Early tirzepatide after kidney transplantation in diabetes is associated with lower cardiovascular events and graft failure: a multinational target trial emulation
F Lemmer, Y Sun, E Rawish, I EitelAbstract
Background
Cardiometabolic risk and graft loss remain major determinants of long-term outcomes after kidney transplantation in patients with diabetes. Evidence on dual GIP/GLP-1 receptor agonism in the early post-transplant period is limited, and conventional observational analyses are vulnerable to immortal time bias and early rejection-related confounding.
Purpose
To evaluate the association of tirzepatide initiation within 90 days after kidney transplantation with (1) major adverse cardiovascular events (MACE) and (2) death-censored graft failure using a prespecified landmark target trial emulation.
Methods
Using multinational federated electronic health records, we emulated a new-user target trial among adult kidney transplant recipients with diabetes. Eligible patients initiated tirzepatide within 90 days post-transplant or received no tirzepatide. To avoid immortal time bias and confounding from early acute rejection, follow-up for outcomes in both groups started at the 90-day landmark and continued to 2 years. The eligible cohort comprised 1,622 tirzepatide-treated and 54,260 control patients. After 1:1 propensity score matching on demographics, cardiometabolic risk factors, renal function (eGFR), BMI, diabetes complications, NT-proBNP, HbA1c, cardiovascular history, and concomitant pharmacotherapy, 1,594 patients per group were analyzed. Co-primary endpoints were MACE (cardiovascular death, myocardial infarction, or stroke) and death-censored graft failure (return to dialysis or re-transplantation). Time-to-event analyses used Cox proportional hazards models reporting hazard ratios (HR) with 95% confidence intervals (CI).
Results
From the 90-day landmark to 2 years, Kaplan–Meier cumulative incidence of MACE was 7.6% with tirzepatide versus 12.9% in controls (event-free survival 92.4% vs 87.1%; HR 0.60, 95% CI 0.45–0.80; log-rank p=0.0006). Death-censored graft failure showed a Kaplan–Meier cumulative incidence of 8.5% versus 12.9% (event-free survival 91.5% vs 87.1%; HR 0.72, 95% CI 0.55–0.95; log-rank p=0.02). Rates of expected gastrointestinal adverse events were comparable between groups.
Conclusions
In a multinational landmark target trial emulation among diabetic kidney transplant recipients, early tirzepatide initiation was associated with clinically meaningful reductions in both cardiovascular events and graft failure over 2 years. These findings suggest that dual GIP/GLP-1 receptor agonism may modify both cardiometabolic and graft-related risk after transplantation and warrant prospective randomized evaluation in the post-transplant setting.