Patients treated with the SGLT2 inhibitor dapagliflozin prior to elective cardiac surgery had a significantly lower risk for postoperative acute kidney injury (AKI), according to results from a randomized trial. Furthermore, there was a low incidence of euglycemic diabetic ketoacidosis, which is a key concern with postoperative SGLT2 inhibitor use.

“To date, no therapies have been identified that reduce the incidence of AKI after cardiac surgery,” the authors wrote in the study, published in JAMA.

The results underscore that AKI “is common after cardiac surgery, consequential, and now potentially modifiable,” co-author Abraham H. Hulst, MD, PhD, of the Department of Anesthesiology at Amsterdam University Medical Center and the Amsterdam Cardiovascular Sciences Research Institute, both in Amsterdam, Netherlands, told Medscape Medical News.

The incidence of AKI after elective cardiac surgery has been estimated to range from 2% to 50%. AKI is associated with potentially serious comorbidities, including chronic kidney disease and mortality. Its causes are multifactorial and include kidney hypoperfusion, hypoxia, and inflammation.

Because effective preventive therapies for AKI have been lacking, interest has grown in SGLT2 inhibitors, which were developed to treat type 2 diabetes but have also demonstrated kidney-protective effects.

MERCURI-2 Design

To evaluate the role of SGLT2 inhibition in cardiac surgery, Hulst and colleagues conducted the MERCURI-2 (“Promoting Effective Renoprotection in Cardiac Surgery Patients by Inhibition of SGLT-2”) trial.

The double-blind trial enrolled 784 patients scheduled to undergo elective cardiac surgery at seven hospitals in Netherlands between June 2023 and January 2025. Patients were randomized 1:1 to receive either oral dapagliflozin 10 mg or placebo (392 patients in each group) once daily, beginning the day before surgery and continuing through the second postoperative day, for a total of four doses.

Exclusion criteria included type 1 diabetes, type 2 diabetes with a BMI below 25, treatment with multiple daily insulin doses, a history of diabetic ketoacidosis, or an estimated glomerular filtration rate (eGFR) below 20 mL/min/1.73 m².

Of the 778 patients who completed follow-up, the median age was 68; 76% were men, and 97% were White. The median BMI was 27, and the median eGFR was 80 mL/min/1.73 m². Overall, 12% had type 2 diabetes and 6% had heart failure.

AKI Risk Nearly Halved

The primary endpoint was AKI within 7 days of surgery, defined as an increase in serum creatinine level of at least 0.3 mg/dL (26.5 µmol/L) within 48 hours, an increase in creatinine of at least 1.5 fold within 7 days, or urine output below 0.5 mL/kg/h for 6-12 hours.

AKI occurred in 28% of patients who received dapagliflozin and 52% of those who received placebo, corresponding to a relative risk of 0.54 (P < .001) over a 7-day follow-up after surgery.

Most of the AKI cases were stage 1. Stage 2 or 3 AKI occurred in 19 patients in the dapagliflozin group and 50 patients in the placebo group.

After adjustment for sex in a multivariate analysis, dapagliflozin remained significantly associated with a lower incidence of AKI (odds ratio, 0.36; P < .001).

There were no significant between-group differences in secondary outcomes, including stage 3 AKI (0.8% with dapagliflozin vs 0.3% with placebo), length of hospital or ICU stay, mortality, major cardiac or kidney events, or quality of life at 30 days.

Atrial fibrillation occurred in 45% of patients in each group. Reoperation rates were also nearly identical, at 11% with dapagliflozin and 10% with placebo.

Hulst said the lack of difference in atrial fibrillation was somewhat surprising.

“Atrial fibrillation is multifactorial, and I would have expected a difference in a study that improved cardio-renal function to have an impact on such an outcome,” he said. “Further research should focus on longer-term renal outcomes.”

The authors acknowledged that the 52% incidence of AKI in the placebo group was relatively high. They attributed this, at least in part, to the inclusion of a urine output below 0.5 mL/kg/h for 6-12 hours as a criterion for the primary outcome.

Of those who developed AKI,48% in the placebo group and 21% in the dapagliflozin group met the primary outcome based on reduced urine output.

Ketoacidosis Was Rare

Only one patient, who was in the dapagliflozin group, developed ketoacidosis. 

That finding is notable because organizations including the American Diabetes Association, the UK Centre for Perioperative Care, and, until recently, the FDA have recommended withholding SGLT2 inhibitors for 3 days in advance of surgery to reduce the risk for euglycemic diabetic ketoacidosis.

Hulst said the results support reconsideration of those recommendations.

“Until now, the perioperative discussion about SGLT2 inhibitors was almost entirely a discussion of about one harm: euglycemic ketoacidosis,” he said. “The chronic benefits of the drug class were assumed not to matter over a few days around surgery.”

“But what MERCURI-2 shows is that the perioperative window is not neutral — the comparison is now between a common, consequential renal complication, AKI, and a rare metabolic one, euglycemic ketoacidosis.”

That being said, for patients taking an SGLT2 inhibitor for heart failure or chronic kidney disease without diabetes — a substantial proportion of users — “the risk that drives the entire withholding recommendation is close to negligible.”

Nevertheless, he cautioned against changing practice before additional supportive evidence becomes available.

“I wouldn’t yet tell anyone to start dapagliflozin before surgery outside a trial,” he said. “But for a patient already established on one, particularly without diabetes and particularly for heart failure, I’d want a positive reason to stop rather than a positive reason to continue.” 

Benefits May Outweigh Risks; Larger Studies Needed

In an accompanying editorial, Wolfgang C. Winkelmayer, MD, of Baylor College of Medicine in Houston, and Glenn M. Chertow, MD, of Stanford University School of Medicine in Stanford, California, agreed that the high AKI rate in the placebo group was a notable caveat.

They also cautioned that relative treatment effects in clinical trials that exceed 40% should be viewed “with a healthy dose of skepticism.”

However, the authors noted that the high event rate was likely related to the “meticulous collection of urine-output data.”

Regarding ketoacidosis, the editorialists wrote that “when balancing risks and benefits, the very low risk of euglycemic diabetic ketoacidosis does not appear to warrant withholding of a drug with the potential to significantly reduce the risk of postoperative AKI.”

“Further studies of AKI prevention by SGLT2 inhibitors will likely require larger sample sizes, particularly in populations with lower event rates or if the true treatment effect falls short of the 46% observed here,” they added.

Elif Ekinci, MBBS, PhD, head of the Department of Medicine at Melbourne Medical School, The University of Melbourne, in Melbourne, Australia, and director of the Australian Centre for Accelerating Diabetes Innovations, said the results were consistent with recent findings from her own team.

Their study found a reduced risk for postoperative AKI among patients with type 2 diabetes who were taking SGLT2 inhibitors before emergency surgery.

“These new findings are consistent with our recent observational study showing lower rates of postoperative acute kidney injury in people with type 2 diabetes taking SGLT2 inhibitors before surgery,” she told Medscape Medical News.

“If these findings are confirmed in other trials, this could become an important strategy for perioperative kidney protection down the track,” Ekinci noted. “Further research is needed to confirm whether these benefits translate into improved long-term clinical outcomes.”

Hulst reported receiving grants from the European Union Horizon 2020 Research and Innovation Program, the European Society of Anaesthesiology and Intensive Care/British Journal of Anaesthesia Charity, and the Netherlands Organisation for Health Research and Development outside the published study. The editorial authors’ disclosures were detailed in the published editorial. Ekinci reported advisory board and speaking relationships with Bayer, Eli Lilly, AstraZeneca, and Boehringer Ingelheim, with funds donated to Ekinci’s institution for diabetes research.