What are the differences between first and second generation insulins?

First and Second Generation Insulins: Classification and Differences

First-generation insulins include human insulins (NPH, Regular/R, and premixed combinations of NPH and R), while second-generation insulins are the insulin analogs designed to improve onset or duration of action through molecular modifications. 1, 2

First-Generation Insulins

Human Insulins

• Regular (R) insulin

  • Short-acting human insulin
  • Onset: 30-60 minutes
  • Peak action: 2-4 hours
  • Duration: 5-8 hours
  • Appearance: Clear solution 2

• NPH insulin (Neutral Protamine Hagedorn)

  • Intermediate-acting human insulin
  • Onset: 1-2 hours
  • Peak action: 6-8 hours
  • Duration: 12-18 hours
  • Appearance: Cloudy suspension 2, 3

• Premixed combinations

  • Combinations of NPH and Regular insulin (e.g., 70/30 - 70% NPH, 30% Regular) 3

Second-Generation Insulins (Insulin Analogs)

Rapid-Acting Analogs

• Insulin lispro (Humalog, Admelog)

  • Onset: 15-30 minutes
  • Peak action: 1-3 hours
  • Duration: 3-5 hours
  • Molecular modification: Proline at position B28 replaced by lysine and lysine at B29 replaced by proline 4

• Insulin aspart (Novolog)

  • Onset: 5-15 minutes
  • Peak action: 1-2 hours
  • Duration: 3-5 hours
  • Appearance: Clear solution 2, 5

• Insulin glulisine

  • Similar profile to other rapid-acting analogs 6

Long-Acting Analogs

• Insulin glargine

  • Onset: 1-2 hours
  • Minimal peak action
  • Duration: 20-24+ hours 2, 7

• Insulin detemir

  • Long-acting insulin analog
  • Lower intraindividual variability compared to NPH and glargine 6, 8

• Insulin degludec

  • Ultra-long-acting insulin
  • Half-life: 25.4 hours
  • Duration: >42 hours 9

Key Differences Between First and Second Generation Insulins

Pharmacokinetic Differences

• Onset of action: Second-generation rapid-acting analogs have faster onset (5-15 minutes) compared to first-generation regular insulin (30-60 minutes) 2, 10
• Duration of action: Second-generation long-acting analogs provide more consistent basal insulin coverage (20-24+ hours) compared to first-generation NPH (12-18 hours) 2, 9
• Peak effect: Second-generation long-acting analogs have minimal peak action compared to the pronounced peak of NPH insulin 7, 9

Clinical Advantages of Second-Generation Insulins

• Improved postprandial glucose control: Rapid-acting analogs better cover post-meal glucose excursions 6, 10
• Reduced hypoglycemia risk: Long-acting analogs show lower risk of hypoglycemia, particularly nocturnal hypoglycemia, compared to NPH insulin 9, 8
• Greater convenience: Rapid-acting analogs can be injected immediately before meals rather than 30 minutes before as with regular insulin 10
• Lower day-to-day variability: Particularly with insulin detemir, leading to more predictable glucose control 6, 8
• Weight management: Some second-generation insulins, particularly detemir, show less weight gain compared to NPH insulin 9, 8

Clinical Applications

• Modern diabetes management often favors basal-bolus regimens using second-generation insulins:
  • Long-acting analogs (glargine, detemir, degludec) for basal insulin needs
  • Rapid-acting analogs (lispro, aspart, glulisine) for mealtime coverage 2
• This approach provides better glycemic control with lower hypoglycemia risk compared to regimens using first-generation insulins 8

The evolution from first to second-generation insulins represents significant progress in diabetes management, with molecular modifications resulting in pharmacokinetic profiles that more closely mimic physiologic insulin secretion patterns.