SGLT2 Inhibitor-Associated Euglycemic Diabetic Ketoacidosis: A Clinical Review

Dr Neeraj Manikath , claude.ai

Abstract

Sodium-glucose cotransporter-2 (SGLT2) inhibitors have revolutionized diabetes management with proven cardiovascular and renal benefits. However, their use is associated with an uncommon but potentially life-threatening complication: euglycemic diabetic ketoacidosis (euDKA). This atypical presentation of DKA, characterized by blood glucose levels typically below 250 mg/dL, challenges traditional diagnostic paradigms and often leads to delayed recognition and treatment. This review provides a comprehensive framework for postgraduate physicians to recognize, diagnose, and manage SGLT2i-associated euDKA, emphasizing the critical importance of maintaining a high index of suspicion in patients on these increasingly prescribed medications.

Introduction

SGLT2 inhibitors—including empagliflozin, dapagliflozin, canagliflozin, and ertugliflozin—have become cornerstones in the management of type 2 diabetes mellitus, heart failure, and chronic kidney disease. Landmark trials such as EMPA-REG OUTCOME, CANVAS, and DAPA-HF have demonstrated significant reductions in cardiovascular mortality, heart failure hospitalizations, and progression of renal disease. Current guidelines recommend SGLT2i as first-line therapy in patients with diabetes and established cardiovascular or kidney disease, independent of glycemic control.

Despite their remarkable benefits, SGLT2 inhibitors carry a unique metabolic risk: the development of diabetic ketoacidosis with paradoxically normal or near-normal blood glucose levels. The reported incidence ranges from 0.1% to 0.6% in clinical trials, but real-world data suggest higher rates, particularly in type 1 diabetes (off-label use) where incidence may reach 5-10%. The FDA issued a warning in 2015 after identifying 73 cases, and subsequent reports have continued to accumulate.

The clinical significance of euDKA cannot be overstated. Traditional teaching emphasizes hyperglycemia as a cardinal feature of DKA, with glucose typically exceeding 250 mg/dL. This paradigm creates a dangerous cognitive bias: clinicians may dismiss the possibility of DKA when confronted with modest glucose elevations, leading to delayed diagnosis, inadequate treatment, and increased morbidity.

Pathophysiology: Understanding the Metabolic Paradox

The SGLT2 Mechanism and Ketogenic State

SGLT2 inhibitors block glucose reabsorption in the proximal renal tubule, causing glycosuria and reducing plasma glucose levels. This mechanism, while therapeutically beneficial, creates a metabolic environment conducive to ketoacidosis through multiple pathways:

Insulin Deficiency and Glucagon Excess: The drug-induced glycosuria lowers blood glucose, triggering a compensatory hormonal response. Insulin secretion decreases while counter-regulatory hormones—particularly glucagon—increase. This shift in the insulin-to-glucagon ratio activates hormone-sensitive lipase, promoting lipolysis and free fatty acid release. In the liver, these fatty acids undergo beta-oxidation, producing ketone bodies (acetoacetate and beta-hydroxybutyrate).

Enhanced Renal Ketone Reabsorption: SGLT2 inhibitors paradoxically increase renal reabsorption of ketone bodies through SGLT1 and SGLT2 transporters in the proximal tubule, preventing their urinary excretion and allowing ketones to accumulate despite ongoing glycosuria.

Volume Contraction: SGLT2i-induced osmotic diuresis leads to volume depletion, activating the sympathetic nervous system and further stimulating lipolysis and ketogenesis.

Direct Metabolic Effects: Emerging evidence suggests SGLT2 inhibitors may directly enhance glucagon secretion from pancreatic alpha cells and increase circulating ketone body levels independent of insulin changes.

Why Glucose Remains "Normal"

The euglycemic presentation results from continued renal glucose excretion despite reduced insulin levels. While insulin deficiency promotes ketogenesis, the kidney continues eliminating glucose, preventing the marked hyperglycemia typically seen in DKA. Blood glucose levels in SGLT2i-associated euDKA typically range from 100-250 mg/dL, with many cases presenting below 200 mg/dL.

Clinical Precipitants: The Perfect Storm

EuDKA rarely occurs spontaneously. Specific clinical scenarios dramatically increase risk:

Major Precipitants

Acute Illness and Physiological Stress: Infections (particularly urinary and respiratory), myocardial infarction, stroke, pancreatitis, and other acute illnesses trigger stress hormone release, exacerbating insulin resistance and ketogenesis.

