(P19) A Case of Euglycemic DKA Associated with an SGLT2 Inhibitor and Exogenous Hormone Use

Chief Complaint : A 35-year-old woman presents for evaluation of two days of dyspnea on exertion, palpitations, and abdominal pain.

History of Present Illness : A 35-year-old woman with a history of type II diabetes mellitus and adenomyosis presented with progressive dyspnea on exertion, palpitations, and abdominal pain for two days. She was receiving long term treatment with insulin glargine 15 units once nightly, dapagliflozin propanedial 10 mg daily, dulaglutide 1.5 mg weekly as well as norethindrone. Two days prior to her presentation to the ED, her norethindrone dose was increased from 5 mg daily to 5mg twice daily due to worsening uterine bleeding. Over the last 48 hours, her blood glucose levels, typically between 150-200, had increased to the 300s. She reported strict compliance with her medication regimen and denied changes to her diet. She denied any recent alcohol use. The morning of her presentation to the emergency department, she took 10 extra units of insulin glargine given the elevated blood glucose readings.

Pertinent Physical Exam: Vitals: HR 130, BP 99/73, RR 24, Rectal Temperature 98.9, Oxygen Saturation 98%
General: moderate acute distress, tachypneic
HEENT: normocephalic, atraumatic, dry mucous membranes
Pulmonary: Lungs CTAB
Cardiac: tachycardic, regular rhythm, no murmurs, rubs, or gallops
Abdomen: soft, nontender, nondistended
Extremities: moving extremities freely, fully alert and oriented, no cyanosis, clubbing or edema on extremities, no calf tenderness bilaterally
Neuro: no slurred speech, no facial droop, no gross weakness

Pertinent Laboratory Data: A bedside fingerstick was 138. EKG revealed sinus tachycardia at a rate of 128 and S1Q3T3 pattern. A stat CT angiogram of the chest was performed and pulmonary embolism was excluded. Laboratory results were remarkable for a venous pH of 7.1, bicarbonate of 10, glucose of 144, anion gap of 20, and 4+ urine ketones. Ethylene glycol and methanol levels were undetectable, and the lactic acid level was within normal limits. A beta-hydroxybutyrate level was >45. The remainder of her diagnostic work up revealed no evidence of infection such as pneumonia, urinary tract infection, bacteremia, or viral syndrome.

Case Discussion: We present the first case, to our knowledge, of euglycemic diabetic ketoacidosis triggered by exogenous hormone use in a patient on an SGLT2 inhibitor. Our patient was on long term norethindrone but had doubled her dose two days prior to her presentation. The increase in dosage likely caused a hyperglycemic state by reducing the efficacy of the dapagliflozin and led to a resultant ketoacidotic state. In this case, the fingerstick of 138 on presentation led to a delayed diagnosis of diabetic ketoacidosis.

There have been several case reports and studies associating the use of SGLT2 inhibitors with euglycemic DKA,2,, leading the FDA to add a warning label about the potential for euglycemic DKA. Careful attention should be paid to the metabolic panel in these patients, as derangements in the anion gap and bicarbonate levels may be the only initial clues to suggest an underlying ketoacidotic state in these patients. Oral contraceptives have been shown to cause increased insulin resistance and could potentially alter the rate of release of insulin from pancreatic beta cells. Furthermore, norethindrone specifically has been shown to possibly alter the peripheral action of insulin causing a decrease in glucose utilization.

There are important lessons gleaned by this case of euglycemic DKA triggered by exogenous hormone use, in a diabetic patient on an SGLT2 inhibitor. Drug interactions are common and can be easily missed. In the Emergency Department setting, it is important to thoroughly investigate diabetic patients with elevated anion gap metabolic acidosis or DKA signs and symptoms regardless of the blood glucose levels. Patients prescribed SGLT2 inhibitors should be educated on the potential adverse effects of the medication and drug interactions including the possibility of DKA, as well as the signs and symptoms to be on the lookout for.

References and Acknowledgements (Optional): Yu X, Zhang S, Zhang L. Newer Perspectives of Mechanisms for Euglycemic Diabetic Ketoacidosis. Int J Endocrinol. 2018;2018:7074868.

Peters AL, Buschur EO, Buse JB, et al. Euglycemic Diabetic Ketoacidosis: A Potential Complication of Treatment With Sodium-Glucose Cotransporter 2 Inhibition. Diabetes Care 2015; 38:1687.

Rosenstock J, Ferrannini E. Euglycemic Diabetic Ketoacidosis: A Predictable, Detectable, and Preventable Safety Concern With SGLT2 Inhibitors. Diabetes Care. 2015 Sep;38(9):1638-42. doi: 10.2337/dc15-1380. PMID: 26294774.

Singh, Mahakpreet & Kumar, Anoop. 2018. Risks associated with SGLT2 Inhibitors: An Overview. Current Drug Safety. 13. 10.2174/1574886313666180226103408.

Zinman, Bernard et al. Empagliflozin, Cardiovascular Outcomes, And Mortality In Type 2 Diabetes. New England Journal Of Medicine, vol 373, no. 22, 2015, pp. 2117-2128. Massachusetts Medical Society, doi:10.1056/nejmoa1504720.

Mahaffey, Kenneth W. et al. Canagliflozin For Primary And Secondary Prevention Of Cardiovascular Events. Circulation, vol 137, no. 4, 2018, pp. 323-334. Ovid Technologies (Wolters Kluwer Health), doi:10.1161/circulationaha.117.032038.

Ueda P, Svanström H, Melbye M, Eliasson B, Svensson AM, Franzén S, Gudbjörnsdottir S, Hveem K, Jonasson C, Pasternak B. Sodium glucose cotransporter 2 inhibitors and risk of serious adverse events: nationwide register based cohort study. BMJ. 2018 Nov 14;363:k4365. doi: 10.1136/bmj.k4365. PMID: 30429124; PMCID: PMC6233755.

Fralick M, Schneeweiss S, Patorno E. Risk of Diabetic Ketoacidosis after Initiation of an SGLT2 Inhibitor. N Engl J Med. 2017 Jun 8;376(23):2300-2302. doi: 10.1056/NEJMc1701990. PMID: 28591538.

FDA Drug Safety Communication. 2020. FDA revises labels of SGLT2 inhibitors for diabetes to include warning. U.S. Food and Drug Administration. https://www.fda.gov/drugs/drug-safety-and-availability/fda-revises-labels-sglt2-inhibitors-diabetes-include-warnings-about-too-much-acid-blood-and-serious.

Wynn, V., Adams P.W., Godsland I., Melrose J., Niththyananthan R., Oakley N.W., and Seed M.. 1979. Comparison of effects of different combined oral-contraceptive formulations on carbohydrate and lipid metabolism. The Lancet 1: 1045–9

Patiño, V.M., Díaz-Toledo B., and del Barrio P.G.. 2008. Anticoncepción en la Mujer con Diabetes. Avances en Diabetología 24: 205–9

Spellacy, W.N., Buhi W.C., and Birk S.A.. 1975. Effects of norethindrone on carbohydrate and lipid metabolism. Obstetrics and Gynecology 46: 560–3