Abstract
Background
Albuminuria is associated with an increased risk of cardiovascular and kidney events. Sodium glucose co‐transporter 2 inhibitors (SGLT2i) reduce albuminuria and improve kidney outcomes in patients with albuminuric chronic kidney disease (CKD). Patients with low‐ or without albuminuria have been underrepresented in randomised clinical trials (RCTs), and the effects of SGLT2i on cardiovascular and kidney outcomes across the full range of albuminuria require further investigation.
Aims
To study the effects of SGLT2i on kidney and cardiovascular outcomes across albuminuria levels in populations with different cardiovascular–kidney–metabolic (CKM) risk.
Methods
Individual‐patient data pooled analysis of RCTs across the CKM spectrum. Outcomes were studied across urinary albumin‐to‐creatinine ratio (UACR) both as categorical and continuous variables using survival and mixed effects models.
Results
A total of 26 750 patients were included. The median (pct25‐75) baseline UACR was 28 (8–240) mg/g: 13 669 (51.1%) had UACR <30 mg/g, 6904 (25.8%) UACR 30–300 mg/g, and 6177 (23.1%) UACR >300 mg/g. Compared to patients with lower UACR, those with higher UACR were younger, with a more frequent history of hypertension, diabetes, and obesity, and lower eGFR. UACR was linearly associated with kidney and cardiovascular outcomes as well as mortality. Compared to placebo, SGLT2i reduced the risk of kidney events, HF hospitalisations, atherothrombotic events, cardiovascular and all‐cause mortality across the full UACR spectrum (Pinteraction >0.1 for all outcomes). Compared to placebo, SGLT2i reduced albuminuria levels by 13%, on average: gMratio 0.87, 95%CI 0.85–0.88, p < 0.001.
Conclusions
Higher albuminuria was associated with an increased risk of cardiovascular and kidney outcomes. SGLT2i improved cardiovascular and kidney outcomes across the full range of albuminuria, including normo‐albuminuria.
Keywords: albuminuria, cardiovascular–kidney–metabolic, kidney outcomes, sodium glucose co‐transported 2 inhibitors
1. INTRODUCTION
Albuminuria is associated with an increased risk of cardiovascular and kidney events and has been used as an endpoint in clinical trials. 1 , 2 The effects of sodium glucose co‐transporter 2 inhibitors (SGLT2i) to reduce albuminuria levels in patients with albuminuric chronic kidney disease (CKD) are well‐established. 3 , 4 , 5 Not only do SGLT2i reduce albuminuria but their effects on cardiovascular and kidney outcomes are independent of albuminuria in patients with CKD and relatively high albuminuria levels. 6 , 7 , 8 , 9
However, the effect of SGLT2i on albuminuria among patients without type 2 diabetes (T2D) who tend to have much lower urinary albumin excretion is less clear. Furthermore, the effects of SGLT2i on kidney outcomes of patients with low‐ or without albuminuria are not well‐established. 10 Despite a lower risk of kidney events among patients with low albuminuria, a substantial proportion of such patients still experience clinically important kidney function deterioration. 11 For example, the impact of mineralocorticoid receptor antagonists (MRA) on kidney outcomes seems to be dependent on albuminuria levels, whereby patients with high albuminuria experience most of the kidney benefit with MRA therapy, likely because albuminuria is a marker of endothelial injury in the glomeruli with overexpression of mineralocorticoid receptors (MR). 12 , 13 Whether albuminuria also influences SGLT2i effects requires further investigation, particularly among patients with low‐ or without albuminuria who have been underrepresented in randomised trials of SGLT2i. 14
To ascertain whether the effects of SGLT2i on kidney and cardiovascular outcomes are influenced by albuminuria levels across populations with different cardiovascular–kidney–metabolic (CKM) risk, we performed a pooled analysis of five placebo‐controlled SGLT2i trials: (1) EMPEROR‐Reduced (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and a Reduced Ejection Fraction; NCT03057977); (2) EMPEROR‐Preserved (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction; NCT03057951); (3) EMPA‐REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients; NCT01131676); (4) CANVAS‐R (A Study of the Effects of Canagliflozin on Renal Endpoints in Adult Participants With Type 2 Diabetes Mellitus; NCT01989754); and (5) CREDENCE (Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy; NCT02065791) trials including nearly 27 000 patients overall, to study (1) the characteristics of patients across urinary albumin‐to‐creatinine rate (UACR) levels, (2) the associations between UACR levels, cardiovascular and kidney outcomes, (3) the impact of SGLT2i on UACR levels over time, and (4) the effects of SGLT2i across the full spectrum of baseline UACR.
