Dapagliflozin-associated euglycemic diabetic ketoacidosis in a patient with type 2 diabetes mellitus

Abstract

Rationale: Rare cases of euglycemic diabetic ketoacidosis (eu-DKA) have been reported after the administration of sodium-glucose cotransporter-2 (SGLT-2) inhibitors. No reports have described eu-DKA complicated by hypernatremia due to SGLT-2 inhibitors. Patient concerns: A 76-year-old woman with a 40-year history of type 2 diabetes mellitus (DM), for which metformin (1000 mg/day) and dapagliflozin (10 mg/day) were prescribed, presented with malaise, fever, and oliguria. On presentation, her white blood cell count (11,800/μL), serum creatinine (3.2 mg/dL), and C-reactive protein (54 mg/L) were abnormal. Bilateral pyeloureteritis and diffuse paralytic ileus were present. She received intravenous antibiotics and total parenteral nutrition, and was asked to fast. Her renal function and ileus briefly improved. Oral hypoglycemic agents, metformin and dapagliflozin, along with enteral feeding were reinstituted on day 3 of hospitalization. However, on day 6 of hospitalization, the patient developed an altered state of consciousness including confusion, lethargy, and stupor. Several laboratory abnormalities suggestive of ketoacidosis with euglycemia were noted. Diagnoses: The patient was diagnosed with eu-DKA accompanied by severe hypernatremia (corrected serum Na+ concentration, 163 mEq/L) and hypokalemia following dapagliflozin re-administration. Interventions: The patient was treated with indicated intravenous fluid therapy. Dapagliflozin use was discontinued. Outcomes: The patient's mental status and laboratory findings improved gradually, and she was discharged on maintenance doses of insulin and metformin on day 14 of hospitalization. Lessons: Acute illnesses such as diffuse paralytic ileus and urinary tract infection, and dietary restrictions or fasting in patients with DM can be considered potential predisposing factors for SGLT-2 inhibitor-associated eu-DKA. For patients with diabetes in the setting of acute morbidity, timely resumption of the SGLT-2 inhibitor therapy should be carefully determined. In addition, eu-DKA due to SGLT-2 inhibitor use may be accompanied by electrolyte disturbances such as hypernatremia and hypokalemia.

Acute Pancreatitis-Induced Euglycemic Diabetic Ketoacidosis

“…SGLT-2is are a class of drugs that work by inhibiting the SGLT2 protein, which decreases the concentrations of plasma glucose by inhibiting proximal tubular reabsorption of glucose in the kidney [ 6 ]. The proposed mechanism of SGLT-2i-induced euDKA suggests that the lowered glucose levels lead to decreased endogenous insulin production by the pancreatic β-cells [ 3 ]. This lower dose of insulin may be insufficient to suppress lipolysis and hepatic ketogenesis.…”

“…This lower dose of insulin may be insufficient to suppress lipolysis and hepatic ketogenesis. It also stimulates the pancreatic α-cells, promoting glucagon secretion [ 3 ]. In addition, SGLT-2 inhibitors increase the reabsorption of acetoacetate in the renal tubules, which increases the blood level of ketone bodies [ 3 ].…”

“…It also stimulates the pancreatic α-cells, promoting glucagon secretion [ 3 ]. In addition, SGLT-2 inhibitors increase the reabsorption of acetoacetate in the renal tubules, which increases the blood level of ketone bodies [ 3 ]. Some predisposing risk factors for SGLT-2 inhibitor-associated DKA include latent autoimmune diabetes in adults, major surgeries, insulin noncompliance, acute medical illness, low-carbohydrate diet, acute pancreatitis, and dehydration [ 3 ].…”

“…Dehydration is an early characteristic of acute pancreatitis which is believed to occur secondary to an increase in [Ca2+]i levels [ 2 ]. The presence of acute pancreatitis and dehydration may serve as predisposing factors for SGLT-2 inhibitor-associated diabetic ketoacidosis (DKA) [ 3 ]. SGLT-2is block the SGLT-2 protein, thereby inhibiting glucose reabsorption from the proximal renal tubule promoting glycosuria [ 4 ].…”

“…SGLT-2is block the SGLT-2 protein, thereby inhibiting glucose reabsorption from the proximal renal tubule promoting glycosuria [ 4 ]. The reduced blood glucose levels decrease the secretion of endogenous insulin by pancreatic β-cells leading to increased hepatic ketogenesis [ 3 ]. In this case report, we present a 41-year-old male who developed acute pancreatitis and euglycemic diabetic ketoacidosis (eu-DKA) in the setting of concomitant GLP1-RAs and SGLT-2i use.…”