Euglycemic Diabetic Ketoacidosis due to Sodium-Glucose Cotransporter-2  Inhibitor in the Intensive Care Unit and Literature Review

M. Roarke Tollar ¹, Eduardo E. Chang ², Esther Segura M.D ³, David Pham M.D ⁴

1. Medical Student Fourth Year, Indiana University School of Medicine, Terre Haute, Indiana.
2. Pulmonary, Sleep, Critical Care Medicine, Adjunct Assistant Professor of Medicine, Indiana University School of Medicine. Terre Haute, Indiana
3. Clinical Researcher, Allianz Research Institute, Aurora, Colorado.
4. Pulmonary Critical Care Medicine, Allianz Research Institute. Aurora, Colorado.

^*Correspondence to: Eduardo E. Chang, M.D., M.B.A., M.P.H, Adjunct Assistant Professor of Medicine, Indiana University School of Medicine.

Copyright

© 2023 Eduardo E. Chang. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Received: 04 August 2023

Published: 20 August 2023

Patient: 46-year-old Male

Final Diagnoses: Euglycemic DKA, Diabetes, SGLT2 inhibitors

Keywords: Diabetic Ketoacidosis, Euglycemic DKA, EDKA, SGLT-2 inhibitors, Diabetes Mellitus, Sodium-glucose-cotransporter-2 inhibitor

Abstract

Sodium glucose cotransporter 2 (SGLT2) medications are the new paradigm shift that have changed the management of Diabetes and improved glucose control for patients.[1] As more patients with diabetes and metabolic diseases are being placed on these new medications, we are seeing more patients presenting with euglycemic diabetic ketoacidosis (EDKA) in our intensive care units. Despite glycemic control, the benefits of losing weight, reducing blood pressure, and glucose management, the incidence of cases of patients admitted with euglycemic DKA continue to increase. These patients typically present after suffering an acute illness (CVA, MI, PE), having carbohydrate restrictive diets, pre and post-operative nil per oral and during pregnancy.[1,2,3] Figure 1 above shows some precipitating factors, this was borrowed from Somagutta et al.[1] The recurrence of DKA in these patients brings new challenges in management, prompting accurate recognition of symptoms. [2] We present a case of euglycemia DKA presented to our ICU, which was managed and eventually discharged. We also provide a comprehensive review of the literature and recommendations on management of these patients in the acute care setting.

Introduction

The prevalence of fast-food restaurants, high-carbohydrate foods, and deserts high in sugar have led to a widespread global epidemic of hyperglycemia, affecting nearly one billion individuals worldwide. Prolonged hyperglycemia can result in the development of diabetes mellitus, a prevalent chronic condition that affects 10% of the population and poses a significant financial burden on public health. Over the past century, various classifications of pharmaceuticals have been developed and introduced to regulate blood glucose levels and safeguard the vasculature and vital organs of affected patients.[3] In 2013, the first sodium glucose cotransporter 2 (SGLT2) inhibitor, canagliflozin, received approval from the Food and Drug Administration (FDA)[1], marking the beginning of a series of similar "flozin" drugs released in subsequent years.[3,4] The mechanism of SGLT2 inhibitors involves modulating the sodium-glucose cotransporters in the nephron, inhibiting glucose reabsorption, and promoting its excretion in the urine, thereby reducing serum glucose levels.[1] 

Extensive research has been conducted on the effects of SGLT2 inhibitors on glucose management, whether used alone or in combination with other glucose-modulating medications like metformin, dipeptidyl peptidase 4 (DPP-4) inhibitors, glucagon-like polypeptide 1 (GLP-1) agonists, or insulin.[1] Although SGLT2 inhibitors have only been available to patients for a relatively short period, scientists have recently begun evaluating their long-term impacts on the human body. Diabetes, a condition studied for decades, is known to contribute to life altering comorbidities and complications. A key evolving entity, known as

“euglycemic diabetic ketoacidosis,” has been linked to the use of SGLT2 inhibitors. [1,3] As the use of

SGLT2 inhibitors increases in the future, episodes of EDKA will continue to present as severe shock to the ICU and incidence is likely to increase. There is limited literature regarding the management and screening for EDKA with respect to intensive care unit protocols.

The purpose of this review and case report is to identify key steps to decrease mortality and morbidity during an ICU clinical course and key treatment goals for preventing the development of EDKA due to SGLT2i’s use in hospitalized patients to minimize admission to the ICU. 

