Evidence current through September 2026

Tirzepatide

Tirzepatide / LY3298176 — synthetic 39-amino-acid lipidated GIPR/GLP-1R dual agonist

Also indexed as LY3298176, LY-3298176

Tirzepatide is one of the best-developed examples of a modern incretin-receptor research program. The molecule began as LY3298176 and is now the active pharmaceutical ingredient in two Eli Lilly finished drug products, Mounjaro and Zepbound.

That distinction matters: the research record is not evidence for every material that carries the name tirzepatide.

Research areas

Molecular identity
GIPR/GLP-1R pharmacology
Type 2 diabetes trials
Body weight and waist circumference
Cardiovascular outcomes
Renal and liver evidence
Obstructive sleep apnea
Safety and regulatory context
Non-Lilly material boundaries

Evidence at a glance

What the current record supports

Tirzepatide has a stable public identity as a defined synthetic peptide active moiety; PubChem, GSRS, and KEGG align on the core identity.

Primary pharmacology supports a unimolecular GIPR/GLP-1R dual agonist with imbalanced and biased signaling features in experimental systems.

SURPASS and SURMOUNT trials support defined glycemic, body-weight, and waist-circumference endpoints for Lilly products under protocol conditions.

Cardiovascular, kidney, liver, sleep-apnea, and body-composition findings come from different study designs and endpoint types and must not be blended into a generalized benefit statement.

Qualification

Limitations and evidence gaps

Limitations and contradictory findings

Several evidence gaps remain publication-relevant. The dossier records many inaccessible or unresolved items, including inaccessible supplemental tables, inaccessible or abstract-level publisher records, registry records without posted results, and unresolved regulatory-process details.

Reported averages depend on each trial's prespecified analysis, including whether it estimates outcomes regardless of treatment discontinuation or focuses on continued treatment, how missing measurements are handled, the follow-up period, and the study design.

Safety and evidence gaps

The safety record is large but product- and population-specific. The record does not support an unqualified safe/unsafe characterization.

The direct non-Lilly evidence located in the dossier consists of an analytical impurity study of sampled compounded tirzepatide/vitamin B12 products and a single-person uncontrolled report. Neither source establishes clinical equivalence, safety, efficacy, or stability for compounded, bulk, salt-form, analog, or research-use-only tirzepatide material.

No human clinical evidence is attached to First Due Biotech material. First Due Biotech products are for laboratory research use only and are not for human consumption.

Research path

Connected research articles

Overview

Tirzepatide: A Research Overview

Read overview

Full review

Tirzepatide Full Evidence Review

A source-bounded review of Tirzepatide identity, dual-receptor pharmacology, clinical evidence, safety, regulatory context, non-Lilly material boundaries, and unresolved evidence gaps.

Read evidence review

Study map

Connected study records

Human controlled primaryStrong for measured surrogate endpointCompleted; peer reviewed

SURPASS-2 active-comparator trial

TIRZEPATIDE-STUDY-P033

Frías et al. (2021), SURPASS-2.

View study

Human controlled primary / post hocModerate; exploratory kidney evidenceCompleted; peer reviewed

SURPASS-4 and post-hoc kidney analysis

TIRZEPATIDE-STUDY-P037-P092

Del Prato et al. (2021); Heerspink et al. (2022), SURPASS-4.

View study

Human controlled primaryStrong for measured body-weight endpointsCompleted; peer reviewed

SURMOUNT-1 obesity trial

TIRZEPATIDE-STUDY-P051

Jastreboff et al. (2022), SURMOUNT-1.

View study

Human controlled primaryStrong for continuation-versus-withdrawal comparisonCompleted; peer reviewed

SURMOUNT-4 continuation-versus-withdrawal trial

TIRZEPATIDE-STUDY-P061

Aronne et al. (2024), SURMOUNT-4.

View study

Human controlled primaryStrong with access limitationCompleted; peer reviewed

SURMOUNT-5 direct active-comparator trial

TIRZEPATIDE-STUDY-P064

Aronne et al. (2025), SURMOUNT-5.

View study

Human controlled primary / registryStrong with full-text access limitationCompleted; peer reviewed; registry results posted

SURPASS-CVOT cardiovascular outcomes trial

TIRZEPATIDE-STUDY-P085-P086

Nicholls et al. (2025); ClinicalTrials.gov NCT04255433.

View study

Human controlled primaryModerate; phase 2Completed; peer reviewed

SYNERGY-NASH phase 2 trial

TIRZEPATIDE-STUDY-P098

Loomba et al. (2024), SYNERGY-NASH.

View study

Human controlled primary / regulatoryStrong for measured apnea-hypopnea index endpointCompleted; peer reviewed; label context verified

SURMOUNT-OSA obstructive sleep apnea trials

TIRZEPATIDE-STUDY-P103

Malhotra et al. (2024), SURMOUNT-OSA.

