Original Article James Thrasher, MD1; Anuj Bhargava, MD, MBA2; Tina M. Rees, PhD3; Tao Wang, PhD3; Cristina B. Guzman, MD, MBA3; Leonard C. Glass, MD3 ABSTRACT with insulin lispro. Overall, both insulin lispro and insulin aspart were well tolerated with similar AEs reported. Objective: This study provides clinical information Conclusion: Insulin lispro and insulin aspart per- regarding the use of insulin lispro versus insulin aspart in formed similarly after 16 weeks of treatment, with non- continuous subcutaneous insulin infusion (CSII) in adult inferiority for HbA1c and no significant difference in patients with type 2 diabetes mellitus (T2D). parameters measured. These findings indicate that insulin Methods: After a 2-week lead-in period, 122 subjects lispro and insulin aspart can both be used safely and effec- treated with CSII therapy were randomized to 32 weeks tively in patients with T2D using CSII. (Endocr Pract. of treatment during 2 separate 16-week treatment peri- 2015;21:247-257) ods (TPs) with crossover beginning with insulin lispro (n = 60) or insulin aspart (n = 62). Glycated hemoglobin Abbreviations: A1c (HbA1c), total daily insulin dose, and weight were AE = adverse event; BG = blood glucose; CI = confi- recorded at the end of TP1 and TP2. Adverse events (AEs) dence interval; CSII = continuous subcutaneous insulin and hypoglycemic events (overall, documented symptom- infusion; HbA1c = glycated hemoglobin A1C; LS = atic, nocturnal, or severe) were recorded throughout the least-squares; MDI = multiple daily injection; OAM = TPs. Data were analyzed using statistical methods that oral antihyperglycemic medication; NIM = noninferior- accounted for repeated measurements. ity margin; SAE = serious adverse event; T1D = type 1 Results: A total of 107 subjects completed the study; diabetes mellitus; T2D = type 2 diabetes mellitus; TP = 7 discontinued in TP1 and 8 discontinued in TP2. Insulin treatment period; TEAE = treatment-emergent adverse lispro was noninferior to insulin aspart in endpoint (weeks event; TZD = thiazolidinedione. 16 and 32) HbA1c over TP1 and TP2 combined. Total daily insulin dose, weight change, and incidence and rates of hypoglycemia were not statistically significantly differ- INTRODUCTION ent between treatments. One case of severe hypoglycemia and 1 of diabetic ketoacidosis was observed with insulin More than one-third of adults with type 2 diabetes mel- aspart. One case of severe infusion site abscess was noted litus (T2D) do not reach the American Diabetes Association goal of glycated hemoglobin A1c (HbA1c) less than 7% (1,2). The use of continuous subcutaneous insulin infusion (CSII) in T2D, although currently less common than in type 1 diabetes (T1D), allows for tight glucose control and has been shown to result in either similar or improved HbA1c Submitted for publication May 29, 2014 Accepted for publication September 15, 2014 values versus multiple daily injection (MDI), no reported From the 1Medical Investigations, Inc, Little Rock, Arkansas; 2Iowa Diabetes increase in hypoglycemia, and improved patient satisfac- and Endocrinology Research Center, Des Moines, Iowa; 3Eli Lilly and tion (3,4). As the number of patients with T2D continues to Company, Lilly Diabetes, Indianapolis, Indiana. Address correspondence to Tina Rees, Eli Lilly and Company; Lilly increase, so does the use of CSII in this population; there- Diabetes, Lilly Corporate Center, Indianapolis, IN 46285. fore, it is valuable to gain more clinical information on the E-mail: [email protected]. effects of different analog insulins in these patients. Published as a Rapid Electronic Article in Press at http://www.endocrine practice.org on November 4, 2014. DOI: 10.4158/EP14242.OR This study compared the efficacy and safety of 2 rapid- To purchase reprints of this article, please visit: www.aace.com/reprints. acting analogs, insulin lispro and insulin aspart, in a T2D Copyright © 2015 AACE. population already using CSII. The primary objective was ENDOCRINE PRACTICE Vol 21 No. 3 March 2015 247 248 to demonstrate that CSII with lispro in patients with T2D Following a screening period of up to 2 weeks, eli- was noninferior (noninferiority margin [NIM] 0.4%) to gible subjects were randomly assigned (1:1) by an inter- CSII with insulin aspart as measured by HbA1c at the end active voice response system to either insulin lispro or of each treatment period (TP). A 0.4% NIM was chosen for insulin aspart for 16 weeks (TP1) followed by crossover this study because it is comparable to other similar stud- to the other treatment for an additional 16 weeks (TP2) for ies (5-7). The secondary objectives of the study were to a total TP of 32 weeks. Subjects were stratified based on compare CSII use of insulin lispro with insulin aspart with screening HbA1c value (≤8% and >8%) and thiazolidin- respect to total daily insulin dose (U/day and U/kg/day) edione (TZD) use (yes or no). Subjects in a crossover study at endpoints of the 2 TPs (i.e., week 16 for TP1 and week serve as their own control, which can