SUN-633 - Severe Non-Diabetic Ketoacidosis Associated with Supratherapeutic Compounded Retatrutide Use

Background: Retatrutide is an investigational triple GIP/GLP-1/glucagon receptor agonist currently in phase 2 clinical trials for obesity and type 2 diabetes. In clinical trials, doses of 1-12 mg weekly demonstrated up to 24% weight loss at 48 weeks, with dose-dependent increases in beta-hydroxybutyrate concentrations up to 66% above baseline attributed to glucagon receptor agonism (Rosenstock et al., Lancet 2023; Jastreboff et al., NEJM 2023). Despite lacking FDA approval, compounded versions are being marketed online, posing significant safety risks.

Case Presentation: A 20-year-old female with history of Graves' disease status post radioactive iodine ablation and hypothyroidism, with no history of diabetes, presented with several days of nausea, vomiting, and inability to tolerate oral intake. Laboratory evaluation revealed severe non-diabetic ketoacidosis with venous pH 7.21, anion gap 21 mEq/L, bicarbonate 9 mEq/L, and beta-hydroxybutyrate 7.0 mmol/L. Hemoglobin A1c was 4.8% and C-peptide was 4.8 ng/mL, confirming no underlying diabetes. The patient had been following a severely restricted 500-calorie daily diet after losing 40 pounds. One month prior, she purchased compounded retatrutide from an online pharmacy and self-administered weekly injections, patient reported escalating from 10 mg to 20 mg to 30 mg. Confirmed doses offered by the compounding pharmacy on their website, suggesting she likely received a dose substantially exceeding the maximum 12 mg studied in clinical trials.
Clinical Course: Endocrinology was consulted for metabolic acidosis. The patient was treated with intravenous fluids, glucose supplementation, and supportive care with resolution of ketoacidosis.

Conclusion: While physiologic ketonemia occurs with retatrutide due to glucagon receptor agonism, only one case of ketoacidosis was reported across phase 2 trials involving over 600 participants receiving controlled doses up to 12 mg weekly. Our patient likely received a supratherapeutic dose from an improperly compounded product, combined with severe caloric restriction and medication-induced inability to eat. This case underscores ADA and AACE recommendations against compounded incretin-based products and highlights the need for clinician counseling regarding unregulated online weight loss medications.

Retatrutide, a GIP, GLP-1 and Glucagon Receptor Agonist, for People With Type 2 Diabetes: A Randomised, Double-Blind, Placebo and Active-Controlled, Parallel-Group, Phase 2 Trial Conducted in the USA.
Lancet. 2023. Rosenstock J, Frias J, Jastreboff AM, et al.

Triple–Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial.
The New England Journal of Medicine. 2023. Jastreboff AM, Kaplan LM, Frías JP, et al.

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