Euglycemic Diabetic Keto Acidosis in a Type 1 Diabetic Patient After Glucose Like Peptide-1 Administration: A Case Presentation

Abstract

Type 1 diabetes mellitus (DM) occurs when insulin-producing beta cells are destroyed. Destruction of these cells and subsequent loss of insulin signaling can cause diabetic keto acidosis (DKA). This case describes a type 1 DM patient who presented to the emergency department (ED) with nausea and vomiting after glucose like peptide-1 (GLP-1) agonist administration. The patient was noted to have elevated anion gap and elevated beta-hydroxybutyrate with euglycemic blood glucose levels. The patient was confirmed to have a functioning insulin pump and then was sent home with nausea control. The patient was not able to consume food without vomiting and therefore did not administer any postprandial insulin. These symptoms were attributed to the GLP-1 agonist. It contributed to suppression of the patient’s appetite while also inhibiting gluconeogenesis, and glycogenolysis resulting in small amounts of blood glucose entering the blood stream, negating the need for a bolus of insulin. The patient was admitted and given dextrose with an insulin drip until the anion gap was returned to normal. As GLP-1 agonists become more popular, this presentation may become more common. If not easily recognized this can lead to patient endangerment and unnecessary medical costs.

Introduction

Type 1 diabetes mellitus (DM) prevalence amounts to about 1.3 million adults in the United States according to the Centers for Disease Control and Prevention (CDC). ¹ One of the complications of type 1 DM is diabetic keto acidosis (DKA), which affects around 560 people per 10 000 people every year. ² When cells fail to receive a sufficient insulin signal, a cascade of events occurs that leads to DKA.^3,4 There are various factors associated with the development of DKA. For instance, in a single study looking at the inciting event of a DKA episode, 36.5% of patients had an underlying infection, 26.8% this was their first presentation of diabetic complications, 22.5% missed doses of insulin or had not taken enough insulin, and in 13.9% of cases there were no DKA risk factors identified. ⁵ Another factor of diabetic management is weight control. One study found 62% of those with type 1 DM were overweight or obese. ⁶ One medical treatment for obesity includes GLP-1 agonists which have been shown to produce a sustained, clinically relevant reduction in body weight. ⁷ Prescribing methods show an increasing number of prescriptions for GLP-1 agonists. ⁸ Patients, like the one seen in this case study, may develop unusual presentations due to comorbidities and drug interactions. It is important to recognize these alternate presentations of treatable conditions.

Case Description

A 40-year-old male with a history of type 1 DM, obesity, hypertension, and dyslipidemia presented for nausea and vomiting. On Monday, May 16th, 2 days prior to admission, his endocrinologist began a glucose-like peptide-1 (GLP-1) agonist (Wegovy) 1.7 mg for weight loss. This was the first medication other than insulin he had taken for his diabetes. Usually, his blood glucose levels are very well controlled with his insulin pump dispensing insulin with continuous glucose monitoring. After his first injection of Wegovy, he began to have chills, nausea, vomiting, and diarrhea. Tuesday morning, May 17th, he presented to the emergency department (ED) and was found to have a blood glucose of 303 mg/dL, anion gap of 16 mEq/L, beta-hydroxybutyrate of 1.4 mmol/L, and was nontoxic appearing. The patient denied consuming any foreign food abnormal from his diet. Exam revealed a Dexcom 6 continuous glucose monitor (CGM) that monitored the patient’s blood sugars. The patient used an insulin pump to deliver 10 units of insulin after meals with 12 units of basal insulin over 24 hours. After confirming his insulin pump was fully functional, conservative management was pursued, and the patient was discharged home with nausea control. On Wednesday, May 18th, he presented with the same worsening symptoms and was noted to have developed a mild leukocytosis with a blood glucose of 171 mg/dL, anion gap of 16 mEq/L, and beta-hydroxybutyrate of 1.8 mmol/L. Again, he was discharged home from the ED with nausea control. Later that evening, he returned to the ED with further worsening symptoms. He reports that he has been unable to keep anything down and that his blood glucose levels on continuous glucose monitoring average around 150 mg/dL. Of note, upon checking his insulin pump, it was found that he had received less than 1 unit of insulin above basal insulin dosing throughout the day. He was not able to eat any food without vomiting so he did not give himself a postprandial insulin dose because he did not want to overdose himself on insulin. His symptoms at this time were chills, nausea, vomiting, body aches, and diarrhea with eating or drinking. He had no prior history of DKA.

Exam in the ED revealed tachycardia, mild hypertension, and normothermia. The diagnostic workup considered a small bowel obstruction because the patient had a history of a hospital visit for a symptomatic small bowel obstruction a few months prior. The patient also received an electrocardiogram and troponin testing for acute coronary syndrome which did not indicate contributing pathology. Infection was considered as persistent leukocytosis was present but was less likely as the patient was afebrile. DKA and other metabolic derangements were considered with labs significant for anion gap of 18 mEq/L, blood glucose 158, and beta-hydroxybutyrate 2 mmol/L. Pancreatic pathology was considered but lipase was within normal limits. The patient admitted to chronic marijuana usage every night before, but did not report any previous episodes of this kind related to its use. A venous blood gas was assessed and found to have a pH of 7.34, PaCO² of 42.3 mm Hg, PaO² of 31.2 mm Hg, HCO^3– 22.2 mMol/L, and a base excess of −3.5 mMol/L (Table 1). The result of the venous blood gas and metabolic findings and patient history made DKA the most likely diagnosis at this time. For treatment, he received 2 liters of intravenous (IV) fluids and was admitted to the family medicine residency service for worsening DKA, after failing outpatient management.

