Are the sodium-glucose cotransporter-2 (SGLT2) inhibitors effective for reducing contrast-associated acute kidney injury?

Introduction
Intravenous administration of iodinated contrast has been associated with acute kidney injury (AKI). Acute kidney injury following contrast is often most accurately described as contrast-associated AKI (CA-AKI) because the specific cause of the injury is unknown; however, in some cases, when contrast is deemed the most likely cause of the injury, the term contrast-induced AKI (CI-AKI also formerly known as contrast-induced nephropathy) may be appropriate.1 The prevalence of CI-AKI (≤2%) is believed to be a small part of overall CA-AKI (15%).2 Although many definitions of CI-AKI have been published, the Kidney Disease Improving Global Outcomes criteria consider CI-AKI to be any of the following:3

  • Absolute serum creatinine (SCr) increase ≥0.3 mg/dL within 48 hours.
  • An increase in SCr ≥1.5-times baseline which is known to have occurred within the prior 7 days.
  • Urine output reduced to <0.5 mL/kg/hour for 6 hours.

Despite its relatively rare occurrence, prevention of CI-AKI is an ongoing area of study. Patients at increased risk of CI-AKI include those with a history of kidney disease, those with diabetes, and those receiving metformin-containing medications.1 Many preventive studies have focused on these patient populations, and 2020 guidelines from the American College of Radiology and National Kidney Foundation recommend prophylaxis in patients who have AKI or an estimated glomerular filtration rate (eGFR) less than 30 mL/min/1.73 m2 who are not undergoing maintenance dialysis.4 The guidelines consider volume expansion with normal saline to be the most appropriate prophylactic method and do not recommend bicarbonate or N-acetylcysteine as prophylaxis.

There has been recent interest in the use of the sodium-glucose cotransporter-2 (SGLT2) inhibitors as CI-AKI prophylactic agents based on their beneficial effects in patients with chronic kidney disease (CKD). The relevant literature is reviewed below.5

SGLT2 inhibitors in CI-AKI
Mechanistically, SGLT2 inhibitors are known to have renal protective effects through multiple pathways including lowered hyperfiltration and tubular reabsorption resulting in reduced kidney workload, oxygen consumption, and renal ischemia.5,6 Through their glucose lowering effects, SGLT2 inhibitors also lower inflammation and renal hypertrophy. The evidence evaluating the SGLT2 inhibitors in patients at risk for CI-AKI is limited to one randomized controlled trial (RCT), several observational studies, and systematic reviews/meta-analyses of these studies.

Systematic reviews/meta-analyses
Meregildo-Rodriguez et al identified 7 trials in 3,022 patients with diabetes treated with SGLT2 inhibitors undergoing coronary angiography or percutaneous coronary intervention (PCI).7 Ultimately, 4 observational studies including 2,572 patients were included in the meta-analysis. Notably, the RCT was excluded from meta-analysis due to extreme values contributing to high heterogeneity. Results of the meta-analysis found a significant reduction in CI-AKI amongst patients receiving SGLT2 inhibitors compared with those not receiving these agents (relative risk, 0.37; 95% confidence interval [CI], 0.24 to 0.58). The meta-analysis is limited by the various definitions of CA-AKI and the observational nature of the included studies.

A 2024 meta-analysis by Basutkar et al also found reduced CI-AKI in patients with type 2 diabetes undoing PCI.8 The study included the single RCT (summarized below) and 3 observational studies. Seventy-two hours after PCI, SCr levels were lower among patients receiving SGLT2 inhibitors (mean difference, -14.40 µmol/L; 95% CI, -28.57 to -0.22; p=0.05). Pooled data from all 4 studies indicated the risk of CI-AKI was also reduced with SGLT2 inhibitor use (risk ratio, 0.46; 95% CI, 0.32 to 0.67; p<0.0001). The risk of hemodialysis was similar among SGLT2 inhibitor users and nonusers (risk ratio, 0.88; 95% CI, 0.19 to 4.07; p=0.87).

