Four doses of dapagliflozin reduced acute kidney injury after elective cardiac surgery from 52% to 28%, suggesting potential kidney protection. However, the small, homogeneous trial conflicts with current guidance to stop SGLT2 inhibitors before surgery.
Acute kidney injury, or AKI, is a common complication of cardiac surgery. It can range from a mild, temporary decline in kidney function to severe injury requiring dialysis.
According to the JAMA randomized clinical trial, postoperative AKI affects approximately 2% to 50% of patients undergoing elective cardiac surgery, depending on the population and definition used.
Even relatively mild AKI has been associated with longer hospital stays and a greater risk of later chronic kidney disease and death. Despite improvements in surgical and intensive-care practices, no medicine has been established as a standard pharmacological strategy for preventing cardiac surgery-associated AKI.
Researchers therefore investigated whether dapagliflozin, a sodium-glucose cotransporter 2 or SGLT2 inhibitor, could protect the kidneys during the perioperative period.
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Four Doses Were Tested Around Elective Surgery
The multicentre, double-blind trial enrolled 784 adults undergoing elective cardiac surgery at seven hospitals in the Netherlands. None had previously been treated with an SGLT2 inhibitor.
Participants were randomly assigned to receive dapagliflozin or a matching placebo. Dapagliflozin was given at a dose of 10 mg once daily for four days:
- One dose on the day before surgery
- One dose on the day of surgery
- One dose on the first postoperative day
- One dose on the second postoperative day
Researchers then monitored participants for AKI during the first seven days after surgery.
The primary outcome used the full Kidney Disease: Improving Global Outcomes definition, which identifies AKI through changes in serum creatinine, reduced urine output or both. This detailed urine monitoring detected events that may have been missed in studies relying only on blood tests.
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Acute Kidney Injury Fell From 52% to 28%
AKI developed in 28% of patients assigned to dapagliflozin, compared with 52% of those receiving placebo.
This represented:
- A 46% relative reduction in risk
- A 24-percentage-point absolute reduction
- A statistically significant result favouring dapagliflozin
The difference was considerably larger than the 20% to 26% reductions in serious AKI reported in previous meta-analyses of longer-term SGLT2 inhibitor trials.
Although the result is striking, it should be understood within the trial’s specific setting. It demonstrates short-term protection among selected, stable adults undergoing elective cardiac surgery—not among all surgical patients or everyone at risk of AKI.(1✔ ✔Trusted Source
Dapagliflozin and Acute Kidney Injury Following Cardiac Surgery
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The Benefit Extended Beyond the Mildest Injuries
Most kidney injuries detected during the trial were classified as stage 1, the mildest AKI category. Many were identified through reduced urine output rather than a rise in serum creatinine.
Dapagliflozin reduced stage 1 AKI by an absolute 16 percentage points and stage 2 AKI by 8 percentage points.
Nineteen participants in the dapagliflozin group developed stage 2 or 3 AKI, compared with 50 in the placebo group. This suggests that the result was not limited entirely to small, temporary changes in urine output.
However, only four stage 3 events occurred across the trial. The study was therefore unable to determine whether dapagliflozin prevents the most severe form of AKI or reduces the need for dialysis.
Why Dapagliflozin Could Protect the Kidneys
SGLT2 inhibitors were initially developed to lower blood glucose in people with type 2 diabetes. Their clinical role has since expanded because they can slow chronic kidney disease and reduce heart-failure complications, including in many patients without diabetes.
The precise mechanism behind the perioperative benefit remains uncertain. SGLT2 inhibitors affect kidney blood flow, sodium handling, energy use and pressure within the filtering units of the kidneys.
In a subgroup of trial participants, those receiving dapagliflozin required numerically less intravenous fluid and lower doses of norepinephrine despite producing more urine. This suggests that the higher urine output was not simply caused by excessive fluid administration.