Table 1.

Patient lab results.

	Blood glucose (mg/dL)		Anion gap (mEq/L)	Beta-hydroxybutyrate (mmol/L)
Tuesday	303		16	1.4
Wednesday	171		16	1.8
Wednesday evening	~150		18	2
Venous blood gas	pH	PaCO2 (mm Hg)	PaO2 (mm Hg)	HCO3– (mMol/L)	Base excess
	7.34	42.3	31.2	22.2	–3.5

An insulin drip with 5% dextrose IV fluids was administered. An insulin bolus was not used secondary to his euglycemia with blood glucose levels around 150 mg/dL. The patient’s anion gap was trended every 4 hours until closure. Insulin drip was stopped, and the patient’s own insulin pump was restarted with good glucose control. As he began eating, the dextrose-containing IV fluid was stopped. He was able to tolerate regular diet well and his nausea completely resolved. He reported feeling well on his home medications without any continued symptoms. He was discharged home with his regular medications and instructed to follow-up with his endocrinologist.

Discussion

Type 1 DM is a result of an autoimmune process involving the destruction of insulin-producing beta cells within the pancreas resulting in an absolute insulin deficiency.^2,9 In the absence of beta cells, the body cannot produce its own insulin. As a result, DKA can occur. ¹⁰ DKA is characterized by an elevated blood glucose level or a familial or personal history of diabetes, the presence of ketones in the blood or urine, and a high anion gap metabolic acidosis.^3,4 An elevated glucose level can arise from liver gluconeogenesis and glycogenolysis. The ketones are a result of cellular metabolism using lipids as a fuel source instead of glucose. The production of these ketones and the process of gluconeogenesis produce acidity in the blood, which is neutralized by the blood’s buffering system, resulting in an anion gap. ¹¹

In the current case, it is important to consider that a therapy that patients can use for weight loss is a GLP-1 agonist. ⁷ GLP-1 agonists are incretin hormones that are inactivated by dipeptidyl peptidase-4 (DPP-4).^12,13 Their effects include increased insulin release with elevated blood glucose, inhibition of glucagon release, and repression of gluconeogenesis.^13,14 GLP-1 also delays gastric emptying and decreases food intake via appetite suppression.^13,15 Apart from the current case, there is a dearth of information linking GLP-1 agonist use and DKA adverse events when performing a literature review. This could be due to a lack of documented reporting or an absence of GLP-1 causing adverse events. A study using the Food and Drug Administration (FDA) adverse event reporting system found a potential association between DKA and GLP-1 agonist use suggesting that there is a lack of documented reports. ¹⁶ One other study could be found comparing the efficacy of sodium-glucose cotransporter-2 (SGLT2) inhibitors with GLP-1 agonists. This study found statistically significant increased rates of DKA with SGLT2 inhibitors, but not with GLP-1 agonists. ¹⁷

Classically DKA presentation includes a patient with elevated blood glucose levels, elevated ketones, and an elevated anion gap metabolic acidosis.^3,4 This patient initially presented in a similar way. When the patient returned to the ED, his blood glucose was more euglycemic which provided an erroneous indication that the patient was receiving insulin from his pump; therefore, reversing the inciting pathology of DKA. Rather, this patient was still not receiving insulin since he was not receiving elevated blood glucose readings. His blood glucose was not increasing because his gluconeogenesis and glycogenolysis pathways were being inhibited by the GLP-1 agonists, not allowing the influx of glucose into his bloodstream. With his insulin pump on standby and his blood glucose levels hyper-stabilized by the GLP-1 agonist, his cells were continuing with fatty acid oxidation therefore continuing his DKA pathology. This pathology is congruent with euglycemic pathology. This alternate presentation led to inappropriate and delayed treatment which is not uncommon. ¹⁸ With increasing prescriptions of GLP-1 agonists, and an increased rate of DKA adverse events associated with GLP-1 agonists patient presentations like this one may become more prevalent.^8,16 In addition, with GLP-1 agonist use and 26.8% of type 1 DM patients presenting as a first occurrence of DKA, this intersection of interacting pathologies may be unavoidably increasing the number of cases seen in emergency departments. ⁵ Misidentification can lead to mistreatment, possibly endangering patients and accruing unnecessary medical cost. This case report cannot support recommendations about future patient care with certainty, but it can be used to suggest that GLP-1 agonists need to be used with caution and increased precautions for GLP-1 agonists use in type 1 DM patients using insulin pumps.

Conclusion

Considerations for euglycemic DKA in type 1 DM patients taking a GLP-1 agonist is important to avoid mistreatment, unnecessary medical costs, and adverse events.