SAFE-PCI
The SAFE-PCI trial was a prospective, open-label, single-center, randomized trial in 42 patients with diabetes undergoing elective PCI.9 Patients were randomized to empagliflozin 25 mg daily at least 15 days prior to PCI or placebo. The authors used Neutrophil Gelatinase-associated Lipocalin (NGAL) as a biomarker of AKI, and this, along with SCr, were the primary outcomes. Mean NGAL levels 6 hours post-procedure were similar between groups (199 ng/dL with empagliflozin and 150 ng/dL with control; p=0.249). At 48 hours post-PCI, SCr levels were also similar between groups (results reported graphically; p=0.065). The incidence of CI-AKI occurred in 3 patients in the SGLT2 inhibitor group (13.6%) compared with 2 patients in the control group (10%; p=0.71); however, the trial was underpowered to detect differences in clinical outcomes.

Observational studies
Numerous observational studies have evaluated the potential efficacy of SGLT2 inhibitors in reducing CI-AKI. The majority of studies have been conducted in patients with diabetes, but diabetes was not a requirement for all studies. A summary of trials published subsequent to the above meta-analyses is provided in the Table.

Table. Recent observational studies evaluating SGLT2 inhibitors for CI- or CA-AKI.10-13
Study design and durationSubjectsInterventionsResultsConclusions
Nardi 202410

Single-center, retrospective

Median follow-up: 13.6 months with SGLT2 inhibitors and 49.9 months in the controls		N=265 patients with HF undergoing contrast for an invasive procedure (diagnosis of diabetes was not required)n=86 patients receiving SGLT2 inhibitors

n=179 controls (no SGLT2 inhibitor)		CI-AKI during hospitalization was lower with SGLT2 inhibitors vs controls (9.3% vs 26.7%; p=0.016).SGLT2 inhibitors may be renal protective for patients with HF undergoing invasive procedures requiring contrast.
Çabuk 202411

Single-center, cross-sectional		N=345 patients with type 2 diabetes undergoing coronary angiographyn=133 patients receiving SGLT2 inhibitors

n=212 controls (no SGLT2 inhibitor)		CA-AKI was lower in patients receiving SGLT2 inhibitors (26.4% vs 9%; p<0.001).

Hospital stays were also shorter in patients receiving SGLT2 inhibitors (2.54 days vs 3.25 days; p=0.001).		CA-AKI was lower in patients with diabetes receiving SGLT2 inhibitors compared to nonusers.
Kültürsay 202412

Single-center, retrospective		N=295 patients with diabetes and STEMI undergoing primary PCIn=130 patients receiving SGLT2 inhibitors

n=165 controls (no SGLT2 inhibitor)		CI-AKI risk was lower with SGLT2 inhibitor use (OR, 0.86; 95% CI, 0.76 to 0.98; p=0.028).

Contrast volume, albumin, SCr, and ejection fraction were also independent predictors of CI-AKI.		SGLT2 inhibitors may be protective against CI-AKI in patients with diabetes and STEMI undergoing PCI.
Liu 202313

Single-center, retrospective		N=512 patients with type 2 diabetes and CKD undergoing an elective coronary proceduren=256 patients receiving dapagliflozin

n=256 controls (no SGLT2 inhibitor)		CI-AKI was lower in the dapagliflozin group compared with controls (10.9% vs 22.3%; HR, 0.81; 95% CI, 0.69 to 0.95; p=0.01).Dapagliflozin may be effective in reducing CI-AKI in patients undergoing elective coronary procedures.
Abbreviations: CA-AKI=contrast-associated acute kidney injury; CI=confidence interval; CI-AKI=contrast-induced acute kidney injury; CKD=chronic kidney disease; HF=heart failure; HR=hazard ratio; OR=odds ratio; PCI=percutaneous coronary intervention; SGLT2=sodium-glucose cotransporter-2; SCr=serum creatinine; STEMI=ST-segment elevation myocardial infarction.

Conclusion
Numerous observational studies support the efficacy of the SGLT2 inhibitors for the reduction of CI- or CA-AKI. The data are primarily observational studies conducted in patients with diabetes undergoing cardiac interventional procedures. One small, single-center, pilot RCT evaluated empagliflozin for at least 15 days prior to PCI. This study found no difference between empagliflozin and standard medical care in SCr at 48 hours or in CI-AKI during hospitalization.

At this time, the literature supports that SGLT2 inhibitors may reduce the risk of CI- or CA-AKI in patients with diabetes or heart failure who are receiving these drugs at the time of a procedure requiring intravenous contrast; however, SGLT2 inhibitors have not been applied as an acute intervention for AKI prophylaxis in the setting of contrast administration and should not be utilized in this manner until further evidence from well-designed clinical trials is available.

