Diabetic Ketoacidosis Risk in Sodium-Glucose Cotransporter-2 Inhibitors vs Glucagon-Like Peptide-1 Receptor Agonists Initiators with CKD Stages 3-4 and Type 2 Diabetes

Feb 2, 2026Kidney360

Risk of Diabetic Ketoacidosis in People with Moderate to Severe Kidney Disease and Type 2 Diabetes Starting SGLT2 Inhibitors Compared to GLP-1 Receptor Agonists

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Abstract

SGLT2i initiators had a 40% increased risk of hospitalization for diabetic ketoacidosis compared to GLP1RA initiators.

The study involved 143,858 patients, equally divided between SGLT2i and GLP1RA initiators.
Incidence rates for hospitalization with diabetic ketoacidosis were 4.37 events per 1,000 person-years for SGLT2i and 3.13 for GLP1RA.
The rate difference was 1.23 events per 1,000 person-years, with confidence intervals indicating statistical significance.
The number needed to harm for SGLT2i compared to GLP1RA was 813 per 1,000 person-years.
Increased risk of hospitalization with diabetic ketoacidosis was consistent across various patient subgroups.

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BACKGROUND: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1RA) are effective in managing chronic kidney disease (CKD) and type 2 diabetes (T2D). However, there are concerns about an increased risk of diabetic ketoacidosis (DKA) associated with the use of SGLT2i, particularly in patients with CKD.

METHODS: The is a population-based, new-user, active comparator cohort study comparing SGLT2i vs. GLP1RA initiators using three U.S. healthcare databases: Optum's de-identified Clinformatics® Data Mart (2014-2024), Merative MarketScan (2014-2022), and Medicare Fee-for-Service (2014-2020). The exposure is initiation of either SGLT2i or GLP1RA, defined as a new prescription without prior use in 365 days. The primary outcome was hospitalization with DKA identified via inpatient ICD-9/10 codes. Incidence rates (IRs), rate differences (RDs), and hazard ratios (HRs) were calculated.

RESULTS: After 1:1 propensity score matching, the study population included 143,858 patients, 71,929 in the SGLT2i arm and 71,929 in the GLP1RA arm. The mean age (standard deviation) was 71.28 (8.16) years, and 48.8% were female. Patients initiating SGLT2i had higher risk of hospitalization with DKA compared to GLP1RA initiators (IR 4.37 vs. 3.13 events per 1,000 person-years; RD 1.23 [95% CI 0.54, 1.92]; HR 1.40 [95% CI 1.16, 1.68]). The number needed to harm was 813 per 1,000 person-years for SGLT2i compared to GLP1RA initiation. Results remained consistent in subgroup analyses stratified by age (<70 vs. ≥70 years), sex, body mass index (<30 vs. ≥30 kg/m2), frailty status, baseline cardiovascular disease, diabetic retinopathy, hyperglycemia, metformin use, and insulin use.

CONCLUSIONS: The incidence rate of DKA among SGLT2i and GLP1RA initiators remained low overall. However, SGLT2i use was associated with a 40% increased risk of hospitalization with DKA compared to GLP1RA use among patients with CKD stages 3-4 and T2D. Clinicians should remain vigilant when monitoring patients with CKD and T2D treated with SGLT2i.

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Diabetic Ketoacidosis Risk in Sodium-Glucose Cotransporter-2 Inhibitors vs Glucagon-Like Peptide-1 Receptor Agonists Initiators with CKD Stages 3-4 and Type 2 Diabetes

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