Highlight
• In an individual participant-level meta-analysis of 23,340 participants from four large randomized trials (EMPA-REG OUTCOME, EMPEROR-Reduced, EMPEROR-Preserved, EMPA-KIDNEY), empagliflozin reduced acute kidney injury markers and adverse events, slowed chronic eGFR decline, and lowered progression to kidney failure.
• These kidney benefits were consistent across subgroups defined by predicted size of the early eGFR dip, diabetes status, heart failure status, baseline kidney function, albuminuria level, and primary kidney disease.
• Empagliflozin’s renal protection coexisted with an initial hemodynamic eGFR dip in some patients, but the dip did not predict loss of long-term benefit; eGFR dips should not generally preclude continued therapy.
Background
Chronic kidney disease (CKD) is a major global health burden and a leading cause of morbidity and mortality. Sodium-glucose co-transporter-2 (SGLT2) inhibitors have emerged as a therapy that slows CKD progression and reduces cardiovascular events in diverse populations with and without diabetes. However, initiation of SGLT2 inhibitors often causes an early decline in estimated glomerular filtration rate (eGFR) that can raise clinician concern about potential acute kidney injury (AKI) or loss of long-term renal benefit. This meta-analysis by Herrington et al. in Lancet Diabetes & Endocrinology (2025) pooled individual participant data to examine empagliflozin’s effects on a broad range of acute and chronic kidney outcomes and to test whether predicted acute eGFR dip magnitude modifies treatment benefit.
Study design
This individual participant-level meta-analysis included 23,340 randomized participants from four large placebo-controlled trials of empagliflozin: EMPA-REG OUTCOME, EMPEROR-Reduced, EMPEROR-Preserved, and EMPA-KIDNEY. The investigators obtained participant-level data directly from the sponsor and harmonized definitions across trials to evaluate conventional and exploratory kidney endpoints. Key endpoints included:
- Markers of acute kidney injury: a prespecified biochemical marker defined as a ≥50% increase in serum creatinine in consecutive follow-up samples, and relevant AKI adverse event reports.
- Chronic kidney outcomes: categorical CKD progression endpoints (often defined by sustained eGFR reductions or initiation of kidney replacement therapy), kidney failure (long-term dialysis, transplantation, or sustained eGFR below a threshold), and slopes of eGFR decline over time.
- Exploratory off-treatment and dip-free slope analyses using randomization and off-treatment eGFR values in a subset of participants (n=10,630).
The investigators also assessed heterogeneity of treatment effects across subgroups defined by predicted magnitude of the acute eGFR dip at initiation and by clinical characteristics including diabetes status, heart failure status, baseline eGFR, albuminuria, and primary kidney disease cause.
Key findings
This meta-analysis reports consistent and clinically important renal benefits with empagliflozin across a range of endpoints:
- Reduction in biochemical marker of AKI: Empagliflozin vs placebo produced a 20% relative risk reduction in a marker defined as a ≥50% consecutive increase in serum creatinine (hazard ratio [HR] 0.80; 95% CI 0.72–0.88; 1,573 events).
- Fewer AKI adverse events: AKI adverse events were reduced by 27% (HR 0.73; 95% CI 0.63–0.85; 694 events).
- Less categorical CKD progression: Empagliflozin lowered risk of categorical CKD progression by 30% (HR 0.70; 95% CI 0.63–0.78; 1,403 events).
- Reduced kidney failure: Risk of kidney failure was reduced by 34% (HR 0.66; 95% CI 0.55–0.79; 490 events).
- Slowed eGFR decline: Empagliflozin slowed the chronic annual rate of eGFR decline by approximately 64% (95% CI 59–69), and in a post-hoc off-treatment dip-free slope analysis in a subset (n=10,630), the benefit estimate was similar (64%; 95% CI 54–73).
Importantly, these benefits were consistent irrespective of the predicted size of the acute eGFR dip, diabetes status, heart failure status, baseline level of kidney function, or albuminuria level. In other words, even participants predicted to experience larger initial eGFR dips derived similar longer-term renal protection compared with those predicted to have smaller dips.
Clinical significance and interpretation
The magnitude of relative risk reductions for hard kidney outcomes (kidney failure and categorical progression) is clinically meaningful and reinforces SGLT2 inhibition as renoprotective therapy across patient groups. The concordant findings for both acute (reductions in AKI markers and events) and chronic outcomes (slower eGFR decline and less progression) address two common clinician concerns: that SGLT2 inhibitors could precipitate AKI via volume depletion or hemodynamic effects, and that an early eGFR dip might foreshadow worse long-term renal trajectory. Instead, the data show fewer AKI events and sustained slowing of CKD progression with empagliflozin.