2. METHODS
2.1. Included studies
The following randomised, double‐blind, parallel‐group, placebo‐controlled and event‐driven SGLT2i trials are included in this pooled analysis using individual patient data (IPD): (1) EMPEROR‐Preserved including adults with chronic symptomatic HF, a left ventricular ejection fraction (LVEF) >40%, and elevated natriuretic peptide levels with evidence of structural heart disease or a HF hospitalisation within 12 months, randomised to either empagliflozin 10 mg/day or placebo 15 , 16 ; (2) EMPEROR‐Reduced including adults with chronic symptomatic HF, a LVEF ≤40%, and elevated natriuretic peptide levels, randomised to either empagliflozin 10 mg/day or placebo 17 ; (3) EMPA‐REG OUTCOME including adults with T2D and a history of cardiovascular events or a high cardiovascular risk, randomised to either empagliflozin 10 or 25 mg/day or placebo 18 , 19 ; (4) CANVAS‐R including adults with T2D with a history of cardiovascular events or a high cardiovascular risk, randomised to either canagliflozin 100 mg/day or placebo 20 , 21 ; and (5) CREDENCE including adults with T2D and albuminuric CKD, randomised to either canagliflozin 100 mg/day or placebo. 22 , 23 Only CREDENCE had mandatory UACR levels between 300 and 5000 mg/g for inclusion.
The respective study protocols were approved by the Ethical Committees of each of the participating sites and countries. All patients gave written informed consent to participate in the studies.
2.2. Study visits
Patients were randomised in a double‐blind manner to receive placebo or SGLT2i (in a 1:1 ratio in all trials except EMPA‐REG OUTCOME where the randomisation was performed 2:1 with 10 and 25 mg of empagliflozin vs. placebo), in addition to their usual therapy. Patients were periodically assessed at study visits for laboratory results, including UACR, which was available at baseline and weeks 12, 32, 52, and every 24 weeks thereafter until the end of the studies. Some variations in the timing of the study visits occurred across studies, but these were uniformised using the closest time point to meet the above referenced visits. All randomised patients were followed for the occurrence of outcomes for the entire duration of the trials. The median duration of follow‐up for the whole cohort was 28.7 months (interquartile range [IQR], 23.1–36.7).
2.3. Study endpoints
The primary endpoint for the present analysis was a composite of sustained decline in eGFR of 40% or greater from baseline, end‐stage kidney disease (ESKD), or dialysis, analysed as time‐to‐first event. Additionally, a sustained eGFR decline ≥50% from baseline, ESKD, or dialysis; doubling in serum creatinine levels from baseline; a composite of cardiovascular death or HF hospitalisation; a composite of cardiovascular death, stroke or myocardial infarction (MI); cardiovascular death; and all‐cause death was also studied.
2.4. Statistical analysis
Baseline UACR levels were categorised into the well‐established categories of: (1) normo‐albuminuria if UACR levels <30 mg/g; (2) microalbuminuria if UACR between 30 and 300 mg/g; and (3) macroalbuminuria if UACR >300 mg/g. Baseline characteristics were compared across these UACR categories. Continuous data are reported as mean ± SD for normal distributions or median (IQR) for skewed distributions, and n (%) for categorical variables using the appropriate statistical trend tests. The association between baseline UACR and occurrence of subsequent outcomes was performed using Cox models, adjusted on baseline age (continuous), sex (women vs. men), race (White vs. other), T2D status (yes vs. no), HF history (yes vs. no), eGFR (continuous), and treatment (SGLT2i vs. placebo), with study stratification (5 levels). The impact of SGLT2i versus placebo on the study outcomes was studied with Cox models across UACR levels, with treatment‐by‐UACR interaction terms in the models. The impact of SGLT2i versus placebo on UACR levels over time was studied using mixed models for repeated measures (MMRM) with Log transformed UACR as the independent variable, treatment as the dependent variable, and adjusting for the above referenced variables, plus a treatment‐by‐time interaction, with random intercepts for study and patient ID with models nested within study, using a restricted maximum‐likelihood (REML) estimation and an unstructured covariance matrix. Geometric means ratio (gMratio) was used to display the changes in UACR relative to the baseline value. All analyses were intention‐to‐treat and complete‐case without data imputation. p‐values and 95% confidence intervals presented in this report have not been adjusted for multiplicity given the exploratory nature of this work. All analyses were performed using STATA® (StataCorp. 2025. Stata Statistical Software: Release 19. College Station, TX: StataCorp LLC) using the virtual environment at Vivli® (https://vivli.org/).
3. RESULTS
3.1. Patients' characteristics across albuminuria levels
A total of 26 750 patients were included in this study. The median (pct25‐75) baseline UACR was 28 (8–240) mg/g, corresponding to median Log UACR levels of 3.3 (2.1–5.5) Log units. At extremes, around 10% of patients had a baseline UACR above 1000 mg/g and another 10% had UACR below 5 mg/g, corresponding to Log UACR levels above 7.0 and below 1.5 Log units, respectively (Figure S1, Supporting Information). Of the 26 750 patients, 13 669 (51.1%) presented with UACR <30 mg/g, 6904 (25.8%) UACR between 30 and 300 mg/g, and 6177 (23.1%) UACR >300 mg/g. Compared to patients with lower UACR (≤300 mg/g) levels, those with higher UACR (>300 mg/g) were younger, more frequently men, non‐White, with a history of hypertension and T2D, a higher body mass index (BMI), and lower haemoglobin and estimated glomerular filtration rate (eGFR). Patients with higher UACR used angiotensin converting enzyme inhibitor/angiotensin receptor blockers (ACEi/ARB) more frequently and mineralocorticoid receptor antagonists (MRA) less frequently. Per trial entry criteria the highest proportion of patients with UACR >300 mg/g was present in CREDENCE (Table 1).
