Finerenone and sodium-glucose cotransporter-2 inhibitors (SGLT2i) independently improve cardiovascular and renal outcomes in diabetic chronic kidney disease (CKD), but real-world evidence on their combined use is understudied. Using the TriNetX Global Collaborative Network, we identified adults with CKD and type 2 diabetes who initiated SGLT2i therapy between July 2020 and December 2024. Patients receiving SGLT2i monotherapy were compared with those who subsequently added finerenone. After excluding end-stage kidney disease and prior mineralocorticoid receptor antagonist use, cohorts were propensity-score matched (1:1) across 31 covariates. Outcomes included all-cause mortality, major adverse cardiovascular events (MACE), major adverse kidney events (MAKE), hyperkalemia, and a negative-control outcome (osteoarthritis). Associations were estimated using risk ratios, hazard ratios, and Kaplan–Meier survival analyses. After matching, 2,317 patients were included in each cohort. Over 1 year, finerenone use was associated with significantly lower all-cause mortality (HR 0.37; 95% CI: 0.25 to 0.55). Rates of MACE (HR 0.89, 95% CI: 0.74 to 1.09) and MAKE (HR 0.95; 95% CI: 0.47 to 1.92) were similar between groups. Hyperkalemia occurred more often with finerenone (HR 1.35; 95% CI: 1.11 to 1.69) although risk-based analyses did not reach statistical significance. Osteoarthritis rates did not differ. In conclusion, adding finerenone to SGLT2i therapy was associated with lower mortality and favorable cardiovascular outcomes without excess kidney risk, supporting complementary cardiorenal benefits with appropriate potassium monitoring.
Chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM) frequently occur simultaneously and confer an elevated risk of cardiovascular morbidity and mortality. Cardiovascular disease persists as the leading cause of death among individuals with CKD and reflects the close interplay between cardiac and renal dysfunction, understood as cardiorenal syndrome. This condition shares pathophysiologic pathways of cardiovascular and renal diseases, including metabolic dysregulation, inflammation, vascular injury, and neurohormonal activation, that contribute to adverse outcomes. This heightened cardiovascular risk underscores this patient population as a high-priority target for therapies that simultaneously modify cardiovascular and renal disease progression. Sodium-glucose cotransporter-2 inhibitors (SGLT2is) have emerged as foundational therapies for patients with CKD and T2DM and demonstrate consistent reductions in heart failure hospitalization, cardiovascular events, and progression of kidney disease across many randomized trials and meta-analyses. ,,, These benefits appear to extend beyond lowering glucose to include evidence supporting reduced risk of kidney failure and cardiovascular outcomes in high-risk populations. Nonsteroidal mineralocorticoid receptor antagonists (MRAs), specifically finerenone, represent an additional efficacious therapeutic option in this patient population. Unlike historic steroidal MRAs, finerenone provides a more selective mineralocorticoid receptor antagonism that allows for targeting of inflammatory and fibrotic pathways that are central to both cardiac and renal disease progression. Multiple randomized trials have demonstrated that finerenone reduces cardiovascular and kidney events when added to background renin-angiotensin system blockade in CKD with T2DM [2]. Specifically, the FIGARO-DKD trial showed that finerenone usage led to a relative risk reduction of cardiovascular (CV) events such as death, stroke, myocardial infarction, and heart failure in patients with CKD and T2DM in comparison to the control group. Whereas in the FIDELIO-DKD study, the use of MRAs showed greater relative risk reduction of CKD progression and albuminuria in comparison to the control group. Despite the independent benefits of SGLT2is and finerenone, evidence guiding their combined use remains limited. Major finerenone trials, FIGARO-DKD and FIDELIO-DKD, included relatively few patients receiving both finerenone and background SGLT2i therapy, leading to residual uncertainty regarding the clinical effectiveness of layered therapy in real-world practice. Given their complementary mechanisms of action and increasing concurrent use in guided contemporary care, evaluating the effectiveness of combination therapy on clinical outcomes is an important unmet need. Accordingly, this large, real-world retrospective study using global electronic health records (EHRs) compares cardiovascular and renal outcomes among adults with concurrent CKD and T2DM treated with SGLT2i monotherapy versus patients receiving finerenone and SGLT2i combination therapy. This study aims to address a critical evidence gap by evaluating the comparative effectiveness of these treatment strategies in a complex patient population representative of contemporary clinical practice.
