Acute kidney injury (AKI) accounts for about 10–15% of hospital admissions in the USA, is more common in people with diabetes and it heralds worse outcomes [1, 2]. Low glomerular filtration rate (GFR), albuminuria, hypertension and cardiovascular (CV) diseases are more prevalent in diabetic patients and are risk factors for AKI [3]. Other common risk factors include preexisting chronic kidney disease (CKD), use of nonsteroidal anti-inflammatory drugs, iodinated radiocontrast agents, antihypertensive medications that can reduce intravascular volume and/or glomerular filtration (diuretics, angiotensin converting enzyme (ACE) inhibitors, and angiotensin receptor blockers), and previous episodes of AKI.

Beyond early identification and mitigation by use of supportive measures, and removal of potential causes, little progress has been made to date in terms of development of effective treatments. Recently, several meta-analyses of clinical trial data have shown that the use of sodium–glucose cotransporter 2 inhibitors (SGLT2i) in type 2 diabetes (DM2) reduces the risk of AKI by 30–40%, or even more if the data come from ‘real world’ observational studies [4]. These findings are critical because the best way to improve AKI outcomes in the diabetic patient is by preventing its occurrence. On the other hand, previous concerns that SGLT2i may promote AKI through volume depletion have not been confirmed in randomized controlled trials (RCTs) in patients with advanced CKD or high CV risk with normal kidney function [2]. Preservation of kidney function in the long term, reduced risk of heart failure, lessened risk of tubular damage from glucotoxicity and reactive oxygen species, attenuation of inflammatory infiltrates and tubulointerstitial fibrosis are all potential contributors to the reduced occurrence and may help to mitigate the detrimental impact of AKI in patients on SGLT2i [5].

Noteworthy, AKI survivors are at high risk of transitioning to acute kidney disease (AKD), then to CKD, and, in turn, to end-stage kidney disease (ESKD) [6] (Fig. 1). AKD is a relatively newly identified entity and represents a critical phase in the AKI-CKD transition; it is defined as subacute damage and/or loss of kidney function occurring 7 to 90 days after AKI. This period represents the window during which key interventions should be initiated to hinder CKD. The importance of AKD has been highlighted by a recent meta-analysis [7] of 21 studies involving 1,114,012 patients, showing that patients with AKD are exposed to higher risk of mortality, ESKD, incident CKD, and progressive CKD than those without AKD. Indeed, in AKD versus non-AKD patients, the all-cause mortality rate was 3 times higher, (26.54% vs. 7.78%), the rate of progression to ESKD was 9 times higher (1.3% vs. 0.14%), and the incident rate of CKD was 5 times higher (37.2% vs. 7.45%). Subgroup analyses according to the size of the diabetic population (< 20% vs. ≥ 20%) of the included trials did not modify the results.

Fig. 1
figure 1

Schematic diagram showing the potential or documented effects of SGLT2 inhibitors and GLP-1 RAs in AKI-CKD transition and beyond. The available evidence indicates that SGLT2i may be associated with a reduced occurrence of AKI (first green vertical line). The evidence that both SGLT2i and GLP-1 RAs may reduce mortality and transition from AKD to CKD is less compelling and needs intervention trials (middle orange vertical line). The evidence that both SGLT2i and GLP-1 RAs are effective means for reducing kidney failure, heart failure, CV and total death is supported by many intervention trials (last green vertical line). SGLT2i sodium–glucose cotransporter 2 inhibitors, GLP-1 RAs glucagon-like peptide 1 receptor agonists, AKI acute kidney injury; AKD acute kidney disease; CKD chronic kidney disease

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Management of AKD includes prevention of repeated episodes of AKI, early and regular follow-up by a nephrologist, resumption and dose adjustment of essential medication, with no indication for discontinuation of statins and renin-angiotensin system inhibitors, optimization of blood pressure control, nutrition management, and nephrotoxin avoidance. To date, no professional association in diabetology or nephrology has recommended the use of the novel nephroprotective agents, SGLT2i or glucagon-like peptide 1 receptor agonists (GLP-1 RAs), to attenuate or even block AKI-CKD transition.

This scenario could now change. Using the TriNetX database, a global health collaborative clinical research platform in Taiwan, Pan et al. [8] have recently assessed the long-term association of SGLT2i with mortality, major adverse kidney events (MAKEs),, i.e. re-dialysis, dialysis dependence or mortality, and major adverse kidney events (MACEs), i.e. cerebral infarction, hemorrhagic stroke, acute myocardial infarction, cardiogenic shock, or mortality within a cohort of 230,366 patients with DM2 and AKD. Use of SGLT2i (5317 diabetic patients) was associated with a 31% lower risk of mortality (95% CI 23 to 38%,), a 38% lower risk of major adverse kidney events (31 to 44%) and a 25% lower risk of major adverse cardiac events (12 to 35%) compared with nonuse (5317 diabetic patients), after propensity score matching and a median follow up of 2.3 years.

