Percutaneous coronary intervention (PCI) is an effective treatment for coronary artery disease (CAD) that can significantly improve myocardial perfusion, alleviate chest pain symptoms, reduce the risk of adverse cardiovascular events, and enhance both the quality of life and survival rates of CAD patients (1). With the widespread use of PCI, there has been an increase in the use of contrast agents, which has led to a rising incidence of contrast-induced acute kidney injury (CIAKI), particularly among high-risk groups such as those with type 2 diabetes mellitus (T2DM) and renal insufficiency. These patients exhibit a reduced tolerance to contrast agents, which significantly increase their risk of developing CIAKI (2). CIAKI is defined as an acute decline in kidney function occurring within 48–72 h following the administration of contrast agents. Not only does CIAKI prolong hospitalization and increase healthcare costs, but it is also strongly associated with higher rates of cardiovascular events, long-term dialysis dependence, and increased mortality (3).

Dapagliflozin, one of the most widely used sodium-glucose cotransporter-2 inhibitors (SGLT2i) in clinical practice, works by inhibiting the SGLT-2 protein in the proximal renal tubules, which reduces glucose reabsorption and increases urinary glucose excretion. Beyond its glucose-lowering effects, dapagliflozin has been shown to provide significant renal and cardiovascular protection, slowing the progression of chronic kidney disease, reducing urinary protein levels, and improving heart failure outcomes (4–7).

A growing body of evidence suggests that chronic administration of SGLT2i may reduce the risk of CIAKI through mechanisms such as the reversal of renal hyperfiltration, alleviating oxidative stress, and reducing inflammation (8, 9). However, the effects of short-term administration of dapagliflozin—defined as less than 2 weeks—remain inadequately explored. In fact, some studies suggest that short-term SGLT2i therapy could potentially increase the risk of CIAKI due to osmotic natriuresis, dehydration, and renal hemodynamic changes such as vasoconstriction of the afferent arterioles and decreased renal perfusion (10). These changes may be particularly pronounced in high-risk populations, including the elderly and those with multiple comorbidities such as renal insufficiency, heart failure, anemia, or those receiving diuretics. There is currently a lack of consensus regarding the use of SGLT2i in the peri-procedural setting, especially in high-risk patients who are undergoing PCI. Clinical guidelines do not provide clear recommendations on whether dapagliflozin should be withheld or continued in patients at high risk for CIAKI before undergoing PCI. Given the conflicting evidence regarding the effects of short-term dapagliflozin use, it is crucial to clarify whether initiating dapagliflozin in the short term increases the risk of CIAKI in patients with T2DM and renal insufficiency undergoing PCI.

This study aims to investigate the impact of short-term (<2 weeks) dapagliflozin administration on the incidence of CIAKI in T2DM patients with renal insufficiency undergoing PCI. By examining the clinical outcomes in patients who received dapagliflozin for a short duration before PCI, we aim to provide evidence that can inform clinical practice, particularly in high-risk T2DM patients with renal insufficiency, and to evaluate whether short-term dapagliflozin therapy should be avoided in these patients to prevent CIAKI.

In this retrospective cohort study, we investigated the impact of short-term (<2 weeks) dapagliflozin administration on the incidence of CIAKI in patients with T2DM and renal insufficiency undergoing PCI. This study found that the incidence of CIAKI was higher in the short-term dapagliflozin group compared to the control group. Additionally, 12 h post-PCI, urinary NGAL levels were higher in the short-term dapagliflozin group compared to the control group. Our study revealed that short-term dapagliflozin therapy was associated with a higher risk of CIAKI compared to the control group. These findings suggest that, while SGLT2i like dapagliflozin offer long-term renal protection in patients with T2DM and renal insufficiency, their short-term therapy before PCI may pose a higher risk of renal injury, particularly in high-risk populations. Therefore, it is recommended to avoid initiating dapagliflozin in high-risk CIAKI patients before PCI whenever possible.

CIAKI is defined as an increase in Scr by more than 26.5 μmol/L above baseline within 48–72 h after contrast exposure, or an increase exceeding 50% of baseline levels within 1 week. This diagnostic criterion is currently the most widely used in clinical practice (3). However, in the early stages of AKI, Scr has several limitations in clinical application. Scr is influenced by factors such as muscle mass, age, gender, and dietary habits, and its elevation typically requires 24 h to several days after the onset of AKI to reflect acute changes in kidney function, which leads to a delay in the early diagnosis of AKI (11). Cys-C is a small molecular protein produced by nucleated cells, which is filtered by the glomerulus and completely reabsorbed and degraded in the renal tubules. It is not affected by muscle mass, age, or gender, and its levels rise within 6–12 h after the onset of AKI, making it an important marker for early detection of AKI (12). NGAL is a small molecular protein expressed in neutrophils and renal tubular epithelial cells. Under normal conditions, NGAL expression in renal tubular tissue is minimal, but it rises significantly within 3–6 h after the onset of various forms of AKI (13). Therefore, Cys-C and NGAL can serve as sensitive biomarkers for early detection of AKI.

