Empagliflozin offers significant renoprotection across multiple patient subgroups

medwireNews: Sodium–glucose cotransporter (SGLT)2 inhibition with empagliflozin significantly reduces the risk for acute and chronic kidney outcomes in people with various treatment indications, regardless of the acute dip in estimated glomerular filtration rate (eGFR) soon after initiation, researchers report.

The benefits occurred irrespective of the reason for treatment and “support arguments for widespread early use of SGLT2 inhibitors to reduce the global burden of kidney disease, and simplification of current guidance on whom to treat,” write William Herrington (Nuffield Department of Population Health, Oxford, UK) and co-authors in The Lancet Diabetes & Endocrinology.

They add: “The findings also provide reassuring data for prescribers regarding kidney safety and acute eGFR dips, and should discourage routine remeasurement of eGFR after initiation in most individuals.”

The researchers explain that although SGLT2 inhibitors are recommended as a standard of care in individuals with chronic kidney disease (CKD) or heart failure (HF) irrespective of diabetes status, the effect of treatment on kidney outcomes is unclear in certain population subtypes. This includes people at risk for large acute eGFR dips on SGLT2 inhibitor initiation, and those at lower risk for CKD progression.

To investigate, Herrington and team carried out an individual-level meta-analysis on data for 23,340 participants (mean age 66 years, 67% men) in four large placebo-controlled trials of empagliflozin treatment. Among them were 7020 people with type 2 diabetes and previous atherosclerotic cardiovascular disease from EMPA-REG OUTCOME, 6609 people with CKD at risk for progression from EMPA-KIDNEY, and 9711 people with HF from the EMPEROR-Reduced and EMPEROR-Preserved trials.

The analysis revealed that, overall, individuals randomly assigned to receive empagliflozin had a significant 20% lower risk for acute kidney injury (AKI), when defined as a 50% or greater increase in serum creatinine in consecutive follow-up samples, than those given placebo.

Empagliflozin use also significantly reduced the risks for AKI adverse events, CKD progression (kidney failure or a sustained decrease in eGFR of at least 40% from baseline), and kidney failure by 27%, 30%, and 34%, respectively, compared with placebo.

Subgroup analyses showed that the benefits of empagliflozin were consistent irrespective of the predicted size of the acute dip in eGFR, measured as the percentage change during early follow-up (4 weeks–2 months), and regardless of diabetes status, HF status, primary cause of kidney disease, level of albuminuria, and other markers of severity for these diseases.

After the acute dip, empagliflozin slowed the chronic annual rate of eGFR decline by a significant 64% relative to placebo.

Of note, the slowing of chronic eGFR decline was greatest among participants with diabetes, at 74%, but also occurred in participants without diabetes with low albuminuria, where the rate of decline was slowed by 47% with empagliflozin versus placebo.

Participants given empagliflozin also had a significant 25% lower risk for the composite outcome of cardiovascular death or hospitalization for HF, and a 30% lower risk for HF hospitalization alone than those given placebo, with similar reductions seen across individuals grouped by predicted size of acute eGFR dip.

In an accompanying comment, Carmine Zoccali and Francesca Mallamaci, both from the Association for Hypertension, Nephrology, and Kidney Transplant in Great Metropolitan Hospital, Reggio Calabria, Italy, say that the study “consolidates the renoprotective effects of SGLT2 inhibition and addresses uncertainties that have persisted in clinical practice and research.”

They continue: “Herrington and colleagues provide robust evidence to support the early and broad use of SGLT2 inhibitors in CKD, irrespective of albuminuria or diabetes status. The demonstration that the acute eGFR dip […] does not attenuate the long-term kidney benefits or confer excess risk of AKI is particularly reassuring.”

They say that the data “should dispel lingering concerns among clinicians and patients and could prompt a re-evaluation of current guidance, which often recommends routine early eGFR monitoring after SGLT2 inhibitor initiation.”

In agreement with Harrington et al, Zoccali and Mallamaci believe that “[t]he data suggest that such monitoring might be unnecessary for most individuals, supporting a streamlined, population-based approach to SGLT2 inhibitor use.”

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Lancet Diabetes Endocrinol 2025; doi:10.1016/S2213-8587(25)00222-0
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