Pan et al. [9] have further explored the associations between GLP-1 RAs and mortality, major adverse cardiac events and major adverse kidney events in the same cohort of individuals with DM2 and AKD, in an effort to provide valuable real-world perspectives on the effects of GLP-1 RAs. In their cohort of 165,860 AKD patients, GLP-1 RA users (7511) exhibited a 43% lower risk of mortality (95% CI 36 to 43%), major adverse cardiac events (12%, 4 to 20%), and major adverse kidney events (27%, 20 to 34%), with respect to non-users, after adjustment for several covariates. As for SGLT2i, multiple mechanisms have been hypothesized to mediate the kidney-preserving effects of GLP-1 RAs, essentially represented by the reduction of excess body fat, hypertension, dyslipidemia, inflammation, and atherogenesis [10].

Despite the retrospective nature of the two studies, and the ensuing limitations, the results emphasize the potential benefits for both SGLT2i and GLP-1 RAs in the management of DM2 patients with AKD, and should prompt randomized intervention trials to confirm this hypothesis (Fig. 1). Noteworthy, the prescription rate of SGLT2i and GLP-1 RAs in the whole cohort of patients was very low (2.3% and 4.5%, respectively), possibly reflecting the current uncertainty about the best way to treat AKD. In this regard, the patients in both studies showed full recovery of kidney function after AKI and before starting the target drugs. This is critical to correctly interpret results because both SGLT2i and GLP-1 RAs associate with a variable natriuretic response that may worsen pre-existing volume depletion and kidney dysfunction [10, 11]. Therefore, in the absence of data in the AKD population at large, implementation of either drug should be limited to hyper- and eu-volemic patients.

For people with DM2 and CKD, the 2024 ADA Standard of Care in Diabetes [2] recommends the use of SGLT2i to prevent CKD progression and cardiovascular events in individuals with an estimated glomerular filtration rate (eGFR) ≥ 20 ml/min/1.73 m2 and urinary albumin ≥ 200 mg/g creatinine, as they slow CKD progression, reduce heart failure risk, and mortality regardless of glucose management [12]. GLP-1 RAs are indicated for CV risk reduction if such risk is a predominant problem, as they reduce the risk of CV events [13] (Fig. 2).

Fig. 2
figure 2

Summary of meta-analyses (ref. [12, 13]) reporting the relative risk reduction of cardiorenal outcomes obtained in large intervention trials. RRR relative risk reduction, CV cardiovascular; HF hospitalization for heart failure, MACE major adverse cardiac events, Renal composite renal outcome

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Similarly, the 2024 KDIGO guidelines [14] issued a 1B recommendation to use long-acting GLP-1 RAs with proven CV benefits as the preferred second-line treatment for glucose lowering in patients not achieving individualized glycemic targets despite the use of metformin and an SGLT2i, or who are unable to tolerate these medications. Noteworthy, GLP-1 RAs may also improve “hard” renal outcomes compared with placebo. The recent results of the FLOW trial (Effect of semaglutide versus placebo on the progression of renal impairment in people with type 2 diabetes and chronic kidney disease) have added solid evidence regarding the cardiorenal benefits of GLP-1 RAs in people with DM2 and CKD [15]. In the trial, semaglutide significantly reduced the risk of the composite primary endpoint (time to first occurrence of kidney failure, that is, persistent eGFR < 15 ml/min/1.73 m2 or initiation of chronic kidney replacement therapy, persistent ≥ 50% reduction in eGFR when compared with baseline, or death due to kidney or CV causes) by 24%, the risk of major CV events by 18% and the risk of death from any cause by 20%; notably, these beneficial effects were obtained in the presence of a better safety profile vs controls.

The revolution in the treatment of type 2 diabetes, which timidly started in the first decade of this millennium, seems unstoppable. The grim outlook of counting more than a billion diabetic patients in the world over the next 15 years and the significant increase in CKD require appropriate treatments to consistently reduce the high cardiorenal risk of diabetic patients. Nowadays, the toll that CV and renal mortality exacts on patients with DM2 is quite substantial. Nonetheless, the results of Pan et al. need confirmation that only RCTs can provide. Meanwhile, considering the obvious difficulties related to the trial design in the acute or subacute setting of renal disease, the absence of specific therapy for AKD, as well as the multiple mechanisms of kidney and cardiovascular protection of the two classes of agents [10, 16], we may hypothesize judiciously extending the use of SGLT2i and GLP-1 RAs to patients with diabetes and AKD.