A 34-year-old woman with a history of type 1 diabetes mellitus (T1DM) with baseline HbA1c of 9.1%, cerebral palsy and chronic constipation was admitted to intensive care unit with intractable vomiting, diarrhea and severe metabolic acidosis. Prior to hospitalization she had been receiving an aggressive bowel regimen due to persistent constipation. Her medication regimen included basal-bolus insulin regimen. Three weeks prior to the presentation she was started on a combination of empagliflozin-linagliptin (SGLT-2 inhibitor + DPP4 inhibitor) and was noted to have improvement in glycemic control by her caregiver. Basal insulin was held two days prior to admission due to her poor oral intake with relatively controlled blood glucose levels. Initial laboratory findings were remarkable for profound anion-gap metabolic acidosis with a pH 7.01, HOC3- 2, pCO2 10, anion gap 33, lactic acid 1.4 and elevated plasma acetone. Blood glucose on admission was 255 mg/dL with most readings below 200 mg/dl on subsequent serial monitoring. Her clinical picture was consistent with diabetic ketoacidosis (DKA), but considered unusual due to relatively mild hyperglycemia.
She was treated with aggressive fluid resuscitation, insulin and bicarbonate infusions. She remained profoundly acidotic for the first 24 hours, but anion gap eventually closed, bicarbonate normalized and her overall clinical condition improved. She was transitioned to a basal-bolus insulin regimen followed by full uneventful recovery over next few days. She was discharged on basal-bolus insulin regimen, but the combination oral agent empagliflozin-linagliptin was discontinued.
Discussion:
DKA is a serious complication of T1DM due to an absolute insulin deficiency and is defined by marked hyperglycemia (>250 mg/dl), high anion gap metabolic acidosis and elevated plasma ketones. Euglycemic DKA (euDKA) is an unusual form of DKA, defined as DKA without marked hyperglycemia (BG <250 mg/dl).
SGLT-2 inhibitors, such as empagliflozin, lower glucose levels by inhibiting proximal tubular glucose reabsorption and increasing glycosuria. This increased renal clearance of glucose leads to deceptively lower blood glucose levels in the setting of illness, causing a reduction in insulin doses at a time of enhanced insulin resistance, thereby tipping the balance toward ketosis. This process remains unrecognized and overlooked by both patient and the provider leading to delay in instituting treatment.
Conclusions:
SGLT-2 inhibitors are not approved by the FDA in the setting of T1DM, and emerging case reports are indicating its association with euDKA. Therefore, hospitalist should be cautious about its off label use in patient with Type 1 DM, especially on admission and discharge medication reconciliation. It is also critical to be aware that DKA can occur in the setting of relative euglycemia, which is under-recognized and under-reported, but a life-threatening complication of diabetes.