Safety/Efficacy
In the Humulin R U-500 Initiation trial, both of these algorithms improved glycemic control and were associated with a low incidence of severe hypoglycemia. In addition, the associated weight gains were similar. Last, the rate of nonsevere hypoglycemia was slightly lower for the 3-times-daily than for the 2-times-daily regimen.34 A real-world outcome analysis of U-500 initiation confirmed the benefits of switching from U-100 to U-500. A clinically significant improvement in glycemic control was found in all the study participants. Dose and frequency of administration, however, were not reported.35
According to a secondary analysis in the Humulin R U-500 Initiation trial, baseline U-100 total daily dose did not yield a difference in efficacy or safety between the 2-times-a-day and 3-times-a-day arms—allowing use of a simpler 2-times-a-day schedule without regard to baseline total daily dose.28,36 The 2-times-a-day regimen is preferred in clinical practice given that the 2 regimens are equivalent in safety and efficacy and that the 2-times-a-day regimen is simpler, allows for easier titrations, improves patient perceptions of the effect of insulin on daily life function and psychological health, lowers daily injection burden, and maximizes adherence.37
Economic Analysis
A retrospective database analysis revealed lower overall cost and lower pharmacy cost associated with U-500 in comparison with high-dose U-100, as well as reduced hypoglycemia-specific costs or resource utilization, even though U-500 was associated with a slightly higher incidence of hypoglycemia.28 However, the fact that hypoglycemia was reported with a billing code (ICD-9) implies the hypoglycemic event was severe enough to require medical attention. Given these findings, 2-times-a-day U-500 seems more cost-effective than high-dose U-100.
Dosing
The U-500 Humulin R package insert recommends converting a dose to U-500 on the basis of most recent HbA1c level. U-500 can be dosed 2 times daily (60%, 40%) or 3 times daily (40%, 30%, 30%). If HbA1c is > 8%, then the starting total daily dose (TDD) of U-500 is 100% of the U-100 TDD. If HbA1c is ≤ 8%, then the starting TDD of U-500 is 80% of the final U-100 TDD (20% reduction). Dose adjustments may range from 5% to 10% depending on subsequent blood glucose readings.32
Recommendations
U-500 is a safe and effective monotherapy alternative for patients who require high doses of U-100. Initial conversion from U-100 is based on HbA1c level. The total daily dose of U-500 is then divided by 2 (60%, 40%) or 3 (40%, 30%, 30%). The 2-times-a-day regimen enhances adherence and thus may be preferred.
Discussion
It has been suggested that large volumes or depots of insulin approaching 100 units impedes absorption and are more painful compared with smaller volume injections.37 For patients with DM who require higher doses of insulin, concentrated insulins offer the advantage of smaller volumes. Also smaller volumes are a substantial benefit in addressing the growing epidemic of DM and the progressive nature of insulin resistance. Furthermore, concentrated insulins are available in pens. Compared with syringes and vials, pens are associated with a lower risk of dosing errors. The major advantages to the use of concentrated insulins include patient acceptability and the potential for decreased volumes and frequency of injections.
Potential disadvantages also exist for the use of concentrated insulins. Depending on insurance coverage, concentrated insulins may be more expensive than U-100 insulin options. Additionally, thorough counseling and education are of paramount importance when concentrated insulins are initiated or switched in patients with DM. The dosing errors that occur with concentrated insulins could increase the risk of hypoglycemia. Pharmacists should provide detailed counseling to DM patients initiating or switching concentrated insulins. It is important to implement or revise institution and clinic safe practices for concentrated insulins to avoid errors in prescribing, distributing, administering, and monitoring these medications.
Conclusion
Concentrated insulins provide expanded treatment options for patients with DM. Clinicians must stay well informed about concentrated insulin characteristics and dosing strategies to optimize DM treatment. As more evidence becomes available, standardized recommendations can be developed to guide clinicians in the appropriate use of concentrated insulins.