CIAKI is one of the most common iatrogenic causes of AKI. Although the incidence of CIAKI in the general population is relatively low (approximately 1–5%), it can increase to 20–50% in patients with high-risk factors (14). Major risk factors for CIAKI include renal insufficiency (eGFR <60 mL/min/1.73 m²), diabetes (especially with concomitant chronic kidney disease), advanced age, heart failure, hypovolemia, anemia, and the use of nephrotoxic drugs. Additionally, the use of large doses or hyperosmolar contrast agents, as well as repeated contrast agent administration within a short period, are important risk factors for CIAKI (15–17). Several studies have shown that CIAKI is closely associated with increased in-hospital mortality, a higher incidence of cardiovascular events, and sustained renal function deterioration (18–20).

Recent studies suggest that contrast agent-induced ischemia and hypoxia in the renal cortex and medulla are key mechanisms in the pathogenesis of CIAKI (21–23). The kidney has a highly complex blood flow distribution, with abundant blood flow in the cortical region and relatively limited blood flow in the medulla, where oxygen tension is naturally lower, putting it in a state of “relative hypoxia” under physiological conditions. This makes the renal medulla more susceptible to further damage from various factors. After exposure to iodinated contrast agents, renal hemodynamics are altered, and the contrast agent can induce vasoconstriction, particularly in the afferent arterioles, leading to reduced renal blood flow, with a significant decrease in medullary perfusion (24). Additionally, contrast agents activate mechanisms such as increased renin release, endothelin-1, and inhibition of nitric oxide and prostaglandin synthesis, which further exacerbate vasoconstriction and reduce medullary blood flow (25). The outer medullary region of the kidney is particularly sensitive to hypoxia, and inadequate perfusion can lead to cellular dysfunction and disturbances in energy metabolism. Moreover, the nephrotoxic effects of contrast agents on renal tubular cells can cause mitochondrial dysfunction, energy metabolism disruption, and cell membrane damage, ultimately leading to renal tubular cell apoptosis or necrosis (26). Furthermore, ischemic and hypoxic conditions activate various oxidative stress pathways, promoting the excessive generation of reactive oxygen species, which causes oxidative stress damage (27), thereby contributing to the development of CIAKI.

SGLT2i have garnered significant attention as a novel class of hypoglycemic agents in recent years, with proven cardiovascular and renal protective effects. Multiple clinical studies have confirmed that dapagliflozin not only effectively delays the decline in renal function but also reduces heart failure hospitalization rates and cardiovascular mortality. Its potential mechanisms include reducing glomerular hyperperfusion and hyperfiltration, delaying renal fibrosis, lowering urinary protein levels, promoting natriuresis, reducing cardiac load, inhibiting myocardial fibrosis, improving ventricular remodeling, lowering blood uric acid levels, reducing body weight, and providing anti-oxidative stress and anti-inflammatory effects (28–30).

Existing studies have shown that chronic administration of SGLT2i has been associated with a reduction in AKI and CIAKI risk (31, 32). Recently, a meta-analysis (33) demonstrated that in populations with long-term time use of SGLT2i (ranging from a minimum of 2 weeks to a maximum of 6 months), and with adequate hydration, SGLT2i reduced the incidence of CIAKI after PCI in patients with T2DM (RR = 0.48, 95% CI: 0.39–0.59, p < 0.001). Hua et al. (34) found that dapagliflozin, when used for at least 6 months before contrast exposure, significantly reduced the risk of CIAKI. Paolisso et al. (35) reported that dapagliflozin, with an average use of 7.3 ± 3.0 months before PCI, was an independent predictor of reduced CIAKI risk (OR = 0.356, 95% CI: 0.134–0.943, p = 0.038). Nardi et al. (36) found that in heart failure patients who had used SGLT2i for at least 6 months, SGLT2i treatment was associated with a reduced risk of CIAKI (OR = 0.41, 95% CI: 0.16–0.90, p = 0.045). Feitosa et al. (37) showed that in T2DM patients who had used SGLT2i for at least 15 days before PCI, SGLT2i did not increase the risk of CIAKI.

