Pooled SGLT2i Data Reaffirm Empagliflozin Safety, Even With Acute eGFR Dips

A new pooled analysis of four major randomized trials confirms that empagliflozin (Jardiance) significantly reduces the risk of acute kidney injury (AKI), regardless of the predicted size of acute eGFR dip at treatment initiation or baseline markers of disease severity.

Presented at the 62nd European Renal Association (ERA 2025) Congress, the study leveraged individual participant-level data from EMPA-REG OUTCOME, EMPEROR-Reduced, EMPEROR-Preserved, and EMPA-KIDNEY trials spanning patients with type 2 diabetes, heart failure, and chronic kidney disease. Across the combined cohort of 23,340 participants, the mean eGFR was 59 mL/min/1.73 m² and the median urinary albumin-to-creatinine ratio was 34 mg/g.

Investigators stratified participants by predicted risk of an acute eGFR dip using multivariable modeling. Two outcomes were assessed: (1) a ≥50% increase in serum creatinine compared with recent baseline and (2) investigator-reported AKI using MedDRA criteria. Empagliflozin reduced the risk of a ≥50% increase in serum creatinine by 19% (HR, 0.81; 95% CI, 0.74 to 0.90) and the risk of 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.

Independent predictors of a larger eGFR dip 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 proportion of patients discontinued therapy during follow-up, with similar rates across risk strata, according to the ERA 2025 data.

In an interview, primary investigator Natalie Staplin, PhD, a senior statistician within the Renal Studies Group at the Clinical Trials Service Unit and Epidemiological Studies Unit at the Nuffield Department of Health at University of Oxford, emphasized that these findings reinforce the safety of empagliflozin in at-risk populations. To explore more on how these findings inform real-world treatment decisions, check out our full interview with Staplin from ERA 2025 below.

Q&A with Natalie Staplin, PhD, on eGFR Dip Data from ERA 2025

HCPLive: Can you offer some historic context on the subject and explain why you wanted to examine this so closely?

Natalie Staplin, PhD: I've worked directly on some of the large trials of SGLT2 inhibitors, particularly the EMPEROR-Kidney trial. My specialty is kidney diseases, as you might guess from attending ERA, and the acute eGFR dip is a question that comes up a lot when we're discussing these studies.

People are often concerned, especially when there's a large dip in eGFR, about whether that might reduce the beneficial effect on outcomes, or even potentially cause harm. So, based on those questions, we gathered as much individual participant data as we could to try to answer it.

It’s not an easy question to address because you need to ensure the analyses are properly randomized. Much of the existing literature has looked at patients who experienced a certain dip in eGFR and then examined outcomes, but without comparing that within a randomized treatment framework. That’s why we set out to do this study.

HCPLive: What were the primary findings, and how does this add to our understanding of the effects of SGLT2 inhibitor use?

Natalie Staplin, PhD: Our main findings came from a meta-analysis where we looked at two key kidney-related outcomes. The first was a 50% or greater increase in serum creatinine across consecutive samples. The second was AKI adverse events, as defined by the MedDRA (Medical Dictionary for Regulatory Activities) preferred terms.

We found that empagliflozin reduced the risk of those large serum creatinine increases by 20%, and reduced AKI adverse events by 27%. These findings held across a broad patient population, including people with chronic kidney disease, diabetes, and heart failure.

A unique part of our study was how we handled the eGFR dip. We developed a prediction model for the size of the acute eGFR dip using data from the empagliflozin arms of four trials. Because the model was based only on baseline characteristics, we could apply it to all participants in both the placebo and treatment arms.

When we stratified participants by the predicted magnitude of eGFR dip and looked at treatment effects across those groups, we saw no evidence of effect modification. The benefits of empagliflozin were consistent across all levels of predicted dip.

To address concerns about AKI occurring around the time of the eGFR dip, we also looked at the timing of those events. There was no indication of increased early AKI risk.

HCPLive: Are you comfortable now concluding on whether these dips are benign? Has your interpretation changed over time?

Natalie Staplin, PhD: That’s a good question, and it actually ties into one of the conclusions I’ll be highlighting in my talk next week. Based on the data so far, including our study, we feel reassured that the acute eGFR dip is a benign event.

We’ve also seen in the data—which will be published soon—that these dips tend to rebound after treatment is stopped. Along with the additional analyses we did on the risks associated with the dip, all of this supports the view that it’s a benign phenomenon.

HCPLive: Was there anything else you wanted to add about the study?

Natalie Staplin, PhD: Yes, one other aspect we looked at was whether the size of the acute dip predicted treatment adherence. We had expected that people with large dips might be more likely to discontinue treatment, but in fact, those with the largest dips were only slightly more likely to stop therapy.

Overall, the discontinuation rate at the visit just after the acute dip was very low. That was reassuring and suggests most patients were kept on the drug.

Our interpretation is that routinely rechecking eGFR shortly after starting an SGLT2 inhibitor might not be necessary for every patient. 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.

HCPLive: How much more confident do you think this data should make clinicians regarding the potential of an eGFR dip?

Natalie Staplin, PhD: I think this data could really help. 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—though that group is likely shrinking.

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. That could help ease some of the hesitation around prescribing these drugs.