Does chronic kidney disease (CKD) affect the efficacy and duration of insulin?

Effect of Chronic Kidney Disease on Insulin Effectiveness and Duration

Yes, chronic kidney disease (CKD) makes insulin more effective and last longer in the body, particularly in advanced stages, leading to an increased risk of hypoglycemia.

Mechanisms of Altered Insulin Metabolism in CKD

Reduced Insulin Clearance

• The kidney is responsible for approximately 30-80% of insulin clearance from the systemic circulation 1
• In CKD, decreased kidney function leads to reduced insulin degradation and clearance 1
• About one-third of insulin degradation is carried out by the kidney, and impaired kidney function is associated with a prolonged half-life of insulin 1

Impaired Gluconeogenesis

• The kidney normally contributes 20-25% of blood glucose via gluconeogenesis during fasting states 1
• As kidney function declines, this gluconeogenic capacity is reduced, impairing the body's ability to defend against hypoglycemia 1
• This is particularly important when patients are taking insulin or insulin secretagogues 1

Changes in Insulin Effectiveness Across CKD Stages

Early CKD (Stages 1-3)

• Characterized by insulin resistance due to:
  • Impaired glucose disposal by muscle and peripheral tissues due to uremia
  • Persistent mild inflammatory state
  • Oversecretion of counterregulatory hormones
  • Accumulation of "uremic toxins" 1
• Despite insulin resistance, there is already an increased risk of hypoglycemia compared to those with normal renal function 1

Advanced CKD (Stages 4-5, including dialysis)

• Higher risk for severe and prolonged hypoglycemia due to:
  • Significantly decreased insulin clearance
  • Decreased renal gluconeogenesis
  • Poor nutritional status
  • Less severe insulin resistance resulting from removal of uremic toxins by dialysis 1
• Patients with type 1 diabetes who have significant creatinine elevations (mean 2.2 mg/dL) experience a 5-fold increase in the frequency of severe hypoglycemia 1
• A phenomenon called "burn-out diabetes" occurs in 15-30% of patients with ESKD (GFR < 20 mL/min/1.73 m²), where they require less or no medications for glycemic control 1

Clinical Implications

Insulin Dosing

• Insulin doses typically need to be decreased in advanced CKD compared to earlier stages 1
• The overall insulin requirement declines as kidney disease progresses, necessitating reassessment and adjustment of insulin doses 2

Monitoring Recommendations

• Close glucose monitoring is imperative for patients with CKD on insulin therapy 1
• Continuous glucose monitoring may be beneficial in detecting hypoglycemic episodes, particularly in advanced CKD 1

Medication Considerations

• First-generation sulfonylureas should be avoided in patients with CKD due to increased risk of hypoglycemia 1
• Metformin is contraindicated with eGFR <30 ml/min/1.73 m² due to risk of lactic acidosis 1
• GLP-1 receptor agonists and selected dipeptidyl peptidase 4 inhibitors can be safer options in advanced CKD 1

Special Considerations for Dialysis Patients

• Hemodialysis can increase the risk of hypoglycemia through:
  • Increased erythrocyte glucose uptake during hemodialysis
  • Variable medication effects as a result of the dialysis procedure 1
• Postprandial and post-dialysis hyperglycemia is common due to impaired osmotic diuresis and post-dialysis meal intake 1
• Glucose levels are affected by the glucose concentration of the dialysate 1

In conclusion, healthcare providers must be vigilant about the increased potency and duration of insulin action in patients with CKD, particularly in advanced stages, and adjust treatment regimens accordingly to prevent dangerous hypoglycemic episodes.