efficiently reduce the 32 for TP2), rate and frequency of hypoglycemic events, impact of the between-subject variability (11) and baseline weight change, and adverse events (AEs) over each of the characteristics to the analysis. Because HbA1c measures 2 TPs. the previous 8 to 12 weeks of glycemic control (12) and is heavily weighted to the 4 weeks preceding the measure- METHODS ment (13), and because insulin lispro and insulin aspart have half-lives measured in minutes (14-16), a 16-week Study Patients TP was selected to minimize the risk of carryover effect Male or female subjects with T2D (8) who were 18 and to ensure that the endpoint measurement (32 weeks) to 85 years of age at screening, treated with CSII therapy in TP2 reflected glycemic control influenced only by the using a rapid-acting analog for at least 6 months before second insulin treatment. Subjects, investigators, and all screening, and had an HbA1c ≤9.0% at screening were other personnel involved in the conduct of the study were included. Subjects taking oral antihyperglycemic medica- blinded to the individual treatment assignments for the tions (OAMs) were required to be on a stable dose for at study duration. least 3 months prior to screening. Clear solutions of insulin lispro (Humalog®, 100 U/ Subjects with more than 1 episode of severe hypo- mL, Eli Lilly and Company, Indianapolis, IN) and insu- glycemia (defined as requiring third-party assistance) lin aspart (NovoLog®, 100 U/mL, Novo Nordisk, A/S, within 6 months before study entry, who had severe insulin Bagsværd, Denmark) were provided separately in 10-mL resistance (required >2 U/kg/day), or who were taking or covered vials to mask insulin type and were used to fill the took OAMs not approved in the U.S. for use with insu- pump reservoirs. Subjects administered the insulin by CSII lin or injectable noninsulin antihyperglycemic medica- in 1 of 2 sequences that were each 16 weeks long. Subjects tions within 3 months of screening were excluded from the used their own insulin pump systems during the study, irre- study. Other exclusion criteria included having a history of spective of brand, and continued with their existing insulin hypoglycemia unawareness (routinely asymptomatic with dosing regimens (basal rates, meal boluses [with/without a blood glucose [BG] level <45 mg/dL); having severe carbohydrate counting algorithms], and correction boluses). infection or an abscess at the infusion site(s) up to 1 year Subjects already using a continuous glucose monitor prior to screening; having a history of lipohypertrophy or were permitted to continue as long as they maintained its lipoatrophy at the infusion site(s); or having multiple, clin- use for the study duration. Subjects were all given the same ically significant, pump-related occlusions, as judged by an model of BG meter, a diary to record BG measurements investigator. and hypoglycemic events for review by site personnel, and other diabetes supplies. Qualified medical staff reviewed Study Design and with the subjects the need to maintain their physical activi- Treatments Administered ties, BG monitoring, and provided training on the BG meter This was a phase 3b, multi-center, randomized, and study diary entry. Signs and symptoms of hypo- and double-blind, active comparator, 2 period (16 weeks hyperglycemia and appropriate treatment were reviewed each), 2-sequence, 32-week crossover trial comparing with subjects. insulin lispro with insulin aspart in subjects with T2D At randomization (week 0) and the crossover visit using CSII. The study was registered with clinicaltrials. (week 16), subjects changed their infusion site and tubing gov (NCT01474538) and was conducted across 12 sites (if using a pump with tubing) and filled a new reservoir in the United States in accordance with the principles with the investigational product under the observation of of the Declaration of Helsinki (9) and the International study site staff. At the last study visit (week 32), subjects Conference on Harmonisation Good Clinical Practices changed their infusion sites and filled the new reservoirs E6 Guideline (10). The protocol and informed consent with their poststudy insulin as designated by their investi- form were approved by an ethical review board. Informed gator or physician. All other reservoir and tubing changes consent was obtained from each patient or their legal were done according to standard practice and the investiga- representative. tors’ recommendations. 249 Subject characteristics and demographic variables incidence of AEs and hypoglycemic events were analyzed were obtained at screening, and baseline hypoglyce- using the Prescott test (17). Incidence of hypoglycemic mia was captured between screening and randomization. episodes was summarized for the individual TPs. The inci- HbA1c was collected at screening, randomization (week dence of hypoglycemic episodes (total, severe, nocturnal, 0), the end of each TP (weeks 16 and 32), and, if applicable, and documented symptomatic) was reported by treatment at early termination.