Although the cardiovascular and renal protective effects of long-term therapy of SGLT2i in patients with T2DM are widely recognized, the impact of short-term SGLT2i therapy on CIAKI remains unclear. At the same time, clinical data show that short-term SGLT2i therapy, particularly within the first 2 weeks of treatment, can lead to transient increases in Scr and decreases in eGFR. These changes in Scr and eGFR typically occur within 2–4 weeks after treatment initiation (38). This outcome of SGLT2i therapy may increase the risk of AKI in the short term administration, particularly in high-risk populations such as the elderly, those with heart failure, renal insufficiency, anemia, diuretic use, hypovolemia, and contrast agent exposure, where the effect may be more pronounced. In our previous study (39), we retrospectively included T2DM patients who had been taking dapagliflozin for at least 4 weeks prior to PCI (224 patients), with an average duration of use of 10.56 ± 2.62 weeks, and compared them with patients who had not used dapagliflozin (240 patients). We found that the incidence of CIAKI was lower in the dapagliflozin group compared with the control group (5.8% vs. 11.7%, χ² = 4.494, p = 0.033). Dapagliflozin appeared to reduce the risk of CIAKI (OR = 0.365, 95% CI: 0.176–0.767, p = 0.008) (38). However, our previous study did not include patients with severe renal insufficiency, or those with short-term dapagliflozin use before PCI. Therefore, it was not possible to determine whether short-term dapagliflozin use affects CIAKI risk in high-risk patients. For this reason, in the present study, we specifically included renal insufficiency patients to analyze the impact of short-term dapagliflozin use on the risk of CIAKI in this vulnerable population.

In this study, the patients in the short-term (<2 weeks) dapagliflozin group had a median duration of dapagliflozin use before PCI of 3 (2, 6) days, with an average duration of 3.56 ± 1.62 days. These patients were mostly newly initiated on dapagliflozin before PCI. Our results showed that the incidence of CIAKI was higher in the short-term dapagliflozin group compared to the control group. Our logistic regression analysis confirmed that short-term dapagliflozin administration increased the risk of CIAKI (OR = 2.308, 95% CI: 1.002–5.314, p = 0.049). Additionally, at 12 h post-PCI, urinary NGAL levels were higher in the short-term dapagliflozin group compared to the control group, suggesting that, during the perioperative period of PCI, initiating dapagliflozin may increase the risk of CIAKI in patients with T2DM and renal insufficiency after PCI. A study on the short-term therapy of SGLT2i and CIAKI incidence reported that patients using SGLT2i for a short duration (1.7 ± 1.4 days) had a significantly higher incidence of CIAKI compared to those using SGLT2i for a long duration (191.5 ± 223.3 days) (20.5% vs. 3.4%, p = 0.018) (10). Lopes et al. (40) reported that, in the early stages of dapagliflozin treatment, the co-administration of dapagliflozin with furosemide significantly increased the risk of AKI (p = 0.006).

The increased risk of CIAKI associated with short-term therapy of SGLT2i may be related to the following pathophysiological mechanisms: (1) In addition to inhibiting glucose reabsorption, SGLT2i also suppress sodium ion reabsorption in the proximal tubules, leading to an increase in sodium delivery to the macula densa. This negative feedback on the tubuloglomerular feedback system triggers the macula densa to signal granular cells to release renin, thereby activating the renin-angiotensin system. This activation causes vasoconstriction of the afferent arterioles in the kidney, leading to reduced renal blood flow and a decrease in renal perfusion pressure. This effect is particularly pronounced when combined with ACEI or ARBs, as these drugs simultaneously dilate the efferent arterioles, the risk of AKI may be heightened (41). (2) The osmotic natriuresis, diuretic, and blood volume-reducing effects of SGLT2 inhibitors, particularly when used in combination with diuretics, may result in a relative insufficiency of effective blood volume in T2DM patients, thereby increasing the risk of AKI (42). (3) SGLT2i may increase the risk of renal medullary hypoxia, particularly in patients with T2DM. Oxygen tension normally decreases at the corticomedullary junction, reaching levels as low as 30 mmHg in the renal medulla, where blood flow is limited and oxygen tension is inherently low, placing the region in a state of “relative hypoxia” even under physiological conditions. SGLT2i promote increased sodium reabsorption in the distal nephron, which raises oxygen consumption in the renal medulla (43). Moreover, studies have shown that SGLT2i can reduce microvascular renal oxygen tension in the cortex and outer medulla of diabetic rats (44, 45). As the renal medulla in T2DM patients is typically already under conditions of inadequate oxygen supply, SGLT2i may make the renal medulla more susceptible to hypoxia and ischemia, leading to further renal function deterioration. This effect may be more evident in patients with anemia or those receiving contrast agents, thereby increasing the risk of CIAKI.

