ArticleDiabetology & metabolic syndrome2026
GLP-1 receptor agonists and cardiorenal outcomes in type 2 diabetes with CKD stages 2-4: a target trial emulation.
Article in Diabetology & metabolic syndrome, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundPatients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) face compounded cardiorenal risk. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have demonstrated cardiovascular and renal benefits in randomized trials, yet real-world evidence in populations with established CKD stages 2 through 4 remains limited. We aimed to compare cardiorenal outcomes between new users of GLP-1 RAs and dipeptidyl peptidase-4 inhibitors (DPP-4i) in this high-risk population.
methodsUsing the TriNetX Global Collaborative Network, we conducted a new-user, active-comparator cohort study emulating a target trial. Adults with T2DM and CKD stages 2-4 who initiated GLP-1 RA or DPP-4i between January 2017 and December 2021 were identified. After 1:1 propensity score matching on 40 covariates, 28,824 patients per group were retained. Three co-primary outcomes-MAKE, MACE, and all-cause mortality-were assessed at 1, 2, and 3 years from the same matched cohort. Secondary outcomes included a safety composite and hypoglycemia. Conjunctivitis served as a negative control outcome. Restricted mean survival time was calculated as a supplementary analysis.
resultsAt 3 years, GLP-1 RA initiation was associated with significantly lower risks of MAKE (hazard ratio [HR] 0.837; 95% confidence interval [CI] 0.796-0.880; P < .001), MACE (HR 0.875; 95% CI 0.843-0.909; P < .001), and all-cause mortality (HR 0.787; 95% CI 0.743-0.834; P < .001) compared with DPP-4i. These associations were evident at 1 year and persisted through 3 years. The safety composite favored GLP-1 RAs (HR 0.905; 95% CI 0.877-0.934; P < .001), with comparable hypoglycemia rates between groups. The negative control outcome yielded null results (HR 0.959; 95% CI 0.865-1.065; P = .436), supporting the validity of the study design.
conclusionsIn this large, propensity score-matched, international real-world cohort, GLP-1 RA initiation was associated with significantly lower risks of adverse kidney events, cardiovascular events, and mortality compared with DPP-4i in patients with T2DM and CKD stages 2 through 4. Benefits emerged early and persisted over 3 years, providing supportive evidence for GLP-1 RAs to a population underrepresented in randomized trials.
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