CARTIZ is a prospective observational clinical registry of adults in Mexico receiving tirzepatide (a dual GLP-1/GIP receptor agonist) under an independent clinical indication - typically type 2 diabetes, insulin resistance, obesity, renal protection, metabolic hypertension, or associated off-label metabolic use. The registry is entirely observational: CARTIZ does not initiate, modify, interrupt, or supply tirzepatide, and does not dictate dose, route, or duration. All pharmacological exposure decisions are made by the treating physician independently of study participation. The registry is operationalized through a four-institute architecture integrating three Mexican National Institutes of Health and one national imaging laboratory. Core 1 (Knee Cartilage Imaging, Ci3M UAM-Iztapalapa) performs bilateral 3T MRI with quantitative T2 mapping at Week 0 and Week 52. Core 2 (Cardiac Imaging, Instituto Nacional de Cardiología Ignacio Chávez) performs non-contrast cardiac computed tomography for radiomic phenotyping of epicardial adipose tissue at Week 0 and Week 52 under cardiovascular Co-Principal Investigator Dr. Erick Alexánderson Rosas. Core 3 (HLA Typing, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Transplant Department) performs Class I and Class II HLA typing by PCR-SSO Reverse Luminex. Core 4 (Body Composition, Universidad La Salle México) performs multi-frequency bioelectrical impedance analysis (seca mBCA) at six longitudinal timepoints capturing visceral adipose tissue trajectory, phase-angle trajectory, appendicular skeletal muscle mass, and hydration ratios at zero marginal cost. The registry enrolls n=30 patients across three clinical sites with identical protocol (IMSS Clínica Río Magdalena, INCMNSZ outpatient clinic, and a private practice site in Mexico City), generating 60 evaluable knees and 30 paired cardiac CT studies. The primary co-endpoints address a mechanistic question no other tirzepatide study is positioned to answer: whether the articular response to tirzepatide in inflammatory arthropathy precedes and mechanistically precedes weight loss, through formal mediation analysis of Week-4 ACR20 response via high-sensitivity C-reactive protein, SERPINB2, and dipeptidyl peptidase-4 activity, restricted to the Mechanistic Analysis Set of patients with tirzepatide exposure ≤16 weeks at Week 0 and delta-BMI <1.0 kg/m² through Week 4. A prespecified Surgical Tissue Subcohort is declared at initial registration to establish public scientific priority on direct human epicardial adipose tissue transcriptomic characterization under dual GIP/GLP-1 receptor agonism. Subcohort participants who undergo clinically indicated cardiac surgery at INCar during follow-up (coronary artery bypass grafting, valve replacement, or combined procedures) are invited to provide specific additional informed consent for collection of epicardial adipose tissue fragments routinely excised during operative access and otherwise discarded as surgical waste. Operational launch is contingent on separate INCar tissue-specific approvals and will proceed via PRS record amendment when ready

Background and rationale. Tirzepatide, a dual agonist of the glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors, has demonstrated unprecedented cardiometabolic potency in registration trials (SURPASS, SURMOUNT, SYNERGY-NASH, SUMMIT). Recent evidence has extended the mechanistic reach of the molecule beyond glycemia and weight to specific tissue compartments. The SUMMIT cardiac magnetic resonance substudy demonstrated reduction of left ventricular mass and paracardiac adipose tissue at 52 weeks in heart failure with preserved ejection fraction with obesity. A prespecified diabetes-stratification analysis of SUMMIT established that these structural effects are partially independent of weight change. The SURPASS cardiovascular outcomes trial established cardiovascular superiority of tirzepatide over GLP-1 monoagonism. A recent randomized clinical trial in psoriatic arthritis with overweight or obesity demonstrated articular response at Week 4 when dual incretin agonism was added to IL-17A inhibition, prior to substantial weight loss. The "multi-nutrient-stimulated-hormone" (multi-NuSH) framework now organizing the field articulates the conceptual reach of dual and multi-incretin agonism beyond glycemia. Mechanistic work on human and murine adipocytes establishes direct GIP receptor effects on visceral adipose depots that are biologically distinct from weight-mediated effects. Bibliographic support for each of these statements is provided in the Citations field of this record.

