Biphasic Insulin Initiation
Initiate biphasic insulin with twice-daily injections (before breakfast and dinner) when intensifying therapy beyond basal insulin, typically starting at 4 units per injection or 0.1-0.2 units/kg/day divided between the two doses. 1
Clinical Context for Biphasic Insulin Use
Biphasic (premixed) insulin is not a first-line insulin regimen for initiating insulin therapy in type 2 diabetes. 1 According to the American Diabetes Association, basal insulin alone remains the most convenient and appropriate initial insulin regimen, starting at 10 units per day or 0.1-0.2 units/kg/day. 1
Biphasic insulin should be considered as a treatment intensification strategy when basal insulin has been titrated to an acceptable fasting blood glucose level (or the dose exceeds 0.5 units/kg/day) but HbA1c remains above target. 1
Starting Regimen Specifics
Dosing Schedule
- Administer twice daily: before breakfast and before dinner 1
- Available formulations include 70/30 NPH/regular insulin mix, 70/30 aspart mix, 75/25 lispro mix, or 50/50 lispro mix 1
- Alternative once- or twice-daily 70/30 degludec/aspart mix can be taken before meals 1
Initial Dose
- Start with 4 units per injection (twice daily = 8 units total daily) 2
- Alternatively, use 0.1-0.2 units/kg/day divided between two injections 3
- When transitioning from basal insulin, the total daily dose can be split between the two biphasic injections 1
Timing Flexibility
- Standard biphasic insulin analogues (aspart or lispro mixes) should be injected within 5 minutes before meals 4
- For elderly patients or those with unpredictable meal timing, postprandial dosing (15-20 minutes after meal onset) is an acceptable alternative, though it may result in slightly higher postprandial glucose excursions 4
Concomitant Medications
Continue metformin when initiating biphasic insulin. 1 Other oral agents should be managed as follows:
- Discontinue sulfonylureas, DPP-4 inhibitors, and GLP-1 receptor agonists when starting a multiple-dose premixed insulin regimen to avoid unnecessarily complex or costly regimens 1
- Thiazolidinediones or SGLT-2 inhibitors may be continued in patients requiring large insulin doses, though potential side effects must be considered 1
Titration Strategy
- Adjust doses based on self-monitored blood glucose values targeting both fasting and postprandial glucose levels 1
- Increase frequency of blood glucose monitoring during the initiation and titration phase 1
- If HbA1c targets are not met with twice-daily dosing, consider advancing to thrice-daily premixed insulin analogues (70/30 aspart mix or 75/25 or 50/50 lispro mix) 1
Important Caveats and Limitations
Disadvantages of Biphasic Insulin
- Requires a relatively fixed meal schedule and consistent carbohydrate content per meal 1, 5
- Less flexibility in meal planning compared to basal-bolus regimens with rapid-acting insulin 1
- May result in greater glycemic variability compared to basal-bolus regimens 5
Hypoglycemia Risk
- The incidence of hypoglycemia with biphasic insulin is similar to other insulin regimens (43-57% of patients experience any hypoglycemia) 6
- Major hypoglycemic events are uncommon (2-8% of patients) and occur less frequently than with biphasic human insulin 6
- Lower risk of nocturnal hypoglycemia compared to biphasic human insulin (relative risk 0.63) 6
Alternative Intensification Options
If biphasic insulin is not appropriate or fails to achieve targets, the American Diabetes Association recommends considering: 1
- Adding a single injection of rapid-acting insulin before the largest meal
- Adding a GLP-1 receptor agonist to basal insulin (associated with weight loss and less hypoglycemia but may be more expensive)
- Advancing to a full basal-bolus regimen with multiple daily injections
Studies have shown noninferiority between basal insulin plus a single rapid-acting injection, basal insulin plus a GLP-1 receptor agonist, and twice-daily premixed insulins. 1