A comprehensive pooled analysis of four major randomized trials has reinforced the kidney safety profile of empagliflozin (Jardiance), demonstrating significant reductions in acute kidney injury risk even among patients predicted to experience acute eGFR dips upon treatment initiation.
The study, presented at the 62nd European Renal Association (ERA 2025) Congress, analyzed individual participant-level data from EMPA-REG OUTCOME, EMPEROR-Reduced, EMPEROR-Preserved, and EMPA-KIDNEY trials. The combined cohort of 23,340 participants had a mean eGFR of 59 mL/min/1.73 m² and median urinary albumin-to-creatinine ratio of 34 mg/g, spanning patients with type 2 diabetes, heart failure, and chronic kidney disease.
Consistent Kidney Protection Across Risk Groups
Investigators stratified participants by predicted risk of acute eGFR dip using multivariable modeling and assessed two primary outcomes: a ≥50% increase in serum creatinine compared with recent baseline and investigator-reported AKI using MedDRA criteria. Empagliflozin reduced the risk of large serum creatinine increases by 19% (HR, 0.81; 95% CI, 0.74 to 0.90) and AKI adverse events by 27% (HR, 0.73; 95% CI, 0.63 to 0.85).
"These effects were consistent across subgroups, including those stratified by predicted eGFR dip size (P for trend = .41 and .65, respectively) as well as baseline characteristics such as eGFR, NT-proBNP, and primary kidney disease," according to the study findings.
Primary investigator Natalie Staplin, PhD, a senior statistician at the University of Oxford's Clinical Trials Service Unit, emphasized the clinical significance of these results. "Based on the data so far, including our study, we feel reassured that the acute eGFR dip is a benign event," Staplin stated in an interview.
Predictors and Clinical Implications
Independent predictors of larger eGFR dips included older age, higher baseline eGFR and albuminuria, use of renin-angiotensin system inhibitors or diuretics, elevated systolic blood pressure, and lower hematocrit or body mass index. Despite initial dips, only a small proportion of patients discontinued therapy during follow-up, with similar rates across risk strata.
The analysis revealed that patients with the largest predicted dips were only slightly more likely to discontinue treatment, with overall discontinuation rates remaining very low at the visit immediately following the acute dip.
"Our interpretation is that routinely rechecking eGFR shortly after starting an SGLT2 inhibitor might not be necessary for every patient," Staplin explained. "If someone is starting multiple foundational therapies at once, you might expect a significant dip and want to monitor. But if you're starting just one of these agents, in most cases, the dip probably isn't something to worry about."
Heart Attack Patients Show Preserved Kidney Function
Complementing these findings, a secondary analysis of the EMPACT-MI trial published in Nature Cardiovascular Research demonstrated that empagliflozin preserves kidney function in heart attack patients. The study randomized 6,522 patients hospitalized with myocardial infarction to receive either empagliflozin or placebo, on average five days after the heart attack.
After two years of follow-up, researchers observed a significant difference in eGFR change between treatment groups, with the empagliflozin group maintaining stable kidney function while the placebo group experienced significant worsening. The difference in eGFR change between empagliflozin and placebo was 4.1 ml/min/1.73 m², indicating substantial kidney function preservation with active treatment.
Lead investigator Deepak L. Bhatt, MD, MPH, MBA, Director of Mount Sinai Fuster Heart Hospital, noted the clinical implications: "SGLT2 inhibitors are underused in clinical practice. These data provide reassurance of the safety of using this class of drugs when indicated—even in patients after a recent heart attack and if the kidney function is impaired."
Addressing Clinical Hesitation
The pooled analysis findings may help address current prescribing hesitation among clinicians concerned about acute eGFR dips. Staplin suggested that existing product label warnings about acute eGFR dips and AKI might be overstated based on this evidence.
"Right now, some of the product labels list acute eGFR dips and AKI as concerns, which could worry prescribers, especially those less familiar with SGLT2 inhibitors," Staplin observed. "Our findings suggest these concerns might be overstated. Based on this evidence, some of those warnings might not need to be on the label at all."
The research demonstrates that empagliflozin's kidney protective effects extend across diverse patient populations, including those with chronic kidney disease, diabetes, heart failure, and recent myocardial infarction, providing clinicians with robust evidence to support treatment decisions in these high-risk groups.