A related pilot study also identified lower postoperative concentrations of kidney-stress biomarkers among patients receiving SGLT2 inhibitors. These exploratory findings support a possible protective effect but do not establish exactly how dapagliflozin prevented AKI.(1✔ ✔Trusted Source
Dapagliflozin and Acute Kidney Injury Following Cardiac Surgery
Safety Remains an Important Concern
Overall adverse-event rates were similar between the dapagliflozin and placebo groups. Atrial fibrillation affected 45% of participants in both groups, while reoperation rates were also comparable.
However, one patient receiving dapagliflozin developed ketoacidosis. Although this represented only 0.26% of the treatment group, the trial was too small to exclude uncommon complications such as euglycaemic diabetic ketoacidosis.
The safety findings are encouraging, but they do not establish that perioperative dapagliflozin is appropriate for every patient.
Findings Challenge Current Surgical Guidance
Current American Diabetes Association guidance recommends withholding SGLT2 inhibitors for three to four days before elective surgery because fasting, dehydration and surgical stress can increase ketoacidosis risk.
This trial tested the opposite approach: dapagliflozin was started one day before surgery and continued for two days afterwards.
The substantial reduction in AKI raises the possibility that kidney protection may outweigh the low ketoacidosis risk in selected patients. Nevertheless, one trial is insufficient to change established perioperative recommendations.
Results Apply to Selected Patients
The trial involved a narrowly defined population undergoing planned cardiac surgery. Participants were a median age of 68, 76% were male and approximately 97% were White, while most had normal or near-normal kidney function.
Patients already taking SGLT2 inhibitors and those undergoing urgent surgery were excluded, as were people with type 1 diabetes, previous ketoacidosis or severely reduced kidney function.
These exclusions limit how confidently the results can be applied to more diverse or medically complex patients.
Larger Trials Must Confirm the Benefit
The reported 46% relative reduction in AKI is unusually large for a trial involving fewer than 800 participants. Treatment effects of this magnitude sometimes become smaller when investigated in larger and more varied populations.
The placebo group’s high AKI rate of 52% may partly reflect detailed urine-output monitoring, which detected many mild stage 1 events.
However, dapagliflozin also reduced stage 2 AKI, suggesting that the benefit was not confined to minor changes in urine production. Larger trials are needed to determine the likely effect in routine care.
Long-Term Kidney Effects Are Unknown
Researchers assessed AKI only during the first seven days after surgery.
The study was not designed to determine whether dapagliflozin reduced dialysis, shortened hospital stays, prevented chronic kidney disease or improved survival.
Future research should examine severe and creatinine-defined AKI, longer-term kidney function and outcomes among patients already using SGLT2 inhibitors. (1✔ ✔Trusted Source
Dapagliflozin and Acute Kidney Injury Following Cardiac Surgery
More evidence is also needed in people with diabetes, advanced kidney disease, urgent surgical needs and more diverse racial and ethnic backgrounds.
Do Not Change Medicines Without Advice
The findings do not mean that patients should start dapagliflozin before an operation or continue an existing SGLT2 inhibitor against medical advice. Perioperative decisions must consider kidney function, diabetes control, insulin use, hydration, fasting and ketoacidosis risk.
Anyone taking an SGLT2 inhibitor should inform their surgeon, anaesthesiologist and prescribing clinician before a planned procedure.
Medicines should be stopped, continued or restarted only through a coordinated clinical plan, and patients should not attempt to reproduce the trial’s four-dose regimen themselves.
Promising but Not Yet Standard Care
The trial provides compelling randomized evidence that short-term dapagliflozin may protect the kidneys during elective cardiac surgery.
Reducing AKI from 52% to 28%, including fewer stage 2 injuries, makes the strategy potentially practice-changing.
However, the evidence comes from one relatively small Dutch trial involving carefully selected, predominantly White patients. Confirmation in larger and more diverse studies along with closer evaluation of ketoacidosis, dialysis and long-term kidney outcomes will determine whether the approach becomes standard care.
References:
- Dapagliflozin and Acute Kidney Injury Following Cardiac Surgery- (https://jamanetwork.com/journals/jama/article-abstract/2852324)
Source-Medindia