TABLE 1.
Baseline patient characteristics by albuminuria levels.
| UACR categories | <30 mg/g | 30–300 mg/g | >300 mg/g | p‐value |
|---|---|---|---|---|
| N (total = 26 750) | 13 669 | 6904 | 6177 | ‐ |
| Age, years | 69.0 ± 12.7 | 70.9 ± 12.6 | 65.2 ± 11.2 | <0.001 |
| Women | 5015 (36.7%) | 2213 (32.1%) | 1943 (31.5%) | <0.001 |
| White race | 10 625 (77.7%) | 5028 (72.8%) | 4118 (66.7%) | <0.001 |
| Hypertension | 11 830 (86.5%) | 6233 (90.3%) | 5890 (95.4%) | <0.001 |
| Type 2 diabetes | 10 373 (75.9%) | 5503 (79.7%) | 5902 (95.5%) | <0.001 |
| Atrial fibrillation/flutter | 2991 (21.9%) | 1875 (27.2%) | 713 (11.5%) | <0.001 |
| Heart failure | 6586 (48.2%) | 3603 (52.2%) | 1760 (28.5%) | <0.001 |
| Myocardial infarction | 5511 (40.3%) | 2707 (39.2%) | 1299 (21.0%) | <0.001 |
| Stroke | 1873 (13.7%) | 988 (14.3%) | 798 (12.9%) | 0.069 |
| Peripheral artery disease | 1442 (10.5%) | 874 (12.7%) | 517 (8.4%) | <0.001 |
| Smoking | 1680 (12.3%) | 824 (11.9%) | 870 (14.1%) | <0.001 |
| COPD | 1061 (7.8%) | 635 (9.2%) | 409 (6.6%) | <0.001 |
| BMI, kg/m2 | 30.3 ± 5.6 | 30.3 ± 5.9 | 31.0 ± 6.1 | <0.001 |
| SBP, mmHg | 130.7 ± 15.9 | 134.0 ± 17.4 | 140.7 ± 16.5 | <0.001 |
| DBP, mmHg | 75.7 ± 9.9 | 76.5 ± 10.5 | 78.6 ± 9.8 | <0.001 |
| Heart rate, bpm | 70.6 ± 10.9 | 71.9 ± 11.5 | 73.4 ± 11.1 | <0.001 |
| Haemoglobin, g/dL | 13.7 ± 1.4 | 13.6 ± 1.6 | 13.3 ± 1.8 | <0.001 |
| Anaemia | 2526 (18.9%) | 1645 (24.3%) | 2064 (36.1%) | <0.001 |
| Creatinine, mg/dL | 1.0 ± 0.3 | 1.2 ± 0.4 | 1.3 ± 0.4 | <0.001 |
| eGFR, mL/min/1.73 m2 | 71.7 ± 21.5 | 65.7 ± 22.2 | 57.5 ± 20.0 | <0.001 |
| UACR, mg/g | 8 (5, 15) | 74 (44, 139) | 952 (527, 1846) | <0.001 |
| ACEi/ARB | 10 705 (78.3%) | 5471 (79.2%) | 5659 (91.6%) | <0.001 |
| Beta‐blocker | 7846 (57.4%) | 4400 (63.7%) | 2977 (48.2%) | <0.001 |
| MRA | 3275 (24.0%) | 1651 (23.9%) | 754 (12.2%) | <0.001 |
| Thiazide diuretic | 2970 (21.7%) | 1417 (20.5%) | 1445 (23.4%) | <0.001 |
| Loop diuretic | 5078 (37.1%) | 2975 (43.1%) | 1953 (31.6%) | <0.001 |
| Study | <0.001 | |||
| EMPEROR‐Preserved | 3474 (25.4%) | 1860 (26.9%) | 629 (10.2%) | |
| EMPEROR‐Reduced | 2078 (15.2%) | 1236 (17.9%) | 396 (6.4%) | |
| EMPA‐REG OUTCOME | 4171 (30.5%) | 2014 (29.2%) | 768 (12.4%) | |
| CANVAS‐Renal | 3915 (28.6%) | 1298 (18.8%) | 510 (8.3%) | |
| CREDENCE | 31 (0.2%) | 496 (7.2%) | 3874 (62.7%) | |
| SGLT2i randomisation | 7514 (55.0%) | 3806 (55.1%) | 3221 (52.1%) | <0.001 |
Abbreviations: ACEi/ARB, angiotensin converting enzyme inhibitor/angiotensin receptor blocker; BMI, body mass index; COPD, chronic obstructive pulmonary disease; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; MRA, mineralocorticoid receptor antagonist; SBP, systolic blood pressure; SGLT2i, sodium‐glucose co‐transported 2 inhibitor.
