c — Baseline and at intervals to track glycemic effect; the Phase 1 readouts confirmed both endpoints respond.
• Body weight and waist circumference — Standard incretin-class outcome measure.
• Lipid panel (total / LDL / HDL / triglycerides) — GIP plays a documented role in dietary lipid handling; lipid effects of selective GIPR agonism are not yet characterized in humans.
• CMP (comprehensive metabolic panel) — Liver and kidney function, electrolytes; standard pre-/on-treatment monitoring for any chronic peptide.
• CBC — Standard hematology surveillance.
• Bone-turnover markers — In a Phase 2 / Phase 3 obesity program, P1NP and CTX would typically be measured given GIP's role in bone metabolism and the overall weight-loss-related bone-density signal in the obesity-drug class.
• Anti-drug antibody titer — Standard immunogenicity surveillance for chronic-use peptide investigational drugs.
• Cardiovascular biomarkers (Phase 3 framing) — NT-proBNP, hsCRP, and event-driven cardiovascular outcome capture for any pivotal program.

Commonly Stacked With

Glumitide is investigational and is not used as part of any clinical-practice combination protocol. There are no community stacking patterns because there is no community supply. The only published co-administration dataset is the single research pairing below.

No glumitide stack pages are available in the Stack Research Tool because the compound is investigational and not part of any clinical-practice combination.

Regulatory Status

Related Compounds

People researching glumitide often also look at these:

Frequently Asked Questions

The questions below are also indexed as FAQ schema for search engines.

• What is glumitide? Glumitide is the proposed nonproprietary name in circulation for LY3537021, Eli Lilly's investigational long-acting selective GIP receptor (GIPR) agonist. It is a once-weekly subcutaneous peptide currently in early clinical development for type 2 diabetes and obesity.
• Is glumitide the same as tirzepatide? No. Tirzepatide is a single-molecule dual GIP / GLP-1 receptor agonist. Glumitide is a selective GIP receptor mono-agonist — it does not engage GLP-1R or GCGR. Tirzepatide is FDA-approved; glumitide is investigational.
• What phase of clinical development is glumitide in? Phase 1. Two Phase 1 trials are complete and peer-reviewed (NCT04586907 SAD/MAD in healthy and T2D; NCT05444569 co-administration with liraglutide in healthy volunteers). No Phase 2 obesity monotherapy trial is registered as of April 2026.
• What is the half-life of glumitide? Approximately 12 days at the 25 mg subcutaneous dose, supporting once-weekly administration. Reported range 11–14 days across the published Phase 1 dataset.
• Was the 2014 Benoist et al. dihexa retraction relevant to glumitide? No. Glumitide is unrelated to dihexa. They engage different receptors (GIP receptor vs proposed HGF/c-Met), come from different sponsors (Eli Lilly vs Washington State University / Athira Pharma), and have entirely different evidence bases. The dihexa retraction is summarized on the Kalios dihexa profile.
• Can I buy glumitide? No. There is no legitimate non-trial supply of glumitide. The compound is available only through Eli Lilly-sponsored clinical trials. It is not FDA-approved, not eligible for 503A or 503B compounding, and not on the FDA PCAC 2026 review list. Any product sold online as "glumitide" is not the authenticated Lilly compound and has no verifiable identity.
• Does glumitide cause nausea? In published Phase 1 data, glumitide alone did not produce the GI adverse-event profile typical of GLP-1R agonists. The co-administration study (NCT05444569) showed a single dose of glumitide reduced nausea and vomiting during liraglutide initiation but did not reduce diarrhea.
• Why is Lilly developing both glumitide (a GIP agonist) and a GIPR antagonist signal isn't this contradictory? The "GIPR paradox" is a real and unresolved scientific question. Glumitide (Lilly, GIPR agonist) and Amgen's MariTide (GIPR antagonist combined with a GLP-1R agonist peptide) both reduce body weight in clinical study. The mechanistic reconciliation of these two findings is an active area of research summarized in the 2025 J Clin Med review by Killion et al.

