Case Presentation: A 64-year-old man with type 2 diabetes mellitus presented with three days of severe epigastric abdominal pain, vomiting, polyuria, and subjective dyspnea. Following the onset of illness, he stopped taking his home medications including insulin glargine and empagliflozin.Temperature was 97.5°F, heart rate 112 beats per minute, blood pressure 130/81 mmHg, respiratory rate 23 breaths per minute, and oxygen saturation 95% on room air. He was alert and oriented but appeared restless with labored breathing. Crackles were auscultated in the right lower lung field. Epigastric tenderness was present without rebound or guarding.Complete blood count was normal. Serum bicarbonate was 8 mg/dL with an anion gap of 28 mEq/L, and blood glucose was 157 mg/dL. Arterial blood gas showed pH 7.10, pCO2 22 mmHg, and pO2 112 mmHg. Serum osmolality was grossly elevated at 363 mOsm/kg. Lipase was 751 IU/L. Urinalysis showed ketones and serum β-hydroxybutyrate was 11.9 mmol/L. Ethanol, volatile alcohols, and urine toxicology were negative. CT of the abdomen revealed edema and fat stranding of the pancreas, consistent with acute pancreatitis. The patient was diagnosed with euglycemic diabetic ketoacidosis and started on a continuous insulin infusion as well as intravenous fluids containing 10% dextrose. The acidemia and anion gap gradually resolved. Pancreatitis improved with supportive care and opioid analgesia. Empagliflozin was discontinued.
Discussion: The sodium-glucose linked transporter 2 (SGLT-2) inhibitors, including empagliflozin, canagliflozin, and dapagliflozin, promote glycosuria by inhibiting glucose resorption in the proximal renal tubule. However, these medications have been associated with euglycemic diabetic ketoacidosis (DKA), prompting the US Food and Drug Administration to issue a warning in 2015. Euglycemic DKA with SGLT-2 inhibitors is thought to result from persistent glycosuria despite ongoing insulin deficiency, poor cellular glucose uptake, and ketogenesis. With full-dose empagliflozin, urinary glucose losses reach 50-100 g/day, which represents 200-400 kcal/day of nutritional content. Decreased plasma glucose removes the stimulus for insulin secretion, promoting lipolysis, fatty acid oxidation, and ketogenesis. SGLT-2 inhibitors also independently increase glucagon secretion by pancreatic alpha cells, further favoring ketoacid production.Euglycemic DKA should remain a consideration in normoglycemic patients with a compatible history, high anion gap metabolic acidosis, and positive ketones. As in all cases of DKA, these patients require aggressive volume resuscitation, electrolyte repletion, and continuous insulin infusion to inhibit ketogenesis. Dextrose-containing fluids are often necessary from the outset to prevent hypoglycemia. Once the ketoacidosis resolves and the patient tolerates oral intake, insulin is switched to the subcutaneous route.
Conclusions: SGLT-2 inhibitors are commonly prescribed in type 2 diabetes, and off-label use in type 1 diabetes is widespread. As such, internists, intensivists, and emergency physicians will likely encounter increasing incidence of euglycemic DKA. Primary care providers and endocrinologists should also educate their patients to use home ketone testing as an early indicator of DKA when experiencing malaise or gastrointestinal symptoms, regardless of blood glucose level.