Methods
Study design and data source
This retrospective observational cohort study was conducted using the TriNetX® Global Collaborative Network, a federated research platform that aggregates de-identified EHRs from participating healthcare organizations. The platform enables real-time cohort creation, propensity-score matching, and outcome analytics using standardized diagnosis, procedure, medication, and laboratory data. Because all data were de-identified according to HIPAA standards, this study was exempt from institutional review board approval.
Cohort construction
Two cohorts were defined based on medication exposure and clinical characteristics. Adult patients aged 18 years or older with CKD and T2DM were eligible for inclusion. CKD was defined by diagnostic codes and/or laboratory evidence of impaired kidney function, including an eGFR ≤60 ml/min/1.73 m² or documentation of albuminuria or proteinuria. To ensure clinically meaningful renal or metabolic risk, patients were required to have an HbA1c ≥6.5% in combination with at least one of the following: urine albumin-creatinine ratio ≥ 30 mg/g, urine protein-creatinine ratio ≥ 150 mg/g, documented proteinuria, or reduced eGFR.
Two cohorts were constructed based on medication exposure. Cohort 1 (SGLT2i only) included patients newly initiated on SGLT2i during the study window who had no exposure to finerenone at any time. Cohort 2 (SGLT2i + finerenone) included patients meeting identical CKD and T2DM criteria who initiated finerenone at least one day after SGLT2i initiation, reflecting add-on therapy with a nonsteroidal MRA. Patients were excluded if they had a history of dialysis dependence, kidney failure, kidney transplant, or recent major cardiovascular events (myocardial infarction, intracranial hemorrhage, or ischemic stroke). Patients receiving spironolactone or eplerenone were excluded to avoid confounding from other mineralocorticoid receptor antagonists. The index date was defined as the earliest date when SGLT2i therapy was started for cohort 1, and combination therapy was started for cohort 2. The start date of our study coincided with the approval of finerenone by the US Food and Drug Administration and was chosen to minimize noncontemporaneous control bias, as SGLT2i was authorized 8 years earlier than finerenone in 2013.
Outcomes
The primary study outcome was all-cause mortality. Secondary outcomes included major adverse cardiovascular events (MACE; composite of myocardial infarction, intracranial hemorrhage, ischemic stroke, or cardiac arrest) and major adverse kidney events (MAKE; composite of CKD stage 5, kidney failure, dialysis, or kidney transplantation). Additional outcomes included hyperkalemia and a negative-control outcome, osteoarthritis. Outcomes were assessed beginning one day after the index date and continued through 365 days of follow-up. Outcomes were defined using diagnosis codes, procedure codes, medication exposure, or laboratory thresholds according to TriNetX outcome definitions. A complete list of International Classification of Diseases, Tenth Revision (ICD-10) and Current Procedural Terminology (CPT) codes used to define exposures, covariates, and outcomes is provided in the supplementary materials (Supplementary Table1) .
Statistical analysis
All analyses were performed using the TriNetX Analytics Platform. Measures of association included absolute risk, risk difference, risk ratio, and odds ratio with 95% confidence intervals (CIs). Time-to-event outcomes were evaluated using Kaplan–Meier survival curves with log-rank testing, and hazard ratios were estimated using Cox proportional hazards models with proportionality testing. For outcomes with recurrent events, the number of distinct event dates was compared between cohorts. To account for baseline differences between treatment groups, 1:1 propensity score matching (PSM) was performed using logistic regression with greedy nearest-neighbor matching and a fixed caliper. Patients were matched on demographic characteristics (age, sex, and race), baseline comorbidities relevant to cardiovascular and renal outcomes, and concurrent cardiometabolic medication use. Patient records were randomly ordered prior to matching to reduce algorithmic bias. All statistical tests were two-sided, and statistical significance was defined as a p-value <0.05.
