Case Presentation: A 62-year-old female presented to the Emergency Department with 48 hours of persistent palpitations and a week of poor oral intake, polydipsia, and polyuria. Her past medical history included Type II Diabetes Mellitus treated long-term with metformin and dapagliflozin. Two weeks before presenting to the Emergency Department, she transitioned from dulaglutide to tirzepatide due to an increase in her hemoglobin A1c to 7.3%.Her physical exam was notable for tachycardia to 140 BPM, volume depletion, and a notable fruity odor of her breath. The initial complete metabolic panel revealed serum bicarbonate of 5 mmol/L with an anion gap of 31. Her blood glucose was 107 mg/dL, lactic acid was 1.5 mmol/L and venous pH was 7.1. The patient was admitted to the intensive care unit for euglycemic diabetic ketoacidosis (EDKA). She was treated with intravenous fluids, bicarbonate, and insulin and her home diabetic medications were held. She was transferred to the medical floor after her anion gap normalized and oral intake improved. She maintained appropriate blood glucose levels without supplemental insulin and was discharged home with recommendations to continue metformin, restart dulaglutide, and stop tirzepatide and dapagliflozin. In follow-up after her admission, she was transitioned back to tirzepatide in combination with metformin, which she has tolerated well.
Discussion: EDKA is defined by blood glucose < 250mg/dL, serum pH < 7.3, and bicarbonate level < 18 mEq/L and can be caused by poor carbohydrate intake, alcoholic ketoacidosis, sepsis, and pancreatitis. More recently, SGLT-2 inhibitors have been identified as triggers of EDKA and carry a warning for this adverse effect. In EDKA, glucose is transported to the urine for excretion via an insulin-independent mechanism. As serum glucose levels decline, insulin secretion decreases, and energy production shifts from glycolysis to ketosis. Less commonly, GLP-1 agonists including semaglutide and tirzepatide have been described in case reports to cause EDKA, likely due to excessive appetite suppression and reduced carbohydrate intake. However, there are no prior reports of EDKA caused by combination therapy with tirzepatide and dapagliflozin as in this case. In this case, we suspect profound appetite suppression due to starting tirzepatide triggered EDKA in the context of dapagliflozin. The patient subsequently tolerated tirzepatide after discontinuation of dapagliflozin without complication. This case highlights an uncommon but life-threatening complication of combination therapy that clinicians should be aware of.
Conclusions: In this case, we describe a patient who developed life-threatening euglycemic diabetic ketoacidosis (EDKA) after initiation of tirzepatide for the treatment of diabetes in combination with dapagliflozin. EDKA was triggered by significant appetite suppression from tirzepatide in the context of dapaglifozin. The patient subsequently tolerated the re-introduction of tirzepatide after discontinuation of dapagliflozin without complication. EDKA is a known adverse effect of SGLT-2 inhibitors and is described rarely in case reports with GLP-1 agonist monotherapy. However, this is to our knowledge the first report of EDKA due to combination therapy with these two agents. With the increased use of both drug classes and evidence supporting combination therapy (1), hospitalists should be aware of life-threatening ketoacidosis as a complication of mono or combination therapies with these drugs.