UACR distribution both in mg/g and log transformed is shown in Figure S1.
3.2. Association of albuminuria levels with outcomes
UACR was linearly associated with kidney and cardiovascular outcomes as well as mortality from any cause (Table 2 and Figure 1). Compared to patients with UACR <30 mg/g, those with UACR between 30 and 300 mg/g had a 1.4 to 1.8‐fold increase in the risk of kidney outcomes, heart failure hospitalisation or cardiovascular death, myocardial infarction, stroke or cardiovascular mortality, and all‐cause mortality; the risk was substantially increased among patients with UACR >300 mg/g, particularly regarding kidney endpoints where a 4 to 5‐fold risk increase was observed; for cardiovascular events and mortality the risk was around 2 to 3‐fold higher.
TABLE 2.
Outcome associations of baseline albuminuria.
| Outcomes by UACR levels, N total = 26 750 | <30 mg/g n/13669 (%) IR100py HR (95%CI) a | 30–300 mg/g n/6904 (%) IR100py HR (95%CI) a | >300 mg/g n/6177 (%) IR100py HR (95%CI) a |
|---|---|---|---|
| Kidney endpoint b |
192 (1.4) 0.6 Ref. Ref. |
167 (2.4) 1.1 1.69 (1.37–2.08) 1.50 (1.22–1.85) |
568 (9.2) 3.9 6.81 (5.61–8.28) 4.84 (3.95–5.94) |
| Kidney endpoint c |
130 (1.0) 0.4 Ref. Ref. |
123 (1.8) 0.8 1.71 (1.33–2.19) 1.58 (1.23–2.03) |
596 (9.7) 4.1 5.01 (3.91–6.42) 4.06 (3.15–5.24) |
| Doubling serum creatinine |
115 (0.8) 0.4 Ref. Ref. |
95 (1.4) 0.6 1.51 (1.15–1.98) 1.40 (1.06–1.85) |
389 (6.3) 2.6 4.39 (3.34–5.77) 3.45 (2.60–4.58) |
| CV death or HF hosp. |
1019 (7.5) 3.4 Ref. Ref. |
961 (13.9) 6.5 1.85 (1.69–2.02) 1.70 (1.56–1.86) |
903 (14.6) 6.2 3.09 (2.79–3.43) 2.72 (2.44–3.04) |
| CV death |
557 (4.1) 1.8 Ref. Ref. |
498 (7.2) 3.2 1.71 (1.51–1.93) 1.60 (1.42–1.81) |
479 (7.8) 3.2 2.63 (2.27–3.04) 2.40 (2.06–2.79) |
| HF hospitalisation |
593 (4.3) 2.0 Ref. Ref. |
618 (9.0) 4.2 2.01 (1.80–2.25) 1.82 (1.62–2.04) |
538 (8.7) 3.7 3.39 (2.96–3.87) 2.88 (2.51–3.31) |
| CV death, stroke, MI |
1081 (7.9) 3.6 Ref. Ref. |
816 (11.8) 5.5 1.51 (1.37–1.65) 1.41 (1.29–1.55) |
838 (13.6) 5.8 2.21 (1.98–2.47) 2.03 (1.81–2.27) |
| All‐cause death |
905 (6.6) 2.9 Ref. Ref. |
765 (11.1) 5.0 1.62 (1.47–1.79) 1.51 (1.37–1.67) |
719 (11.6) 4.8 2.49 (2.21–2.80) 2.25 (2.00–2.55) |
Note: All p‐values are <0.05, unless otherwise specified. The adjusted HR (95%CI) per Log UACR increase is: (1) kidney endpoint b : HR 1.59, 95%CI 1.52–1.65, p < 0.001; (2) kidney endpoint c : HR 1.55, 95%CI 1.48–1.63, p < 0.001; (3) doubling serum creatinine: HR 1.52, 95%CI 1.44–1.60, p < 0.001; (4) cardiovascular death or heart failure hospitalisation: HR 1.25, 95%CI 1.22–1.27, p < 0.001; (5) cardiovascular death: HR 1.21, 95%CI 1.17–1.24, p < 0.001; (6) heart failure hospitalisation: HR 1.27, 95%CI 1.24–1.31, p < 0.001; (7) cardiovascular death, stroke, or myocardial infarction: HR 1.17, 95%CI 1.14–1.19, p < 0.001; (8) all‐cause mortality: HR 1.20, 95%CI 1.17–1.23, p < 0.001.
Abbreviations: CV, cardiovascular; HF, heart failure; HR, hazard ratio with 95% confidence interval; IR, incidence rates per 100 person‐years; MI, myocardial infarction; Ref., referent category; UACR, urinary albumin‐to‐creatinine ratio.
First line = crude model; second line = adjusted model on age, sex, race, diabetes status, heart failure, baseline estimated glomerular filtration rate (eGFR), and study treatment.