Results
Study cohorts
A total of 122,640 adult patients with CKD and T2DM met eligibility criteria for treatment with SGLT2i. Of these patients, 120,321 received SGLT2i therapy alone, while 2,319 initiated finerenone following SGLT2i exposure. Patients were stratified according to subsequent finerenone use prior to PSM. Before matching, substantial imbalances were observed between treatment groups, reflecting the smaller size and higher clinical complexity of patients receiving combination therapy. After 1:1 PSM, 2,317 patients remained in each cohort ( Figure 1 ). Post-matching assessment demonstrated adequate balance across demographic variables, baseline comorbidities, medication exposures, and available laboratory parameters, with standardized mean differences below accepted thresholds, indicating effective covariate balance ( Table 1 ).
Flow chart showing the total sample size and the two cohorts after propensity score matching. CKD = chronic kidney disease, eGFR = estimated glomerular filtration rate, ESRD = end stage renal disease, HbA1c = hemoglobin A1c, HCOs = healthcare organizations, MI = myocardial infarction, SGLT2i = sodium–glucose cotransporter-2 inhibitor, T2DM = type 2 diabetes mellitus
Table 1
Baseline characteristics of SGLT2i and SGLT2i + finerenone cohorts before and after propensity-score matching
| Before PSM | After PSM | ||||||
|---|---|---|---|---|---|---|---|
| SGLT2i | SGLT2i + finerenone | p-value | SGLT2i | SGLT2i + finerenone | p-value | SMD | |
| (n = 120,321) | (n = 2,319) | (n = 2,317) | (n = 2,317) | ||||
| Demographics | |||||||
| Age at Index, years | 68.7 ± 10.4 | 67.5 ± 10.7 | <0.001 | 67.6 ± 10.9 | 67.5 ± 10.7 | 0.772 | 0.008 |
| Female | 50,977 (42.4%) | 936 (40.4%) | 0.053 | 992 (42.8%) | 935 (40.4%) | 0.089 | 0.05 |
| Black or African American | 22,357 (18.6%) | 396 (17.1%) | 0.065 | 374 (16.1%) | 396 (17.1%) | 0.385 | 0.026 |
| White | 71,811 (59.7%) | 1,006 (43.4%) | <0.001 | 1,013 (43.7%) | 1,006 (43.4%) | 0.836 | 0.006 |
| Asian | 9,498 (7.9%) | 572 (24.7%) | <0.001 | 603 (26.0%) | 570 (24.6%) | 0.265 | 0.033 |
| Diagnoses (comorbidities) | |||||||
| Disorders of lipoprotein metabolism | 76,833 (63.9%) | 1,573 (67.8%) | <0.001 | 1,549 (66.9%) | 1,571 (67.8%) | 0.491 | 0.02 |
| Hypertensive diseases | 90,446 (75.2%) | 1,853 (79.9%) | <0.001 | 1,850 (79.8%) | 1,851 (79.9%) | 0.971 | 0.001 |
| Heart failure | 26,335 (21.9%) | 326 (14.1%) | <0.001 | 340 (14.7%) | 326 (14.1%) | 0.558 | 0.017 |
| Acute myocardial infarction | 6,565 (5.5%) | 55 (2.4%) | <0.001 | 64 (2.8%) | 55 (2.4%) | 0.403 | 0.025 |
| Atrial fibrillation/flutter | 17,773 (14.8%) | 225 (9.7%) | <0.001 | 226 (9.8%) | 225 (9.7%) | 0.96 | 0.001 |
| Cerebrovascular diseases | 11,649 (9.7%) | 210 (9.1%) | 0.312 | 193 (8.3%) | 210 (9.1%) | 0.375 | 0.026 |
