Real-world renoprotective effects of polyethylene glycol-loxenatide in type 2 diabetes: a multicenter, ambispective cohort study

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Patients with type 2 diabetes mellitus and chronic kidney disease face persistent risks despite standard care. Polyethylene glycol-loxenatide lacks real-world renoprotective evidence in high-risk Chinese populations relative to non-incretin-based standard care. This multicenter, ambispective cohort study enrolled 3305 patients with type 2 diabetes mellitus, renal impairment, and elevated cardiovascular risk at six Chinese tertiary institutions (median follow-up 36.4 months; trial registration: ChiCTR2300073001). Data were extracted via an artificial intelligence-enhanced pipeline. Co-primary analyzes comprised multivariable-adjusted Cox regression and 1:1 propensity score matching (332 per group); pre-specified landmark analyzes at 6 and 12 months addressed immortal time bias. Polyethylene glycol-loxenatide was associated with a reduced risk of the primary kidney composite outcome in the original cohort (hazard ratio [HR], 0.49; 95% CI, 0.25-0.95; P = 0.035), which was corroborated in the propensity score matched cohort (HR, 0.44; 95% CI, 0.20-0.97; P = 0.043) and progressive across 6-month (HR, 0.40; 95% CI, 0.19-0.84) and 12-month (HR, 0.33; 95% CI, 0.14-0.75) landmarks. While a reduction in 3-point major adverse cardiovascular events was observed in the unmatched cohort (HR, 0.60; 95% CI, 0.43-0.85; P = 0.004), this association was not sustained in the matched analysis (HR, 0.92; 95% CI, 0.57-1.48; P = 0.735). In conclusion, long-term therapy was associated with an attenuated risk of major renal events. Given the null findings in the matched cohort, the cardiovascular observations are exploratory and require randomized confirmation.