Case Report: Chest Pain as an Uncommon Presentation for Euglycemic Diabetic Ketoacidosis in a Female Patient Using SGLT2 inhibitor

Introduction

Diabetic ketoacidosis (DKA) is one of the frequent complications of diabetes mellitus (DM), and it is characterized by the presence of hyperglycemia, ketosis, and high anion gap metabolic acidosis. Unlike DKA, euglycemic diabetic ketoacidosis (EuDKA) is characterized by a blood glucose level <11.1 mmol/L.¹ EuDKA is an uncommon diagnosis with an incidence ranging between 2.6% to 3.2% of admissions.²

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are relatively new antihyperglycemic medications that were introduced into the market in the last decade.³ Due to its scientifically proven cardiac and renal protective effects in diabetic patients, it has gained a lot of popularity in clinical practice. However, as with any medication, there’s a risk of side effects, and one of its rarely reported side effects is the development of euglycemic diabetic ketoacidosis.⁴

Typically, EuDKA presents clinically with symptoms similar to those of DKA, such as nausea, vomiting, and abdominal pain.⁴ Furthermore, chest pain as a presenting symptom for EuDKA is relatively rare, and only a few cases have been reported in the literature.

In this case report, we are reporting a 46-year-old female with a past medical history of type 2 diabetes mellitus (T2DM) on SGLT2 inhibitor (Dapagliflozin) therapy for three years who presented to the hospital with central chest pain radiating to the back associated with shortness of breath and vomiting and was found to have high anion gap metabolic acidosis. She was diagnosed as a case of SGLT2 inhibitor-induced euglycemic DKA after excluding all other possible etiologies of EuDKA.

Case presentation

A 46-year-old non-pregnant Indian female with a past medical history of type 2 diabetes mellitus, hypertension, and hypertriglyceridemia presents to the hospital with central chest pain that radiates to the back and is associated with mild shortness of breath and one bout of vomiting. According to the patient, the pain has been present for more than a week but has significantly increased in the past two days. She denied any history of coughing, paroxysmal nocturnal dyspnea, or orthopnea. A review of other systems revealed no abnormalities. The patient denied any recent change in her diet or exercise, as well as her alcohol intake. She has had type 2 diabetes mellitus for more than six years, which has been previously treated. Four years ago she started taking an SGLT2 inhibitor, dapagliflozin (10 mg), but she has not improved her lifestyle and is not taking her medications consistently, and her HbA1C has consistently been elevated (11.3%). In addition to dapagliflozin, she was taking fenofibrate (200 mg) for hypertriglyceridemia and lisinopril-hydrochlorothiazide (20 mg/12.5 mg) for hypertension.

In the emergency department, her blood pressure was 156/82 mmHg, her temperature was 36.8°C, her heart rate was 91 beats per minute, her respiratory rate was 19 breaths per minute, and her oxygen saturation (SpO₂) was 99% on room air. On physical examination, she was mildly distressed, and auscultation of the lung revealed clear lung fields with no rhonchi or crackles. A cardiac examination showed normal S1 and S2 with no added sounds. Examination of other systems was unremarkable. Two sets of troponin T enzymes were within the normal range (9 ng/dl), and her electrocardiogram (ECG) showed normal sinus rhythm with no ST changes. The result of the chest X-ray was unremarkable. A computed tomography (CT) scan was done, and it showed no evidence of pulmonary embolism (PE).

A point-of-care venous blood gas test (VBG) result showed a blood glucose level of 7.7 mmol/L, a pH of 7.24, a PCO₂ level of 19 mmHg, a HCO₃ level of 13 mmHg, and a beta-hydroxybutyrate level of 3.2 mmol. Results of the basic metabolic panel showed a sodium (Na) level of 134 mmol/L, a potassium (K) level of 4 mmol/L, a chloride (Cl) level of 101 mmol/L, and a bicarbonate level of 13 mmol/L with a calculated anion gap of 20. Her lipid profile results showed triglyceride levels of 14.6 mmol/L, cholesterol levels of 9.6 mmol/L, and low-density lipoprotein levels of 4.8 mmol/L. In addition to that, high levels of glucosuria (+2) and ketonuria (+4) were also detected in the patient’s urine. A toxicology screening result showed normal levels of acetaminophen, ethanol, and salicylate.

A diagnosis of SGLT2 inhibitor-induced euglycemic DKA (EuDKA) was made, and the patient started on IV fluid therapy with 0.45% sodium chloride (NaCL) with 5% dextrose (D5) (250 ml/hr), insulin infusion of 0.1 units/kg/hr, and potassium chloride (KCL) infusion of 20 mEq/L (125 ml/min) according to the local protocol. The patient was admitted to the medical floor for more observation and the potassium chloride (KCL) infusion was escalated to 40 mEq/L. She was on insulin infusion for 16 hours then shifted to subcutaneous insulin. Two days later, the patient’s chest pain improved, she was tolerating food, her lab results showed an HCO₃ level of 23 mmol/L, and the anion gap was closed. Dapagliflozin was discontinued, and she was discharged home on oral metformin 500 mg, subcutaneous insulin aspart 20 units, and subcutaneous insulin glargine 30 units. She was advised to use a glucometer at home to monitor and record her blood glucose levels. A follow-up appointment was scheduled at the general medicine clinic. During her follow-up visit, the patient’s home readings were within the normal range.

