Cartilage, Arthropathy and Imaging Under Tirzepatide in Zone-stratified Cohorts (CARTIZ): A Prospective Observational Multi-Institutional Registry of the VAT-Articular-Cardiac-Aging Axis in Adults Exposed to Tirzepatide in Mexico, With Quantitative Knee Cartilage T2 Mapping, Cardiac CT Epicardial Adipose Tissue Radiomic Phenotyping, HLA Stratification, Longitudinal Multi-Frequency Bioimpedance Body Composition, and a Prespecified Surgical Tissue Acquisition Subcohort
试验速览
- 阶段
- 不适用
- 状态
- 尚未招募
- 发起方
- 入组人数
- 30
- 试验地点
- 1
研究概览
简要总结
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
详细描述
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.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •1. Age ≥18 years at the time of informed consent.
- •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.
排除标准
- •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.
研究组 & 干预措施
Retrospective-Prospective
Patients currently under the Principal Investigator's care who are already receiving tirzepatide for an independent clinical indication at the time of registry enrolment, with pre-tirzepatide articular, metabolic, and clinical documentation available in the medical record. Baseline pre-tirzepatide state is reconstructed retrospectively from structured medical record review under a specific informed consent attestation; Week-0 biospecimen and imaging acquisition is prospective. Expected n=10-20 from the Principal Investigator's existing patient pool. Recruitment Status: Not yet recruiting.
干预措施: Tirzepatide (Drug)
Fully Prospective
Patients identified across the three clinical sites (IMSS Clínica Río Magdalena, INCMNSZ outpatient clinic, private practice in Mexico City) who are initiating tirzepatide under an independent clinical indication during the registry enrolment window, enrolled at or before Week 0 of tirzepatide exposure. Protocol is identical to Cohort 1 from Week 0 forward; the difference is the absence of pre-tirzepatide retrospective reconstruction. Expected n=10-20 recruited over 6-12 months. Recruitment Status: Not yet recruiting.
干预措施: Tirzepatide (Drug)
Surgical Tissue Subcohort
Subset of enrolled Cohort 1 or Cohort 2 participants undergoing clinically indicated cardiac surgery at the Instituto Nacional de Cardiología Ignacio Chávez during follow-up (coronary artery bypass grafting, valve replacement, or combined procedures), providing additional informed consent for intraoperative collection of epicardial adipose tissue fragments routinely excised during cardiac access and discarded as surgical waste. Tissue acquisition does not modify the surgical procedure. This subcohort is declared at initial registration to establish scientific priority on direct human epicardial adipose tissue transcriptomic characterization under dual GIP/GLP-1 receptor agonism. Operational launch requires (a) favorable opinion of INCar Comité de Investigación and Comité de Ética en Investigación for the tissue-specific protocol, (b) formal agreement with INCar Servicio de Cirugía Cardiovascular, (c) PRS amendment reflecting operational launch. Recruitment Status: Not yet recruiting.
干预措施: Tirzepatide (Drug)
研究者
JULIO GRANADOS MONTIEL
Investigador en Ciencias Médicas
Universidad La Salle, Mexico