GLP-2 TZ — Tirzepatide · Dual-Incretin Research Reagent

The dual-incretin
analog examined
across metabolic research.

A dual-receptor peptide that engages both the GIP and GLP-1 pathways simultaneously — the two key incretin signals studied in glucose handling, appetite regulation, and lipid metabolism. The most studied dual-incretin compound in peer-reviewed research literature.

NEJM 2022SURMOUNT-1 · N=2,539Peer-Reviewed LiteratureSURPASS-CVOT 2025

Jastreboff et al. SURMOUNT-1 — 72-wk Phase 3 RCT. All data from peer-reviewed literature. For Research Use Only — Not for Human Consumption.

-22.5%

Mean BW change observed — SURMOUNT-1 Phase 3

Jastreboff NEJM 2022 · Research findings

-58.7%

Mean AHI change observed — OSA model (non-PAP)

Malhotra NEJM 2024 · Research findings

-93%

T2D progression rate observed — 3-yr prediabetic cohort

SURMOUNT-1 extension · Research findings

-38%

HF composite events observed — SUMMIT HFpEF model

Kosiborod NEJM 2024 · Research findings

Published Research Data

Five trials.
One molecule.

The SURMOUNT program represents one of the most comprehensive peer-reviewed pharmacology datasets assembled for a single dual-incretin analog. All findings are independent published research.

-22.5_%

Mean body weight change observed at 15mg vs placebo in SURMOUNT-1 Phase 3 trial.

Jastreboff et al. NEJM 2022 · Research findings

96_%

Proportion achieving ≥5% BW change at 15mg vs 28% placebo in SURMOUNT-1.

SURMOUNT-1, NEJM 2022 · Research findings

25.8_%

Mean BW change observed at 88 weeks — longest tirzepatide dataset in published literature.

Aronne et al. JAMA 2024 · Research findings

2,539

SURMOUNT-1 enrollment across 4 arms, 16 countries, no T2D.

SURMOUNT-1, NCT04184622

SURMOUNT Program — Mean Body Weight Change

Phase 3 RCTs · Tirzepatide 10–15 mg/wk · p<0.001 vs placebo all trials

SURMOUNT-1 · 72 wk, 15mg, N=2,539-22.5%

SURMOUNT-3 · 72 wk, MTD, post-lifestyle run-in-26.6%

SURMOUNT-4 · 88 wk, MTD, continuation-25.8%

SURMOUNT-5 · 72 wk, vs semaglutide 2.4mg-20.2%

SURMOUNT-2 · 72 wk, 15mg, with T2D-15.7%

Note: SURMOUNT-3 used a lifestyle run-in requiring ≥5% BW loss before randomization. SURMOUNT-5 was head-to-head vs semaglutide 1.7/2.4 mg.

Jastreboff NEJM 2022 · Wadden Nat Med 2023 · Aronne JAMA 2024 · Garvey Lancet 2022 · SURMOUNT-5 2024. Research use only.

Mechanism of Action

Two receptors.
One sequence.

Tirzepatide is a GIP analogue with GLP-1 activity engineered in — not the reverse. Its GIPR dominance is intentional, enabling engagement of both incretin receptors within a single 39-residue backbone. Examined in peer-reviewed literature for its dual-agonist pharmacology.

GIPR — Primary

GIP Receptor

~1 nM

Equal affinity to native GIP

Direct adipocyte lipid metabolism

Insulin sensitization & adiponectin

Lower GI side-effect profile observed vs GLP-1 monoagonists in published trials

GLP-1R — Biased

GLP-1 Receptor

~3–5 nM

~5x weaker, cAMP-biased

Preferential cAMP, less desensitization

Hypothalamic appetite suppression

Glucose-dependent insulin release

Why weaker GLP-1R affinity still wins

Cryo-EM (PNAS 2022) confirms biased cAMP signaling at GLP-1R reduces receptor internalization — sustained surface expression = prolonged effect. GIPR tolerability allows full dose escalation, delivering more total GLP-1R activation than selective agonists at their tolerable ceiling.

