What is the best insulin regimen for a patient with uncontrolled diabetes on Mixtard (premix insulin, NPH insulin and regular insulin) with CKD and CLD?

Optimal Insulin Management for Uncontrolled Diabetes on Mixtard with CKD and CLD

Switch from Mixtard 20/16 to a basal-bolus regimen using long-acting basal insulin analog (glargine or degludec) once daily plus rapid-acting insulin before meals, as this provides superior glycemic control with reduced hypoglycemia risk compared to premixed insulin, particularly critical in patients with chronic kidney disease. 1, 2

Why Change from Mixtard (Premixed Insulin)?

• Premixed insulins like Mixtard (70% NPH/30% regular) offer convenience but lack the flexibility needed for patients with CKD and chronic liver disease (CLD), where insulin requirements fluctuate unpredictably due to altered insulin clearance 1, 3
• The NPH component in Mixtard has a pronounced peak at 4-6 hours, significantly increasing nocturnal hypoglycemia risk—a dangerous complication in CKD patients who have impaired counter-regulatory responses 2, 3
• Patients with CKD stages 3-4 experience 3 times more nocturnal hypoglycemia with NPH-based regimens compared to long-acting analogs 2

Recommended Transition Strategy

Step 1: Calculate Starting Doses

• Total current insulin dose: 20 units (morning) + 16 units (evening) = 36 units/day
• Convert to basal insulin: Start with 80% of total Mixtard dose = 29 units of glargine or degludec once daily 1
• Add prandial insulin: Start with 4 units of rapid-acting insulin (lispro, aspart, or glulisine) before the largest meal, or 10% of basal dose = 3 units 1
• Maintain metformin if renal function permits (eGFR >30 mL/min) 1

Step 2: Timing and Administration

• Administer basal insulin (glargine/degludec) once daily at the same time each day, preferably bedtime for consistency 4, 2
• Give rapid-acting insulin immediately before meals (0-15 minutes), not 30-45 minutes prior as with regular insulin 1, 5
• In CKD/CLD, start conservatively due to decreased insulin clearance and increased half-life 3

Step 3: Titration Protocol

For basal insulin:

• Check fasting blood glucose daily
• If fasting glucose >130 mg/dL for 3 consecutive days, increase basal dose by 2 units 1, 6
• Target fasting glucose <130 mg/dL (can aim for <100 mg/dL if no hypoglycemia risk) 1, 6

For prandial insulin:

• Check 2-hour postprandial glucose
• If consistently >180 mg/dL, increase pre-meal dose by 1-2 units 1, 7
• Add prandial insulin to additional meals sequentially (start with largest meal, then add to next largest) 1

Critical adjustment for CKD/CLD:

• Reduce all doses by 10-20% if hypoglycemia occurs without clear cause 1, 3
• Monitor glucose every 4-6 hours initially when transitioning 8, 3
• Overall insulin requirements typically decrease by 25-50% as CKD progresses from stage 3 to 5 3

Why Basal Analogs Over NPH in CKD/CLD

• Reduced hypoglycemia: Glargine U100 demonstrated 0.91% HbA1c reduction with 3-fold fewer nocturnal hypoglycemic events compared to NPH in CKD stages 3-4 patients 2
• Peakless profile: Long-acting analogs provide steady 24-hour coverage without the pronounced peak that causes nocturnal hypoglycemia 4, 2
• Predictable pharmacokinetics: Less variability in absorption compared to NPH, crucial when renal clearance is impaired 2, 3
• Once-daily dosing: Improves adherence and reduces injection burden 4, 2

Special Considerations for CKD and CLD

Chronic Kidney Disease Impact:

• Insulin degradation decreases as GFR declines, prolonging insulin action and increasing hypoglycemia risk 2, 3
• Start with lower doses (reduce by 25% if eGFR <30 mL/min) 3
• Avoid sulfonylureas due to accumulation and severe hypoglycemia risk 3
• Consider discontinuing metformin if eGFR <30 mL/min 3

Chronic Liver Disease Impact:

• Hepatic insulin clearance is impaired, further prolonging insulin action 3
• Gluconeogenesis is reduced, increasing hypoglycemia susceptibility 3
• Use even more conservative dosing (reduce initial doses by 30-50% in advanced cirrhosis) 3

Alternative: Basal Insulin Plus GLP-1 RA

• If cost is not prohibitive and patient is not severely catabolic, consider adding a GLP-1 receptor agonist instead of prandial insulin 1
• Fixed-ratio combinations (IDegLira or iGlarLixi) provide both basal insulin and GLP-1 RA in one injection 1
• This approach reduces hypoglycemia risk and may cause weight loss rather than weight gain 1
• However, GLP-1 RAs require dose adjustment in severe renal impairment (eGFR <30 mL/min for most agents) 1

Common Pitfalls to Avoid

• Continuing premixed insulin in CKD: The rigid dosing schedule and NPH peak create unacceptable hypoglycemia risk 2, 3
• Failing to reduce insulin doses: As kidney function declines, insulin requirements decrease; failure to adjust leads to severe hypoglycemia 3
• Using sliding scale insulin alone: This reactive approach is inferior to scheduled basal-bolus regimens for achieving glycemic targets 7
• Inadequate glucose monitoring: Check glucose at least 4 times daily (fasting, pre-meals, bedtime) during transition 8, 3
• Ignoring liver disease: CLD compounds the hypoglycemia risk from CKD; be even more conservative with dosing 3

Monitoring Parameters

• Blood glucose: Minimum 4 times daily (fasting, before meals, bedtime) during transition 8, 3
• Target glucose: 100-180 mg/dL (can be more relaxed to 100-200 mg/dL in advanced CKD/CLD to minimize hypoglycemia) 8, 3
• HbA1c: Check every 3 months, target <7% if achievable without hypoglycemia (consider relaxing to <8% in advanced disease) 1, 3
• Renal function: Monitor eGFR and adjust insulin doses as kidney function changes 3
• Hypoglycemia awareness: Educate patient on symptoms and treatment; provide glucagon if appropriate 1