Can neutral protamine Hagedorn (NPH) insulin be used in a patient with uncontrolled type 1 or type 2 diabetes mellitus, and what starting dose and titration schedule are recommended?

NPH Insulin in Uncontrolled Diabetes: Dosing and Titration

Yes, NPH insulin can be given to patients with uncontrolled diabetes mellitus (both type 1 and type 2), and it remains a viable basal insulin option when long-acting analogs are unavailable or cost-prohibitive. However, NPH requires more frequent dosing and careful titration compared to modern basal analogs like glargine or detemir.1

Initial Dosing Strategy

Type 2 Diabetes (Insulin-Naïve)

• Start NPH at 10 units once daily or 0.1–0.2 units/kg/day for patients with moderate hyperglycemia (A1C <9%, fasting glucose 140–250 mg/dL), administered at bedtime.1
• For severe hyperglycemia (A1C ≥9%, fasting glucose >300 mg/dL), initiate a basal-bolus regimen with total daily dose of 0.3–0.5 units/kg/day, split as 50% NPH and 50% short-acting/rapid-acting insulin divided among meals.1
• Continue metformin at maximum tolerated dose (up to 2000–2550 mg/day) unless contraindicated, as this reduces total insulin requirements by 20–30%.12

Type 1 Diabetes

• Begin with 0.5 units/kg/day total daily dose for metabolically stable patients, allocating 40–50% as NPH (basal) and 50–60% as short-acting/rapid-acting insulin (prandial).12
• NPH is typically given twice daily (before breakfast and at bedtime) in type 1 diabetes due to its 10–15 hour duration of action.13

NPH Dosing Frequency

NPH requires more frequent administration than long-acting analogs:

• Once-daily NPH (bedtime) may suffice initially in type 2 diabetes with mild-to-moderate hyperglycemia.14
• Twice-daily NPH (morning and bedtime) is standard for type 1 diabetes and often necessary in type 2 diabetes as insulin requirements increase.156
• In real-world practice, NPH averages 1.9 injections/day in type 1 diabetes and 1.6 injections/day in type 2 diabetes.5

Titration Protocol

Basal NPH Adjustment

• Increase NPH by 2 units every 3 days if fasting glucose is 140–179 mg/dL.1
• Increase NPH by 4 units every 3 days if fasting glucose is ≥180 mg/dL.1
• Target fasting glucose 80–130 mg/dL.1
• If unexplained hypoglycemia (<70 mg/dL) occurs, reduce the dose by 10–20% immediately.1

Transitioning to Twice-Daily NPH

• When once-daily NPH reaches 0.5 units/kg/day without achieving fasting glucose targets, consider splitting to twice-daily dosing (2/3 before breakfast, 1/3 before dinner) rather than further escalating the single dose.1
• Alternatively, add prandial insulin (4 units before the largest meal or 10% of NPH dose) if postprandial hyperglycemia persists despite controlled fasting glucose.1

Special Considerations

Steroid-Induced Hyperglycemia

• Administer NPH in the morning (not bedtime) to match the peak hyperglycemic effect of glucocorticoids, which occurs 4–8 hours after morning prednisone dosing.17
• Start NPH at 0.3–0.4 units/kg for patients on high-dose steroids.7
• Increase prandial insulin by 40–60% in addition to NPH to counteract steroid-induced insulin resistance.17

Hospitalized Patients

• In non-critically ill hospitalized patients, NPH can be used in a basal-bolus regimen with short-acting/rapid-acting insulin before meals.64
• Start with 0.3–0.5 units/kg/day total insulin (50% NPH, 50% prandial), or 0.1–0.25 units/kg/day in high-risk patients (elderly, renal impairment, poor oral intake).1
• Once-daily NPH in hospitalized patients achieved better glycemic control (58.3% at target) compared to twice-daily (42.4%) or three-times-daily (48.9%) regimens, with similar hypoglycemia rates.4

Comparison to Long-Acting Analogs

• NPH requires higher total daily insulin doses (0.76 IU/kg in type 1,0.63 IU/kg in type 2) compared to glargine (0.74 IU/kg in type 1,0.67 IU/kg in type 2) at similar glycemic control.5
• NPH has a peak action at 4–8 hours, increasing nocturnal hypoglycemia risk compared to peakless analogs like glargine.13
• Consider switching from evening NPH to a basal analog if the patient develops recurrent hypoglycemia or frequently forgets evening doses.1

Monitoring Requirements

• Daily fasting glucose during titration to guide NPH adjustments.1
• Pre-meal and bedtime glucose (minimum 4 checks/day) when using basal-bolus regimens.1
• 2-hour postprandial glucose after meals to assess prandial insulin adequacy.1
• HbA1c every 3 months during intensive titration.1

Critical Pitfalls to Avoid

• Do not use NPH as monotherapy in type 1 diabetes without prandial insulin, as this can precipitate diabetic ketoacidosis.1
• Do not continue escalating NPH beyond 0.5 units/kg/day without addressing postprandial hyperglycemia; add prandial insulin instead to avoid overbasalization.1
• Do not administer NPH at bedtime for steroid-induced hyperglycemia; morning dosing is required to match glucocorticoid pharmacokinetics.17
• Do not discontinue metformin when starting NPH in type 2 diabetes unless contraindicated, as this increases insulin requirements and worsens outcomes.12
• Never use sliding-scale insulin as monotherapy; NPH must be part of a scheduled basal-bolus regimen with correction doses as adjuncts only.1

Expected Outcomes

• NPH-based basal-bolus regimens achieve equivalent glycemic control to detemir/aspart regimens in type 2 diabetes (mean daily glucose 158 mg/dL vs. 160 mg/dL), with similar hypoglycemia rates (25.4% vs. 32.8%).6
• In type 1 diabetes, NPH achieves similar HbA1c (7.98%) and severe hypoglycemia rates (11.06%) compared to glargine (8.07%, 10.86%) and detemir (7.98%, 11.93%).5
• Properly titrated NPH can produce HbA1c reductions of 1.5–2.0% when used as basal insulin, with additional 2–3% reduction when combined with prandial insulin.1