GIP backbone — not GLP-1

C20 diacid at Lys20 — ~120 hr t½

Aib2 — DPP-IV resistant

39 amino acids — 4,813 Da

Cryo-EM confirmed biased GLP-1R

Integrated signaling cascade

GIPR Full Agonism GIP

Equal affinity to native GIP. C20 diacid at Lys20 drives albumin binding, extending half-life to ~120 hr without sacrificing GIPR potency.

Biased GLP-1R Activation GLP-1

~5x weaker but cAMP-preferential. Tyr1 and C20 lipid destabilize beta-arrestin coupling — less internalization, sustained receptor surface expression.

Synergistic cAMP Elevation Both

Both receptors converge on adenylate cyclase. Dual Gs input produces synergistic beta-cell insulin secretion beyond GIP + GLP-1 administered separately.

Systemic Downstream Signaling Both

Adipocyte remodeling (GIPR), hypothalamic GLP-1R engagement, altered lipid metabolism, and inflammatory marker changes. In SURMOUNT-1: 33.9% fat mass change vs 10.9% lean mass change observed (Jastreboff NEJM 2022).

JCI Insight 2020 · PNAS 2022 · Nature Comms 2022

Comorbidity Research Models

Four disease models.
One compound.

Tirzepatide has been examined in peer-reviewed Phase 2 and Phase 3 trials across four distinct cardiometabolic research models. All findings cited from independent published literature.

-58.7_%

OSA Research Model

Mean AHI change observed in moderate-to-severe OSA with obesity cohort (non-PAP arm). Examined in peer-reviewed Phase 3 trial.

SURMOUNT-OSA · Malhotra, NEJM 2024 · N=469

-38_%

HFpEF Research Model

Composite worsening HF events or CV death observed. HR 0.62 (p=0.026). Examined in peer-reviewed Phase 3 trial in HFpEF-obesity model.

SUMMIT · Kosiborod, NEJM 2024

44–62_%

MASH / Liver Fibrosis Model

MASH resolution without worsening fibrosis rate observed vs 10% placebo. Examined in peer-reviewed Phase 2 histological study.

SYNERGY-NASH · Loomba, NEJM 2024

-93_%

T2D Progression Research Model

T2D progression rate observed at 3 years in prediabetic cohort vs placebo. Examined in SURMOUNT-1 3-year extension analysis.

SURMOUNT-1 3-yr extension · 2024

Compound Comparison

Where GLP-2 TZ fits.

GLP-2 is the first dual incretin agonist with a published head-to-head comparative trial vs GLP-1. Data sourced from peer-reviewed literature across distinct trial populations.

-20.2%

GLP-2 TZ · GLP-2

10/15 mg/wk · 72 wks

Head-to-Head

SURMOUNT-5 · Phase 3b RCT
p<0.001

-13.7%

GLP-1 SM · GLP-1

1.7/2.4 mg/wk · 72 wks

Mean Body Weight Change by Compound — Published Literature

Highest studied dose · non-diabetic population where available · trial designs, populations, and durations differ · independent peer-reviewed data only

Tirzepatide

-22.5%

Semaglutide

-14.9%

Liraglutide

-8.0%

SURMOUNT-5 Phase 3b open-label RCT. Trial designs, populations, and durations differ across compounds. Not a definitive comparative-effectiveness claim. All findings from independent peer-reviewed literature. For Research Use Only — Not for Human Consumption.

Compound Profile

Full specification

39-amino acid GIP analogue engineered for dual receptor co-activation. Built from the GIP sequence up — not adapted from GLP-1.