Reduced Carbohydrate Intake: Fasting for procedures, gastrointestinal illness with nausea and vomiting, intentional low-carbohydrate or ketogenic diets, and poor oral intake during illness all reduce carbohydrate availability, shifting metabolism toward fat oxidation and ketone production.

Insulin Dose Reduction or Omission: Patients or clinicians may inappropriately reduce insulin doses in response to lower glucose readings while on SGLT2i, removing the brake on ketogenesis. This is particularly dangerous in type 1 diabetes or insulin-dependent type 2 diabetes.

Surgery and Perioperative Period: The combination of preoperative fasting, surgical stress, and potential insulin dose adjustments creates high-risk conditions. Multiple case series have documented euDKA developing postoperatively in patients continuing SGLT2i through the perioperative period.

Alcohol Consumption: Alcohol inhibits gluconeogenesis while promoting ketogenesis, synergizing with SGLT2i effects to increase DKA risk.

Pregnancy: Although SGLT2i are contraindicated in pregnancy, inadvertent use or failure to discontinue before conception increases risk, as pregnancy itself is a ketogenic state.

Patient-Specific Risk Factors

Type 1 diabetes patients using SGLT2i off-label face substantially higher risk. Other risk factors include: longstanding diabetes with beta-cell dysfunction, low baseline C-peptide levels, history of prior DKA, and concurrent use of insulin pumps (particularly with pump failure or catheter problems).

The Diagnostic Challenge: Recognizing the Wolf in Sheep's Clothing

The Diagnostic Triad

EuDKA diagnosis requires recognition of three key features:

1. Metabolic Acidosis: Arterial pH <7.3 or venous pH <7.25, serum bicarbonate <18 mEq/L, and elevated anion gap (typically >12 mEq/L). The anion gap is calculated as: [Na] - ([Cl] + [HCO3]).

2. Ketonemia or Ketonuria: Beta-hydroxybutyrate ≥3.0 mmol/L (the gold standard), or positive serum or urine ketones. Point-of-care ketone meters measuring capillary beta-hydroxybutyrate provide rapid, quantitative assessment.

3. Normal or Mildly Elevated Glucose: Blood glucose <250 mg/dL, often 100-200 mg/dL. This is the defining feature distinguishing euDKA from classic DKA.

The Critical Clinical Maneuver

PEARL #1: Check ketones in every sick diabetic patient on an SGLT2 inhibitor, regardless of glucose level.

This single action prevents diagnostic delay. Traditional DKA screening protocols based on hyperglycemia thresholds will miss euDKA. Institutions should implement protocols requiring ketone measurement for all patients on SGLT2i presenting with acidosis, abdominal pain, nausea, vomiting, altered mental status, or any acute illness.

Clinical Presentation

Patients typically present with classic DKA symptoms: nausea, vomiting, abdominal pain, dyspnea, and malaise. Kussmaul respirations (deep, labored breathing) may be present. However, the absence of marked hyperglycemia and associated osmotic symptoms (polyuria, polydipsia) may lead clinicians astray.

OYSTER #1: A patient on SGLT2i presenting with abdominal pain and normal glucose is euDKA until proven otherwise. The abdominal pain can be severe enough to mimic an acute abdomen, leading to unnecessary surgical consultations and imaging.

Differential Diagnosis

The combination of anion gap metabolic acidosis and normal glucose should prompt consideration of:

SGLT2i-associated euDKA (if patient on medication)
Starvation ketosis (typically milder, beta-hydroxybutyrate usually <3 mmol/L)
Alcoholic ketoacidosis (history of alcohol use, often with vomiting)
Lactic acidosis (elevated lactate, check in sepsis or hypoperfusion)
Toxic ingestions (methanol, ethylene glycol, salicylates)
Uremia (elevated BUN and creatinine)

Laboratory Evaluation: Beyond the Basic Metabolic Panel

Essential Initial Tests

Arterial or venous blood gas: pH, pCO2, bicarbonate
Basic metabolic panel: Electrolytes, BUN, creatinine, glucose
Serum beta-hydroxybutyrate: Quantitative ketone measurement (preferred over urine ketones)
Anion gap calculation: [Na] - ([Cl] + [HCO3])
Serum lactate: Rule out concurrent lactic acidosis
Complete blood count: Assess for leukocytosis suggesting infection
Urinalysis: Ketones, glucose, signs of infection

