The Expanding Spectrum of Euglycemia in Diabetes Management: A Critical Care Perspective

Dr Neeraj Manikath , claude.ai

Abstract

Background: The traditional paradigm of diabetic ketoacidosis (DKA) characterized by the triad of hyperglycemia, ketosis, and acidosis is evolving. Euglycemic DKA, defined as ketoacidosis with plasma glucose <250 mg/dL (13.9 mmol/L), represents a diagnostic challenge that can delay appropriate treatment and worsen outcomes.

Objective: This review examines the expanding spectrum of euglycemic presentations in diabetes management, focusing on euglycemic DKA, insulin omission patterns, SGLT2 inhibitor-associated complications, and starvation ketosis differentiation.

Methods: Comprehensive literature review of peer-reviewed articles from 2015-2024, focusing on critical care and emergency medicine perspectives.

Conclusions: Recognition of euglycemic DKA requires high clinical suspicion, particularly in patients on SGLT2 inhibitors, with recent illness, or following procedural fasting. Early identification and appropriate management protocols can significantly improve patient outcomes.

Keywords: Euglycemic diabetic ketoacidosis, SGLT2 inhibitors, insulin omission, starvation ketosis, critical care

Introduction

The landscape of diabetes management has undergone significant transformation with the introduction of sodium-glucose co-transporter 2 (SGLT2) inhibitors and evolving insulin regimens. Traditional diabetic ketoacidosis (DKA) presentations with the classic triad of hyperglycemia (>250 mg/dL), ketosis, and metabolic acidosis are increasingly accompanied by euglycemic variants that challenge conventional diagnostic approaches¹.

Euglycemic DKA, first described in the 1970s but gaining renewed attention with SGLT2 inhibitor use, presents unique diagnostic and therapeutic challenges in critical care settings². The failure to recognize these atypical presentations can result in delayed treatment, prolonged ICU stays, and increased morbidity³.

This review synthesizes current evidence on euglycemic presentations in diabetes management, providing critical care practitioners with diagnostic frameworks and management strategies essential for contemporary practice.

Euglycemic Diabetic Ketoacidosis: Redefining the Paradigm

Definition and Diagnostic Criteria

Euglycemic DKA is defined by the presence of:

Plasma glucose <250 mg/dL (13.9 mmol/L)
Serum or urine ketones: β-hydroxybutyrate ≥3.0 mmol/L or ketonuria ≥2+
Metabolic acidosis: pH <7.3 and/or bicarbonate <18 mEq/L
Elevated anion gap (>10-12 mEq/L)⁴

Pathophysiology

The pathophysiology of euglycemic DKA involves several key mechanisms:

1. SGLT2 Inhibitor-Mediated Glucosuria: SGLT2 inhibitors promote renal glucose elimination, maintaining relatively normal plasma glucose levels despite ongoing ketogenesis. The continued insulin deficiency or resistance allows lipolysis and ketone production to proceed unchecked⁵.

2. Preserved Insulin Sensitivity for Glucose: Residual insulin activity may be sufficient for glucose uptake but inadequate to suppress lipolysis, creating a dissociation between glucose homeostasis and ketone metabolism⁶.

3. Counter-regulatory Hormone Activation: Stress-induced elevation of cortisol, catecholamines, and glucagon promotes lipolysis while SGLT2 inhibitors prevent the expected hyperglycemic response⁷.

Clinical Presentation and Risk Factors

High-Risk Scenarios:

SGLT2 inhibitor use (risk increases 2-3 fold)⁸
Recent illness or infection
Prolonged fasting or reduced oral intake
Perioperative period
Pregnancy (particularly with gestational diabetes)
Alcohol use disorders

Clinical Pearl: The absence of significant hyperglycemia should not reassure clinicians when evaluating patients with diabetes presenting with nausea, vomiting, abdominal pain, and altered mental status.

Diagnostic Challenges and Pitfalls

Common Misdiagnoses:

Gastroenteritis
Sepsis without metabolic complications
Alcohol-related ketosis
Starvation ketosis

Diagnostic Hack: In any diabetic patient with unexplained metabolic acidosis and anion gap elevation, measure ketones regardless of glucose level. Point-of-care ketone testing can provide rapid results and prevent diagnostic delays⁹.