The Mexican off-label access asset. Access to tirzepatide in the United States and Europe is restricted by payer prior-authorization to narrow on-label indications. In Mexico, out-of-pocket access permits a phenotypic breadth of clinical exposure not replicable in sponsor-led trials, including patients who receive tirzepatide for insulin resistance, metabolic hypertension, renal protection, and off-label metabolic indications. This pharmacological natural experiment allows the registry to capture the articular, cardiac, compositional, and aging-biology response to dual GIP/GLP-1 agonism across a clinical breadth sponsor trials cannot access. The window is finite: as label expansion advances, the uniqueness of Mexican off-label exposure attenuates. The registry is positioned to capture this window.

Four-institute architecture. CARTIZ operates through four specialized cores, each led by a qualified investigator at an independent institution, producing endpoints of differentiated resolution and relevance.

Core 1 - Knee Cartilage Imaging Core (Level 3A). Bilateral 3T knee MRI with quantitative T2 mapping at Week 0 and Week 52, performed at Ci3M UAM-Iztapalapa (CONACYT National Laboratory) under Dr. Andres Moron and Dr. Luis Jimenez Angelez departamento de ingenieria en sistemas biomedicos, Facultad de Ingenieria UNAM. All imaging at a single Philips 3T platform with harmonized pulse-sequence parameters. Central overread. 60 evaluable knees at n=30.

Core 2 - Cardiac Imaging Core (Level 3B). Non-contrast cardiac computed tomography with prospective electrocardiographic gating at Week 0 and Week 52, performed at the Instituto Nacional de Cardiología Ignacio Chávez under cardiovascular Co-Principal Investigator Dr. Erick Alexánderson Rosas, Chief of the Departamento de Cardiología Nuclear e Imagen Cardiovascular Molecular. Radiomic phenotyping of epicardial adipose tissue (EAT) following the Imaging Biomarker Standardization Initiative (IBSI) specifications using PyRadiomics, with quantification of EAT volume, mean attenuation (Hounsfield units), attenuation distribution (standard deviation, skewness, kurtosis), and texture features (first-order, gray-level co-occurrence matrix, gray-level run-length matrix, gray-level size-zone matrix, neighborhood gray-tone difference matrix). Fat Attenuation Index (FAI) quantification in the adventitia of proximal left anterior descending, circumflex, and right coronary artery territories per published perivascular FAI methodology. 30 paired cardiac CT studies.

Core 3 - HLA Typing Core (Level 2). Class I (A, B, C) and Class II (DRB1, DQB1, DPB1) HLA typing by PCR-SSO Reverse Luminex at the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ) Transplant Department under Dr. Mario Vilatoba. Anonymized archival for population comparison and kinship-linkage analysis.

Core 4 - Body Composition Core (Level 4). Multi-frequency bioelectrical impedance analysis (seca mBCA) at six longitudinal timepoints (Week 0, 2, 4, 12, 24, 52) at Universidad La Salle México, capturing visceral adipose tissue trajectory, phase-angle trajectory (an established aging-biology biomarker), appendicular skeletal muscle mass, total body water, extracellular water, and hydration ratios. Available at zero marginal cost to the registry.

Five-level endpoint structure. Endpoints are organized in five levels of differentiated resolution: Level 1 - mechanistic deconvolution (PI-executed, primary); Level 2 - biomarker and HLA stratification (sponsor-executed under MTA, hypothesis-generating); Level 3A - knee structural imaging (Ci3M, PI-executed); Level 3B - cardiac structural imaging (INCar, PI-executed); and Level 4 - body composition and aging biology (La Salle, PI-executed).

Primary co-endpoints. (1) ACR20 response rate at Week 4 in the Mechanistic Analysis Set (MAS), defined as patients with tirzepatide exposure ≤16 weeks at Week 0 and delta-BMI <1.0 kg/m² through Week 4. (2) Proportion of Week-4 ACR20 response mediated by the combined biomarker panel (high-sensitivity C-reactive protein, SERPINB2, dipeptidyl peptidase-4 activity) in the MAS, assessed by the MacKinnon product-of-coefficients method with 10,000 bias-corrected and accelerated bootstrap iterations.