Mechanistic insights
The renal effects of SGLT2 inhibitors are biologically plausible through multiple mechanisms. By inhibiting proximal tubular glucose and sodium reabsorption, empagliflozin increases distal sodium delivery, restores tubuloglomerular feedback, and reduces intraglomerular pressure. This hemodynamic change can cause an early reversible reduction in eGFR (an expected pharmacodynamic effect). In the longer term, reduced glomerular hyperfiltration, attenuated intrarenal inflammation, favorable effects on interstitial hypoxia, reduced albuminuria, and improvements in blood pressure and metabolic milieu likely contribute to slowed structural progression. The observation of fewer AKI events may be attributable to improved renal oxygenation and decreased congestion (particularly in heart failure), along with favorable effects on systemic hemodynamics.
Expert commentary and limitations
Strengths of this analysis include the large pooled sample, access to individual participant data allowing harmonized endpoint definitions, and the ability to examine treatment effect modification across clinically relevant subgroups. The finding that predicted acute eGFR dip magnitude did not modify benefit addresses an important practical question for clinicians starting empagliflozin.
However, limitations deserve emphasis. First, despite individual-level data, the analysis pooled trials with different inclusion criteria and durations; residual heterogeneity in patient management or follow-up could influence some estimates. Second, the definition of biochemical AKI (≥50% creatinine rise) captures severe kidney function changes but may miss clinically relevant but smaller creatinine fluctuations; the trials’ adverse event reporting systems also vary. Third, the off-treatment dip-free slope analysis was available in a subset only, which may limit generalizability. Fourth, participants in randomized trials are selected and monitored more closely than many real-world patients; rare safety signals or challenges with polypharmacy and frailty may be underrepresented. Lastly, the analysis does not provide granular guidance on managing large early eGFR dips in specific clinical contexts (for example, severe volume depletion, concomitant nephrotoxins, or rapidly progressive glomerulonephritis). Clinical judgment remains necessary.
How to apply these findings in practice
- Anticipate an early hemodynamic eGFR dip in some patients after starting empagliflozin (typically modest and occurring within weeks). This dip does not predict lack of long-term benefit and, unless there are other clinical concerns (severe volume depletion, hyperkalemia, or rapidly progressive renal disease), should not automatically lead to drug discontinuation.
- Monitor renal function after initiation per local practice and patient risk (e.g., baseline eGFR, concomitant RAAS blockade, diuretic therapy, or intercurrent illness). Typical guidance is to check creatinine and potassium within 1–2 weeks in higher-risk patients.
- Evaluate reversible contributors if a large eGFR decline occurs (volume status, medication changes such as NSAIDs or iodinated contrast, sepsis). If the patient is clinically stable and the decline appears consistent with an expected hemodynamic effect, continuation with close monitoring is reasonable because long-term renal outcomes are improved.
- Consider SGLT2 inhibition across a wide range of patients with CKD or at risk of progression — including those without diabetes or with low albuminuria — recognizing benefits on both renal and cardiovascular outcomes.
Conclusion
This robust individual participant-level meta-analysis demonstrates that empagliflozin reduces the risk of acute kidney injury markers and events, slows chronic eGFR decline, decreases progression to kidney failure, and confers renal protection across diverse patient subgroups. Importantly, the magnitude of an early eGFR dip does not identify patients who lack benefit. These findings strengthen the evidence base supporting the use of SGLT2 inhibitors as renoprotective therapy across a broad CKD spectrum, while reinforcing prudent clinical monitoring when initiating therapy.
Funding and clinicaltrials.gov
The meta-analysis reports funding: None. The pooled trials (EMPA-REG OUTCOME, EMPEROR-Reduced, EMPEROR-Preserved, and EMPA-KIDNEY) were previously registered and reported; readers should consult individual trial registrations and publications for trial-specific funding and registration details.
References
Herrington WG, Che ZJ, Sardell R, et al. Effects of empagliflozin on conventional and exploratory acute and chronic kidney outcomes: an individual participant-level meta-analysis. Lancet Diabetes Endocrinol. 2025 Dec;13(12):1003-1014. doi: 10.1016/S2213-8587(25)00222-0. PMID: 41082889.
Additional relevant trial programs and background literature include EMPA-KIDNEY, EMPA-REG OUTCOME, EMPEROR-Reduced, EMPEROR-Preserved, and prior SGLT2 inhibitor CKD trials and meta-analyses (readers should refer to primary trial publications and guideline documents for further detail).
Thumbnail prompt
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