Objective Glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) have cardioprotective and kidney‐protective benefits among patients with type 2 diabetes (T2D). We sought to determine whether GLP‐1RA use improves cardiovascular (CV) and kidney outcomes among patients with systemic lupus erythematosus (SLE) and lupus nephritis (LN). Methods We emulated a pragmatic target trial to evaluate the impact of GLP‐1RA versus comparator hypoglycemic agents, dipeptidyl peptidase 4 inhibitors (DPP4i), on CV and kidney outcomes among patients with SLE and T2D using a large, US multicenter electronic health record database. We used propensity score overlap weighting to emulate randomization among treatment groups. Outcomes included major adverse CV events, venous thromboembolism (VTE), kidney disease progression (estimated glomerular filtration rate decline ≥ 30% or new onset end‐stage kidney disease), and all‐cause mortality. We used Cox regression to compare hazard ratios (HR) based on the weighted populations. In a secondary analysis, we only included patients with LN. Results There were 910 and 1,004 initiators of GLP‐1RA and DPP4i, respectively, including 267 and 324 patients with LN, respectively. Baseline covariates were balanced after propensity score overlap weighting. The risks of major adverse cardiac events (MACEs; hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.48–0.91), VTE (HR 0.49, 95% CI 0.24–0.97), kidney disease progression (HR 0.77, 95% CI 0.60–0.98), and all‐cause mortality (HR 0.26, 95% CI 0.10–0.68) were lower with GLP‐1RA versus DPP4i use. GLP‐1RA use was similarly associated with lower risks of MACE and kidney disease progression among patients with LN. Conclusion We found lower risks of adverse CV and kidney outcomes and mortality with GLP‐1RA use compared with DPP4i use among patients with lupus and T2D.

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