Type 2 diabetes, acute kidney injury (AKI), and chronic kidney disease (CKD) are closely entwined. Type 2 diabetes is a risk factor for AKI, while both type 2 diabetes and AKI are risk factors for CKD. Recently, it has come to light that acute kidney disease (AKD) is a transitional stage between AKI and CKD, lasting 7 to 90 days after an incidence of AKI. Individuals with AKD have a higher risk of mortality, end-stage kidney disease, incident CKD, and progressive CKD, making it clear that managing AKD is crucial to preventing additional kidney damage and negative outcomes.
Sodium-glucose cotransport protein 2 inhibitors (SGLT-2is) have shown promise in terms of kidney-related and cardiovascular outcomes. They are a new class of oral hypoglycemic agents that inhibit the reabsorption of glucose and sodium in the kidneys, which results in reduced blood pressure, intraglomerular pressure, and albuminuria. In clinical trials, SGLT-2is were associated with slowing the progression of CKD, improving kidney function, and reducing the risk of death in patients with type 2 diabetes. Clinical trials also found that SGLT-2is may be associated with a lower risk of AKI in patients with type 2 diabetes.
To better understand the associations of SGLT-2is with mortality, major adverse kidney events (MAKEs), and major adverse cardiovascular events (MACEs) in patients with type 2 diabetes and AKD, a team of researchers led by Heng-Chih Pan, MD, conducted a longitudinal study using data from the global TriNetX database spanning from September 30, 2002, to September 30, 2022. Results were reported in JAMA Network Open. The researchers used propensity score matching (PSM) to select a cohort of patients, and follow-up was conducted with a maximum duration of 5 years or until the occurrence of an outcome or death. The primary outcome was mortality; secondary outcomes were MAKEs (redialysis, dialysis dependence, or mortality) and MACEs (cerebral infarction, hemorrhagic stroke, acute myocardial infarction, cardiogenic shock, or mortality).
The total cohort consisted of 230,366 patients with AKD with a mean (SD) age of 67.1 (16.4) years; 119,253 (51.8%) were men and 111,113 (48.2%) were women. Researchers identified 5319 individuals (2.3%) who were SGLT-2i users and did not undergo dialysis or die within 3 months of discharge. They also identified 225,047 patients who had type 2 diabetes and did not use SGLT-2is. The median follow-up duration for the full cohort was 2.3 (interquartile range, 1.2-3.5) years, with the 90th percentile extending to 4.3 years.
Using PSM, the researchers identified 5317 SGLT-2i users and 5317 nonusers as controls for analysis; mean (SD) age was 63.8 (12.3) years in the SGLT-2i group and 67.4 (15.5) years in the control group. The SGLT-2i group included 3181 (59.8%) men and 2136 (40.2%) women; most patients were White (3493 [65.7%]). The control group included 3175 (59.7%) men and 2142 (40.3%) women, most of whom were White (3496 [65.8%]). After PSM, the two groups had small and well-matched differences in age, sex, race and ethnicity, comorbidities, medication use, and most other lab results. The mean (SD) estimated glomerular filtration rates in the SGLT-2i and control groups were 76.9 (32.9) and 74.2 (40.5) mL/min/1.73 m2, respectively. The SGLT-2i group had a greater percentage of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker users compared with the control group.
After withdrawal from dialysis for AKI, the overall incidence rate was 13.9% for 5-year mortality, 15.3% for MAKEs, and 21.0% for MACEs. The 5-year all-cause mortality rate was 9.0% (481) in the SGLT-2i group and 18.7% (994) in the control group. Use of SGLT-2is was associated with a lower mortality rate (adjusted hazard ratio [aHR], 0.69; 95% CI, 0.62-0.77). Additionally, researchers noted a lower risk of MAKEs in the SGLT-2i group (504 [9.5%]) compared with the control group (1119 [21.0%]; aHR, 0.62; 95% CI, 0.56-0.69).
The baseline characteristics of the patients selected for MACE analysis were comparable with those observed in the primary analysis. In the SGLT-2i group, researchers observed a lower risk of MACEs (233 of 1732 [13.5%]) compared with the control group (690 of 2670 [25.8%]; aHR, 0.75; 95% CI, 0.65-0.88). These results further support the effectiveness of SGLT-2is in reducing the occurrence of MACEs.
Furthermore, researchers performed a subgroup analysis based on various comorbidities, such as advanced CKD and hypertension, and medication use. The use of SGLT-2is was associated with a lower risk of mortality, regardless of whether insulin or renin-angiotensin-aldosterone system (RAAS) blockers or diuretics were used. The association between SGLT-2i use and a lower risk of MAKEs was observed consistently among patients with advanced CKD and among those who used RAAS blockers or diuretics, although the association was more pronounced in patients without hypertension and those who were not receiving insulin or other oral hypoglycemic agents (OHAs). Researchers observed an association between a lower risk of MACEs and the use of SGLT-2is consistently among patients with hypertension and those using RAAS blockers, and particularly among those with advanced CKD and those who were not receiving insulin or other OHAs or diuretics.
The authors noted several limitations to their study. Most participants were White, potentially limiting generalizability of the results. Information bias may have occurred due to significant differences in comorbidities and medication use between the SGLT-2i users and nonusers. The use of diagnostic codes to classify diseases may have led to ascertainment bias by causing the researchers to underestimate the presence of mild conditions or those occurring outside the medical system. Misclassification bias and residual confounding could be present. The limitations of TriNetX’s tools curbed the use of competing risk models, potentially biasing results. This was a retrospective study lacking raw data, which hampered a time-varying analysis. Cases with incomplete outcome data were excluded, which could have led to selection bias, and the dataset did not include detailed causes for redialysis or death.
“In this cohort study, we provide compelling clinical evidence supporting the associations of SGLT-2is in reducing the risk of mortality among patients with type 2 diabetes and AKD during a median follow-up period of 2.3 years,” the authors summarized. “Use of SGLT-2is was associated with a lower risk of MAKEs and MACEs compared with nonuse. These findings highlight the potential benefit of SGLT-2is and suggest that clinicians should consider incorporating them into the management of type 2 diabetes with AKD.”
Source: JAMA Network Open
© 2025 Mashup Media, LLC, a Formedics Property. All Rights Reserved.