Endpoint of sustained decline in eGFR of 40% or greater from baseline, end‐stage kidney disease (ESKD), or dialysis.
Endpoint of sustained decline in eGFR of 50% or greater from baseline, end‐stage kidney disease (ESKD), or dialysis.
FIGURE 1.
Risk of clinical outcomes by albuminuria levels. UACR, urinary albumin‐to‐creatinine ratio. Superscript 1: endpoint of sustained decline in eGFR of 40% or greater from baseline, end‐stage kidney disease (ESKD), or dialysis.
3.3. Treatment effect across albuminuria levels
Compared to placebo, SGLT2i reduced the risk of kidney events, HF hospitalisations, atherothrombotic events, cardiovascular and all‐cause mortality across albuminuria levels (Pinteraction >0.1 for all outcomes). The absolute risk reduction of kidney outcomes with SGLT2i was more pronounced among patients with UACR >300 mg/g who had a higher risk of events (Table 3 and Figure 2).
TABLE 3.
Treatment effect of SGLT2i versus placebo across albuminuria levels.
| UACR levels, N total = 26 750 | <30 mg/g | 30–300 mg/g | >300 mg/g | |||
|---|---|---|---|---|---|---|
| Treatment |
Pbo. n/6155 (%) IR100py |
SGLT2i n/7514 (%) IR100py |
Pbo. n/3098 (%) IR100py |
SGLT2i n/3806 (%) IR100py |
Pbo. n/2956 (%) IR100py |
SGLT2i n/3221 (%) IR100py |
| Kidney endpoint a |
107 (1.7) 0.8 |
85 (1.1) 0.5 |
87 (2.8) 1.4 |
80 (2.1) 1.0 |
320 (10.8) 4.7 |
248 (7.7) 3.2 |
| HR 0.63, 95%CI 0.48–0.84 | HR 0.75, 95%CI 0.55–1.01 | HR 0.69, 95%CI 0.58–0.81 | ||||
| aARR 0.3, 95%CI 0.3–0.4 | aARR 0.4, 95%CI 0.3–0.5 | aARR 1.5, 95%CI 1.3–1.6 | ||||
| NNTyr 333 | NNTyr 250 | NNTyr 67 | ||||
| Kidney endpoint b |
74 (1.2) 0.6 |
56 (0.8) 0.3 |
60 (1.9) 0.9 |
63 (1.7) 0.7 |
349 (11.8) 5.1 |
247 (7.7) 3.2 |
| HR 0.64, 95%CI 0.45–0.90 | HR 0.89, 95%CI 0.63–1.27 | HR 0.67, 95%CI 0.57–0.79 | ||||
| aARR 0.3, 95%CI 0.2–0.3 | aARR 0.2, 95%CI 0.1–0.3 | aARR 1.9, 95%CI 1.8–2.1 | ||||
| NNTyr 333 | NNTyr 500 | NNTyr 53 | ||||
| Doub. serum creatinine |
64 (1.0) 0.5 |
51 (0.7) 0.3 |
48 (1.6) 0.7 |
47 (1.2) 0.5 |
224 (7.6) 3.2 |
165 (5.1) 2.1 |
| HR 0.68, 95%CI 0.47–0.98 | HR 0.84, 95%CI 0.56–1.26 | HR 0.70, 95%CI 0.57–0.85 | ||||
| aARR 0.2, 95%CI 0.2–0.3 | aARR 0.2, 95%CI 0.1–0.3 | aARR 1.1, 95%CI 1.0–1.2 | ||||
| NNTyr 500 | NNTyr 500 | NNTyr 91 | ||||
| CV death or HF hosp. |
533 (8.7) 4.1 |
486 (6.5) 2.8 |
529 (17.1) 8.5 |
432 (11.4) 5.1 |
494 (16.7) 7.3 |
409 (12.7) 5.3 |
| HR 0.78, 95%CI 0.69–0.88 | HR 0.70, 95%CI 0.61–0.79 | HR 0.72, 95%CI 0.63–0.82 | ||||
| aARR 1.3, 95%CI 1.2–1.4 | ARR 3.4, 95%CI 3.1–3.6 | 2.0, 95%CI 1.9–2.1 | ||||
| NNTyr 77 | NNTyr 29 | NNTyr 50 | ||||
| Cardiovasc. death |
272 (4.4) 2.0 |
285 (3.8) 1.6 |
269 (8.7) 4.1 |
229 (6.0) 2.6 |
247 (8.4) 3.5 |
232 (7.2) 2.9 |
| HR 0.89, 95%CI 0.75–1.05 | HR 0.73, 95%CI 0.61–0.87 | HR 0.85, 95%CI 0.71–1.01 | ||||
| aARR 0.4, 95%CI 0.3–0.5 | aARR 1.5, 95%CI 1.3–1.6 | aARR 0.6, 95%CI 0.5–0.6 | ||||
| NNTyr 250 | NNTyr 67 | NNTyr 167 | ||||
| HF hospitalisation |
334 (5.4) 2.6 |
259 (3.5) 1.5 |
348 (11.2) 5.6 |
270 (7.1) 3.2 |
309 (10.5) 4.6 |
229 (7.1) 3.0 |
| HR 0.69, 95%CI 0.58–0.81 | HR 0.68, 95%CI 0.58–0.80 | HR 0.65, 95%CI 0.55–0.77 | ||||
