Why should empagliflozin (Empagliflozin) not be started in patients with high Hemoglobin A1C (HbA1C) levels?

Empagliflozin Use in Patients with High HbA1C

Empagliflozin should not be initiated in patients with very high HbA1C levels due to increased risk of euglycemic diabetic ketoacidosis, particularly in patients with poor oral intake or those undergoing surgical procedures. 1

Rationale for Caution with High HbA1C

• The pivotal trials demonstrating cardiovascular benefits of empagliflozin primarily enrolled patients with baseline HbA1C ≥7% but with average values around 8%, suggesting that the drug's safety profile is best established within this range 1
• Secondary analyses from the EMPA-REG OUTCOME trial suggest that cardiovascular benefits may be independent of baseline HbA1C, but safety concerns remain for those with very high HbA1C levels 1
• Patients with markedly elevated blood glucose may be at higher risk for complications including euglycemic diabetic ketoacidosis when starting SGLT2 inhibitors like empagliflozin 1

Risk of Diabetic Ketoacidosis

• SGLT2 inhibitors including empagliflozin can increase the risk of euglycemic diabetic ketoacidosis, which is particularly concerning in patients with very poor glycemic control 1
• This risk is heightened in patients with:
  • Poor oral intake 1
  • Acute illness 1
  • Surgical procedures (empagliflozin should be discontinued at least 3 days before planned surgery) 2
  • Concurrent insulin dose reduction 2

Appropriate Initial Therapy for Very High HbA1C

• For patients with very high HbA1C (≥8.5% or ≥69 mmol/mol), initial treatment with insulin is often recommended until glycemic control improves 1
• In children and adolescents with type 2 diabetes, insulin is recommended as initial therapy when HbA1C ≥8.5% until fasting and postprandial glycemia have been restored to normal or near-normal levels 1
• This principle can be applied to adults with markedly elevated HbA1C as well, with transition to oral agents including empagliflozin after initial stabilization 1

Recommendations for Safe Initiation

• Consider starting empagliflozin only after HbA1C has been reduced to more moderate levels with other agents like insulin or metformin 1
• When initiating empagliflozin in patients with diabetes:
  • Start with 10 mg once daily as the standard dose 2
  • Consider reducing or stopping sulfonylureas/glinides or reducing total daily insulin dose by approximately 20% to prevent hypoglycemia 2
  • Do not initiate if eGFR is below 45 mL/min/1.73 m² 2, 3
  • Monitor for hypotension, especially in patients with renal impairment, elderly patients, or those on diuretics 3

Clinical Decision Algorithm

1. For patients with very high HbA1C (≥8.5%):

   • Start with insulin therapy to rapidly improve glycemic control 1
   • Add metformin if not contraindicated 1
   • Monitor for resolution of glycemic toxicity 1

2. Once HbA1C improves to more moderate levels:

   • Consider adding empagliflozin 10 mg daily for its cardiovascular and renal benefits 2, 3
   • Adjust concomitant diabetes medications to prevent hypoglycemia 2
   • Monitor for signs of ketoacidosis, genital infections, and hypotension 1, 3

3. For patients with established cardiovascular disease:

   • Empagliflozin 10 mg daily provides optimal cardiovascular risk reduction regardless of HbA1C level, but should still be initiated after glycemic stabilization if HbA1C is very high 2, 4

Evidence from Clinical Trials

• The EMPEROR-Reduced trial showed that empagliflozin improved cardiovascular and renal outcomes independent of baseline diabetes status and across the continuum of HbA1C 4
• However, most clinical trials excluded patients with extremely high HbA1C levels, limiting safety data in this population 1
• In clinical trials, empagliflozin has demonstrated dose-dependent reductions in HbA1C (0.4-0.6%) compared to placebo, but these studies typically enrolled patients with moderate hyperglycemia 5

By following these guidelines, clinicians can safely initiate empagliflozin in appropriate patients while minimizing the risk of adverse events, particularly in those with initially high HbA1C levels.