Case Report 

We report a case of a 46-year-old male with history of hyperlipidemia and type 2 diabetes, with no other past medical history except for morbid obesity, OSA having a BMI of 34.5 kg/M2. The patient presented with 3 days of polyuria, polydipsia, poor appetite, and vomiting. He was being followed by his internist and had been taking metformin, glipizide and dapagliflozin for diabetes mellitus type 2 and atorvastatin for hyperlipidemia. He had been taking dapagliflozin for 3 months, at his time of presentation to the ICU. Our patient had elevated anion gap and hypovolemia with diarrhea. On physical exam he had oral dry mucosa and some abdominal cramping.  Pertinent laboratory data showed serum glucose of 121 mg /dl, bicarbonate of 17, anion gap of 21 and creatinine of 0.4 mg/dl, triglycerides of 345 and total cholesterol of 125. His glycated hemoglobin was 9.8 and his venous pH was 7.29.  Serum lipase, amylase and liver function tests were normal. Urine ketones were present and serum β-Hydroxybutyrate was elevated at 5.45 mmol/l. Alcohol and urine drug screen were both negative. The patient was treated with an insulin drip, IV fluids and followed in the ICU for closure of anion gap. After 24 hours in the ICU his anion gap closed and his clinical status improved, he was hydrated and transferred to the medical floor.

Discussion

There has been an increase in reports of diabetic ketoacidosis (DKA) associated with the use of SGLT-2 inhibitors. The exact incidence rate of SGLT-2 inhibitor-induced DKA is not known; the estimated range is from 0.16 to 0.76 events/1000 patient/years in clinical trials.[2] The use of DKA with SGLT2 inhibitors (SGLT2i) have shown potential benefits for various body systems. In central nervous system disorders, it reduces oxidative stress, protects the blood-brain barrier, and by decreasing microglia burden and acetylcholinesterase levels, which are mechanisms linked to cognitive function. Empagliflozin has demonstrated promising results in reducing senile plaque density and amyloid beta levels in mice with

Alzheimer's disease pathology. SGLT2i’s have also shown neuroprotective effects against hyperglycemia, enhanced angiogenesis, and neurogenesis. Similarly, dapagliflozin has shown to be effective in rat experiments reducing seizure activity, protecting against neuronal injury and motor dysfunction in rats with Parkinson's disease, and reducing stroke risk factors.[6] These neuroprotective effects make SGLT2 inhibitors a potential therapeutic option for central nervous system disorders.

The cardiovascular benefits of SGLT2 inhibitors have shown efficacy in reducing adverse cardiovascular events in patients with type 2 diabetes, primarily attributed to their impact on the myocardium and the reduction of proinflammatory chemokine secretion. [3,4,5,6] Additionally, SGLT2 inhibitors contribute to weight loss, particularly in body fat, which further enhances their cardiovascular benefits. Meta-analyses have indicated that dapagliflozin and empagliflozin decrease death and hospitalization rates independent of diabetes status and have blood pressure-lowering effects.[3] These inhibitors have also been associated with a reduced incidence of various cardiovascular diseases, such as atrial fibrillation, hypertension, acute cardiac failure, and sleep apnea syndrome. Studies have suggested there is a further need to study the role of

SGLT2i’s use for patients with heart failure with preserved ejection fraction and those with heart failure and decreased ejection fraction. [3,5].

The respiratory benefits of SGLT2 inhibitors, including the prevention and reduction of acute pulmonary edema, asthma, and sleep apnea syndrome, require further research to understand the underlying mechanisms. Nonetheless, these drugs have demonstrated the ability to rapidly reduce pulmonary artery pressures, a critical measure of heart failure, thereby decreasing the risk of adverse events. SGLT2 inhibitors have also been associated with increased hematocrit levels, elevation in HDL and LDL cholesterol, and reductions in triglycerides and uric acid levels. The clinical relevance of these lipid level changes and their potential impact on cardiovascular consequences warrant further investigation.