| aARR 1.1, 95%CI 1.0–1.2 | aARR 2.4, 95%CI 2.2–2.6 | aARR 1.6, 95%CI 1.5–1.7 | ||||
| NNTyr 91 | NNTyr 42 | NNTyr 63 | ||||
| CV death, stroke, MI |
498 (8.1) 3.9 |
583 (7.8) 3.5 |
390 (12.6) 6.1 |
426 (11.2) 5.1 |
422 (14.3) 6.2 |
416 (12.9) 5.4 |
| HR 0.92, 95%CI 0.81–1.04 | HR 0.87, 95%CI 0.76–1.00 | HR 0.86, 95%CI 0.75–0.98 | ||||
| aARR 0.4, 95%CI 0.3–0.5 | aARR 1.0, 95%CI 0.9–1.1 | aARR 0.8, 95%CI 0.7–0.8 | ||||
| NNTyr 250 | NNTyr 100 | NNTyr 125 | ||||
| All‐cause death |
433 (7.0) 3.3 |
472 (6.3) 2.7 |
391 (12.6) 5.9 |
374 (9.8) 4.3 |
363 (12.3) 5.1 |
356 (11.1) 4.5 |
| HR 0.93, 95%CI 0.82–1.06 | HR 0.82, 95%CI 0.71–0.95 | HR 0.89, 95%CI 0.77–1.03 | ||||
| aARR 0.6, 95%CI 0.5–0.6 | aARR 1.6, 95%CI 1.4–1.8 | aARR 0.6, 95%CI 0.6–0.7 | ||||
| NNTyr 167 | NNTyr 63 | NNTyr 167 | ||||
Note: The p‐values for the interaction trend across UACR categories are: (1) kidney endpoint a : Pinteraction = 0.74; (2) kidney endpoint b : Pinteraction = 0.30; (3) doubling serum creatinine: Pinteraction = 0.67; (4) cardiovascular death or heart failure hospitalisation: Pinteraction = 0.41; (5) cardiovascular death: Pinteraction = 0.25; (6) heart failure hospitalisation: Pinteraction = 0.88; (7) cardiovascular death, stroke, or myocardial infarction: Pinteraction = 0.73; (8) all‐cause mortality: Pinteraction = 0.44.
Abbreviations: aARR, annualised absolute risk reduction; CV, cardiovascular; HF, heart failure; HR, hazard ratio with 95% confidence interval of SGLT2i versus Placebo; IR, incidence rate per 100 person‐years; MI, myocardial infarction; NNTyr, approximate round number‐needed‐to‐treat‐to‐benefit per year of treatment; Pbo., placebo; SGLT2i, sodium glucose co‐transported 2 inhibitor; UACR, urinary albumin‐to‐creatinine ratio.
Endpoint of sustained decline in eGFR of 40% or greater from baseline, end‐stage kidney disease (ESKD), or dialysis.
Endpoint of sustained decline in eGFR of 50% or greater from baseline, end‐stage kidney disease (ESKD), or dialysis.
FIGURE 2.
Treatment effect across the full spectrum of albuminuria. UACR, urinary albumin‐to‐creatinine ratio; HR, hazard ratio of SGLT2i versus placebo with the corresponding 95% confidence interval. Superscript 1: endpoint of sustained decline in eGFR of 40% or greater from baseline, end‐stage kidney disease (ESKD), or dialysis. Treatment‐by‐continuous UACR p‐value for interaction: (A) Pinteraction = 0.70; (B) Pinteraction = 0.46; (C) Pinteraction = 0.80.
The reduction of events with SGLT2i across UACR levels was not influenced by baseline eGFR (Pinteraction >0.1 for all outcomes) (Table S1).
3.4. Effect of treatment on albuminuria levels over time
Compared to placebo, SGLT2i reduced albuminuria levels over time in the overall population by 13% compared to the baseline level: gMratio 0.87, 95%CI 0.85–0.88, p < 0.001. The effect was most pronounced among patients with higher UACR levels: UACR <30 mg/g gMratio 0.99, 95%CI 0.98–1.01; UACR 30–300 mg/g gMratio 0.94, 95%CI 0.92–0.95; UACR >300 mg/g gMratio 0.85, 95%CI 0.83–0.87; Interaction p trend across UACR categories <0.001 (Figure 3).
FIGURE 3.
