Abstract
Background: The risk of contrast-associated acute kidney injury is relatively higher in patients with diabetes mellitus compared to non-diabetics. Recent trials have revealed the renoprotective effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors. We aimed to investigate the possible preventive effect of SGLT2 inhibitors against contrast-associated acute kidney injury in the diabetic population who underwent coronary angiography with a diagnosis of stable angina or acute coronary syndrome.
Methods: This was a cross-sectional and single-center study. We enrolled 345 patients with type II diabetes mellitus who were divided into 2 groups: using an SGLT2 inhibitor (group 1; n = 133) in addition to other antidiabetic medication and not using an SGLT2 inhibitor (group 2; n = 212). Both groups were compared in terms of contrast-associated acute kidney injury incidence. We also compared groups for the duration of hospitalization.
Results: Baseline characteristics (age, sex, risk factors and medications) and laboratory findings were similar between the 2 groups. The means of administered contrast volume were also similar (160.42 (± 70.31) mL vs. 158.72 (± 81.24) mL, P = 0.83) between groups 1 and 2, respectively. We found that contrast-associated acute kidney injury incidence was significantly higher in group 2 compared to group 1 (n = 56 (26.4%) vs. n = 12 (9.0%), P < 0.001). The duration of hospitalization was significantly longer in group 2 (3.25 (± 2.03) days) than in group 1 (2.54 (± 1.39) days) (P = 0.001).
Conclusion: We found that contrast-associated acute kidney injury was significantly lower, and the duration of hospitalization was significantly shorter in diabetic patients using SGLT2 inhibitors compared to non-users.
Highlights
- We found that contrast-associated acute kidney injury (CA-AKI) incidence was significantly lower in patients using an sodium-glucose cotransporter 2 (SGLT2) inhibitor compared to non-users.
- Another important finding of our study was the difference in duration of hospitalization in the study groups; it was significantly shorter in patients using an SGLT2 inhibitor.
- We think this study is going to strengthen the evidence of another renal-protective effect of SGLT2 inhibitors.
Introduction
Contrast-associated acute kidney injury (CA-AKI) is a complication of angiographic procedures using intravascular iodinated contrast media (CM). Although CA-AKI is often regarded as a reversible event (in approximately 80% of cases), it portends a variety of short- and long-term adverse events, such as longer hospital stays and in-hospital mortality.1,
As mentioned above, DM is accepted as a non-modifiable risk factor for CA-AKI development, particularly in patients with concomitant nephropathy. Diabetes itself may be the independent cause of CA-AKI after CM exposure by means of several mechanisms such as pronounced alterations in glomerular filtration rate (GFR), increased renal tubular transport and oxygen consumption, aggravation of medullary hypoxia, and enhanced generation of reactive oxygen species.6
Renoprotective effects of a new class of antidiabetic agents—sodium-glucose cotransporter 2 (SGLT2) inhibitors—have recently been demonstrated by several clinical trials.7,
It is also known that patients who underwent urgent revascularization procedures due to acute coronary syndrome (ACS) have a higher risk for the development of CA-AKI compared to patients without ACS.9 Our aim was to investigate the possible protective effect of SGLT2 inhibitors on the development of CA-AKI in a high-risk population with DM who underwent elective coronary angiography (CAG) and/or percutaneous coronary intervention (PCI) and patients with ACS who were treated medically or underwent PCI after CAG.
Methods
Study Design
This was a cross-sectional and single-center study. This study was carried out in accordance with the conditions of the Declaration of Helsinki and approved by our local ethical committee. Informed consent was obtained from all participants.
Study Population
We enrolled patients with DM (type II DM) (n = 345) who had refractory angina pectoris despite optimal medical therapy and a diagnosis of ACS between April 2022 and February 2023. Patients with type I DM and non-diabetic patients were excluded. We defined 2 study groups as patients who were using an SGLT2 inhibitor (empagliflozin or dapagliflozin) for at least 6 months, confirmed by electronic medical records, until the date of CAG (including the day of CAG) in addition to other anti-diabetic medication (group 1, n = 133) and patients not using an SGLT2 inhibitor (group 2, n = 212). We further divided these 2 groups into sub-groups: patients who underwent elective angiography with a diagnosis of stable angina and those who had urgent angiography due to ACS (
Patients with a history of HFrEF (left ventricular EF < 40%), preprocedural eGFR <30 mL/min/m2 and acute renal failure or end-stage renal failure requiring dialysis, CM exposure within 15 days, anemia (Hb <10g/dL), abnormal thyroid hormone levels, active infectious disease (including coronavirus disease 2019), cardiogenic shock and/or the use of an intra-aortic balloon pump, and excessive exposure to CM (>500 mL) during percutaneous intervention were excluded from the study. Pregnant patients, patients using nephrotoxic drugs (e.g., amphotericin, aminoglycosides, cisplatin, non-steroidal anti-inflammatory drugs, furosemide), or patients who underwent repeated CAG in-hospital (due to complications such as stent thrombosis or for the purpose of complete revascularization) and patients treated by coronary artery bypass grafting surgery were also excluded from the study.