Surgical Tissue Subcohort (prespecified secondary arm). A subset of enrolled participants who undergo clinically indicated cardiac surgery at INCar during registry follow-up (coronary artery bypass grafting, valve replacement, or combined procedures) will be invited to provide specific informed consent for collection of epicardial adipose tissue fragments routinely excised during operative access to the heart (e.g., during aortic root exposure for AVR, coronary target exposure for CABG, or mitral annular exposure for MVR). These fragments are ordinarily discarded as surgical waste. Under this subcohort they are collected intraoperatively, divided into fresh-frozen aliquots (RNAlater, OCT) and formalin-fixed aliquots (10% neutral-buffered formalin), and processed for bulk and/or single-nucleus RNA sequencing, histological characterization, and biobanking for prespecified future analyses. Tissue acquisition does not modify the surgical procedure. Operational launch is contingent on favorable opinion of the INCar Comité de Investigación and Comité de Ética en Investigación for the tissue-specific protocol, formal operational agreement with the INCar Servicio de Cirugía Cardiovascular, and PRS record amendment. This subcohort is declared at initial registration to establish scientific priority for direct human epicardial adipose tissue transcriptomic characterization under dual GIP/GLP-1 receptor agonism - a gap explicitly identified in the multi-NuSH framework and not filled by any currently published or registered study.

Governance and oversight. Independent Scientific Advisory Board (ISAB) with advisory competence over the Statistical Analysis Plan, publication policy, and database lock. Cryptographic provenance infrastructure: SHA-256 hash chain for every biospecimen manifest entry, every DICOM series, and every database snapshot, anchored to an append-only audit log under version control, with three-server email timestamping. Informed consent is modular: each attestation (prospective participation, serum biobanking, HLA typing, knee MRI, cardiac CT, body composition, medical record review, and - for the surgical subcohort - tissue collection) is consented separately within a single document. All data transferred to sponsors is de-identified to HIPAA Safe Harbor and LFPDPPP Mexican standards, with cryptographic separation between re-identification key and transferred dataset.

Intellectual property status. Four United States Provisional Patent Applications are active, filed pro se by the Principal Investigator as micro entity: PROV-001 (64/019,134, 27 March 2026, DPP4-Incretin-SERPIN axis for chondroprotection); PROV-002 (64/031,635, 7 April 2026, BMP/ROCK/DPP4/Mechanosensory axis); PROV-003 (64/039,918, 15 April 2026, cartilage companion biomarkers); PROV-004 (64/043,606, 19 April 2026, HLA-guided GIPR companion diagnostics). All four are referenced as Secondary IDs in this registration.

Inclusion Criteria:

• 1. Age ≥18 years at the time of informed consent. 2. Currently receiving tirzepatide under an independent clinical indication (type 2 diabetes, insulin resistance, obesity with or without associated metabolic disease, renal protection, metabolic hypertension, or associated off-label metabolic use) prescribed by the treating physician independently of the registry.

  3. Presence of at least one objectively documented musculoskeletal manifestation - current or historical - defined as any of: (i) inflammatory arthralgia affecting one or more joints with clinical, imaging, or serological support; (ii) CASPAR-positive psoriatic arthritis; (iii) radiographically documented knee osteoarthritis; (iv) enthesitis on physical examination or ultrasound; (v) documented inflammatory arthropathy of the spine or peripheral joints with a specialist diagnosis.

  4. For the retrospective-prospective component: availability of clinical documentation of articular state prior to tirzepatide initiation in the patient's medical record. Documentation may include physical examination notes, imaging, laboratory values, or specialist consultation notes.

  5. Signed informed consent for registry enrolment, longitudinal serum biobanking, HLA typing at INCMNSZ, quantitative knee MRI with T2 mapping at Ci3M UAM-Iztapalapa at Week 0 and Week 52, non-contrast cardiac CT at INCar at Week 0 and Week 52, multi-frequency bioelectrical impedance analysis at Universidad La Salle México at six timepoints, and (where applicable) medical record review. Each attestation is consented modularly within a single document.

  6. Clinical plan to continue tirzepatide for at least 52 weeks from registry Week 0, based on the treating physician's evaluation of current clinical indication. Discontinuation during follow-up is captured as an outcome variable and does not remove the patient from the registry.

  7. Capacity to attend scheduled follow-up visits and to undergo bilateral knee MRI at Ci3M (without severe claustrophobia requiring sedation, without absolute contraindication to MRI - see Exclusion 6) and non-contrast cardiac CT at INCar (without uncontrolled arrhythmia precluding ECG-gated imaging of diagnostic quality).

