Is Jardiance (Empagliflozin) safe to use in patients with End-Stage Renal Disease (ESRD) on Hemodialysis (HD)?

Jardiance (Empagliflozin) in ESRD on Hemodialysis

Jardiance (empagliflozin) is contraindicated in patients with end-stage renal disease (ESRD) on hemodialysis and should not be used in this population. 1

Rationale for Contraindication

The FDA label for Jardiance explicitly states that the medication is contraindicated in:

• Severe renal impairment
• End-stage renal disease
• Patients on dialysis 1

This contraindication is based on several important factors:

1. Mechanism of Action: Empagliflozin works by inhibiting sodium-glucose co-transporter 2 (SGLT2) in the proximal renal tubules, which reduces renal glucose reabsorption. This mechanism requires functioning kidneys to be effective.

2. Pharmacokinetics in ESRD: While studies show that empagliflozin exposure (AUC) increases by approximately 48% in patients with renal failure/ESRD compared to those with normal renal function 2, the more critical issue is the lack of efficacy rather than increased drug levels.

3. Pharmacodynamics in ESRD: Urinary glucose excretion (UGE), which is the primary mechanism by which empagliflozin exerts its therapeutic effect, decreases significantly with increasing renal impairment and correlates with decreased eGFR 2. In patients with ESRD, there would be minimal to no glucose-lowering effect.

Clinical Evidence

While the EMPA-KIDNEY trial demonstrated benefits of empagliflozin in patients with chronic kidney disease, including those with eGFR as low as 20 ml/min/1.73m², it did not include patients on dialysis 3. The study showed that empagliflozin led to a lower risk of progression of kidney disease or death from cardiovascular causes compared to placebo, but these findings cannot be extrapolated to the ESRD population on hemodialysis.

Alternative Management for ESRD Patients with Diabetes

For patients with ESRD on hemodialysis who require glycemic control:

1. Insulin therapy: Remains the cornerstone of treatment for most ESRD patients with diabetes on dialysis, with dose adjustments based on dialysis schedule.

2. Selected oral agents:

   • Dipeptidyl peptidase-4 (DPP-4) inhibitors (with appropriate dose adjustments)
   • Certain sulfonylureas with minimal renal clearance

3. Glycemic targets: Consider less stringent glycemic targets (HbA1c 7-8%) in this population due to:

   • Increased risk of hypoglycemia in ESRD
   • Limited utility of HbA1c in ESRD due to shortened red blood cell lifespan 4
   • Higher mortality associated with both very low and very high HbA1c values in dialysis patients

Important Considerations in ESRD Patients

• Glycemic monitoring challenges: HbA1c may be less reliable in ESRD patients due to anemia, shortened red blood cell lifespan, and use of erythropoiesis-stimulating agents 4

• Hypoglycemia risk: ESRD patients are at increased risk of hypoglycemia due to:

  • Impaired renal gluconeogenesis
  • Altered insulin clearance
  • Defective insulin degradation due to uremia
  • Increased erythrocyte glucose uptake during hemodialysis 4

• Medication clearance: Many medications require dose adjustments or are contraindicated in ESRD

Conclusion

Jardiance (empagliflozin) should not be used in patients with ESRD on hemodialysis due to its explicit contraindication in the FDA label, lack of efficacy in this population, and absence of supporting clinical evidence. Alternative diabetes management strategies should be employed for these patients.