SGLT2 inhibitor use associated with increased diabetic ketoacidosis risk, especially with elevated HbA1c

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Diabetes, obesity & metabolism Published June 1, 2026 Medically reviewed June 1, 2026 Study authors: Seidu Samuel, Kunutsor Setor K, Taguiam Erwin, Khunti Kamlesh PubMed ↗ DOI ↗ By Dr. Amelia Tan, PhD · Internal Medicine & Chronic Disease

Key Takeaway

Consider that SGLT2 inhibitor use is associated with increased DKA risk, particularly in patients with elevated HbA1c.

This is a systematic review and meta-analysis of observational and randomized trials examining the risk of diabetic ketoacidosis (DKA) with SGLT2 inhibitor use in adults with type 2 diabetes. The authors synthesized evidence on DKA risk overall and stratified by baseline HbA1c level. In observational studies, DKA risk was higher with elevated HbA1c (RR 1.63, 95% CI 1.46-1.81) but not significantly increased with lower HbA1c (RR 1.10, 95% CI 0.80-1.51). In randomized trials, DKA risk was increased in both high HbA1c (RR 2.37, 95% CI 1.44-3.90) and low HbA1c groups (RR 2.01, 95% CI 0.84-4.79). Elevated HbA1c was independently associated with DKA risk among SGLT2 inhibitor users (RR 1.50, 95% CI 1.17-1.92). The authors note a narrow range of HbA1c values across studies limits definitive conclusions and that further research is warranted. Practice relevance is that SGLT2 inhibitor use is associated with increased DKA risk, particularly in those with elevated baseline HbA1c, especially in real-world settings. Evidence certainty ranged from high to low, and the association does not establish causation.

Study Details

Study typeMeta analysis

EvidenceLevel 1

PublishedJun 2026

PMID41943706

View Original Abstract ↓

AIMS: There is ongoing uncertainty about whether initiating sodium-glucose co-transporter 2 inhibitor (SGLT-2i) therapy in individuals with type 2 diabetes (T2D) who have elevated baseline HbA1c levels may lead to an additive or potentially synergistic increase in the risk of diabetic ketoacidosis (DKA). This systematic review and meta-analysis aimed to investigate the interrelationship between baseline HbA1c, SGLT-2i use and the risk of DKA in adults with T2D. MATERIALS AND METHODS: Observational cohort studies and randomized controlled trials (RCTs) comparing SGLT-2is with placebo or active comparators in adults with T2D that reported baseline HbA1c and DKA events were identified through searches in MEDLINE, Embase, CENTRAL, ClinicalTrials.gov and bibliographies up to January 2026. Key characteristics of the study design, patients, interventions and outcomes were extracted. Risk of bias was evaluated. Risk ratios (RRs) were pooled and stratified by HbA1c (high vs. < low). Effect modification was assessed using random-effects meta-regression. RESULTS: Twenty-two studies (15 cohorts, 7 RCTs) were included. SGLT-2is were associated with increased DKA risk overall. In observational studies, risk was higher in those with elevated HbA1c (RR 1.63, 95% CI 1.46-1.81) but not in those with lower HbA1c (RR 1.10, 0.80-1.51), with significant effect modification (p = 0.018). In RCTs, pooled RRs were 2.37 (1.44-3.90) and 2.01 (0.84-4.79) in high and low HbA1c groups, respectively, without significant interaction (p = 0.73). Elevated HbA1c was independently associated with DKA among SGLT-2i users (RR 1.50, 1.17-1.92). Evidence certainty ranged from high to low. CONCLUSIONS: SGLT-2i use is associated with an increased risk of DKA in adults with T2D, with a higher risk observed in those with elevated baseline HbA1c, particularly in real-world settings. However, the narrow range of HbA1c values across studies limits definitive conclusions, and further research is warranted. TRIAL REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/view/CRD420251149386: CRD420251149386.