Effect of treatment on albuminuria levels over time. UACR, urinary albumin‐to‐creatinine ratio; SGLT2i, sodium glucose co‐transporter 2 inhibitor; Pbo., placebo. Compared to placebo, the effect of SGLT2i on albuminuria levels was: overall population (A) geometric means ratio (gMratio) 0.87, 95%CI 0.85–0.88, p < 0.001; UACR <30 mg/g (B) gMratio 0.99, 95%CI 0.98–1.01; UACR 30–300 mg/g (C) gMratio 0.94, 95%CI 0.92–0.95; UACR >300 mg/g (D) gMratio 0.85, 95%CI 0.83–0.87; Interaction p‐value for trend across UACR categories <0.001.
The odds of progression to a higher albuminuria category (i.e., any increase in albuminuria category) were reduced by 19% with SGLT2i at week 52: OR 0.81, 95%CI 0.77–0.85, p < 0.001. More specifically, the odds of progression from normoalbuminuria to micro‐ or macroalbuminuria were reduced by 13% at week 52: OR 0.87, 95%CI 0.83–0.92, p < 0.001, and the odds of progression from microalbuminuria to macroalbuminuria were reduced by 35% at week 52: OR 0.65, 95%CI 0.60–0.71, p < 0.001.
4. DISCUSSION
This study confirms that UACR is positively associated with a linear increase in the risk of cardiovascular and, particularly, kidney outcomes, with a 4 to 5‐fold higher risk of kidney events in patients with UACR >300 mg/g compared to those with UACR <30 mg/g. Compared to placebo, SGLT2i consistently reduced the risk of kidney and cardiovascular events across the full spectrum of albuminuria, without evidence of benefit attenuation even with albuminuria levels <30 mg/g. Such SGLT2i benefits across the full spectrum of UACR were independent of eGFR, whereby even patients without albuminuria and preserved kidney function benefited from SGLT2i therapy. Additionally, SGLT2i reduced UACR levels over time, with overall reductions of around 13% relative to baseline, mostly driven by UACR reduction among patients with baseline UACR >300 mg/g and by reducing the progression from micro‐ to macroalbuminuria.
Patients with T2D, obesity, hypertension, and/or low eGFR tend to have higher albuminuria levels, as also shown in the present study. 24 , 25 Albuminuria may also be increased by venous congestion in the context of HF; still, such congestive HF‐induced albuminuria increase is relatively modest compared to T2D with albuminuric CKD, although such conditions may coexist. 26 Albuminuria has been associated with systemic endothelial dysfunction, atherosclerotic cardiovascular disease, HF, and kidney failure. 27 , 28 , 29
SGLT2 and RAAS inhibitors, including MRAs, are well‐established therapies for reducing albuminuria and the progression of kidney disease in patients with albuminuric CKD. 2 , 11 , 30 Our study expands these findings by showing that the effects of SGLT2i on cardiovascular and kidney outcomes are independent of albuminuria levels, as the benefits were consistent across the full range of albuminuria and, in addition, not influenced by eGFR. Findings suggest that SGLT2i should be used regardless of albuminuria and eGFR, as even patients without albuminuria and normal kidney function benefit from SGLT2i both in terms of cardiovascular and kidney outcomes. In other words, the effects of SGLT2i are not mediated by albuminuria as patients without (or little) albuminuria reduction (e.g., those with UACR <300 mg/g), still experience marked benefit with SGLT2i therapy. These effects contrast with those observed with RAAS inhibitors and MRAs, whose kidney effects are uncertain among patients without albuminuria. 12 , 31
Prior analyses on the effect of SGLT2i on kidney outcomes among patients included in HF trials, who tend to have low albuminuria levels, showed heterogeneous results, without a consistent benefit of SGLT2i on kidney outcomes. 32 , 33 , 34 , 35 , 36 These heterogeneous findings are likely related to a lack of power to ascertain treatment effects on relatively infrequent kidney outcomes. Moreover, it is possible that patients with HF experience different degrees of congestion and “right sided” pressures that may influence kidney function. 37 , 38 In this regard, our analysis provides sufficient power to ascertain that the effect of SGLT2i on kidney and cardiovascular outcomes was consistent across the full range of UACR, including among patients with UACR <30 mg/g and, at least, as low as 5 mg/g without any “hint” of heterogeneity.
Some limitations should be acknowledged in this study. These are post hoc findings and these results should be interpreted with caution. Still, our study, with nearly 27 000 patients, is largely powered to assess various kidney endpoints. Additionally, most patients with macroalbuminuria came from the CREDENCE trial and the generalisability of findings to broader populations may be limited.
5. CONCLUSION
Higher albuminuria was associated with an increased risk of cardiovascular and kidney outcomes across the CKM spectrum. SGLT2i improved cardiovascular and kidney outcomes across the full range of albuminuria, including patients with low or without albuminuria.
AUTHOR CONTRIBUTIONS
J.P.F. performed the analyses and wrote the original version of the manuscript and its subsequent revisions. All other authors read, edited and approved the final version of the manuscript.
FUNDING INFORMATION
EMPEROR‐Reduced, EMPEROR‐Preserved, and EMPA‐REG OUTCOME were funded by the Boehringer Ingelheim and Eli Lilly; CANVAS‐R and CREDENCE were funded by Janssen Research and Development.