Additional Considerations

Blood and urine cultures: If infection suspected
Troponin and ECG: If cardiac event possible
Lipase: If pancreatitis in differential
Toxicology screen: If ingestion suspected
C-peptide: May help assess endogenous insulin production

HACK #1: Point-of-care ketone meters measuring capillary beta-hydroxybutyrate provide results in seconds, enabling rapid diagnosis. Every emergency department and inpatient unit should have immediate access to these devices.

Management: Adapting the DKA Protocol

The Core Principles

Management parallels traditional DKA but requires important modifications:

1. Discontinue SGLT2 Inhibitor Immediately

The first step is stopping the offending agent. The drug should remain discontinued during hospitalization and potentially permanently, depending on circumstances.

2. Aggressive Fluid Resuscitation

Volume repletion remains paramount. Initial fluid resuscitation with 0.9% normal saline at 15-20 mL/kg/hour (1-1.5 L) in the first hour for most patients, then 250-500 mL/hour. Adjust based on cardiovascular status, renal function, and volume status.

PEARL #2: Unlike typical DKA, patients with euDKA may not be as profoundly dehydrated since hyperglycemic osmotic diuresis is less prominent. Tailor fluid administration to clinical assessment.

3. Insulin Therapy: The Ketone-Shutoff Switch

Continuous intravenous insulin infusion is essential to suppress ketogenesis, even with normal glucose levels. Start regular insulin at 0.1 units/kg/hour (typically 5-10 units/hour). The goal is not primarily glucose lowering but turning off lipolysis and ketone production.

CRITICAL DISTINCTION: In euDKA, glucose may fall rapidly with insulin, requiring earlier dextrose supplementation.

4. Dextrose Administration: The Key Difference

PEARL #3: Add dextrose to IV fluids much earlier than in traditional DKA—often immediately or within the first few hours.

Once glucose falls below 250 mg/dL (which may be at presentation), switch to D5-0.45% NS or D10-0.45% NS to maintain glucose between 150-200 mg/dL while continuing insulin infusion. The insulin is needed for ketone suppression, while dextrose prevents hypoglycemia.

HACK #2: Some centers use a "two-bag system" with one bag containing 0.9% NS and another containing D10-0.45% NS. Adjusting the infusion rates of each bag allows precise control of dextrose delivery while maintaining consistent fluid and insulin administration.

5. Potassium Repletion

Monitor potassium closely and begin repletion when K+ <5.3 mEq/L (unless anuric). Insulin drives potassium intracellularly, and aggressive repletion (20-40 mEq/L in IV fluids) is often necessary.

6. Bicarbonate Therapy

Generally not recommended unless pH <6.9, as it may worsen intracellular acidosis and delay ketone clearance. If given, use cautiously (100 mmol in 400 mL sterile water over 2 hours if pH <6.9).

7. Monitoring

Hourly: Point-of-care glucose and ketones (beta-hydroxybutyrate)
Every 2-4 hours: Electrolytes, anion gap
Every 4 hours: Venous or arterial blood gas until improving
Continuous: Cardiac monitoring, urine output

OYSTER #2: Beta-hydroxybutyrate is the primary ketone elevated in DKA. Standard nitroprusside-based urine ketone tests primarily detect acetoacetate and may paradoxically become more positive as beta-hydroxybutyrate converts to acetoacetate during treatment. Use quantitative serum beta-hydroxybutyrate for monitoring.

Resolution Criteria

DKA resolution requires meeting ALL of the following:

Beta-hydroxybutyrate <1.0 mmol/L (or anion gap <12 mEq/L)
Venous pH >7.3
Serum bicarbonate >18 mEq/L
Patient able to tolerate oral intake

Transition to Subcutaneous Insulin

Once resolution criteria are met, overlap subcutaneous and IV insulin. Give subcutaneous rapid-acting insulin with a meal, then continue IV insulin for 1-2 hours before discontinuing (prevents rebound ketosis).