View study

Source ledger

References

P001Pharmacology/biochemical database record

PubChem CID 156588324
P003Regulatory record

FDA/NCATS GSRS UNII OYN3CCI6QE
P007Pharmacology/biochemical database record

KEGG DRUG D11360
P011Pharmacology/biochemical primary + Animal primary + Human controlled primary (phase 1); PEER REVIEWED

Coskun et al. 2018 discovery paper

(2018). DOI: 10.1016/j.molmet.2018.09.009
P012Pharmacology/biochemical primary + ex-vivo Animal primary; PEER REVIEWED

Willard et al. 2020 biased-signaling paper

(2020). DOI: 10.1172/jci.insight.140532
P013In-vitro/structural primary; PEER REVIEWED

Sun et al. 2022 structural paper

(2022). DOI: 10.1073/pnas.2116506119
P014Animal primary + ex-vivo human tissue primary; PEER REVIEWED

El et al. 2023 human-islet paper

(2023). DOI: 10.1038/s42255-023-00811-0
P031Human controlled primary, PEER REVIEWED

Frías et al. 2018 phase 2 trial

(2018). DOI: 10.1016/S0140-6736(18)32260-8
P032Human controlled primary, PEER REVIEWED

Rosenstock et al. 2021 SURPASS-1

(2021). DOI: 10.1016/S0140-6736(21)01324-6
P033Human controlled primary, PEER REVIEWED; RESULTS POSTED

Frías et al. 2021 SURPASS-2

(2021). DOI: 10.1056/NEJMoa2107519
P034Human controlled primary, PEER REVIEWED

Ludvik et al. 2021 SURPASS-3

(2021). DOI: 10.1016/S0140-6736(21)01443-4
P037Human controlled primary, PEER REVIEWED

Del Prato et al. 2021 SURPASS-4

(2021). DOI: 10.1016/S0140-6736(21)02188-7
P040Human controlled primary, PEER REVIEWED

Dahl et al. 2022 SURPASS-5

(2022). DOI: 10.1001/jama.2022.0078
P041Human controlled primary, PEER REVIEWED

Rosenstock et al. 2023 SURPASS-6

(2023). DOI: 10.1001/jama.2023.20294
P051Human controlled primary (phase 3, double-blind, placebo-controlled), PEER REVIEWED

Jastreboff et al. 2022 SURMOUNT-1

(2022). DOI: 10.1056/NEJMoa2206038
P061Human controlled primary (36-wk open-label lead-in then randomised withdrawal); PEER REVIEWED; RESULTS POSTED

Aronne et al. 2024 SURMOUNT-4

(2024). DOI: 10.1001/jama.2023.24945
P064Human controlled primary (phase 3b, open-label, active-controlled); PEER REVIEWED

Aronne et al. 2025 SURMOUNT-5

(2025). DOI: 10.1056/NEJMoa2416394
P085Human controlled primary; PEER REVIEWED, randomised, double-blind, active comparator; RESULTS POSTED

Nicholls et al. 2025 SURPASS-CVOT

(2025). DOI: 10.1056/NEJMoa2505928
P086Trial registry or protocol; COMPLETED

ClinicalTrials.gov NCT04255433
P092Human controlled primary, POST HOC; PEER REVIEWED

Heerspink et al. 2022 SURPASS-4 kidney analysis

(2022). DOI: 10.1016/S2213-8587(22)00243-1
P095Human controlled primary, pre-specified exploratory analysis; PEER REVIEWED

Zoungas et al. 2026 SURPASS-CVOT kidney analysis

(2026). DOI: 10.1016/S2213-8587(26)00032-X
P098Human controlled primary (phase 2); PEER REVIEWED

Loomba et al. 2024 SYNERGY-NASH

(2024). DOI: 10.1056/NEJMoa2401943
P103Human controlled primary; PEER REVIEWED, randomised, placebo-controlled

Malhotra et al. 2024 SURMOUNT-OSA

(2024). DOI: 10.1056/NEJMoa2404881
P115Regulatory record

FDA Zepbound NDA 217806 summary review

(2024)
P116Regulatory record (contains reviewer re-analysis of Human controlled primary data)

FDA Zepbound multidisciplinary/medical review

(2024)
P132Regulatory record

Mounjaro USPI rev. 01/2026

(2026)
P137Regulatory record

Mounjaro DailyMed label rev. 08/2026

(2026)
P138Regulatory record

Zepbound USPI rev. 02/2026

(2026)
P140Regulatory record

Zepbound DailyMed label rev. 08/2026

(2026)
P141Regulatory record

Drugs@FDA NDA 215866 history
P142Regulatory record

Drugs@FDA NDA 217806 history
P153Regulatory record (describing human controlled primary evidence)

FDA OSA approval announcement
P166Regulatory record

FDA tirzepatide-shortage declaratory order

(2024)
P167Regulatory record

FDA tirzepatide-shortage decision memorandum

(2024)
P168Regulatory record

FDA compounding-policy updates

(2026)
P169Regulatory record

FDA unapproved-GLP-1 concerns page

(2026)
P189Regulatory record

FDA resolved-shortage record
P192In-vitro / analytical primary — PEER REVIEWED

Jordan et al. 2026 compounded tirzepatide/B12 impurity study

(2026). DOI: 10.1080/14740338.2026.2663185
P195Human uncontrolled primary — n = 1 author self-experiment — PEER REVIEWED (compounding-specialty journal)

Guth 2025 compounded-tirzepatide self-experiment

(2025)