Laboratory Measurements
Serum creatinine levels were measured by Jaffe assay (IDMS traceable calibration) with Beckman Coulter AU5800 (Beckman Coulter, Inc. Diagnostics Division Headquarters 250 South Kraemer Boulevard Brea, CA, USA) before angiography and after 48-72 hours. eGFR was calculated using the Levey-modified modification of diet in renal disease (MDRD) formula: (186.3 × serum creatinine [mg/dL]−1.154 × age [years]−0.203 × (0.742 if female).10 Contrast-associated acute kidney injury was defined (which is widely accepted criteria in the literature) by an increase in serum creatinine of ≥0.5 mg/dL or an absolute increase of ≥25% from baseline 72 hours after CM exposure.
Coronary Angiography
All coronary angiography procedures were performed via the femoral/radial approach, and all patients received intravenous isotonic saline infusion (0.9% NaCl, 1.5 mL/kg/h) starting at the beginning of angiography and continuing for at least 12 hours after the procedure. Patients with ST elevation myocardial infarction (STEMI) were immediately taken to the catheter laboratory for PCI, while patients with non-STEMI (NSTEMI) or unstable angina pectoris underwent coronary angiography within 24 hours after admission according to recommendations of recent guidelines.11 We used a non-ionic and low osmolality contrast agent (Optiray© [Ioversol]) and administered it manually to all patients, and the amount used was recorded at the end of each intervention.
Statistical Analysis
Statistical Package for Social Sciences 21.0 (SPSS, Chicago, Ill, USA) was used for statistical analysis. The Kolmogorov–Smirnov test was applied to determine the normal distribution of variables. Categorical variables were demonstrated as number and percentage; continuous variables were demonstrated as mean (± SD) when normally distributed, while nonparametric variables were shown as median and the percentiles. Categorical variables were analyzed using the chi-square test or by Fisher’s exact test, as appropriate. In order to minimize selection bias, we matched patients using SGLT2 inhibitors to control subjects by performing nearest neighbor propensity score matching algorithm. The Student’s
Results
A total of 345 patients with type II DM were included in this trial. Baseline characteristics [age: 61.68 ± 9.91 vs. 63.58 ± 9.85, female: (n = 50 (37.6%) vs. n = 81 (38.2%)), risk factors and medications] and laboratory findings (including baseline creatinine and eGFR values) were similar between the 2 groups (
In group 1, 61 patients (45.9%) were using dapagliflozin, and 72 patients (54.1%) were using empagliflozin. We found that CA-AKI incidence was significantly higher in group 2 compared to group 1 (n = 56 [26.4%] vs. n = 12 [9.0%],
We also analyzed creatinine and eGFR values before and after coronary angiography for both groups. While these 2 parameters significantly changed in group 2, they did not change significantly in group 1 (
In group 2, 3 patients died in-hospital (one of them received dialysis) and 3 other patients needed dialysis due to contrast nephropathy (their renal functions recovered in-hospital). In group 1, none of the patients needed dialysis and we did not observe any mortality. Another important finding of our study was the difference in duration of hospitalization between the study groups: It was significantly longer in group 2 (3.25 ± 2.03 days) than in group 1 (2.54 ± 1.39 days) (
We also analyzed results separately according to CAG indication and baseline left ventricular ejection fraction (LVEF). We found that CA-AKI incidence was similar between the 2 groups in patients who underwent elective angiography; whereas it was significantly higher in group 2 compared to group 1 in patients with ACS (
Discussion
We found that the incidence of CA-AKI incidence was significantly lower in patients with DM using SGLT2 inhibitors than in those not using this medication. This finding might suggest a new renoprotective effect of SGLT2 inhibitors, as several recent trials have revealed. The renoprotective effects such as renal outcomes of SGLT2 inhibitors have already been demonstrated in patients with heart failure, DM (± nephropathy), or coronary heart disease by recent randomized controlled trials.12-
