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 |
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| Institution: | 1. From the Rockwood Clinic, Spokane, Washington;2. Endocrine Clinic of Southeast Texas, Beaumont, Texas;3. Physicians East, PA, Greenville, North Carolina;4. Eli Lilly and Company, Indianapolis, Indiana;5. Lilly USA, LLC, Indianapolis, Indiana.;1. Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration (FDA), Silver Spring, Maryland 20993;2. Office of New Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration (FDA), Silver Spring, Maryland 20993 |
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| Abstract: | 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 highdose/high-volume U-100 insulin were analyzed across baseline U-100 TDD units and units/kg subgroups (≤300 units n = 224, 68.9%] and >300 units n = 101, 31.1%]; ≤2 units/kg n = 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.Abbreviations:AE = adverse eventBID = twice dailyHbA1c = glycated hemoglobinQID = 4 times dailyRCT = randomized clinical trialT2D = type 2 diabetesTDD = total daily doseTID = thrice dailyU-500R = human regular U-500 insulin |
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