Discussion

Euglycemic DKA (EuDKA) is a life-threatening condition that needs emergent management. It may occur in type 1 or type 2 DM, and it’s characterized by milder degrees of hyperglycemia with blood glucose levels <11.1 mmol/l, which can result in delayed diagnosis and treatment with potentially adverse metabolic consequences.¹

Numerous conditions were reported to trigger euglycemic DKA, such as inadequate oral intake, insulin treatment before arrival at the emergency department, pregnancy, and sodium-glucose co-transporter 2 (SGLT2) inhibitors.⁵ The latest was the probable cause of our patient’s illness.

It’s worth mentioning that EuDKA does not necessarily present typical manifestations of DKA. In which marked hyperglycemia and the resultant dehydration are the usual causes. For example, patients with EuDKA treated with SGLT2 inhibitors may have less polyuria and polydipsia due to the milder degree of hyperglycemia, and these patients may only present with malaise, anorexia, tachycardia, or tachypnea with or without fever.⁶ However, chest pain as a manifestation of EuDKA or DKA has rarely been reported in the literature. A previous study reported a case of EuDKA presenting with chest pain in diabetic patients using SGLT2 inhibitor therapy who had recently started a ketogenic diet.⁷ In our case, the patient denied any recent changes in her diet.

Another study also reported a case of DKA presenting with chest pain after skipping insulin therapy while fasting. She was found to have a high blood glucose level of 17.1 mmol/L.⁸ Unlike our patient, who was only on SGLT2 therapy and had a blood glucose level of 7.7 mmol/L. Moreover, a case of ST-segment elevation myocardial infarction (STEMI) induced by SGLT2 inhibitor therapy presenting with chest pain has also been reported.⁹ In contrast, our patient presented with chest pain, but his ECG showed no ST-segment changes.

The presence of hypertriglyceridemia has been associated with lower levels of blood glucose in EuDKA. The concomitant presence of hypertriglyceridemia and SGLT2-induced EuDKA has been previously reported in the literature.¹⁰ Although our patient had a very high level of triglyceride (14.6 mmol/L), it remains uncertain if his high triglyceride levels have contributed to his EuDKA.

SGLT2 inhibitors were approved by the Food and Drug Administration (FDA) in 2013. Their main mechanism of action aims to reduce glucose reabsorption by targeting the kidneys. SGLT2 proteins normally facilitate the reabsorption of glucose back into plasma, inhibiting this process leads to glucosuria and in turn lowering serum glucose levels.

SGLT2 inhibitors are an effective class of agents for controlling blood glucose levels in T2DM. Evidence in literature showed significantly improved outcomes in diabetics with cardiovascular disease, including decreased stroke and myocardial infarction related mortality.¹¹ SGLT2 inhibitors also impose a reduced risk of hypoglycemia,¹² unlike other hypoglycemic agents. Considering the desirable outcome associated with SGLT2 inhibitors they are often preferred by doctors and patients. However, our case represents a rare undesirable outcome which is EuDKA.

The pathophysiology of EuDKA in SGLT2 inhibitor users is believed to be a result of hormonal adaptations involved in glucose metabolism in response to increased urinary excretion of glucose. Low glucose in serum reduces insulin secretion from beta-cells. The low insulin levels result in fatty acid accumulation due to increased lipolysis activity; fatty acids are converted to ketone bodies by Beta- oxidation in hepatocytes. Previous evidence suggests that SGLT2 inhibitors induce glucagon secretion from alpha- cells by direct stimulation of pancreas or either by secondary stimulation as a consequence of reduced insulin levels.¹³ SGLT2 inhibitors mimic starvation conditions by inhibiting glucose resorption, this leads to increased ketone production and resorption in blood.¹⁴ As a result the body is predisposed to acidemia by ketogenesis and the ongoing glucosuria results in normal to mildly elevated glucose serum levels manifesting as EuDKA.

It is also important to note the mechanism behind hypertriglyceridemia observed in our patient. Increased lipolysis leads to formation of free fatty acids being transported into the liver and forming high levels of low density lipoproteins (LDL), reflecting high triglycerides levels in blood.¹⁰

The management of EuDKA is similar to the management of DKA. The end goal of the treatment is to close the anion gap, address the electrolyte imbalance through insulin therapy, and correct dehydration through appropriate fluid resuscitation. However, it’s very important to maintain potassium levels between 4-5 while receiving insulin therapy, as it can result in hypokalemia and subsequent life-threatening arrhythmias. In addition, addressing the underlying triggers is a cornerstone of management.¹⁵

Our patient was successfully managed with fluid therapy, insulin infusion, and potassium chloride, and her 2-day hospital course went smoothly; her chest pain had significantly improved, and she was tolerating food. Her lab results revealed an HCO3 level of 23, and she was discharged home on oral metformin and subcutaneous insulin, with discontinuation of dapagliflozin. She was advised to monitor her blood glucose level at home. On the follow up visit, the recorded result were within normal ranges.

Conclusion

EuDKA is a serious medical emergency that carries a sizable risk of delayed diagnosis and management, which could have detrimental metabolic effects.

The wide use of SGLT2 inhibitors among diabetic patients has been linked with development of EuDKA. Furthermore, chest pain as presenting symptoms in patients using SGLT2 inhibitors should be carefully evaluated by clinician for possible EuDKA.

Consent

Written informed consent for publication of their clinical details and/or clinical images was obtained from the patient.