SGLT2 Inhibitors: Benefits and Pitfalls in Critical Care

Mechanism and Metabolic Effects

SGLT2 inhibitors (empagliflozin, dapagliflozin, canagliflozin) block glucose reabsorption in the proximal tubule, promoting glucosuria of 60-90g daily¹⁰. This glucose loss triggers compensatory mechanisms including:

Increased gluconeogenesis
Enhanced lipolysis
Elevated ketone production
Activation of sympathetic nervous system

SGLT2 Inhibitor-Associated DKA: Recognition and Management

Incidence: Studies report euglycemic DKA rates of 0.16-0.76 per 1000 patient-years with SGLT2 inhibitors, compared to 0.03-0.11 per 1000 patient-years with other antidiabetic agents¹¹.

Precipitating Factors:

Surgery or procedures requiring fasting
Acute illness with reduced oral intake
Dehydration
Insulin dose reduction or omission

Clinical Oyster: Patients may present with relatively mild symptoms despite significant metabolic derangement due to the absence of severe hyperglycemia and its associated osmotic effects.

Perioperative Management Protocol

Pre-operative Considerations:

Discontinue SGLT2 inhibitors 3-7 days before elective procedures¹²
Ensure adequate carbohydrate intake until procedure
Monitor ketones if fasting >12 hours

Post-operative Monitoring:

Daily ketone monitoring for 48-72 hours
Resume SGLT2 inhibitors only after normal oral intake established
Consider alternative antidiabetic agents during recovery period

Insulin Omission: Patterns and Consequences

Epidemiology and Risk Factors

Insulin omission occurs in 15-20% of young adults with type 1 diabetes annually¹³. Risk factors include:

Eating disorders (particularly in young women)
Fear of hypoglycemia
Cost concerns
Psychological factors (depression, diabetes distress)
Social stigma

Clinical Consequences

Acute Complications:

Recurrent DKA (including euglycemic variants)
Increased hospitalization rates
Higher mortality risk

Chronic Complications:

Accelerated microvascular complications
Increased cardiovascular risk
Diabetic ketoacidosis recidivism

Clinical Pearl: Recurrent DKA, especially in young patients, should prompt investigation for insulin omission behaviors. Non-judgmental questioning and eating disorder screening are essential.

Recognition Strategies

Red Flags:

Recurrent hospitalizations for DKA
Poor glycemic control despite apparent adherence
Weight loss in the presence of normal or increased appetite
Discrepancy between reported insulin use and prescription refill patterns

Diagnostic Hack: Calculate insulin-to-weight ratios. Requirements <0.5 units/kg/day in type 1 diabetes patients should raise suspicion for omission¹⁴.

Starvation Ketosis: Differential Diagnosis and Management

Pathophysiology

Starvation ketosis results from prolonged fasting (>12-24 hours) leading to:

Depletion of hepatic glycogen stores
Increased lipolysis and ketogenesis
Protein catabolism for gluconeogenesis

Unlike diabetic ketoacidosis, insulin levels remain appropriate for glucose concentrations, preventing severe acidosis¹⁵.

Distinguishing Features

Parameter	Starvation Ketosis	Diabetic Ketoacidosis
pH	>7.30	<7.30
Bicarbonate	>15 mEq/L	<15 mEq/L
Anion Gap	<15 mEq/L	>15 mEq/L
β-hydroxybutyrate	<3 mmol/L	>3 mmol/L
Response to glucose	Rapid ketone clearance	Requires insulin

Clinical Context

Common Scenarios:

Prolonged illness with poor oral intake
Eating disorders
Postoperative fasting
Severe morning sickness in pregnancy

Management Approach:

Dextrose-containing fluids typically sufficient
Monitor response to carbohydrate administration
Insulin rarely required unless diabetic

Clinical Management Protocols

Emergency Department Approach

Initial Assessment:

