What are the risks of metabolic acidosis associated with Jardiance (Empagliflozin)?

Jardiance and Metabolic Acidosis Risk

Jardiance (empagliflozin) carries a significant risk of euglycemic diabetic ketoacidosis (EDKA), a life-threatening form of metabolic acidosis that occurs even with normal or near-normal blood glucose levels, requiring immediate discontinuation and aggressive treatment when suspected. 1

Understanding the Risk: Euglycemic DKA vs. Traditional Lactic Acidosis

Jardiance does not cause traditional lactic acidosis like metformin 2. Instead, it causes a distinct and dangerous condition called euglycemic diabetic ketoacidosis (EDKA), characterized by:

• Metabolic acidosis with pH <7.35 1, 3
• Blood glucose often <250 mg/dL (sometimes even <200 mg/dL), which is deceptively "normal" 4, 5
• Elevated ketones in blood or urine 3, 6
• High anion gap metabolic acidosis 5

This presentation is diagnostically challenging because the relatively normal glucose levels can delay recognition and treatment, leading to severe complications 5.

FDA Black Box Warning and Contraindications

The FDA label explicitly warns about ketoacidosis risk with Jardiance 1:

• Assess patients presenting with signs/symptoms of metabolic acidosis for ketoacidosis, regardless of blood glucose level 1
• If suspected, discontinue JARDIANCE immediately, evaluate and treat promptly 1
• Contraindicated in severe renal impairment (eGFR <45 mL/min/1.73 m²), end-stage renal disease, or dialysis 1

High-Risk Clinical Scenarios Requiring Vigilance

The ADA/EASD consensus identifies specific situations where EDKA risk increases 7:

• Insulin deficiency states (reduced insulin dose, insulin discontinuation) 7, 3
• Acute illness or infection (including COVID-19) 3, 4
• Severe dehydration or vomiting 4, 6
• Decreased carbohydrate intake (ketogenic diets, fasting, prolonged NPO status) 3, 5
• Surgery or procedures requiring NPO status 7

Clinical Presentation: What to Look For

Patients with empagliflozin-induced EDKA typically present with 3, 4, 6, 5:

• Nausea and vomiting (most common initial symptoms) 4, 6, 5
• Dyspnea and tachypnea 3, 5
• Generalized weakness and fatigue 6, 5
• Confusion or altered mental status 6
• Abdominal pain (less common but possible) 7

Critical pitfall: The relatively normal glucose levels (often 150-250 mg/dL) can mislead clinicians into dismissing DKA as a diagnosis, causing dangerous delays in treatment 4, 5.

Diagnostic Workup

When EDKA is suspected, immediately obtain 1, 3:

• Arterial or venous blood gas (looking for pH <7.35, low bicarbonate) 3, 6
• Serum or urine ketones (will be elevated) 3, 6
• Anion gap calculation (will be elevated, typically >16) 5
• Blood glucose (often deceptively normal at 150-250 mg/dL) 4, 5
• Renal function tests (creatinine, BUN, eGFR) 1
• Electrolytes (particularly potassium, which shifts with treatment) 7

Management Algorithm

Immediate Actions (First Hour)

1. Discontinue empagliflozin immediately 1, 6, 5
2. Admit to ICU or monitored setting for severe cases (pH <7.2) 6
3. Begin aggressive IV fluid resuscitation with isotonic saline (15-20 mL/kg/h initially) 2, 8
4. Start continuous IV insulin infusion (do NOT wait for glucose to rise) 6, 5

Ongoing Management (Hours 2-24)

1. Add dextrose-containing fluids once glucose approaches 250 mg/dL to prevent hypoglycemia while continuing insulin 7, 8
2. For refractory acidosis: Consider high-calorie glucose infusion (10-20% dextrose) with tight glycemic control using insulin 9
3. Monitor and replace potassium (20-30 mEq/L in IV fluids once renal function confirmed) 8, 10
4. Avoid sodium bicarbonate unless pH <7.0 with hemodynamic instability, as it does not improve outcomes and may worsen intracellular acidosis 2, 8

Novel Approach for Refractory Cases

For severe EDKA with persistent acidosis despite standard treatment: High-calorie glucose infusion (≥10% dextrose) coupled with aggressive insulin titration to maintain euglycemia has shown success in correcting refractory acidosis 9. This represents a paradigm shift from traditional DKA management and addresses the unique pathophysiology of SGLT2 inhibitor-induced ketoacidosis 9.

Prevention Strategies

The ADA/EASD guidelines recommend 7:

• Provide appropriate patient education about EDKA risk factors and warning signs 7
• Use with caution in patients with insulin deficiency 7
• Temporarily discontinue before surgery or procedures requiring prolonged NPO status 7
• Hold during acute illness with vomiting, dehydration, or reduced oral intake 7
• Avoid in patients on very low carbohydrate diets 5

Key Differences from Other Forms of Metabolic Acidosis

Unlike metformin-associated lactic acidosis 2:

• EDKA occurs with normal or mildly elevated glucose 4, 5
• EDKA presents with elevated ketones (not elevated lactate) 3, 6
• EDKA requires insulin therapy (not just supportive care) 6, 5
• EDKA can occur with normal renal function 5

Prognosis and Long-Term Management

• Most patients recover within 24 hours with appropriate treatment 5
• Empagliflozin should be permanently discontinued after an EDKA episode 6, 5
• Alternative diabetes medications should be selected for ongoing management 6
• Patient education about never restarting SGLT2 inhibitors is critical 6