Tirzepatide therapy reduces subclinical leaflet thrombosis and paravalvular leak after transcatheter aortic valve replacement in obese patients: The TAVR-MET trial.

BACKGROUND: Obesity is increasingly recognized as a critical modifier of outcomes following transcatheter aortic valve replacement (TAVR), predisposing patients to subclinical leaflet thrombosis (SLT), hypo-attenuated leaflet thickening (HALT), and paravalvular leak (PVL). Metabolic inflammation, endothelial dysfunction, and pro-thrombotic states associated with obesity contribute to impaired bioprosthetic valve healing. Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, has demonstrated robust metabolic, anti-inflammatory, and vascular protective effects. However, its impact on post-TAVR valve performance has not been previously evaluated. OBJECTIVES: To determine whether tirzepatide therapy initiated before TAVR and continued post-procedure reduces the incidence of HALT and PVL in obese patients undergoing TAVR. METHODS: TAVR-MET was a prospective, randomized, open-label, multicenter trial enrolling obese patients (BMI ≥ 30 kg/m) undergoing transfemoral TAVR. Patients were randomized to tirzepatide therapy or standard care. The primary endpoint was HALT incidence at 6 months assessed by 4D-CT or transesophageal echocardiography (TEE). Secondary endpoints included PVL severity, major adverse valve events (MAVE), inflammatory biomarker changes, weight reduction, and bleeding outcomes. RESULTS: Among 260 randomized patients, tirzepatide therapy significantly reduced HALT incidence (8.4% vs 21.6%, p = 0.002) and ≥ mild PVL (10.7% vs 25.3%, p = 0.006) at 6 months. Tirzepatide was associated with marked reductions in CRP and body weight without an increase in major bleeding. Multivariable analysis identified tirzepatide use, CRP reduction >30%, and BMI <32 kg/mat follow-up as independent predictors of HALT absence. CONCLUSIONS: Metabolic modulation with tirzepatide significantly improves post-TAVR valve healing and hemodynamics in obese patients. These findings introduce a novel cardio-metabolic strategy to reduce structural valve complications following TAVR. TRIAL SUMMARY: TAVR-MET STUDY: The TAVR-MET trial was a prospective, randomized, multicenter study designed to evaluate whether metabolic modulation with tirzepatide, a dual GIP/GLP-1 receptor agonist, could improve bioprosthetic valve outcomes following transcatheter aortic valve replacement (TAVR) in obese patients. Obesity is increasingly recognized as a key determinant of post-TAVR complications, particularly subclinical leaflet thrombosis (HALT) and paravalvular leak (PVL), driven by chronic inflammation, endothelial dysfunction, and a prothrombotic state. Tirzepatide has demonstrated potent weight-reducing, anti-inflammatory, and vascular protective effects, but its role in structural valve outcomes had not previously been explored. The trial enrolled 260 obese patients (BMI ≥ 30 kg/m) undergoing transfemoral TAVR across eight high-volume centers. Participants were randomized to receive tirzepatide initiated four weeks before TAVR and continued for 12 months, or standard care alone. All patients received guideline-directed antithrombotic therapy. The primary endpoint was the incidence of HALT at six months assessed by advanced imaging. Secondary endpoints included PVL severity, major adverse valve events, inflammatory biomarker changes, weight reduction, and bleeding outcomes. At six months, tirzepatide therapy was associated with a significant reduction in HALT compared with standard care, as well as a marked decrease in ≥ mild paravalvular leak. These structural valve improvements were accompanied by substantial weight loss and significant reductions in systemic inflammatory markers, without an increase in major bleeding or adverse safety signals. Multivariable analysis confirmed tirzepatide use and inflammation reduction as independent predictors of improved valve outcomes. In conclusion, the TAVR-MET trial provides the first clinical evidence that targeted metabolic therapy can favorably influence bioprosthetic valve healing after TAVR. These findings support a novel cardio-metabolic strategy for improving post-TAVR outcomes in obese patients and highlight the importance of addressing metabolic inflammation alongside procedural excellence in contemporary structural heart interventions.