Structural Features

Key engineering modifications on the native GIP backbone

Common Name	Tirzepatide
Code	LY3298176
Backbone	39-aa GIP analogue — not GLP-1
Mol. Weight	4,813.5 Da
EC50 GIPR	~1 nM — equal to native GIP
EC50 GLP-1R	~3–5 nM — cAMP-biased
Half-life	~120 hr via C20 diacid albumin binding
DPP-IV	Resistant — Aib2 substitution at position 2
Reference Approvals	T2D 2022Obesity 2023OSA 2024
Eon Purity	≥99% HPLC — 6-panel COA every batch
Form	Lyophilized powder · sealed vial
Regulatory	Research Use Only — Not for Human Use

Receptor Binding Affinity

GIPR-dominant by design. The imbalance is intentional and pharmacologically critical.

GIPR

~1 nM

GLP-1R

~3–5 nM

JCI Insight 2020 (Willard et al.) · PNAS 2022. Biased cAMP signaling at GLP-1R compensates for weaker affinity. Research use only.

GIP Backbone — Built from Native GIP

GIP-unique residues give full GIPR agonism; engineered GLP-1-like residues add GLP-1R activity. One molecule, two native-affinity pathways.

C20 Fatty Diacid at Lys20

Longer chain than semaglutide (C18 at Lys26). Mid-sequence attachment preserves GIP-native N-terminal GIPR binding geometry. ~120 hr half-life.

Biased GLP-1R Signaling

Cryo-EM (PNAS 2022): Tyr1 and C20 moiety destabilize beta-arrestin coupling. Less internalization = sustained receptor surface expression = prolonged signaling.

Research Timeline

Three indications
in a decade.

From first-in-human studies to three approved reference indications — each milestone expanding the published research dataset on dual-incretin pharmacology.

Reference approved indications — T2D (2022), Obesity (2023), OSA (2024)

2,539

SURMOUNT-1 participants across 4 arms in 16 countries

Major Phase 3 SURMOUNT trials plus the 5-trial SURPASS T2D series

Key Findings at a Glance

33.9% fat mass change vs 10.9% lean mass change — body-composition ratio observed in SURMOUNT-1.

Jastreboff et al., NEJM 2022

KCCQ-CSS +7.5 pts, 6-min walk +18m observed in HFpEF model. HR 0.62 composite event reduction (SUMMIT).

Kosiborod et al., NEJM 2024

AHI −58.7% observed in non-PAP OSA cohort. Phase 3 findings (SURMOUNT-OSA).

Malhotra et al., NEJM 2024

SURMOUNT-5: −20.2% vs semaglutide −13.7% mean BW change at 72 wk (p<0.001). First powered head-to-head comparative trial.

SURMOUNT-5, 2024

Now

Active

SURMOUNT-MMO & Expansion

SURMOUNT-MMO (N=~15,000): event-driven morbidity/mortality trial. Active trials in CKD, MASH Phase 3, and Alzheimer disease research.

2024

4 Results

OSA Approval, SUMMIT, SYNERGY-NASH, 3-yr SURMOUNT-1

Approved for OSA. SUMMIT: −38% HF composite. SYNERGY-NASH: 44–62% MASH resolution. 93% T2D risk reduction at 3 yr. SURPASS-CVOT: expanded MACE HR 0.88.

2023

Obesity Approval

Approval for Chronic Weight Management

SURMOUNT-3: −26.6% mean BW change after lifestyle run-in — largest published dataset for this compound class at the time of approval.

2022

Dual Approval

T2D Approval + SURMOUNT-1 Published

SURMOUNT-1 in NEJM: −22.5%, N=2,539. Cryo-EM structures in PNAS and Nature Comms. SURPASS-2 head-to-head vs semaglutide 1.0 mg published in NEJM.

2018–20

Discovery

Phase 1 & Mechanistic Characterization

Phase 1 confirms ~120 hr half-life. JCI Insight 2020 formalizes imbalanced agonism. The "twincretin" concept established.

Storage & Laboratory Handling

Maintain sample
integrity.

