Levels of kidney function alone had no apparent impact on the risk for diabetic ketoacidosis (DKA) among adults with type 1 diabetes (T1D), regardless of the use of kidney protective medication, according to results of a new study.

In people with type 2 diabetes, SGLT inhibitors have been shown to reduce late-stage kidney outcomes; however, they also increase DKA risk, noted Abdulmohsen Bakhsh, MD, an endocrinologist at Mount Sinai Hospital, Toronto, Canada, in the study published in Diabetes Care.

Although about 3 in 10 people with T1D develop chronic kidney disease, “renoprotective agents such as SGLT inhibitors are not routinely approved for T1D,” he noted. Further, the impact of a reduced estimated glomerular filtration rate (eGFR), with or without SGLT inhibitor use, on the risk for DKA in patients with T1D remains unclear, they said.

Therefore, he and his fellow researchers wanted “to determine whether reduced kidney function alone confers higher DKA risk in order to inform the design and risk‑stratify trials of SGLT inhibitors for kidney protection in T1D,” he said.

Data From the DCCT/EDIC Study

The researchers analyzed 35 years of data from the DCCT/EDIC study using proportional hazard models. The study population included 1441 adults with T1D, with a mean duration of approximately 6 years. The mean age of the study population was 26.8 years; 47% were female; and 97% were White. The primary outcome was DKA events.

During the 34-year follow-up, 297 participants experienced at least one DKA event, with a total of 488 DKA events.

In unadjusted analysis, rates of DKA among individuals with an eGFR between 30 and 90 mL/min/1.73 m² showed no statistical difference compared with those with an eGFR between 90 and 120 mL/min/1.73 m², which was designated as the reference range (0.65 events per 100 person-years).

Compared with the reference group, the incidence rate of the first DKA was 0.81 for eGFR < 30 mL/min/1.73 m², 0.44 for eGFR in the 30-59 mL/min/1.73 m² range, and 0.51 for eGFR in the 60-90 mL/min/1.73 m² range.

Similarly, in an adjusted analysis, the hazard ratio (HR) for the first DKA among those with an eGFR > 120 mL/min/1.73 m² was not significantly higher than that of the reference group (HR, 1.33).

“I was not surprised, given the cohort’s characteristics and the small number of events in the lower eGFR strata,” which limits the ability to detect modest effects, Bakhsh said.

Limitations also included the relatively young baseline age and good health of the volunteer participants, lack of central adjudication to confirm DKA, and the lack of data on potentially confounding variables, including socioeconomic status and alcohol intake, the study researchers noted.

However, the results were strengthened by the large size and long time frame of the study, they pointed out.

The lack of increased DKA risk for individuals with T1D and reduced eGFR supports the design of clinical trials of SGLT inhibitors in this patient population to identify kidney-protective benefits, they concluded. 

In Contrast With Previous Data

The researchers acknowledged that their findings contrast with those from a previous study, the FinnDiane study, which reported higher DKA risk among individuals with baseline end-stage kidney disease and in those with baseline eGFR ≤ 60 mL/min/1.73 m², excluding end-stage kidney disease (HRs, 2.09 and 1.71, respectively).

Yet, Bakhsh and colleagues noted in their discussion that their time-updated analysis, which classified the eGFR level immediately preceding each DKA event, potentially resulted in a more relevant estimate of risk associated with current kidney function compared to the FinnDiane study.

“Ongoing SGLT inhibitor trials in T1D and emerging tools like continuous ketone monitors may enable safer, targeted use in selected patients,” Bakhsh told Medscape Medical News. Looking ahead, future studies should prospectively assess DKA risk in patients with established CKD (including eGFR < 30 mL/min/1.73 m²), use central adjudication/ketone data, identify benefit subgroups, and test implementation strategies such as education and ketone monitoring to mitigate DKA risk, Bakhsh said. 

“Positive results could inform regulatory reconsideration of on‑label indications,” he added. 

‘Less Than Convincing at Present’

As kidney‑protective medicines are being considered more broadly, research to clarify whether reduced kidney function contributes to DKA risk on its own is important, Charles Leonard, PharmD, MSCE, MPH, associate professor at the Perelman School of Medicine, University of Pennsylvania, in Philadelphia, told Medscape Medical News.

“Distinguishing causation from correlation is critical before concluding that low eGFR is a risk‑enhancing state,” added Leonard, who was not involved in the study.

“The new data were noteworthy in that lower eGFR didn’t appear to be associated with higher DKA risk after adjustment, particularly given FinnDiane’s earlier signals, although with wide confidence intervals at the lowest eGFR levels,” said Leonard. 

However, non-significance does not automatically convey an absence of risk, he pointed out. 

“Given limited precision at very low eGFR and the study’s potentially misplaced emphasis on statistical significance, I see this as less than convincing evidence at present,” said Leonard. 

“Further research is needed, such as a rigorously designed prospective study, to better define the kidney‑benefit vs DKA‑risk balance in T1D, especially in advanced kidney disease where uncertainty remains high,” he added.

The study was funded by Diabetes Canada. The researchers disclosed having no financial conflicts of interest, and Bakhsh noted that the researchers used the publicly available data from the National Institutes of Health Data Repository and conducted the research independent of the DCCT/EDIC Study Group. Leonard disclosed having no financial conflicts of interest.