References

  1. ACR Manual on Contrast Media. American College of Radiology. 2023. Accessed July 12, 2024. https://www.acr.org/-/media/acr/files/clinical-resources/contrast_media.pdf
  2. Davenport MS, Perazella MA, Nallamothu BK. Contrast-Induced Acute Kidney Injury and Cardiovascular Imaging: Danger or Distraction? Circulation. 2023;147(11):847-849. doi:10.1161/CIRCULATIONAHA.122.062783
  3. International Society of Nephrology. KDIGO Clinical Practice Guideline for Acute Kidney Injury 2012. Accessed July 16, 2024. https://kdigo.org/wp-content/uploads/2016/10/KDIGO-2012-AKI-Guideline-English.pdf
  4. Davenport MS, Perazella MA, Yee J, et al. Use of Intravenous Iodinated Contrast Media in Patients with Kidney Disease: Consensus Statements from the American College of Radiology and the National Kidney Foundation. Radiology. 2020;294(3):660-668. doi:10.1148/radiol.2019192094
  5. Nusca A, Piccirillo F, Viscusi MM, et al. Contrast-induced Acute Kidney Injury in Diabetic Patients and SGLT-2 Inhibitors: A Preventive Opportunity or Promoting Element? J Cardiovasc Pharmacol. 2022;80(5):661-671. doi:10.1097/FJC.0000000000001329
  6. Heerspink HJ, Perkins BA, Fitchett DH, Husain M, Cherney DZ. Sodium Glucose Cotransporter 2 Inhibitors in the Treatment of Diabetes Mellitus: Cardiovascular and Kidney Effects, Potential Mechanisms, and Clinical Applications. Circulation. 2016;134(10):752-772. doi:10.1161/CIRCULATIONAHA.116.021887
  7. Meregildo-Rodriguez ED, Asmat-Rubio MG, Vásquez-Tirado GA. SGLT-2 inhibitors and prevention of contrast-induced nephropathy in patients with diabetes undergoing coronary angiography and percutaneous coronary interventions: systematic review and meta-analysis. Front Endocrinol (Lausanne). 2023;14:1307715. doi:10.3389/fendo.2023.1307715
  8. Basutkar RS, Cutinha RM, Sathish V, Shahil A, Saneen Ck N. Impact of SGLT2 Inhibitors on Renal Function in Type 2 Diabetic Patients with Coronary Artery Disease Undergoing Percutaneous Intervention: A Systematic Review and Meta-Analysis. Curr Diabetes Rev. doi:10.2174/0115733998301228240625065230
  9. Feitosa MPM, Lima EG, Abizaid AAC, et al. The safety of SGLT-2 inhibitors in diabetic patients submitted to elective percutaneous coronary intervention regarding kidney function: SAFE-PCI pilot study. Diabetol Metab Syndr. 2023;15(1):138. doi:10.1186/s13098-023-01107-9
  10. Nardi G, Marchi E, Allinovi M, et al. Contrast-Induced Acute Kidney Injury in Patients with Heart Failure on Sodium-Glucose Cotransporter-2 Inhibitors Undergoing Radiocontrast Agent Invasive Procedures: A Propensity-Matched Analysis. J Clin Med. 2024;13(7):2041. doi:10.3390/jcm13072041
  11. Çabuk G, Hazır KE. Do Sodium-Glucose Cotransporter 2 Inhibitors Decrease the Risk of Contrast-Associated Acute Kidney Injury in Patients with Type II Diabetes Mellitus?. Anatol J Cardiol. Published online March 20, 2024. doi:10.14744/AnatolJCardiol.2024.3980
  12. Kültürsay B, Yılmaz C, Güven B, Mutlu D, Karagöz A. Potential renoprotective effect of SGLT2 inhibitors against contrast-induced AKI in diabetic STEMI patients undergoing primary PCI. Kardiol Pol. 2024;82(1):29-36. doi:10.33963/v.kp.98260
  13. Liu T, Jian X, Li L, Chu S, Fan Z. The Association between Dapagliflozin Use and the Risk of Post-Contrast Acute Kidney Injury in Patients with Type 2 Diabetes and Chronic Kidney Disease: A Propensity-Matched Analysis. Kidney Blood Press Res. 2023;48(1):752-760. doi:10.1159/000535208

Prepared by:
Courtney Krueger, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

August 2024

The information presented is current as of July 12, 2024. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.