Obtain arterial blood gas, basic metabolic panel
Measure serum or urine ketones (β-hydroxybutyrate preferred)
Review medication history (emphasis on SGLT2 inhibitors)
Assess hydration status and hemodynamic stability

Treatment Algorithm:

Mild-Moderate Euglycemic DKA (pH 7.20-7.30):

IV normal saline 1-2 L over first 2 hours
Regular insulin infusion 0.1 units/kg/hour
Dextrose 5-10% when glucose <250 mg/dL
Potassium replacement as indicated
Monitor hourly: glucose, ketones, electrolytes, pH

Severe Euglycemic DKA (pH <7.20):

Aggressive fluid resuscitation
Higher insulin infusion rates (0.14-0.15 units/kg/hour)
Early ICU consultation
Consider bicarbonate if pH <7.0 (controversial)

ICU Management Considerations

Monitoring Parameters:

Hourly glucose and ketones
ABG every 2-4 hours until pH >7.30
Electrolytes every 2-4 hours
Continuous cardiac monitoring (risk of arrhythmias)

Resolution Criteria:

pH >7.30
Bicarbonate >18 mEq/L
Anion gap <12 mEq/L
β-hydroxybutyrate <1.0 mmol/L

Clinical Oyster: Resolution of ketosis may lag behind improvement in pH and glucose, requiring continued insulin therapy and monitoring.

Prevention Strategies

Patient Education

Key Messages:

Never omit insulin, even during illness
Maintain adequate fluid intake during illness
Monitor ketones during stress or illness
Seek medical attention for persistent vomiting or abdominal pain

Healthcare Provider Education

SGLT2 Inhibitor Prescribing:

Screen for DKA risk factors before initiation
Provide clear instructions for sick day management
Establish protocols for perioperative management
Regular monitoring and patient education

Clinical Pearl: Develop institutional protocols for SGLT2 inhibitor management during hospitalization, including clear discontinuation and resumption criteria.

Emerging Concepts and Future Directions

Dual SGLT1/SGLT2 Inhibitors

Newer agents combining SGLT1 and SGLT2 inhibition may have different ketogenic profiles, requiring modified monitoring approaches¹⁶.

Continuous Ketone Monitoring

Development of continuous ketone monitors may enable real-time detection of ketosis, particularly valuable for high-risk patients¹⁷.

Artificial Intelligence Applications

Machine learning algorithms incorporating medication history, clinical parameters, and biomarkers may improve early detection of euglycemic DKA¹⁸.

Practical Clinical Pearls and Oysters

Pearls for Critical Care Practice

The "SGLT2 Sign": Any diabetic patient on SGLT2 inhibitors presenting with nausea, vomiting, and normal glucose requires ketone measurement.
The "Fasting Paradox": Prolonged fasting in SGLT2 inhibitor users paradoxically increases DKA risk despite glucose control.
The "pH-Glucose Dissociation": Normal glucose with significant acidosis should immediately trigger ketone evaluation.
The "Insulin Efficiency Test": In euglycemic DKA, insulin requirements may be higher than expected due to ongoing ketogenesis.

Clinical Oysters (Common Misconceptions)

"Normal glucose rules out DKA" - Euglycemic DKA is increasingly common and can be life-threatening.
"Mild symptoms mean mild disease" - The absence of hyperglycemic symptoms can mask significant metabolic derangement.
"Stop SGLT2 inhibitors only if DKA occurs" - Proactive discontinuation during high-risk periods prevents complications.
"Ketones always correlate with severity" - Clinical presentation and acid-base status are better severity indicators than absolute ketone levels.

Conclusion

The expanding spectrum of euglycemic presentations in diabetes management represents a paradigm shift requiring updated diagnostic and therapeutic approaches. Critical care practitioners must maintain high clinical suspicion for euglycemic DKA, particularly in patients using SGLT2 inhibitors or with risk factors for insulin omission.

Key takeaways include the need for routine ketone monitoring in high-risk scenarios, understanding the pathophysiologic differences between various ketotic states, and implementing evidence-based management protocols. As diabetes therapeutics continue to evolve, ongoing education and protocol development will be essential to optimize patient outcomes in critical care settings.