Prevention and Discharge Planning: Closing the Loop

Patient Education: The Foundation

PEARL #4: Structured "sick day rules" education prevents recurrence. Patients must understand:

SICK DAY RULES FOR SGLT2 INHIBITOR USERS

STOP your SGLT2 inhibitor during any illness, before surgery, or if you cannot eat normally
NEVER reduce or skip insulin doses just because your sugar is lower
CHECK KETONES (urine or blood) if you feel unwell, even with normal glucose
DRINK PLENTY OF FLUIDS to prevent dehydration
SEEK MEDICAL ATTENTION if ketones are moderate to high, if you're vomiting and cannot keep fluids down, or if you have severe abdominal pain

When to Resume SGLT2 Inhibitors

Decision-making regarding SGLT2i continuation requires individualized risk-benefit assessment:

Consider permanent discontinuation in:

Type 1 diabetes (relative contraindication)
Recurrent euDKA episodes
Patients unable to reliably follow sick day rules
Very low C-peptide suggesting minimal endogenous insulin

May cautiously resume in:

Type 2 diabetes with preserved beta-cell function
Clear precipitant (e.g., postoperative) unlikely to recur
Strong cardiovascular or renal indication
Patient demonstrates understanding of prevention strategies

If resuming, start at low dose, reinforce education, provide home ketone testing supplies, and ensure close follow-up.

Perioperative Management

Given high perioperative risk, establish clear protocols:

Discontinue SGLT2i at least 3-4 days before elective surgery
Hold throughout hospitalization for acute surgery
Resume only after patient fully recovered, eating normally, and medically stable

HACK #3: Create a patient wallet card listing their SGLT2i medication and sick day rules. This ensures the information is available during emergency situations.

Special Populations and Scenarios

Type 1 Diabetes

SGLT2 inhibitors are not FDA-approved for type 1 diabetes, though dapagliflozin and sotagliflozin have approval in some countries. EuDKA risk is substantially higher (5-10 fold) in this population. If used, extremely careful patient selection, intensive education, and close monitoring are mandatory.

Pregnancy

SGLT2 inhibitors are contraindicated in pregnancy. Women of childbearing age should use effective contraception, and medication should be discontinued when pregnancy is planned or discovered.

Chronic Kidney Disease

While SGLT2i provide renal protection, severe renal impairment may alter drug clearance and ketone metabolism. Monitor more closely in advanced CKD.

Systems-Based Approach: Building Institutional Safety

Protocol Development

Institutions should implement:

EMR alerts flagging patients on SGLT2i presenting with acidosis
Order sets requiring ketone measurement in this population
Standardized treatment protocols for euDKA management
Pharmacy alerts for perioperative SGLT2i discontinuation
Patient education materials provided at prescription initiation

Interdisciplinary Communication

Ensure seamless communication between:

Endocrinology and primary care
Inpatient teams and surgeons
Pharmacists and prescribers
Emergency department and admitting services

Conclusion

SGLT2 inhibitors represent a major therapeutic advance with proven mortality benefits in diabetes, heart failure, and chronic kidney disease. Their expanding indications mean physicians across multiple specialties will increasingly encounter patients on these medications. Euglycemic DKA, while uncommon, is a potentially life-threatening complication that challenges diagnostic conventions and requires heightened clinical awareness.

The key to successful management lies in abandoning the dogma that DKA requires marked hyperglycemia. By maintaining a high index of suspicion, checking ketones liberally in at-risk populations, and implementing modified treatment protocols, clinicians can rapidly diagnose and effectively treat this condition.

Patient education remains the cornerstone of prevention. Empowering patients with knowledge about sick day rules, ketone monitoring, and when to seek care can prevent many cases. For those that occur, prompt recognition, appropriate fluid resuscitation, continuous insulin with early dextrose supplementation, and careful monitoring lead to excellent outcomes.

As SGLT2 inhibitors continue to reshape cardiovascular and renal care, every internist and emergency physician must be prepared to recognize and manage euDKA. This metabolic complication should not limit our use of these life-saving medications but rather inform our approach to prescribing, monitoring, and patient education.

Key Takeaways for Clinical Practice

Check ketones in every sick diabetic on SGLT2i, regardless of glucose
Suspect euDKA with: acidosis + ketones + glucose <250 mg/dL
Management requires insulin for ketosis + early dextrose to prevent hypoglycemia
Prevention depends on patient education: sick day rules save lives
Always discontinue SGLT2i before surgery and during acute illness

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