Does initiating SGLT2 (Sodium-Glucose Linked Transporter 2) inhibitors in patients with low C-peptide levels increase the risk of euglycemic ketoacidosis?

Risk of Euglycemic Ketoacidosis with SGLT2 Inhibitors in Patients with Low C-peptide Levels

Yes, initiating SGLT2 inhibitors in patients with low C-peptide levels significantly increases the risk of euglycemic diabetic ketoacidosis (euDKA) due to relative insulin deficiency. 1

Mechanism and Risk Assessment

SGLT2 inhibitors can precipitate euDKA through several mechanisms:

1. Insulin deficiency: Low C-peptide levels indicate reduced endogenous insulin production

   • Insulin is needed to suppress ketogenesis
   • SGLT2 inhibitors reduce insulin secretion and increase glucagon levels 1

2. Glucose-independent ketosis promotion:

   • SGLT2 inhibitors cause urinary glucose excretion while maintaining normal or near-normal blood glucose
   • This creates a state of perceived starvation despite euglycemia 2
   • Ketone body production increases as an alternative energy source

3. Risk amplification in insulin-deficient states:

   • Low C-peptide indicates reduced pancreatic beta-cell function
   • Without adequate insulin to suppress hepatic ketogenesis, ketone production accelerates 1

High-Risk Patient Identification

Patients at highest risk for euDKA when starting SGLT2 inhibitors include:

• Those with low C-peptide levels (indicating insulin deficiency) 1
• Patients with late-onset type 1 diabetes (approximately 5-10% of adult-onset diabetes) 1
• Insulin-dependent type 2 diabetes patients 1
• Patients with reduced pancreatic reserve from any cause

Clinical Management Algorithm

Pre-Initiation Assessment:

1. Measure C-peptide levels before starting SGLT2 inhibitors
2. Consider alternative therapies if C-peptide is significantly low
3. Screen for undiagnosed type 1 diabetes in patients with atypical type 2 diabetes presentation

If SGLT2 Inhibitor Is Still Indicated Despite Low C-peptide:

1. Maintain baseline insulin therapy

   • Do not reduce insulin doses by >20% when initiating SGLT2 inhibitors 1
   • Maintain at least low-dose insulin therapy in insulin-dependent patients 1

2. Patient Education (mandatory):

   • Teach patients to recognize euDKA symptoms (nausea, vomiting, abdominal pain, weakness)
   • Instruct on when to seek immediate medical attention 1
   • Provide ketone monitoring instructions (blood or urine) 1

3. Risk Mitigation Plan:

   • Temporary discontinuation during:
     • Acute illness
     • Surgical procedures
     • Prolonged fasting
     • Other physiologic stressors 1, 3
   • Consider blood ketone monitoring during high-risk periods 1

Special Considerations

• Ketogenic/low-carbohydrate diets: Represent a significant risk factor when combined with SGLT2 inhibitors 4, 5
• Non-diabetic patients: Even patients without diabetes can develop euDKA with SGLT2 inhibitors during periods of reduced oral intake 6, 7
• Coordination of care: Complex insulin regimens should be managed in collaboration with diabetes specialists 1

Warning Signs Requiring Immediate Action

Patients should discontinue SGLT2 inhibitors and seek immediate medical attention if they experience:

• Nausea, vomiting, abdominal pain
• Generalized weakness or fatigue
• Rapid breathing or shortness of breath
• Confusion or unusual behavior

Conclusion

The risk of euDKA is significantly elevated when SGLT2 inhibitors are initiated in patients with low C-peptide levels. While these medications offer substantial cardiorenal benefits, careful patient selection, education, and monitoring are essential to minimize this potentially life-threatening complication.