Is there evidence supporting the use of human regular insulin (Actrapid) three times daily for post‑prandial glucose control in type 1 and insulin‑requiring type 2 diabetes?

Evidence for Human Regular Insulin (Actrapid) Three Times Daily

Human regular insulin (Actrapid) administered three times daily before meals is a well-established regimen for prandial glucose control in both type 1 and type 2 diabetes, though it requires injection 30 minutes before meals for optimal effect and has been largely superseded by rapid-acting analogs that offer more convenient timing.

Pharmacologic Basis and Timing Requirements

• Human regular insulin has distinct pharmacokinetics with delayed onset and prolonged duration compared to rapid-acting analogs, requiring administration 30 minutes before meals to achieve optimal postprandial glucose control 1.
• When regular insulin (Actrapid) is injected only 5 minutes before meals versus 30 minutes before, there is a tendency toward greater 90-minute postprandial glucose increases, though overall glycemic control (HbA1c) may remain similar in well-controlled patients 2.
• The 30-minute pre-meal timing requirement is a significant practical disadvantage compared to rapid-acting analogs, which can be administered 0-15 minutes before eating 3, 1.

Guideline-Supported Use in Type 2 Diabetes

• The American Diabetes Association explicitly recognizes human regular insulin as an option for prandial coverage in type 2 diabetes, stating that meta-analyses comparing rapid-acting analogs with human regular insulin have not reported important differences in A1C or hypoglycemia 4.
• For initiating prandial insulin in type 2 diabetes, start with 4 units or 10% of basal insulin dose at the largest meal, then intensify to three daily doses based on postprandial glucose patterns 4.
• Human regular insulin is often a less costly alternative to rapid-acting analogs, making it an important option when cost is a barrier to care 4.

Comparative Efficacy with Rapid-Acting Analogs

• In type 2 diabetes patients with residual beta-cell function, regular insulin (Actrapid) injected 30 minutes before meals achieves postprandial glucose control equivalent to rapid-acting insulin aspart given immediately before meals 1.
• However, when Actrapid is given immediately before meals (0-5 minutes), it produces significantly worse postprandial control than rapid-acting analogs, with higher glucose excursions and peak concentrations 1.
• The improved convenience of rapid-acting analogs (no 30-minute wait) makes them preferred when conditions permit, though both achieve postprandial glucose targets <180 mg/dL when dosed appropriately 5.

Practical Implementation Algorithm

Step 1: Determine if three-daily dosing is needed

• If fasting glucose is controlled on basal insulin but HbA1c remains ≥7%, postprandial hyperglycemia is the dominant problem and requires prandial insulin 6.
• Target postprandial glucose <180 mg/dL measured 1-2 hours after meal start 4, 6.

Step 2: Initiate regular insulin dosing

• Begin with 4 units of regular insulin 30 minutes before the largest meal or the meal producing the greatest glucose excursion 4.
• If using Actrapid specifically, the 30-minute pre-meal timing is critical for optimal effect 2, 1.

Step 3: Titrate and expand coverage

• Increase dose by 1-2 units every 3 days based on 2-hour postprandial readings 6.
• Add second and third pre-meal doses as needed to cover remaining meals 4.
• When adding significant prandial insulin (especially at dinner), reduce basal insulin to prevent nocturnal hypoglycemia 4.

Step 4: Monitor for overbasalization signals

• Basal dose >0.5 units/kg suggests overbasalization; shift insulin to prandial coverage 4.
• Bedtime-to-morning glucose differential ≥50 mg/dL indicates excessive basal insulin 4.

Critical Pitfalls to Avoid

• Do not inject regular insulin immediately before meals (0-5 minutes); this produces suboptimal postprandial control compared to the required 30-minute pre-meal timing 2, 1.
• Do not discontinue metformin when adding prandial insulin in type 2 diabetes; combination therapy reduces total insulin requirements 6.
• Do not give regular insulin as a bedtime correction dose; its prolonged duration markedly increases nocturnal hypoglycemia risk 6.
• Do not continue escalating oral agents when postprandial glucose remains >250 mg/dL despite controlled fasting glucose; this delays necessary insulin therapy 6.

Alternative Concentrated Formulation

• U-500 regular insulin is five times more concentrated than standard U-100 regular insulin and has pharmacokinetics resembling intermediate-acting (NPH) insulin with delayed onset and longer duration 4.
• U-500 can be used as two or three daily injections in highly insulin-resistant patients requiring large doses, offering greater convenience and comfort 4.
• U-500 is available in both prefilled pens and vials; when vials are prescribed, U-500-specific syringes must be used to prevent potentially fatal dosing errors 4.

Cost Considerations

• Human regular insulin vials are available at significantly lower cost than rapid-acting analogs, with some formulations (e.g., Walmart) priced at approximately $25/vial 4.
• The median cost of U-100 regular insulin is substantially lower than rapid-acting analogs: $165 AWP per 1,000 units for vials versus $330-408 for rapid-acting analog vials 4.
• Cost barriers contribute to treatment nonadherence, making human regular insulin an important option when analog insulins are financially prohibitive 4.

When to Choose Rapid-Acting Analogs Instead

• If the 30-minute pre-meal wait is impractical or reduces adherence, rapid-acting analogs are strongly preferred as they can be given 0-15 minutes before meals 3, 1.
• In type 1 diabetes, rapid-acting analogs offer better postprandial control and greater dosing flexibility for variable meal timing and content 3, 5.
• When meal size is unpredictable, rapid-acting analogs allow postprandial dosing adjusted to actual carbohydrate intake, though preprandial dosing still produces superior glucose profiles 5.

Human regular insulin three times daily remains a viable, evidence-based option for prandial coverage, particularly when cost is a barrier, but requires strict adherence to 30-minute pre-meal timing and has been largely replaced by more convenient rapid-acting analogs in contemporary practice.