Comparative Rates of Diabetic Ketoacidosis in T2D According to Drug Class

Diabetic ketoacidosis concept. Doctor holding book about disorder.
A higher rate of diabetic ketoacidosis was found with newly prescribed SGLT2 inhibitors vs DPP-4 inhibitors and sulfonylureas in those with type 2 diabetes.

Rates of diabetic ketoacidosis (DKA) were higher among patients with type 2 diabetes (T2D) who were newly prescribed sodium-glucose cotransporter 2 (SGLT2) inhibitors than those who were prescribed dipeptidyl peptidase 4 (DPP-4) inhibitors or sulfonylureas. These findings were recently published in Diabetes Care.

The data for this study were sourced from Optum’s Clinformatics Data Mart Database. Adults with T2D who were prescribed SGLT2 inhibitors, DPP-4 inhibitors, or sulfonylureas for the first time between 2013 and 2019 were assessed for instances of DKA. A propensity matching approach was used to balance cohort differences. Two pairwise comparisons of SGLT2 inhibitors compared with DPP-4 inhibitors (n=85,125) or sulfonylureas (n=72,436) were performed.

The patient cohorts were aged ~60 years and more than half of the cohorts were men and White.

For the SGLT2 inhibitor and DPP-4 inhibitor comparison, the rate of DKA was 6.0 per 1000 person-years (py) for new users of SGLT2 inhibitors and 4.3 per 1000 py for new users of DPP-4 inhibitors.

Stratified by drug, DKA risk was increased among users of canagliflozin (adjusted hazard ratio [aHR], 1.49; 95% CI, 1.19-1.87), dapagliflozin (aHR, 2.16; 95% CI, 1.13-4.10), and empagliflozin (aHR, 1.69; 95% CI, 1.19-2.40).

The rate of DKA for new users of SGLT2 inhibitors was 6.3 per 1000 py compared with 4.5 per 1000 py for new users of sulfonylurea. Stratified by drug, risk for DKA was increased among users of canagliflozin (aHR, 1.73; 95% CI, 1.38-2.18) but not dapagliflozin (aHR, 1.64; 95% CI, 0.96-2.80) or empagliflozin (aHR, 1.19; 95% CI, 0.85-1.68).

In all sensitivity analyses, SGLT2 inhibitors were associated with increased risk for DKA. A significant interaction was observed for gender in the comparison with sulfonylureas (P =.02).

This study may have been limited by not having access to data about glycemic control.

“Clinicians need to be vigilant about this safety signal,” the study authors concluded.

Disclosure: Multiple authors declared affiliations with industry. Please refer to the original article for a full list of disclosures.


Dawwas GK, Flory JH, Hennessy S, Leonard CE, Lewis JD. Comparative safety of sodium–glucose cotransporter 2 inhibitors versus dipeptidyl peptidase 4 inhibitors and sulfonylureas on the risk of diabetic ketoacidosis. Diabetes Care. 2022;dc212177. doi:10.2337/dc21-2177