For the Surgical Tissue Subcohort (Cohort 3) only - additional criteria applied at the time of subcohort enrolment:

8s. Scheduled clinically indicated cardiac surgery at the Instituto Nacional de Cardiología Ignacio Chávez (coronary artery bypass grafting, valve replacement, or combined procedures) during registry follow-up.

9s. Specific additional informed consent for intraoperative collection of epicardial adipose tissue fragments.

Exclusion Criteria:

• 1. Initiation or modification of a biologic disease-modifying antirheumatic drug (biologic DMARD) or JAK inhibitor within the 12 weeks prior to Week 0, or clinically anticipated initiation or modification during the first 12 weeks of follow-up. Washout may permit re-screening.

  2. Major joint surgery within the 3 months prior to Week 0, or planned major joint surgery within the 12 months following Week 0, involving any joint scheduled for evaluation in the registry.

  3. Intra-articular corticosteroid or hyaluronic acid injection within the 6 weeks prior to baseline biospecimen collection in any joint. Patients beyond the 6-week washout are eligible.

  4. Active malignancy, with the exception of adequately treated non-melanoma skin carcinoma. History of malignancy in remission ≥5 years is permitted at the discretion of the treating investigator.

  5. Current pregnancy, lactation, or planned pregnancy within the 12-month observation period.

  6. Absolute contraindication to MRI, including non-MRI-compatible cardiac pacemaker or implanted defibrillator, ferromagnetic intracranial vascular clips, non-documented non-MRI-compatible cochlear implants, or other contraindication per the local MRI safety protocol.

  7. Systemic rheumatologic disease other than psoriatic arthritis or osteoarthritis requiring active immunomodulation, specifically: seropositive rheumatoid arthritis on biologic therapy, active systemic lupus erythematosus on immunomodulation, active vasculitis on immunosuppression, or other systemic disease whose treatment confounds the inflammatory axis the registry is designed to characterize.

  8. Inability to provide informed consent (cognitive impairment, language barrier not resolvable with site interpreter, or other incapacity to understand the protocol), or anticipated inability to complete the 52-week follow-up.

For the Surgical Tissue Subcohort (Cohort 3) only - additional exclusions:

9s. Prior major cardiac surgery resulting in extensive pericardial adhesions that preclude safe intraoperative EAT fragment collection, as assessed by the operating cardiac surgeon.

10s. Emergency cardiac surgery precluding the specific informed consent process.

Adults receiving tirzepatide under an independent clinical indication (type 2 diabetes, insulin resistance, obesity with or without associated metabolic disease, renal protection, metabolic hypertension, or off-label metabolic use) with current or historical documented musculoskeletal manifestation, enrolled across three clinical sites in Mexico City with identical protocol: IMSS Clínica Río Magdalena, INCMNSZ outpatient clinic, and a private practice site. The population is deliberately heterogeneous in tirzepatide indication and articular diagnosis to permit stratified analysis across the VAT-articular-cardiac-aging axis.

De-identified individual participant data (clinical, imaging, laboratory, biomarker, and - in the Surgical Tissue Subcohort - transcriptomic) will be available for sharing under the registry's predefined Sponsor Access Framework (SAF v2.0). The framework defines four access tiers: T1 Mutual Non-Disclosure Agreement for scientific evaluation discussions; T2 Material Transfer Agreement + Data Use Agreement for serum aliquot transfer and baseline CRF access; T3 Option Agreement on provisional patent applications with longitudinal CRF, DICOM archive, and biomarker dataset access; T4 License + Co-Financing Agreement with full intellectual property license and registry expansion co-financing. All data transferred under any tier is de-identified to HIPAA Safe Harbor and LFPDPPP Mexican standards.

From approximately 6 months after primary publication, under the access tiers defined in the Sponsor Access Framework. T1 discussions may begin at any time under Mutual Non-Disclosure Agreement

Access is governed by the Sponsor Access Framework v2.0 of the CARTIZ registry. Pharmaceutical, diagnostic, and academic requesters are eligible under the framework's tiered instruments. Initial inquiries are directed to the Principal Investigator (contact details in Module 10). T2 access requires an executed Material Transfer Agreement and Data Use Agreement. T3 and T4 access require commercial terms and Independent Scientific Advisory Board consultation.