4.8 kDa acylated peptide. C20 diacid stable under lyophilized storage but susceptible to aggregation on freeze-thaw after reconstitution. Proper laboratory handling is essential for research reproducibility.

-20°C

Long-term storage

Up to 24 months. Original sealed vial, protect from light.

2–8°C

Post-reconstitution

Up to 28 days. Do not freeze — C20 aggregates on freeze-thaw.

BAC H2O

Reconstitution

Bacteriostatic water preferred. Benzyl alcohol extends stability.

2 mL

Volume

2 mL BAC water per vial via U100 insulin syringe.

Laboratory Reconstitution Reference

Standard laboratory protocol for research preparations. For qualified researchers only.

Equilibrate to ambient laboratory temperature

Allow sealed vial to reach room temperature (approx. 15–20 min). Do not apply external heat sources.

Add 2 mL bacteriostatic water

Use calibrated laboratory syringe. Bacteriostatic water (0.9% benzyl alcohol) preferred for post-reconstitution stability.

Direct along interior vial wall

Introduce solvent slowly along the glass wall — not directly onto the lyophilized cake. Minimizes foaming and maintains peptide integrity.

Roll gently 30–60 seconds

Do not vortex. Solution should be clear to slightly opalescent. Discard if cloudy or particulate.

Label and store refrigerated

2–8°C. Record reconstitution date. Do not freeze reconstituted material — C20 diacid chain susceptible to aggregation on freeze-thaw cycling.

For Research Use Only — Not for Human Consumption. ≥99% purity by HPLC · independent 6-panel COA (Freedom Diagnostic) · This product is not a drug, food, dietary supplement, cosmetic, or medical device and is not intended to diagnose, treat, cure, or prevent any disease. For lawful laboratory research use only by qualified researchers.

Research Active

Indexed literature

11 studies across SURMOUNT, SURPASS, mechanistic, and comorbidity trials.

NEJM2022

Tirzepatide Once Weekly for the Treatment of Obesity — SURMOUNT-1

Jastreboff AM, Aronne LJ, Ahmad NN, et al.

Phase 3 RCTN=2,539

72-week randomized trial. Tirzepatide 5/10/15mg vs placebo, no T2D. Mean BW reduction 16.0%/21.4%/22.5% vs 2.4% placebo (p<0.001 all). 96% achieving ≥5% reduction on 10/15mg vs 28% placebo. Fat mass reduced 33.9% vs lean mass 10.9%.

NEJM2024

Tirzepatide for the Treatment of Obstructive Sleep Apnea — SURMOUNT-OSA

Malhotra A, Grunstein RR, Fietze I, et al.

Phase 3N=469

Two 52-week Phase 3 trials. Trial 1 (non-PAP): AHI −58.7% (p<0.001). Trial 2 (PAP users): AHI −50.7%. Reduced hypoxic burden, hsCRP, systolic BP.

PNAS2022

Structural Determinants of Dual Incretin Receptor Agonism by Tirzepatide

Coskun T, Urva S, Roell WC, et al.

Cryo-EM

Near-atomic cryo-EM structures of tirzepatide bound to GIPR and GLP-1R. At GIPR: Tyr1 allows full agonism equal to native GIP. At GLP-1R: same Tyr1 and lipid moiety destabilize beta-arrestin coupling, confirming biased agonism structurally.

Showing 3 of 11

Indexed from PubMed and peer-reviewed journals. Independent published research — not Eon Peptides claims. GLP-2 TZ (Tirzepatide) is for Research Use Only — Not for Human Consumption. Not a drug, food, or dietary supplement.

Cited Sources

References

All scientific claims from peer-reviewed literature or official regulatory records.

Peer-reviewed11 sources2020–2025

[1]

Jastreboff AM, Aronne LJ, Ahmad NN, et al.

Tirzepatide Once Weekly for the Treatment of Obesity.

