What is the best approach to manage diabetes in a patient who cannot use GLP-1 receptor agonists?

Managing Diabetes Without GLP-1 Receptor Agonists

For patients who cannot use GLP-1 receptor agonists, the best approach is to use basal insulin with or without oral antidiabetic medications, followed by progression to basal-bolus insulin therapy if needed. 1

Initial Therapy Options

When GLP-1 receptor agonists cannot be used, consider the following algorithm based on glycemic control:

For Mild Hyperglycemia (A1C <8%, BG <200 mg/dL)

• Continue metformin as first-line therapy if not contraindicated
• Add a DPP-4 inhibitor with or without low-dose basal insulin (0.1 U/kg/day) 1
• Consider SGLT2 inhibitors, particularly for patients with cardiovascular or renal disease 1

For Moderate Hyperglycemia (A1C 8-9%, BG 200-300 mg/dL)

• Start or continue metformin
• Add basal insulin at 0.2-0.3 U/kg/day 1
• Consider adding SGLT2 inhibitors if appropriate 1

For Severe Hyperglycemia (A1C >9%, BG >300 mg/dL)

• Initiate basal-bolus insulin regimen
• Start with 0.3 U/kg/day (half as basal, half as bolus) 1
• For insulin-experienced patients using >0.6 U/kg/day, reduce home insulin total daily dose by 20% 1

Basal Insulin Optimization

When initiating basal insulin:

• Use long-acting insulin analogs (glargine or detemir) rather than NPH insulin to reduce risk of hypoglycemia 1, 2
• Longer-acting basal analogs (U-300 glargine or degludec) provide lower nocturnal hypoglycemia risk than U-100 glargine 1
• Titrate dose based on fasting glucose targets 1
• Watch for signs of overbasalization: high bedtime-to-morning glucose differential (≥50 mg/dL), hypoglycemia, or high glucose variability 1

Progression to Combination Injectable Therapy

If basal insulin has been optimized (dose >0.5 units/kg/day) and A1C remains above target:

1. Add prandial insulin 1

   • Start with a single prandial dose at the largest meal (4 units, 10% of basal dose, or 0.1 units/kg) 1
   • Progress to multiple prandial doses if needed
   • Consider reducing basal insulin dose by 10-20% if A1C <8% when starting prandial insulin 1

2. Consider adding SGLT2 inhibitors to insulin 1

   • Can lower blood glucose without increasing insulin doses
   • Provides weight loss benefits and reduced hypoglycemia risk
   • May need to reduce insulin dose to prevent hypoglycemia 1

Special Considerations

Insulin Formulations

• For patients requiring large insulin doses, consider concentrated insulin preparations:
  • U-500 regular insulin (five times more concentrated than U-100)
  • U-300 glargine or U-200 degludec 1
• For patients who cannot manage multiple daily injections, consider premixed insulin formulations twice daily 1
  • Less flexible but more convenient
  • Higher risk of hypoglycemia compared to basal-bolus regimens

Monitoring and Adjustment

• Monitor blood glucose before meals and at bedtime
• Evaluate A1C every 3 months until stable
• Adjust insulin doses based on patterns in glucose readings
• Be vigilant for hypoglycemia, especially with insulin dose increases 2, 3

Important Precautions

• Hypoglycemia risk: Long-acting insulin analogs have lower risk of hypoglycemia compared to NPH insulin 1
• Drug interactions: Be aware that certain medications can affect insulin requirements (corticosteroids increase needs; beta-blockers may mask hypoglycemia symptoms) 2, 3
• Cost considerations: Human insulins (NPH, regular) are less expensive alternatives to insulin analogs 1
• Injection site reactions: Rotate injection sites to reduce risk of lipodystrophy 2, 4

While GLP-1 receptor agonists are preferred for their weight benefits and lower hypoglycemia risk 1, 5, basal insulin with progression to basal-bolus therapy remains an effective strategy for patients who cannot use these agents.