CONFLICT OF INTEREST STATEMENT
J.P.F. has received research support from Boehringer Ingelheim, Astra Zeneca, Novartis, Bayer, Bial, Amgen, and Salamandra. P.M. reports receiving speaker fees from Bial and Novartis. A.S. reports consulting/research support from Janssen, Bayer, Roche Diagnostics, AstraZeneca, Boehringer Ingelheim, Novartis, Servier and Novo Nordisk. Founder/equity in Area19, PercAssist, AeroCardia. S.D.A. has received grants and personal fees from CSL Vifor and Abbott Laboratories, and personal fees for consultancies, trial committee work and/or lectures from Actimed, Alleviant, Astra Zeneca, Bayer, Berlin Heals, Boehringer Ingelheim, Brahms, Cardiac Dimensions, Cardior, Cordio, Corvia, CVRx, Cytokinetics, Edwards, Impulse Dynamics, Lilly, Mankind Pharma, Novo Nordisk, Occlutech, Pfizer, Regeneron, Relaxera, Repairon, Scirent, Sensible Medical, Vectorious, Vivus, and V‐Wave. Named co‐inventor of two patent applications regarding MR‐proANP (DE 102007010834 and DE 102007022367), but he does not benefit personally from the related issued patents. J.B. reports consultancy from Abbott, Adaptyx, American Regent, Amgen, AskBio, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardiac Dimension, Cardior, CSL Vifor, CVRx, Cytokinetics, Daxor, Diastol, Edwards, Element Sciences, Faraday, Idorsia, Impulse Dynamics, Imbria, Innolife, Intellia, Inventiva, Levator, Lexicon, Eli Lilly, Mankind, Medtronic, Merck, New Amsterdam, Novartis, NovoNordisk, Pfizer, Pharmacosmos, Pharmain, Prolaio, Pulnovo, Regeneron, Renibus, Reprieve, Roche, Rycarma, Saillent, Salamandra, Salubris, SC Pharma, SQ Innovation, Secretome, Sequanna, Transmural, TekkunLev, Tenex, Tricog, Ultromic, Vera, Zoll. F.V.N. has received consulting or speaker fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi‐Sankyo, Novartis, and Ultragenyx. J.S.N. reports having received consulting and speaker fees from AstraZeneca, BIAL, Boehringer Ingelheim, Eli Lilly, and Novo Nordisk and speaker fees from Merck. M.P. has received research support from 89bio, Abbvie, Actavis, Altimmune, Alnylam, Amgen, Ardelyx, ARMGO, AstraZeneca, Attralus, Biopeutics, Boehringer Ingelheim, Caladrius, Casana, CSL Behring, Cytokinetics, Daiichi Sankyo, Imara, Lilly, Medtronic, Moderna, Novartis, Pharmacocosmos, Regeneron, Salamandra. G.F. reports lecture fees and/or advisory and/or trial committee membership by Bayer, Boehringer Ingelheim, Servier, Novartis, Impulse Dynamics, Vifor, Medtronic, Merck, Cardior, Novo Nordisc and research grants from the European Union.
Supporting information
Data S1. Supporting Information.
ACKNOWLEDGEMENTS
The present analysis was performed through the Vivli® (https://vivli.org/) platform with the number 00011001 for the EMPEROR‐Preserved, EMPEROR‐Reduced, and EMPA‐REG OUTCOME trials, with concomitant access from the YODA® (https://yoda.yale.edu/) platform with the project number 2025‐0024 for the CANVAS‐R and CREDENCE trials. A.S. is supported by a CIHR grant 203856. J.P.F. is the 2025 recipient of the Roth Visiting Professor in the McGill Department of Medicine, division of Cardiology. Neither Vivli® nor YODA® has contributed to, approved, or is in any way responsible for the contents of this publication. Open access publication funding provided by FCT (b‐on).
Ferreira JP, Marques P, Anker SD, et al. Effects of SGLT2 inhibitors across the spectrum of albuminuria in cardiovascular–kidney–metabolic conditions: A pooled analysis of randomised trials. Diabetes Obes Metab. 2026;28(2):1105‐1115. doi: 10.1111/dom.70289
DATA AVAILABILITY STATEMENT
The present analysis was performed through the Vivli® (https://vivli.org/) platform with the number 00011001 for the EMPEROR‐Preserved, EMPEROR‐Reduced and EMPA‐REG OUTCOME trials, with concomitant access from the YODA® (https://yoda.yale.edu/) platform with the project number 2025‐0024 for the CANVAS‐R and CREDENCE trials.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data S1. Supporting Information.
Data Availability Statement
The present analysis was performed through the Vivli® (https://vivli.org/) platform with the number 00011001 for the EMPEROR‐Preserved, EMPEROR‐Reduced and EMPA‐REG OUTCOME trials, with concomitant access from the YODA® (https://yoda.yale.edu/) platform with the project number 2025‐0024 for the CANVAS‐R and CREDENCE trials.