Mechanism of Jardiance-Induced Euglycemic DKA
Jardiance (empagliflozin) causes euglycemic DKA through a combination of increased glucagon-to-insulin ratio, enhanced ketogenesis from metabolic shift to fat utilization, and persistent glycosuria that masks hyperglycemia while ketoacidosis develops. 1
Core Pathophysiologic Mechanisms
Primary Metabolic Alterations
SGLT2 inhibition creates a carbohydrate deficit state by forcing urinary glucose excretion (glucosuria), which paradoxically signals the body that glucose is scarce despite adequate intake 2, 3
The glucosuria-induced carbohydrate deficit increases the glucagon-to-insulin ratio, shifting metabolism from glucose to lipid utilization and triggering ketogenesis 2, 3
Empagliflozin maintains a baseline low level of ambient ketones during normal use; any additional ketone formation from stress or illness rapidly precipitates ketoacidosis while the drug's glycosuric effect simultaneously prevents hyperglycemia 3
Insulin Deficiency Component
Euglycemic DKA requires underlying insulin deficiency as a prerequisite, which can be absolute (as in type 1 diabetes) or relative (as in type 2 diabetes under stress conditions) 4
The relative insulinopenia during SGLT2 inhibitor therapy promotes lipolysis and ketogenesis while maintaining near-normal glucose levels through continued urinary glucose losses 5
Clinical Precipitating Factors
High-Risk Situations
The following conditions dramatically increase euglycemic DKA risk when combined with Jardiance use:
- Reduced food intake or prolonged fasting (from acute illness, surgery, or intentional dietary restriction) 4, 1
- Very-low-carbohydrate or ketogenic diets that compound the carbohydrate deficit state 4
- Dehydration and volume depletion from any cause 4
- Excessive alcohol intake (both chronic heavy use and acute binge drinking) 4, 1
- Acute illness, infection, or surgical stress that increases counter-regulatory hormones 4, 5
- Reduction or discontinuation of insulin doses in insulin-treated patients 1, 6
- Pregnancy, which creates a physiologic state predisposing to ketosis 4
- Pancreatic disorders suggesting insulin deficiency (history of pancreatitis or pancreatic surgery) 1
Important Clinical Caveat
The pharmacologic effects of empagliflozin persist beyond several half-lives of elimination (average half-life 11-13 hours), meaning euglycemic DKA can develop even after the drug has been stopped, particularly in the perioperative period 2, 5
Why Glucose Remains Normal or Mildly Elevated
The Euglycemic Paradox
SGLT2 inhibition forces continuous urinary glucose excretion regardless of blood glucose levels, preventing the typical hyperglycemia (>250 mg/dL) seen in classic DKA 4, 7
Approximately 10% of all DKA cases present with glucose <200 mg/dL, and this euglycemic variant is strongly associated with SGLT2 inhibitor use 4, 8
The normal or mildly elevated glucose creates a diagnostic challenge, as clinicians may not suspect DKA when blood glucose is <250 mg/dL, leading to delayed diagnosis and treatment 1, 6, 7
Diagnostic Recognition
Key Clinical Features
Patients present with signs of severe metabolic acidosis rather than hyperglycemia: 1
- Nausea and vomiting
- Abdominal pain
- Generalized malaise and tiredness
- Shortness of breath (Kussmaul respirations)
- Dehydration
Laboratory Confirmation
Diagnosis requires checking ketones even when glucose is <250 mg/dL: 4, 1
- Elevated serum or urine ketones
- High anion gap metabolic acidosis (anion gap >10-12 mEq/L) 8
- Arterial pH typically <7.3
- Serum bicarbonate <18 mEq/L
- Blood glucose <200 mg/dL (defining euglycemic DKA) 4
Prevention Strategies
Before Initiating Jardiance
Screen for factors predisposing to ketoacidosis: 1
- Pancreatic insulin deficiency from any cause
- History of type 1 diabetes or autoimmunity
- History of pancreatitis or pancreatic surgery
- Patterns of caloric restriction or fasting
- Alcohol abuse history
During Treatment
Temporarily discontinue Jardiance in high-risk clinical situations: 4, 1
- Stop 3-4 days before any elective surgery (3 days for empagliflozin specifically) 4, 2
- Hold during acute illness with reduced oral intake
- Discontinue during prolonged fasting
- Stop with fluid losses from gastrointestinal illness or heat exposure
Monitor for ketoacidosis symptoms and consider ketone monitoring in patients at higher baseline risk 1
Management When Euglycemic DKA Occurs
Immediate Actions
Discontinue Jardiance immediately and do not restart until the episode is fully resolved and precipitating factors addressed 1
Treat as standard DKA despite normal glucose: 1, 3
- Aggressive IV fluid resuscitation with isotonic saline
- Insulin therapy to suppress ketogenesis (even with normal glucose)
- Electrolyte replacement, particularly potassium
- Immediate use of glucose-containing IV fluids to induce endogenous insulin secretion and stop ketogenesis 3
Duration Considerations
Euglycemic DKA associated with SGLT2 inhibitors may be more prolonged than classic DKA due to the drug's half-life and persistent pharmacologic effects 3