Growing evidence indicating favorable cardiovascular and renal outcomes with SGLT2 inhibitors has sparked particular interest among scientists. Multifactorial mechanisms have been described in the literature to explain the renal protective effects of SGLT2 inhibitors: (a) reducing proximal tubular sodium reabsorption, thereby increasing distal sodium delivery to the macula densa which activates tubulo-glomerular feedback and leads to efferent arteriolar vasodilation and decreasing glomerular hyperfiltration; (b) it is a well-known fact that the reabsorption of electrolyte and organic solutes in the proximal tubule requires much energy.15,
Several pathogenetic factors have been found to be related to the development of CA-AKI. These include increased secretion of vasoactive amines (such as angiotensin, endothelin, etc.) after contrast exposure, which may be responsible for reduced nitric oxide synthesis, enhanced oxidative stress, and the secretion of proinflammatory cytokines. Interstitial inflammation due to complementary system activation and tubular obstruction have been proposed as underlying mechanisms for the development of CA-AKI.23 Furthermore, the upregulation of SGLT2 in the proximal renal tubules due to hyperglycemia and hyperinsulinemia is well-known in patients with DM. Enhanced action of SGLT2 has been found to be linked to enhanced oxidative stress, mitochondrial dysfunction, and inflammation even without hyperglisemia.24 Therefore, these deleterious effects, which may contribute to the development of CA-AKI, could be mitigated by SGLT2 inhibitors. We enrolled patients who had been using an SGLT2 inhibitor for at least 6 months (excluding patients who started using an SGLT2 inhibitor in the last 6 months) because it was shown that these agents may exhibit beneficial renoprotective effects after a 6-month period. This was done in order to avoid the GFR decreasing effect of SGLT2 inhibitors in the first days of starting the drug.25
Some preventive strategies have been studied to avoid the development of CA-AKI, such as volume expansion with oral and/or intravenous isotonic saline,
Another important finding of our study was the shorter hospital stay in patients using SGLT2 inhibitors due to a lower incidence of CA-AKI. This finding might be speculated as a cost-effectiveness of this medication in patients with DM and ACS. However, this should be studied prospectively in a larger population to claim that kind of cost-effective benefit.
While CA-AKI incidence was significantly lower in group 1 in patients with ACS, CA-AKI incidences were similar between groups in patients who underwent elective angiography. This finding might be due to the limited number of events in the stable angina subgroup (
There are limited data investigating SGLT2 inhibitors in CA-AKI prevention; nevertheless, in a propensity match analysis, it was shown that SGLT2 inhibitor usage was found to be an independent protective factor for the occurrence of CA-AKI in patients with DM who had undergone elective CAG.28 In a recent multicenter registry, it was shown in a cohort with ACS that the rate of CA-AKI was significantly lower in patients with DM who were using an SGLT2 inhibitor compared to non-users.29 This trial was published while we were analyzing our findings, and we found similar results. We also analyzed the duration of hospitalization in addition to their findings. In a retrospective study, they also found that the use of SGLT2 inhibitors significantly reduced the risk of CA-AKI [odds ratio (OR): 0.41, 95% CI: 0.142–0.966,
Study Limitations
Although we showed that SGLT2 inhibitors might decrease the incidence of CA-AKI, our study had some limitations. Due to the cross-sectional design of our study, we could not investigate the prognostic value of SGLT2 inhibitors in this particular population. We had a relatively small sample size and a limited number of events (CA-AKI) due to being a single-center study. We could not include patients using canagliflozin because it has not been refunded in our country yet; therefore, our findings might not be generalized to all types of SGLT2 inhibitors. Lastly, we did not measure BNP levels and look for microalbuminuria in our study groups; as a matter of fact, Yıldız et al35 found that brain natriuretic peptide (BNP) levels and the absence/presence of microalbuminuria were not related to the risk of CA-AKI in patients with ACS who underwent coronary angiography.
Conclusion
We found that in a high-risk patient population who had type II DM, CA-AKI incidence was lower and duration of hospitalization was shorter in patients using SGLT2 inhibitors in addition to other anti-diabetic therapy compared to non-users.
Footnotes
References
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