Regarding the pancreas and glucose regulation, SGLT2 inhibitors have demonstrated effects on glucagon secretion and insulin sensitivity. Glucagon levels increase after administering SGLT2 inhibitors due to reduced glucose uptake, leading to increased glycogenolysis and gluconeogenesis. This results in a decrease in ATP formation, triggering glucagon secretion. However, prolonged hyperkalemia caused by excessive glucagon secretion may have cardiac manifestations. SGLT2 inhibitors also impact insulin sensitivity by inducing changes in βeta cells, leading to increased βeta cell mass and proliferation, decreased apoptosis, and altered insulin resistance. These adaptations, facilitated via β-cells compensation, allow for enhanced insulin sensitivity and release in postprandial settings. While cases of pancreatitis have been reported in a small percentage of patients taking SGLT2 inhibitors, the increased risk may be influenced by confounding variables such as diabetes and hyperglycemia.

The hepatic system also experiences metabolic benefits from SGLT2 inhibitors. These drugs aim to improve glycemic control in patients with type 1 and type 2 diabetes mellitus. Clinical trials have demonstrated that SGLT2 inhibitors can reduce HbA1c levels and lower the required insulin dosage for patients taking insulin, with a low incidence of adverse events such as hypoglycemia and diabetic ketoacidosis.  As clinicians, one must be aware the incidence will increase if patients have prolonged fasting or are on ketogenic diets.  Additionally, SGLT2 inhibitors have shown potential for improving liver health. They have been associated with improvements in liver biomarkers, promoting liver injury recovery, and reducing hepatic fibrosis and steatosis. Non-alcoholic fatty liver disease (NAFLD), a common condition in individuals with type 2 diabetes, has shown improvement with SGLT2 inhibitors, although the exact mechanism remains unclear. Combination therapy with SGLT2 inhibitors and agents like exenatide, an incretin mimetic, has demonstrated significant improvements in liver enzymes, fatty liver biomarkers, and weight loss compared to monotherapy or placebo.

Mechanism

The development of euglycemic diabetic ketoacidosis (EDKA) in patients taking SGLT2 inhibitors (SGLT2i) is a notable concern, despite currently having relatively low reported incidence. Despite their overall favorable effects, SGLT2 inhibitors can disrupt glucose homeostasis and lead to this potentially life threatening condition. The mechanism underlying the development of EDKA involves several interconnected factors.

SGLT2 inhibitors function by inhibiting the reabsorption of glucose in the proximal renal tubules, leading to increased urinary glucose excretion. This results in glycosuria, which contributes to the lowering of blood glucose levels. However, the enhanced glycosuria caused by SGLT2 inhibitors can also induce volume depletion and osmotic diuresis. These effects can lead to decreased effective circulating volume and activation of the sympathetic nervous system and renin-angiotensin-aldosterone system (RAAS). Consequently, there is an increase in renal tubular sodium reabsorption, further exacerbating the intravascular volume depletion.

This volume depletion and reduced effective circulating volume trigger compensatory mechanisms in the body. Including the activation of the hypothalamic-pituitary-adrenal (HPA) axis and the release of stress hormones such as cortisol and catecholamines. These stress hormones stimulate lipolysis in adipose tissue and promote the breakdown of triglycerides into free fatty acids (FFAs) in the liver. The increased levels of FFAs are then converted into ketone bodies, including beta-hydroxybutyrate and acetoacetate, through hepatic ketogenesis. 

In a normal physiological state, the presence of insulin inhibits lipolysis and ketogenesis, while promoting glucose utilization. However, in the context of SGLT2 inhibitor therapy, insulin levels may be relatively decreased due to reduced glucose reabsorption and lower blood glucose levels. As a result, insulin deficiency or relative insulin deficiency can occur, impairing the inhibition of lipolysis and allowing ketogenesis to proceed unchecked. This leads to the accumulation of ketone bodies in the bloodstream, resulting in a metabolic state characterized by ketosis while blood sugar remains at relatively normal levels. 

Importantly, EDKA is distinct from typical diabetic ketoacidosis (DKA) in that it occurs despite near normal or only mildly elevated blood glucose levels (euglycemia).[3] This can delay diagnosis and increase the risk of complications if physicians are not vigilant in recognizing the condition or the patient does not disclose their use of SGLT2i, especially in the context of ICU and intensivist management. The preserved or mildly elevated blood glucose levels in EDKA can be attributed to various factors, including ongoing hepatic gluconeogenesis and glycogenolysis, counter-regulatory hormone release (e.g., glucagon, cortisol, and catecholamines), and reduced renal glucose reabsorption.[6] Any factor that occurs concomitantly with SGLT2i use, likely has a synergistic increase in risk for developing EDKA, although no study thus-far has elucidated this precise connection. 

