EFFECT OF TOTAL DAILY DOSE ON EFFICACY, DOSING, AND SAFETY OF 2 DOSE TITRATION REGIMENS OF HUMAN REGULAR U-500 INSULIN IN SEVERELY INSULIN-RESISTANT PATIENTS WITH TYPE 2 DIABETES.

Objective: To examine the influence of baseline U-100 insulin total daily dose (TDD) on clinical outcomes in severely insulin-resistant patients with inadequately controlled type 2 diabetes treated with human regular U-500 insulin (U-500R) from the perspective of current dosing recommendations. Methods: Data from a recent prospective, randomized trial comparing thrice-daily (TID) and twice-daily (BID) U-500R in 325 patients transitioned from high-dose/high-volume U-100 insulin were analyzed across baseline U-100 TDD units and units/kg subgroups (300 units [n = 224, 68.9%1 and >300 units [n = 101, 31.1%]; units/kg = 96, 29.5%] and >2 units/kg [n = 229, 70.5%]). Subgroup effects on treatment differences were evaluated, and outcomes between treatment-pooled subgroups were compared. Results: At 24 weeks, significant reductions in glycated hemoglobin (HbA1c) were observed for all subgroups (range: 1.01% to 1.38%, P<.05). Within-subgroup treatment effects were similar with no treatment-by-subgroup interactions; however, a greater reduction was noted in the >300-units subgroup (P = .04). No TID/BID differences within subgroups or treatment-by-subgroup interactions were observed for TDD or weight increase from baseline. Overall hypoglycemia rates were similar between treatments (within subgroups) and showed no interactions. However, rates were higher in the >300-units subgroup for severe hypoglycemia (P = .04) and in both higher-dose subgroups for documented symptomatic hypoglycemia <= 70 mg/dL (P<.001, units; P = .001, units/kg). Conclusion: Both TID and BID U-500R were efficacious and safe across TDD subgroups, though higher hypoglycemia rates were observed in higher-dose, treatment-pooled subgroups. U-500R dosing recommendations have been updated accordingly.