ENDOCRINE PRACTICE Vol 15 No. 1 January/February 2009 71 Review Article HIGH-DOSE INSULIN THERAPY: IS IT TIME FOR U-500 INSULIN? Wendy S. Lane, MD 1 ; Elaine K. Cochran, MSN, CRNP 2 ; Jeffrey A. Jackson, MD, CDE 3 ; Jamie L. Scism-Bacon, PhD 3 ; Ilene B. Corey, RN, PNP 3 ; Irl B. Hirsch, MD 4 ; Jay S. Skyler, MD, MACP 5 Submitted for publication September 3, 2008 Accepted for publication October 15, 2008 From the 1 Mountain Diabetes and Endocrine Center, Asheville, North Carolina; 2 National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland; 3 US Medical Division, Eli Lilly and Company, Indianapolis, Indiana; 4 University of Washington Medical Center, Seattle, Washington; and 5 University of Miami Miller School of Medicine, Miami, Florida. Address correspondence and reprint requests to Dr. Wendy Lane, Mountain Diabetes and Endocrine Center, 1998 Hendersonville Road, Asheville, NC 28803. E-mail: mountaindiabetes@msn.com. © 2009 AACE. ABSTRACT Objective: To provide an overview of U-500 regular insulin action, review published clinical studies with U- 500 regular insulin, and offer guidance to practicing endo- crinologists for identifying patients for whom U-500 regu- lar insulin may be appropriate. Methods: This review has been produced through a synthesis of relevant published literature compiled via a literature search (MEDLINE search of the English-lan- guage literature published between January 1969, and July 2008, related to U-500, insulin resistance, concentrated insulin, high-dose insulin, insulin pharmacokinetics, and diabetes management) and the authors’ collective clinical experience. Results: The obesity epidemic is contributing to an increase in the prevalence of type 2 diabetes, as well as to increasing insulin requirements in insulin-treated patients. Many of these patients exhibit severe insulin resistance, manifested by daily insulin requirements of 200 units or greater or more than 2 units/kg. Delivering an appropri- ate insulin volume to these patients can be difficult and inconvenient and may be best accomplished with U-500 regular insulin by multiple daily injections or with con- tinuous subcutaneous insulin infusion, rather than with standard U-100 insulin. Implementation of U-500 regular insulin in patients previously on other insulin formulations is described with a treatment algorithm covering dosage requirements ranging from 150 to more than 600 units per day on the basis of the authors’ experience. Conclusion: Regimen conversion of appropriately selected patients from high-dose, U-100 insulin to U-500 regular insulin therapy on the basis of the recommenda- tions presented in this article may potentially result in improved glycemic control and lower cost. (Endocr Pract. 2009;15:71-79) Abbreviations: CSII = continuous subcutaneous insulin infusion; DM = diabetes mellitus; HbA 1c = hemoglobin A 1c ; NPH = neutral protamine Hagedorn; TZD = thiazolidinedi- one; UKPDS = United Kingdom Prospective Diabetes Study INTRODUCTION U-500 regular insulin was first introduced into clini- cal practice in 1952. The original formulation, beef U- 500 regular insulin (Eli Lilly and Company, Indianapolis, Indiana), was developed to address high insulin require- ments of patients with type 1 diabetes mellitus (DM) or type 2 DM and severe insulin resistance caused by high levels of insulin antibodies to animal species insulins. This formulation was replaced by pork U-500 regular in 1980 and subsequently by U-500 regular human insulin (Humulin R U-500; Eli Lilly and Company, Indianapolis, Indiana) in 1997. Worldwide, Humulin R U-500 is now the only available formulation of insulin at a greater con- centration than U-100 since withdrawal of Actrapid U-500 (Novo Nordisk, Bagsværd, Denmark) from the UK market in late 2007–early 2008. Severe insulin resistance is encountered in clinical practice more commonly today than in the past. The most prevalent cause is obesity, which is an epidemic in the United States and worldwide (1), contributing not only to an increase in type 2 DM prevalence, but also to increas-