The MERCURI-2 (Promoting EffectiveRenoprotection in Cardiac Surgery Patients by Inhibition of SGLT-2) trial investigated whether a short perioperative course of dapagliflozin could prevent acute kidney injury (AKI) after elective cardiac surgery. AKI occurs in approximately 2% to 50% of patients after cardiac operations and is associated with subsequent chronic kidney disease and increased mortality. Its causes are multifactorial, including renal hypoperfusion and hypoxia, ischaemia–reperfusion injury, oxidative stress and inflammation.
No medication had previously been established to prevent postoperative AKI. Sodium–glucose cotransporter 2 (SGLT2) inhibitors, originally developed for type 2 diabetes, have demonstrated kidney-protective effects in chronic disease and may reduce AKI through lower glomerular pressure and workload, preserved renal perfusion, reduced hypoxia, and anti-inflammatory and haemodynamic effects. The trial therefore tested whether dapagliflozin, started one day before surgery, would reduce AKI during the first seven postoperative days.
MERCURI-2 was an investigator-initiated, multicentre, double-blind, placebo-controlled superiority trial conducted at seven hospitals in the Netherlands. Adults scheduled for elective cardiac surgery were eligible. Important exclusions included type 1 diabetes, certain insulin-treated patients with type 2 diabetes and low body mass index, an estimated glomerular filtration rate below 20 mL/min/1.73 m², previous diabetic ketoacidosis, low systolic blood pressure, current SGLT2 inhibitor use, allergy to this drug class, pregnancy and breastfeeding. Participants were randomised equally to dapagliflozin or placebo, with stratification by sex, type 2 diabetes and study site.
Participants assigned to dapagliflozin received 10 mg orally once daily for four doses: the afternoon or evening before surgery, the morning of surgery, and the first and second postoperative days. Matching placebo was administered identically to maintain blinding. The primary outcome was AKI within seven days, defined using Kidney Disease: Improving Global Outcomes criteria: a serum creatinine rise of at least 0.3 mg/dL within 48 hours, a rise to at least 1.5 times baseline within seven days, or urine output below 0.5 mL/kg/hour for 6 to 12 hours. Creatinine was measured daily while patients remained in hospital, and hourly urine output was recorded while a urinary catheter was present.
Secondary outcomes included severe stage 3 AKI, change in estimated glomerular filtration rate, new atrial fibrillation, intensive care and hospital length of stay, major adverse cardiac and kidney events at 30 days, disability, quality of life, and days alive and outside hospital. Safety outcomes included genital fungal infection, ketoacidosis and hypoglycaemia. Because numerous secondary outcomes were tested without multiplicity adjustment, the authors considered them exploratory.
Between June 2023 and January 2025, 2,551 patients were screened, 800 consented and 784 were randomised, with 392 allocated to each group. Six did not undergo surgery, but all 784 were included in the primary analysis. Participants had a median age of 68 years; 76% were male and 97% were White. Median body mass index was 27, median baseline estimated glomerular filtration rate was 80 mL/min/1.73 m², 12% had type 2 diabetes and 6% had heart failure. Baseline and operative characteristics were similar between groups. Adherence was high: 88% of dapagliflozin recipients and 87% of placebo recipients took all four doses.
Dapagliflozin substantially reduced the primary outcome. AKI occurred in 111 of 392 participants in the dapagliflozin group, or 28%, compared with 205 of 392, or 52%, in the placebo group. This represented an absolute risk reduction of 23.98 percentage points and a relative risk of 0.54, with a 95% confidence interval of 0.45 to 0.65 and P<.001. Adjustment for sex produced a similar result, and there was no evidence that treatment effect differed between males and females. The per-protocol analysis also supported the main finding, with AKI occurring in 27% of fully adherent dapagliflozin recipients and 51% of fully adherent placebo recipients.
Post hoc analyses suggested that the reduction mainly involved stage 1 and stage 2 AKI. Stage 1 occurred in 23% of the dapagliflozin group versus 40% of the placebo group, while stage 2 occurred in 4% versus 13%. Stage 3 AKI was rare and did not differ significantly. Importantly, when AKI was defined only by creatinine criteria, rates were similar, at 14% and 15%. By contrast, when defined only by low urine output, AKI occurred in 21% with dapagliflozin and 48% with placebo. This indicates that the primary benefit was largely driven by prevention of postoperative oliguria rather than differences in creatinine-defined injury.
No significant improvements were found in secondary clinical outcomes, including new atrial fibrillation, major adverse cardiac or kidney events, intensive care or hospital stay, days at home, disability or quality of life. Adverse events were broadly similar. Atrial fibrillation occurred in 45% of both groups, and reoperation in 11% versus 10%. One participant receiving dapagliflozin experienced each of genital fungal infection, ketoacidosis and hypoglycaemia.
The authors concluded that four doses of dapagliflozin, beginning the day before elective cardiac surgery, reduced seven-day postoperative AKI.
Source: JAMA
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