NGAL as a biomarker for distal tubular injury, Darawshi et al. (46) reported that serum and urinary NGAL significantly increased in hospitalized patients treated with SGLT2i who presented with AKI upon admission, as compared with hospitalized patients treated with SGLT2i who did not develop AKI. Additionally, both serum and urinary NGAL levels were significantly correlated with the degree of acute renal damage. Interestingly, in our study, we also observed a significant increase in urinary NGAL in both groups compared to pre-PCI levels, with the short-term dapagliflozin group showing higher urinary NGAL levels than the control group. These results suggest that short-term dapagliflozin therapy may enhance renal tubular injury following contrast administration by affecting renal medullary hypoxia. Meanwhile, in this study, all patients in the dapagliflozin group continued the treatment throughout the study period without interruption, which avoided the fluctuations in eGFR due to the initiation or withholding of SGLT2i, thus preventing a major confounder of changes in GFR that could influence the study results.

In contrast, chronic therapy of SGLT2i may stimulate erythropoietin production and the expression of renal hypoxia-inducible factors, promoting adaptive responses to ischemia and hypoxia and enhancing tolerance to low oxygen conditions. Furthermore, chronic SGLT2i therapy may improve cardiac function through osmotic diuresis and natriuresis, thereby enhancing renal perfusion, and may reduce the risk of CIAKI through its anti-inflammatory and antioxidative stress effects (9, 47–50).

Therefore, based on the results of this study and the aforementioned research (31–40), the following recommendations are made: (1) For patients who have been receiving long-term dapagliflozin therapy, continuation of the drug before PCI may be safe, as long-term exposure to SGLT2 inhibitors has been shown to improve renal hemodynamics and reduce CIAKI risk. (2) It is advisable to avoid initiating dapagliflozin therapy in high-risk patients immediately before PCI, especially in those with severe renal insufficiency, heart failure, or other comorbid conditions that may predispose them to renal injury. (3) For high-risk patients with CIAKI risk factors, it is recommended to discontinue SGLT2i during the perioperative period of PCI to avoid increasing the risk of CIAKI. (4) According to the clinical guidelines for the use of SGLT2i (51), renal function should be closely monitored post-PCI. For patients with a decrease in eGFR exceeding 30% or those who develop CIAKI, it is recommended to discontinue SGLT2i and promptly address the underlying causes of CIAKI.

Indeed, this study has several limitations. First, it is a single-center, retrospective cohort study with non-randomized grouping, which introduces potential selection bias. In this study, patients in the short-term dapagliflozin group were older than that in the control group and had lower LVEF, this difference may be due to the active use of dapagliflozin by cardiologists for patients with heart failure and T2DM, as heart failure patients are often older. This selection bias may have some impact on the results. Second, the exact mechanism by which short-term dapagliflozin increases the risk of CIAKI in this group cannot be fully explained. A more detailed mechanistic study, would be valuable in further elucidating the physiological and biochemical pathways contributing to the observed renal injury. Third, While our study focused on the impact of short-term dapagliflozin administration (less than 2 weeks), the exact optimal duration of therapy for balancing renal protection and minimizing adverse outcomes remains unclear. Further studies are required to evaluate the optimal time for the initiation of SGLT2i after PCI. Fourth, during PCI treatment, patients are usually anxious and commonly show increased heart rate and blood pressure, leading to hypertension. A small proportion of PCI patients may experience hypotension due to pain or anxiety-induced vasovagal reflexes. A very small number of patients may experience coronary no-reflow or slow-flow phenomena during PCI, leading to hypotension. These blood pressure fluctuations may have some impact on the occurrence of CIAKI.

Our study provides evidence that short-term dapagliflozin administration may increase the risk of CIAKI in T2DM patients with renal insufficiency undergoing PCI. Clinicians should exercise caution when considering the initiation of dapagliflozin in high-risk patients before PCI. While long-term therapy of SGLT2i has clear benefits, short-term initiation of these drugs may exacerbate renal injury. Careful monitoring of renal function and appropriate timing of dapagliflozin initiation are critical to optimizing patient outcomes and minimizing the risk of CIAKI.