Key References

1. Pratt EJ, Roell W, Knop FK, Urva S, et al. Long-acting GIPR agonist LY3537021 reduces body weight and fasting blood glucose in patients with T2D: Preclinical development and phase 1 randomized ascending dose studies. PMID: 41391569; PMC: PMC12808604.
2. Knop FK, Roell W, Pratt EJ, et al. A long-acting glucose-dependent insulinotropic polypeptide receptor agonist improves the gastrointestinal tolerability of glucagon-like peptide-1 receptor agonist therapy. Diabetes Obes Metab. 2024. DOI: 10.1111/dom.15875.
3. Knop FK, Urva S, Rettiganti M, Benson C, Roell W, Mather KJ, Haupt A, Pratt EJ. 56-OR: A Long-Acting Glucose-Dependent Insulinotropic Polypeptide Receptor Agonist Shows Weight Loss without Nausea or Vomiting. Diabetes 2023;72(Supplement_1):56-OR. DOI: 10.2337/db23-56-OR.
4. Killion EA, Lu SC, Véniant MM. The Premise of the Paradox: Examining the Evidence That Motivated GIPR Agonist and Antagonist Drug Development Programs. J Clin Med. 2025;14(11):3812.
5. ClinicalTrials.gov. NCT04586907 — A Study of LY3537021 in Healthy Participants and Participants With Type 2 Diabetes Mellitus. Sponsor: Eli Lilly and Company.
6. ClinicalTrials.gov. NCT05444569 — A Study of LY3537021 With Liraglutide in Healthy Participants. Sponsor: Eli Lilly and Company.
7. Coskun T, Urva S, Roell WC, et al. 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 Metab. 2022;34(9):1234-1247. PMID: 35985340. (Companion Lilly molecular-pharmacology paper showing the cAMP-assay platform used to characterize LY3537021.)
8. Urva S, Coskun T, Loh MT, et al. 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. Lancet. 2022;400(10366):1869-1881. PMID: 36354040. (Adjacent Lilly Phase 1b methodology reference.)
9. Coskun T, Sloop KW, Loghin C, et al. LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: From discovery to clinical proof of concept. Mol Metab. 2018;18:3-14. PMC: PMC6308032. (Tirzepatide discovery paper — the dual-agonist comparator that motivated the LY3537021 mono-agonist program.)
10. Jastreboff AM, Kaplan LM, Frías JP, et al. Triple-Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial. N Engl J Med. 2023;389(6):514-526. (Phase 2 obesity readout for the triple-agonist counterpart that contextualizes the GIPR-only mono-agonist hypothesis.)
11. Eli Lilly and Company. Lilly's triple agonist, retatrutide, demonstrated significant reductions in A1C and weight in first Phase 3 trial for treatment of type 2 diabetes. Press release, March 19, 2026. (Lilly pipeline context — published Phase 3 multi-agonist readout against which mono-agonist GIPR programs are benchmarked.)
12. Borner T, Reiner BC, Crist RC, et al. GIP receptor agonism blocks chemotherapy-induced nausea and vomiting. (Animal-model anti-emetic paper underpinning the GIPR-tolerability hypothesis tested in NCT05444569.)
13. FDA. Investigational New Drug Application — Code of Federal Regulations Title 21 Part 312. (Regulatory framework under which LY3537021 is being developed.)
14. WHO. International Nonproprietary Names (INN) — INN-bio review 2022. who.int. (Methodology context for the proposed INN naming process glumitide is being put through.)
15. Aronne LJ, Sattar N, Horn DB, et al. Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity (SURMOUNT-4). JAMA. 2024;331(1):38-48. (Tirzepatide weight-maintenance reference for understanding the dual-agonist comparator class.)
16. Aronne LJ, Horn DB, le Roux CW, et al. Tirzepatide as Compared with Semaglutide for the Treatment of Obesity. N Engl J Med. 2025;393(1):26-36. (SURMOUNT-5 head-to-head — the dual-agonist standard of care that any selective GIPR mono-agonist program will be benchmarked against.)

Related Research

• TirzepatideApproved dual GIP/GLP-1 agonist — the molecule glumitide is decomposing
• RetatrutideLilly's triple GIP/GLP-1/glucagon agonist — the combinatorial counterpoint
• SemaglutideApproved selective GLP-1R agonist — the other half of the dual-agonist signal
• LiraglutideApproved daily GLP-1R agonist; co-admin partner in NCT05444569
• Semaglutide vs Tirzepatide head-to-headSURMOUNT-5 — the standard of care backdrop for GIPR-only programs
• Stack Research ToolPair any of the approved incretin compounds with 112 others — citation-driven