What are the first and second generation long-acting insulins?

First and Second Generation Long-Acting Insulins

First-generation long-acting insulins include NPH (Neutral Protamine Hagedorn) insulin, while second-generation long-acting insulins include insulin glargine, insulin detemir, insulin degludec, and U-300 glargine. 1

First-Generation Long-Acting Insulins

• NPH (Neutral Protamine Hagedorn) insulin
  • Intermediate-acting insulin with a cloudy appearance
  • Onset: 1-2 hours
  • Peak action: 6-8 hours
  • Duration: 12-18 hours 1
  • Characterized by pronounced peak action and shorter duration compared to second-generation insulins 1

Second-Generation Long-Acting Insulins

• Insulin glargine (U-100)

  • First long-acting insulin analog approved by FDA in 2000 2
  • Onset: 1-2 hours
  • Minimal peak action
  • Duration: 20-24+ hours 1
  • Produced by recombinant DNA technology with amino acid modifications 3

• Insulin detemir

  • Long-acting insulin analog with lower intraindividual variability
  • Lower day-to-day variability compared to NPH and glargine
  • Associated with less weight gain compared to NPH insulin 1

• Insulin degludec

  • Ultra-long-acting insulin analog
  • Half-life of 25.4 hours
  • Duration of action >42 hours
  • Forms multi-hexamers when injected subcutaneously, creating a depot effect 4
  • Molecular structure includes modification with glutamic acid and C16 fatty acid 4

• Insulin glargine U-300

  • Higher concentration formulation of insulin glargine
  • Longer duration of action than U-100
  • Less variable plasma insulin exposure
  • Associated with lower incidence of hypoglycemic events 5

Key Differences Between Generations

• Pharmacokinetic profile:

  • First-generation NPH has a pronounced peak at 6-8 hours and shorter duration (12-18 hours)
  • Second-generation analogs have minimal peak action and longer duration (20-42+ hours) 6, 1

• Hypoglycemia risk:

  • Second-generation long-acting analogs show lower risk of hypoglycemia, particularly nocturnal hypoglycemia, compared to NPH insulin 6, 1
  • In clinical trials, long-acting basal analogs (U-100 glargine or detemir) demonstrated reduced risk of symptomatic and nocturnal hypoglycemia compared with NPH insulin 6

• Consistency of action:

  • Second-generation insulins provide more consistent basal insulin coverage (20-24+ hours) compared to first-generation NPH (12-18 hours) 1
  • Newer formulations like U-300 glargine and degludec may confer even lower hypoglycemia risk compared with U-100 glargine 6

Clinical Implications

• Second-generation long-acting insulins offer several advantages:

  • More predictable glucose control due to flatter action profile
  • Reduced risk of hypoglycemia, especially nocturnal hypoglycemia
  • Once-daily dosing for most patients
  • Less weight gain with some formulations (particularly detemir) 1

• The American Diabetes Association notes that despite the advantages of insulin analogs, for some patients the expense may be prohibitive, and NPH remains a viable option 6

• When initiating basal insulin therapy, starting doses can be estimated based on body weight (0.1–0.2 units/kg/day) and the degree of hyperglycemia 6

Newest Developments

The newest second-generation long-acting insulins (U-300 glargine and degludec) offer even more prolonged and stable glucose-lowering effects compared to earlier second-generation insulins, with potential for further reductions in hypoglycemia risk 7, 8.