Future research should focus on risk stratification tools, optimal monitoring strategies, and prevention protocols to minimize the impact of these increasingly recognized complications.

References

Dhatariya KK, Glaser NS, Codner E, Umpierrez GE. Diabetic ketoacidosis. Nat Rev Dis Primers. 2020;6(1):40.
Munro JF, Campbell IW, McCuish AC, Duncan LJ. Euglycaemic diabetic ketoacidosis. Br Med J. 1973;2(5866):578-580.
Goldenberg RM, Berard LD, Cheng AYY, et al. SGLT2 inhibitor-associated diabetic ketoacidosis: Clinical review and recommendations for prevention and diagnosis. Diabetes Care. 2016;39(11):2032-2039.
Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN. Hyperglycemic crises in adult patients with diabetes. Diabetes Care. 2009;32(7):1335-1343.
Bonner C, Kerr-Conte J, Gmyr V, et al. Inhibition of the glucose transporter SGLT2 with dapagliflozin in pancreatic alpha cells triggers glucagon secretion. Nat Med. 2015;21(5):512-517.
Ferrannini E, Mark M, Mayoux E. CV Protection in the EMPA-REG OUTCOME Trial: A "Thrifty Substrate" Hypothesis. Diabetes Care. 2016;39(7):1108-1114.
Burke KR, Schumacher CA, Harpe SE. SGLT2 Inhibitors: A Systematic Review of Diabetic Ketoacidosis and Related Risk Factors in the Primary Literature. Pharmacotherapy. 2017;37(2):187-194.
Fralick M, Schneeweiss S, Patorno E. Risk of Diabetic Ketoacidosis after Initiation of an SGLT2 Inhibitor. N Engl J Med. 2017;376(23):2300-2302.
Klocker AA, Phelan H, Twigg SM, Craig ME. Blood β-hydroxybutyrate vs. urine acetoacetate testing for the prevention and management of ketoacidosis in Type 1 diabetes: a systematic review. Diabet Med. 2013;30(7):818-824.
Abdul-Ghani MA, Norton L, DeFronzo RA. Role of sodium-glucose cotransporter 2 (SGLT 2) inhibitors in the treatment of type 2 diabetes. Endocr Rev. 2011;32(4):515-531.
Ueda P, Svanström H, Melbye M, et al. Sodium glucose cotransporter 2 inhibitors and risk of serious adverse events: nationwide register based cohort study. BMJ. 2018;363:k4365.
Handelsman Y, Henry RR, Bloomgarden ZT, et al. American Association of Clinical Endocrinologists and American College of Endocrinology position statement on the association of SGLT-2 inhibitors and diabetic ketoacidosis. Endocr Pract. 2016;22(6):753-762.
Polonsky WH, Anderson BJ, Lohrer PA, et al. Insulin omission in women with IDDM. Diabetes Care. 1994;17(10):1178-1185.
Pinhas-Hamiel O, Hamiel U, Boyko V, et al. Trajectories of HbA1c Levels and Body Mass Index in Children and Adolescents with Type 1 Diabetes. PLoS One. 2014;9(10):e109109.
Owen OE, Caprio S, Reichard GA, et al. Ketosis of starvation: A revisit and new perspectives. Clin Endocrinol Metab. 1983;12(2):359-379.
Rosenstock J, Marquard J, Laffel LM, et al. Empagliflozin as adjunctive to insulin therapy in type 1 diabetes: the EASE trials. Diabetes Care. 2018;41(12):2560-2569.
Burnett A, Zimmerman B, Harris D, Dewan S. Continuous ketone monitoring in acute care settings. J Diabetes Sci Technol. 2020;14(1):32-38.
Chen JH, Asch SM. Machine Learning and Prediction in Medicine — Beyond the Peak of Inflated Expectations. N Engl J Med. 2017;376(26):2507-2509.

Conflicts of Interest: The authors declare no conflicts of interest. Funding: No specific funding was received for this work.

Monday, August 25, 2025