Comparative effectiveness of tirzepatide versus GLP-1 receptor agonists on cardiovascular-kidney-metabolic stage progression: a real-world cohort study.

BACKGROUND: Cardiovascular-kidney-metabolic (CKM) syndrome represents a progressive disease continuum linking metabolic risk factors with cardiovascular and kidney disease. Patients in early CKM stages (stages 1-2) represent a critical therapeutic window; however, comparative evidence on pharmacologic strategies to prevent progression to advanced CKM stages remains limited. Tirzepatide, a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, has demonstrated superior metabolic efficacy compared with conventional GLP-1 receptor agonists (GLP-1 RAs), but its impact on CKM stage progression in real-world practice is unknown. METHODS: We conducted a retrospective cohort study using the TriNetX US Collaborative Network (January 2022-September 2025). Adults with CKM stage 1 or 2 who newly initiated tirzepatide or another GLP-1 RA were identified. A new-user design with 1:1 propensity score matching was applied to balance demographic characteristics, comorbidities, medications, and laboratory parameters. The primary outcome was progression to CKM stage 3 or 4, defined by incident heart failure, coronary artery disease, ischemic stroke, atrial fibrillation, peripheral artery disease, or very high-risk chronic kidney disease. Secondary outcomes included major adverse cardiovascular events (MACE), individual cardiovascular outcomes, and all-cause mortality. Hazard ratios (HRs) were estimated to use Cox proportional hazards models with one-year follow-up. RESULTS: After matching, 448,591 patients were included in each group. During follow-up, progression to CKM stage 3-4 occurred in 2.2% of patients receiving tirzepatide and 3.3% receiving GLP-1 RAs (HR 0.88, 95% CI 0.86-0.91; P<0.001). Tirzepatide was also associated with lower risks of MACE (HR 0.85, 95% CI 0.80-0.89), coronary artery disease, peripheral artery disease, ischemic stroke, heart failure, very high-risk chronic kidney disease, and all-cause mortality. No significant difference was observed for atrial fibrillation. Associations were consistent across prespecified subgroups, including age, sex, baseline CKM stage, obesity status, and statin use. CONCLUSIONS: In this large real-world cohort of patients with early-stage CKM syndrome, initiation of tirzepatide was associated with a lower risk of progression from CKM stages 1-2 to stages 3-4 compared with other GLP-1 RAs, along with consistent reductions in multiple cardiovascular outcomes. These findings suggest that therapeutic choices made earlier along the CKM continuum may be associated with early differences in disease trajectories, although longer-term studies are needed to determine their sustained clinical impact.