Tirzepatide: Failing the Acid Test

Introduction: High anion gap metabolic acidosis (HAGMA) is defined by a pathophysiological reduction in blood bicarbonate concentration, a blood pH <7.35, and an anion gap >12 mEq/L. Ketoacidosis is a common cause of HAGMA. Tirzepatide is a glucagon-like peptide1/glucose-dependent insulinotropic peptide receptor agonist, approved for weight management. We report a rare case of life-threatening trizepatide induced euglycemic ketoacidosis that was rapidly followed by refeeding syndrome. Case Description: A 34-year-old female with class 3 obesity presented with multiple episodes of vomiting and nausea for 4 days. She denied illicit drug use, alcohol consumption, fever, chills, abdominal pain, muscle aches, foreign toxic ingestion, sick contacts, or travel. All her close contacts were asymptomatic. Four months ago, she was started on and gradually increased to 10mg Tirzepatide. She lost 35 pounds with minimal gastrointestinal symptoms. Physical exam showed a clinically well patient with no abdominal pain on palpation. Initial labs were notable for: anion gap of 26.3, bicarbonate of 6.7, pH of 7.01, pCO2 of 21, B-hydroxybutyrate 9.45, lactate of 0.9, and a normal osmolar gap. She was hospitalized for HAGMA and given 2 liters of Isolyte,150 mEq of sodium bicarbonate, and Dextrose 5% with NaHCO3 for 12 hours. She was started on metoclopramide and required multiple substantial potassium and phosphorus repletion. Her anion gap and symptoms resolved by day 3. She still had metabolic acidosis on discharge, but her pH normalized and Tirzepatide was discontinued. Discussion: Glucose is the primary energy source and when glucose is limited, the liver produces ketone bodies by breaking down free fatty acids mobilized from adipose tissue. This process is stimulated by the combination of low insulin levels and high glucagon levels; which is common in type 1 diabetics, insulin-resistant type 2 diabetics and with malnutrition. Tirzepatide is approved for weight management in non-diabetic obese patients, and HAGMA secondary to ketoacidosis has been reported, but rarely with life-threatening acidemia. In this healthy young patient, just four days of symptoms resulted in life-threatening metabolic derangements. She was profoundly malnourished with lab values indicating refeeding syndrome only 12 hours after treatment. This case highlights the potential of life-threatening starvation ketoacidosis induced by the tirzepatide.