It is worth noting that EDKA is more likely to occur in individuals with risk factors such as type 1 diabetes, type 2 diabetes, insulin deficiency, stressors such as infections or surgery, fasting, severe illness, or a history of excessive alcohol consumption.[1,2]  It is important to note that at the time of this article, the use of these mediations has not been approved for type 1 diabetes by the FDA, but its use has been reported as off label in the literature. These factors can further contribute to the imbalance between insulin availability and counter-regulatory hormone release, exacerbating ketogenesis in the presence of SGLT2i’s. These highacuity issues inherently implicate the ICU as an area high in incidence of EDKA, making effective SGLT2i management a crucial evolving skill of the intensivist.

Recommendations

We recommend several steps in establishing an EDKA protocol. Early recognition and inclusion of EDKA on an appropriately wide differential in anyone with evidence of shock, elevated anion gap, and euglycemic status, as being fundamental.  Judicious monitoring of fluid volume to manage hypovolemia, shock, and safe  discontinuation of an SGLT2i (may or may not be transient in nature), is appropriate. Frequent monitoring of anion gap and ketones in blood and urine is recommended. Initiate early fluid resuscitation treatment, continue to monitor in the ICU for deterioration and further evolution of EDKA. Given hypovolemia is a precipitant of EDKA, aggressive fluid resuscitation is a distinguishing difference in treatment protocol for EDKA vs classical DKA.  

Conclusions

SGLT2i’s have modified the management and have become a new game-changer in delaying disease progression for patients with diabetes, obesity, and heart failure. As many patients can potentially start to use these new medications, it is important to be more aware and look for evidence of ketoacidosis with normal glucose.  A delayed diagnosis and treatment could have deleterious effects due to the adverse consequence of metabolic decompensations. Low intravascular volumes may be more than those seen in normal DKA, requiring a larger resuscitation volume.  Prompt referral to the emergency room and ICU is warranted and should not be delayed. A normal point of care glucometer may not be enough to rule out the presence of DKA while transporting patients to the emergency room. High suspicion of this condition has to be considered when patients are taking SGLT2 in conjunction with insulin.

References

1. Somagutta, M. R., Agadi, K., Hange, N., et al. (2021). Euglycemic Diabetic Ketoacidosis and SodiumGlucose Cotransporter-2 Inhibitors: A Focused Review of Pathophysiology, Risk Factors, and Triggers. Cureus, 13(3), e13665. https://doi.org/10.7759/cureus.13665

2. Nasa, P., Chaudhary, S., Shrivastava, P. K., & Singh, A. (2021). Euglycemic diabetic ketoacidosis: A missed diagnosis. World Journal of Diabetes, 12(5), 514-523. https://doi.org/10.4239/wjd.v12.i5.514

3. Yau, K., Dharia, A., Alrowiyti, I., & Cherney, D. Z. I. (2022). Prescribing SGLT2 Inhibitors in Patients With CKD: Expanding Indications and Practical Considerations. Kidney Int Rep, 7(7), 1463-1476. doi:10.1016/j.ekir.2022.04.094

4. Fatima, T., Sedrakyan, S., Awan, M. R., Khatun, M. K., Rana, D., & Jahan, N. (2020). Use of SodiumGlucose Co-Transporter-2 Inhibitors in Type 1 Diabetics: Are the Benefits Worth the Risks? Cureus, 12(8), e10076. https://doi.org/10.7759/cureus.10076

5. Brust-Sisti, L., Rudawsky, N., Gonzalez, J., & Brunetti, L. (2022). The Role of Sodium-Glucose Cotransporter-2 Inhibition in Heart Failure with Preserved Ejection Fraction. Pharmacy (Basel), 10(6), 166. https://doi.org/10.3390/pharmacy10060166

6. Jasleen, B., Vishal, G. K., Sameera, M., et al. (2023). Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors: Benefits Versus Risk. Cureus, 15(1), e33939. https://doi.org/10.7759/cureus.33939

7. Perry, R. J., & Shulman, G. I. (2020). Sodium-glucose cotransporter-2 inhibitors: Understanding the mechanisms for therapeutic promise and persisting risks. Journal of Biological Chemistry, 295(42), 14379-14390. https://doi.org/10.1074/jbc.REV120.008387