N Engl J Med2022;387:205-216Phase 3 RCTdoi:10.1056/NEJMoa2206038

[2]

Malhotra A, Grunstein RR, Fietze I, et al.

Tirzepatide for the Treatment of Obstructive Sleep Apnea and Obesity.

N Engl J Med2024;391:1193-1205Phase 3 RCTdoi:10.1056/NEJMoa2404881

[3]

Kosiborod MN, Abildstrom SZ, Borlaug BA, et al.

Tirzepatide in Heart Failure with Preserved Ejection Fraction and Obesity.

N Engl J Med2024;390:1585-1598Phase 3 RCTdoi:10.1056/NEJMoa2313225

[4]

Loomba R, Hartman ML, Lawitz EJ, et al.

Tirzepatide for MASH with Liver Fibrosis — SYNERGY-NASH.

N Engl J Med2024;391:299-310Phase 2 RCTdoi:10.1056/NEJMoa2401943

[5]

Coskun T, Urva S, Roell WC, et al.

Structural Determinants of Dual Incretin Receptor Agonism by Tirzepatide.

PNAS2022;119(8):e2116506119Cryo-EMdoi:10.1073/pnas.2116506119

[6]

Willard FS, Douros JD, Gabe MB, et al.

Tirzepatide is an Imbalanced and Biased Dual GIP and GLP-1 Receptor Agonist.

JCI Insight2020;5(17):e140532Mechanisticdoi:10.1172/jci.insight.140532

[7]

Frias JP, Davies MJ, Rosenstock J, et al.

Tirzepatide versus Semaglutide Once Weekly in Type 2 Diabetes — SURPASS-2.

N Engl J Med2021;385:503-515Phase 3b RCTdoi:10.1056/NEJMoa2107519

[8]

Wadden TA, Chao AM, Machineni S, et al.

Tirzepatide After Intensive Lifestyle Intervention — SURMOUNT-3.

Nat Med2023;29:2909-2918Phase 3 RCTdoi:10.1038/s41591-023-02620-1

[9]

Aronne LJ, Sattar N, Horn DB, et al.

Continued Treatment with Tirzepatide for Maintenance — SURMOUNT-4.

JAMA2024;331(1):38-48Phase 3 RCTdoi:10.1001/jama.2023.24082

[10]

Nicholls SJ, Bhatt DL, Buse JB, et al.

Comparison of Tirzepatide and Dulaglutide on MACE — SURPASS-CVOT.

N Engl J Med2025CV Outcomesdoi:10.1056/NEJMoa2410802

[11]

Mamas MA, Bays H, Li R, et al.

Tirzepatide vs Semaglutide and 10-Year CVD Risk Reduction — SURMOUNT-5.

Eur Heart J Open2025;5(5):oeaf117Post-Hocdoi:10.1093/ehjopen/oeaf117

Showing 3 of 11

The dual-incretin
analog examined
across metabolic research.

Five trials.
One molecule.

Two receptors.
One sequence.

39 residues.
Drawn to scale.

Four disease models.
One compound.

Where GLP-2 TZ fits.

Binding affinity
visualized.

Half-life by
molecular design.

Full specification

Three indications
in a decade.

Maintain sample
integrity.

Indexed literature

References

The dual-incretinanalog examinedacross metabolic research.

Five trials.One molecule.

Two receptors.One sequence.

39 residues.Drawn to scale.

Four disease models.One compound.

Where GLP-2 TZ fits.

Binding affinityvisualized.

Half-life bymolecular design.

Full specification

Three indicationsin a decade.

Maintain sampleintegrity.

Indexed literature

References

The dual-incretin
analog examined
across metabolic research.

Five trials.
One molecule.

Two receptors.
One sequence.

39 residues.
Drawn to scale.

Four disease models.
One compound.

Binding affinity
visualized.

Half-life by
molecular design.

Three indications
in a decade.

Maintain sample
integrity.