Sodium-glucose cotransporter-2 (SGLT2) inhibitor-associated ketoacidosis (KA) may have a prolonged duration or potential for relapse, which is otherwise uncharacteristic of classical DKA in patients with diabetes not treated with SGLT2 inhibitors.

At the time of this writing, there are six single-ingredient SGLT2 inhibitors approved by the United States Food and Drug Administration (FDA). Canagliflozin,1 Dapagliflozin,2 Empagliflozin,3 Ertugliflozin,4 and Bexagliflozin5 are indicated as an adjunct to diet and exercise to improve glycemic control in adults with Type 2 diabetes mellitus (T2DM) and are not recommended for use to improve glycemic control in patients with Type 1 diabetes mellitus (T1DM). Sotagliflozin,6 which does not have United States Prescribing Information (USPI) indication to improve glycemic control, is indicated to reduce the risk of cardiovascular death, hospitalization for heart failure and urgent heart failure visit in adults with heart failure or T2DM, chronic kidney disease, and other cardiovascular risk factors. Empagliflozin and dapagliflozin have indications in patients with heart failure, and also in adults with chronic kidney disease, in addition to above stated indications for glycemic control. The heart failure and chronic kidney disease indications for sotagliflozin, empagliflozin and dapagliflozin apply to patients without diabetes, as well as patients with T2DM. Canagliflozin has cardiovascular disease and kidney disease indications in adults with T2DM. This is not a complete list of indications and several fixed dose combination products containing SGLT2 inhibitors are also approved by the FDA. Additional details can be found at Drugs@FDA.7

Information about KA associated with SGLT2 inhibitor use is conveyed in the Warnings and Precautions (WP) of all U.S. approved SGLT2 inhibitors and has also been communicated in multiple FDA Drug Safety Communications published in May 2015, March 2020, and March 2022.8 Characteristics of SGLT2 inhibitor associated KA listed in the WP section of the USPI include signs and symptoms, risk factors, as well as precipitating conditions (e.g., under-insulinization due to insulin dose reduction or missed insulin doses, acute febrile illness, reduced caloric intake, ketogenic diet, surgery, volume depletion, and alcohol abuse) and monitoring.2

SGLT2 inhibitors increase the risk of KA in patients. KA in patients treated with SGLT2 inhibitors may present with blood glucose levels (e.g., glucose less than 250 mg/dL) that are below those typically expected for patients with diabetes not using SGLT2 inhibitors who experience KA. This may be related to the glucosuric effect of SGLT2 inhibitors,9 resulting from inhibition of filtered glucose reabsorption in the proximal tubules of the kidney.10 Furthermore, the pharmacologic half-life of SGLT2 inhibitors ranges from 11-35 hours1, 2, 3, 4, 5, 6 and would be expected to contribute to the duration of this effect.

For comparison, classical DKA generally resolves with intravenous insulin treatment and fluid/electrolyte replenishment, resulting in anion gap improvement and ketosis resolution, which may take hours to days.11,12 The term ‘classical DKA’ will be used here to refer to a biochemical state of hyperglycemia, ketonemia and metabolic acidosis, generally related to an absolute or relative insulin deficiency with concurrent elevated counter-regulatory hormones (glucagon, catecholamines, cortisol, growth hormone) resulting in increased glucose synthesis, ketogenesis and decreased glucose utilization, that more commonly occurs in patients with T1DM, but can also occur in patients with T2DM.13 During treatment of classical DKA (in patients with diabetes not receiving an SGLT2 inhibitor), hyperglycemia tends to improve faster than KA, and dextrose is often added to fluid therapy to avoid hypoglycemia with continued insulin therapy, until ketonemia is resolved.11

This safety signal evaluation of prolonged or relapsed KA associated with SGLT2 inhibitor use was prompted by a literature report by Bobrowski et al. of an 81-year-old female patient with T2DM, who was diagnosed with euglycemic DKA and continued to have elevated serum ketone levels 13 days after discontinuation of canagliflozin despite initiation of insulin and dextrose infusions to treat euglycemic DKA.14 A cohort study from Jeon at al. noted that intensive care treatment of KA was longer in SGLT2 inhibitor users compared to non-users (4 vs. 2 days).15

The purpose of this review is to describe the characteristics of cases of prolonged KA or relapsed KA, as well as related terms persistent ketonemia, persistent ketonuria and persistent glucosuria in adults with T2DM receiving SGLT2 inhibitors that have been reported to the FDA Adverse Event Reporting System (FAERS) database, medical literature, or both.