| Peripheral vascular disease | 7,851 (6.5%) | 132 (5.7%) | 0.107 | 124 (5.4%) | 132 (5.7%) | 0.607 | 0.015 |
| Anemia/bone marrow failure | 18,756 (15.6%) | 376 (16.2%) | 0.411 | 363 (15.7%) | 375 (16.2%) | 0.63 | 0.014 |
| Chronic lower respiratory disease | 19,114 (15.9%) | 281 (12.1%) | <0.001 | 298 (12.9%) | 281 (12.1%) | 0.45 | 0.022 |
| Inflammatory liver disease | 1,108 (0.9%) | 14 (1.3%) | 0.186 | 10 (1.0%) | 14 (1.3%) | 0.412 | 0.036 |
| Medications | |||||||
| Statins | 58,439 (48.6%) | 1,210 (52.2%) | 0.001 | 1,163 (50.2%) | 1,209 (52.2%) | 0.176 | 0.04 |
| Fibrates | 4,917 (4.1%) | 101 (4.4%) | 0.518 | 84 (3.6%) | 101 (4.4%) | 0.202 | 0.037 |
| Ezetimibe | 5,337 (4.4%) | 174 (7.5%) | <0.001 | 157 (6.8%) | 174 (7.5%) | 0.332 | 0.028 |
| Diuretics | 39,939 (33.2%) | 671 (28.9%) | <0.001 | 638 (27.5%) | 671 (29.0%) | 0.282 | 0.032 |
| Insulin | 44,122 (36.7%) | 849 (36.6%) | 0.953 | 835 (36.0%) | 848 (36.6%) | 0.691 | 0.012 |
| Beta-blockers | 43,527 (36.2%) | 792 (34.2%) | 0.045 | 777 (33.5%) | 791 (34.1%) | 0.664 | 0.013 |
| Calcium channel blockers | 33,379 (27.7%) | 792 (34.2%) | <0.001 | 778 (33.6%) | 792 (34.2%) | 0.664 | 0.013 |
| ARBs | 30,522 (25.4%) | 925 (39.9%) | <0.001 | 890 (38.4%) | 923 (39.8%) | 0.321 | 0.029 |
| ACE inhibitors | 22,409 (18.6%) | 333 (14.4%) | <0.001 | 333 (14.4%) | 333 (14.4%) | 1 | <0.001 |
| Metformin | 34,103 (28.3%) | 601 (25.9%) | 0.01 | 571 (24.6%) | 601 (25.9%) | 0.311 | 0.03 |
| Recent laboratory values | |||||||
| eGFR (MDRD), ml/min/1.73m² | 50.5 ± 18.6 | 45.8 ± 18.8 | <0.001 | 47.5 ± 19.6 | 45.8 ± 18.8 | 0.005 | 0.089 |
| 60–89 ml/min/1.73m² | 35,735 (29.7%) | 490 (21.1%) | <0.001 | 500 (21.6%) | 490 (21.1%) | 0.72 | 0.011 |
| 45–59 ml/min/1.73m² | 54,675 (45.4%) | 792 (34.2%) | <0.001 | 812 (35.0%) | 792 (34.2%) | 0.537 | 0.018 |
| 30–44 ml/min/1.73m² | 42,839 (35.6%) | 1,029 (44.4%) | <0.001 | 1,038 (44.8%) | 1,027 (44.3%) | 0.745 | 0.01 |
| 15–29 ml/min/1.73m² | 13,570 (11.3%) | 448 (19.3%) | <0.001 | 430 (18.6%) | 446 (19.2%) | 0.548 | 0.018 |
| 0–15 ml/min/1.73m² | 2,643 (2.2%) | 30 (1.3%) | 0.003 | 22 (0.9%) | 30 (1.3%) | 0.265 | 0.033 |
| Hemoglobin, g/dl | 12.6 ± 2.1 | 13.1 ± 2.1 | <0.001 | 12.8 ± 2.0 | 13.1 ± 2.1 | <0.001 | 0.143 |
| Hemoglobin ≤12 g/dl | 58,035 (48.2%) | 1,243 (53.6%) | <0.001 | 1,279 (55.2%) | 1,241 (53.6%) | 0.262 | 0.033 |
| LDL cholesterol, mg/dl | 79.4 ± 36.2 | 76.2 ± 33.6 | 0.002 | 79.4 ± 33.8 | 76.3 ± 33.6 | 0.018 | 0.093 |
| LDL ≥190 mg/dl | 919 (0.8%) | 12 (0.5%) | 0.176 | 11 (0.5%) | 12 (0.5%) | 0.834 | 0.006 |
| BMI, kg/m² | 32.3 ± 7.3 | 31.2 ± 7.2 | <0.001 | 31.2 ± 7.2 | 31.2 ± 7.2 | 0.907 | 0.004 |
| BMI ≥30 kg/m² | 49,068 (40.8%) | 841 (36.3%) | <0.001 | 813 (35.1%) | 841 (36.3%) | 0.391 | 0.025 |
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