Cardiovascular outcome of glucagon-like peptide-1 receptor agonists vs dipeptidyl peptidase-4 inhibitor on end-stage kidney disease patients with heart failure: an emulated target trial in patients with diabetes

Figures

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  Fig. 1. Flowchart of study population selection. After identifying patients with both type 2 diabetes mellitus (T2DM) and end-stage kidney disease (ESKD), we enrolled those who also had a diagnosis of heart failure (HF), including prevalent HF (HF diagnosed before ESKD) and incident HF (HF diagnosed after ESKD) (Supplementary Fig. 1). We then applied a prespecified new-user, target trial–eligible design: patients were required to initiate a study medication after having both (i) a recorded HF diagnosis and (ii) a recorded ESKD diagnosis, with initiation occurring within 2 years of each diagnosis, yielding the eligible ESKD–HF new-user population. The primary analysis population (Primary ESKD–HF population) was defined by ICD-10-CM I50 and N18.6 (excluding kidney transplant status [Z94.0]). We further evaluated a prespecified higher-specificity nested confirmatory dialysis-dependence–coded subset requiring Z99.2 in addition to I50 and N18.6 (I50 and N18.6 + Z99.2); 1:1 propensity score matching was repeated within this subset. ESKD end-stage kidney disease, HF heart failure, HCOs healthcare organizations, ICD-10-CM International Classification of Diseases, Tenth Revision, Clinical…

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  Fig. 2. Propensity score density plots before and after matching for GLP-1 RA and DPP-4i groups. The figure shows the distribution of propensity scores for the GLP-1 RA and DPP-4i groups before (left panel) and after (right panel) 1:1 matching, demonstrating well-balanced distributions between the two groups post-matching. DPP-4i dipeptidyl peptidase-4 inhibitor, GLP-1 RA glucagon-like peptide-1 receptor agonist.

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  Fig. 3. Kaplan–Meier time-to-event curves comparing GLP-1 RA and DPP-4i groups. Kaplan–Meier curves depict cumulative event-free or survival probabilities over time in the GLP-1 RA (purple) and DPP-4i (teal) cohorts after propensity score matching for a composite ischemic cardiovascular and heart failure exacerbation events; b heart failure exacerbation events; c ischemic cardiovascular events; d all-cause mortality; e composite ischemic cardiovascular, heart failure exacerbation events, and all-cause mortality; and f composite ischemic cardiovascular and heart failure exacerbation events in the dialysis-dependence–coded subset. Solid lines represent Kaplan–Meier estimates (center), and shaded bands indicate 95% confidence intervals (error bands). P-values were calculated using two-sided log-rank tests. Exact P-values are reported when applicable; P-values < 0.0001 are presented as such. No adjustment for multiple comparisons was performed. Source data are provided as a Source data file. DPP-4i dipeptidyl peptidase-4 inhibitor, GLP-1 RA glucagon-like peptide-1 receptor agonist.

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  Fig. 4. Subgroup analyses of primary outcome, composite ischemic cardiovascular and heart failure exacerbation events. Forest plots display hazard ratios for GLP-1 RA versus DPP-4i across prespecified subgroups after propensity score matching. Squares represent hazard ratio estimates (center), and horizontal lines indicate 95% confidence intervals (error bars). Hazard ratios and corresponding 95% confidence intervals were estimated using Cox proportional hazards models. Interaction P-values were derived from likelihood-ratio tests comparing Cox proportional hazards models with and without treatment-by-subgroup interaction terms. All statistical tests were two-sided. Exact P-values are reported when applicable; P-values < 0.001 are presented as such. No adjustment for multiple comparisons was performed. Source data are provided as a Source data file. BMI body mass index, DPP-4i dipeptidyl peptidase-4 inhibitor, GLP-1 RA glucagon-like peptide-1 receptor agonist, HbA1c glycated hemoglobin, HFmrEF heart failure with mildly reduced ejection fraction, HFpEF heart failure with preserved ejection fraction, HFrEF heart failure with reduced ejection fraction, MRA mineralocorticoid receptor…