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
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 thricedaily (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%] 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 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 Conclusion Both TID and BID U-500R were efficacious and safe across TDD subgroups, though higher hypoglycemia rates were obser…
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U-500 regular insulin has similar onset but a delayed, blunted, and prolonged peak effect and longer duration of action compared with U-100 regular insulin.
“U-500 regular insulin has distinct pharmacokinetics with similar onset but a delayed, blunted, and prolonged peak effect and longer duration of action compared with U-100 regular insulin; thus, it has characteristics more like a premixed intermediate-acting (NPH) and regular insulin product and can be used as two or three daily injections (177,178).”
From 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes—2025 (2025) · cites this paper as [178]
U-500 regular insulin has characteristics more like a premixed intermediate-acting (NPH) and regular insulin product.
“U-500 regular insulin has distinct pharmacokinetics with similar onset but a delayed, blunted, and prolonged peak effect and longer duration of action compared with U-100 regular insulin; thus, it has characteristics more like a premixed intermediate-acting (NPH) and regular insulin product and can be used as two or three daily injections (177,178).”
From 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes—2025 (2025) · cites this paper as [178]
Cites
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9. Pharmacologic Approaches to Glycemic Treatment: <i>Standards of Medical Care in Diabetes—2022</i>
American Diabetes Association Professional Practice Committee (2022) · Diabetes Care · doi:10.2337/dc22-s009 · Cited by 1,555 · see citing works
“U-500 regular insulin has distinct pharmacokinetics with delayed onset and longer duration of action, has characteristics more like an intermediateacting (NPH) insulin, and can be used as two or three daily injections (98).”
Background9. Pharmacologic Approaches to Glycemic Treatment: <i>Standards of Medical Care in Diabetes—2021</i>
American Diabetes Association (2021) · Diabetes Care · doi:10.2337/dc21-s009 · Cited by 972 · see citing works
“Regular U-500 has distinct pharmacokinetics with delayed onset and longer duration of action, has characteristics more like an intermediate-acting (NPH) insulin, and can be used as two or three daily injections (89).”
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“Regular U-500 insulin has characteristics similar to those of intermediate-acting (NPH) insulin and may be administered in 2 or 3 injections per day (58).”
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Self-citationHuman Regular 500 units/mL Insulin Therapy: A Review of Clinical Evidence and New Delivery Options
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“Rates of both severe and mild hypoglycemia were observed to be higher in patients taking >300 units of insulin per day at baseline (31).”
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“Other than the greater dose change magnitude, our study results align in general direction with previous clinical and observational studies of U-500R initiation, despite pre-index dosage and HbA1c differences [9, 18, 19, 29, 30].”
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Clinical Challenges With Concentrated Insulins: Setting the Record Straight
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“Recommended dose transitions to prandial/basal insulin U-500R are based on U-100 insulin TDDs: oneto-one dosing for patients with an A1C >8% and a 20% dose reduction for those with an A1C ≤8% (20,27).”
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Hood, R. C. (2017) · Diabetes Technology & Therapeutics · doi:10.1089/dia.2017.0094 · Cited by 5 · see citing works
“>300 U).(30) Both regimens reduced glycemic variability,(29) pain scores, and measures of disease burden, while improving compliance domains.”
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“These results [5] along with those of a prespecified TDD subgroup analysis of the study [6] have allowed the first RCT-based update of the U-500R initiation algorithm for patients with high-dose insulin requirements [6].”
MethodResultSelf-citationHematopoietic stem cell transplantation-associated partial lipodystrophy
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“The randomized controlled trial, to which the author(s) of the letter refer, was e-published in January of 2016 which is after our paper was submitted [3].”
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- Authors
- Wysham, C., Hood, R. C., Warren, M. L., Wang, T., Morwick, T. M., & Jackson, J. A.
- Affiliations
- Rockwood Clinic (US)
- Physicians East (US)
- Eli Lilly (United States) (US)
- Corresponding author
- Wysham, Carol
- Venue
- Endocrine Practice
- Publisher
- Elsevier BV
- Published
- 2016-06
- Volume
- 22
- Issue
- 6
- Pages
- 653-665
- ISSN
- 1530-891X (ISSN-L)
- OpenAlex
- W2276815245
- Cited by
- 29
- References
- 35
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 2 · 2023: 1 · 2022: 2 · 2021: 5 · 2020: 5 · 2019: 2 · 2018: 1 · 2017: 6 · 2016: 2
- FWCI
- 3.67
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Endocrine Practice (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- insulin dose adjustment, total daily dose, insulin resistance, type 2 diabetes, HbA1c, hypoglycemia, weight gain, twice-daily insulin, subgroup analysis, treatment-by-subgroup interaction, HbA1c reduction
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