What is the appropriate dosing schedule for splitting the total daily dose of NPH (Neutral Protamine Hagedorn) insulin throughout the day?

From the Guidelines

NPH insulin should be dosed twice daily, with two-thirds of the total daily dose given in the morning (before breakfast) and one-third given in the evening (before dinner or at bedtime). For example, if the total daily dose is 30 units:

• Morning dose: 20 units (before breakfast)
• Evening dose: 10 units (before dinner or at bedtime) This split dosing regimen aligns with NPH insulin's action profile, which has a peak effect 4-6 hours after injection and a duration of action of 10-16 hours, as suggested by the most recent guidelines 1. The larger morning dose helps cover insulin needs during the day, while the smaller evening dose provides coverage overnight.

Key considerations for this dosing schedule include:

• Adjusting doses based on blood glucose monitoring, targeting fasting glucose levels of 80-130 mg/dL and postprandial levels below 180 mg/dL 1
• Fine-tuning the timing of the evening dose (dinner vs. bedtime) based on individual response and nighttime glucose patterns
• Recognizing that NPH is an intermediate-acting insulin, which may need to be combined with short-acting insulin before meals for optimal glucose control in some patients 1
• Always individualizing insulin regimens based on patient needs and response, as emphasized in the latest standards of care in diabetes 1.

It's crucial to note that the total NPH dose should be adjusted to 80% of the current dose when splitting it throughout the day, with the option to add short/rapid-acting insulin to each injection or 10% of the reduced NPH dose, as outlined in the guidelines 1. However, the most recent and highest quality study 1 provides the basis for the recommended dosing schedule, prioritizing morbidity, mortality, and quality of life outcomes.

From the FDA Drug Label

In one non-blinded clinical study (Study A, n=409), adult patients with type 1 diabetes were randomized to treatment with either LEVEMIR at 12-hour intervals, LEVEMIR morning and bedtime or NPH human insulin morning and bedtime. Differences in timing of LEVEMIR administration (or flexible dosing) had no effect on HbA1c, FPG, body weight, or risk of having hypoglycemic episodes In a non-blinded, randomized, controlled clinical study (Study D, n=347), pediatric patients (age range 6 to 17) with type 1 diabetes were treated for 26 weeks with a basal-bolus insulin regimen LEVEMIR and NPH human insulin were administered once- or twice-daily (bedtime or morning and bedtime) according to pretrial dose regimen. In a 24-week, non-blinded, randomized, clinical study (Study E, n=476), LEVEMIR administered twice-daily (before breakfast and evening) was compared to a similar regimen of NPH human insulin as part of a regimen of combination therapy with one or two of the following oral antidiabetes agents (metformin, insulin secretagogue, or α–glucosidase inhibitor) The appropriate dosing schedule for splitting the total daily dose of NPH insulin throughout the day is:

• Twice-daily: morning and bedtime, or before breakfast and with the evening meal, or at 12-hour intervals 2. It is essential to note that the specific dosing schedule may vary depending on individual patient needs and should be determined by a healthcare professional.

From the Research

Dosing Schedule for NPH Insulin

The appropriate dosing schedule for splitting the total daily dose of NPH (Neutral Protamine Hagedorn) insulin throughout the day can be considered based on the following evidence:

• A study 3 compared the evening and night glycemic control when the evening premeal lispro dose was reduced by 20% and the bedtime basal NPH dose increased by 25%, or when the basal NPH dose was moved to before dinner at 1800. The results showed that postprandial blood glucose concentrations were lower after reduced-dose lispro compared with human regular insulin.
• Another study 4 compared the daytime metabolic profile after either premeal lispro alone or premeal lispro with optimal daytime NPH insulin and with standard human regular insulin. The results showed that reduced-dose lunchtime lispro plus NPH maintained the improvement in postprandial blood glucose control with no deterioration in interprandial blood glucose control.
• A study 5 compared the blood glucose control between different regimens of optimized basal insulin substitution in type 1 diabetic patients given lispro insulin at meals, i.e., NPH injected four times a day versus glargine insulin once daily at dinner or at bedtime. The results showed that mean daily blood glucose was lower with dinnertime glargine or bedtime glargine versus NPH.
• A study 6 evaluated a multiple daily injections (MDI) regimen combining lispro with multiple NPH insulin injections in order to replace basal insulin optimally. The results showed that the variability of capillary blood glucose values was significantly lower with lispro and the frequency of severe hypoglycaemic events was reduced with lispro.
• A study 7 compared the safety and efficacy of 3 basal-bolus regimens of neutral protamine hagedorn (NPH)/regular insulin in the management of inpatient hyperglycemia. The results showed that NPH insulin given in a once-daily regimen was associated with better glycemic control compared to twice daily and three times daily regimens.

Key Findings

Some key findings from these studies include:

• Administering NPH insulin in a once-daily regimen may result in improvement in glycemic control with similar rates of hypoglycemia compared to a twice-daily and a three times-daily regimen 7.
• Reduced-dose lispro plus NPH may maintain the improvement in postprandial blood glucose control with no deterioration in interprandial blood glucose control 4.
• The frequency of severe hypoglycaemic events may be reduced with lispro compared to human regular insulin 6.
• Mean daily blood glucose may be lower with dinnertime glargine or bedtime glargine versus NPH 5.

Considerations for Dosing Schedule

Considerations for the dosing schedule of NPH insulin include:

• The total daily dose of NPH insulin may be split into multiple injections throughout the day, with the exact schedule depending on the individual patient's needs and response to therapy.
• The use of a basal-bolus regimen, with NPH insulin as the basal component and a rapid-acting insulin analog as the bolus component, may help to improve glycemic control and reduce the risk of hypoglycemia.
• The dosing schedule of NPH insulin may need to be adjusted based on the patient's meal schedule, physical activity level, and other factors that may affect blood glucose control.