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Li Z, Liu M, Tao Y, Wan L, Chen Y, Zhu M, Zhao H, Tang C. Pharmacokinetics, Pharmacodynamics, and Bioequivalence of Test Insulin Glargine Versus Reference Preparation (Lantus ®) in Healthy Male Volunteers-By Euglycemic Clamp Technique. Pharmaceutics 2025; 17:418. [PMID: 40284414 PMCID: PMC12030383 DOI: 10.3390/pharmaceutics17040418] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2025] [Revised: 03/08/2025] [Accepted: 03/21/2025] [Indexed: 04/29/2025] Open
Abstract
The aim of this study was to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), and safety of two insulin glargine preparations in healthy Chinese male subjects. Methods: Forty healthy Chinese male subjects were enrolled in this randomized, open, two-sequence, four-period, single-dose, crossover study and were randomly divided into RTRT or TRTR (first-period injection of test preparation, second-period injection of reference preparation, third-period injection of test preparation, fourth-period injection of reference preparation) groups. A 24 h euglycemic clamp test measured GIR. Plasma insulin glargine concentration and C-peptide were collected during the trial and analyzed by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) and enzyme-linked immunosorbent assay (ELISA). WinNonLin calculated PD/PK parameters and the equivalence of the two preparations was testified by SAS9.2. Results: The average concentration of C-peptide was lower than the baseline and the blood glucose was close to the targeted value in each sequence. PK parameters cmax of the test and the reference preparation insulin glargine were 0.580 and 0.614 ng·mL-1, and the AUC0-24h were 9.782 and 10.436 h·ng·mL-1, respectively. PD parameters GIRmax were 42.748 and 45.279 mg·kg-1·min-1, and AUCGIR,0-24h were 2.924 and 3.096 h·mg·kg-1·min-1, respectively. There was no clinically significant adverse reaction observed during the experiment. Conclusions: The glucose clamp has been established and bioequivalence between test preparation and reference preparation has been demonstrated.
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Affiliation(s)
- Zhongping Li
- Phase I Clinical Trial Center, Bishan Hospital of Chongqing Medical University, Chongqing 402760, China; (Z.L.); (M.L.); (L.W.); (Y.C.); (M.Z.); (H.Z.)
| | - Min Liu
- Phase I Clinical Trial Center, Bishan Hospital of Chongqing Medical University, Chongqing 402760, China; (Z.L.); (M.L.); (L.W.); (Y.C.); (M.Z.); (H.Z.)
| | - Yi Tao
- Office of Academic Research, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China;
| | - Lei Wan
- Phase I Clinical Trial Center, Bishan Hospital of Chongqing Medical University, Chongqing 402760, China; (Z.L.); (M.L.); (L.W.); (Y.C.); (M.Z.); (H.Z.)
| | - Yuan Chen
- Phase I Clinical Trial Center, Bishan Hospital of Chongqing Medical University, Chongqing 402760, China; (Z.L.); (M.L.); (L.W.); (Y.C.); (M.Z.); (H.Z.)
| | - Mingxue Zhu
- Phase I Clinical Trial Center, Bishan Hospital of Chongqing Medical University, Chongqing 402760, China; (Z.L.); (M.L.); (L.W.); (Y.C.); (M.Z.); (H.Z.)
| | - Hongtao Zhao
- Phase I Clinical Trial Center, Bishan Hospital of Chongqing Medical University, Chongqing 402760, China; (Z.L.); (M.L.); (L.W.); (Y.C.); (M.Z.); (H.Z.)
| | - Chengyong Tang
- Phase I Clinical Trial Center, Bishan Hospital of Chongqing Medical University, Chongqing 402760, China; (Z.L.); (M.L.); (L.W.); (Y.C.); (M.Z.); (H.Z.)
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Liu H, Li T, Chen XL, Yu HL, Yu YR. Impact of setting distinct target blood glucose levels on endogenous insulin suppression and pharmacodynamics of insulin preparations. World J Diabetes 2025; 16:101779. [PMID: 39959272 PMCID: PMC11718471 DOI: 10.4239/wjd.v16.i2.101779] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Revised: 11/15/2024] [Accepted: 12/05/2024] [Indexed: 12/30/2024] Open
Abstract
BACKGROUND Insulin therapy plays a crucial role in managing diabetes. Regulatory guidelines mandate assessing the pharmacokinetics (PK) and pharmacodynamics (PD) of new insulin formulations with euglycemic clamp techniques before entry into the market. Typically, blood glucose (BG) levels are maintained at 5% below baseline to suppress endogenous insulin secretion in healthy volunteers. However, in scenarios where BG baseline is relatively low, maintaining it at 5% below baseline can increase hypoglycemic risk. Consequently, we adjusted to maintain it at 2.5% below a baseline of < 4.00 mmol/L. It remains uncertain whether this adjustment impacts endogenous insulin inhibition or the PD of study insulin. AIM To evaluate and compare the PD and C-peptide status using two different target BG setting methods. METHODS Data came from euglycemic clamp trials assessing the PK/PD of insulin aspart (IAsp) in healthy participants. Target BG was set at 2.5% below baseline for those with a basal BG of < 4.00 mmol/L (group A), and at 5% below baseline for others (group B). The area under the curve (AUC) of IAsp (AUCIAsp, 0-8 h) and GIR from 0 to 8 hours (AUCGIR, 0-8 h) was used to characterize the PK and PD of IAsp, respectively. The C-peptide reduction and PK/PD of IAsp were compared between the two groups. RESULTS Out of 135 subjects, 15 were assigned to group A and 120 to group B; however, group B exhibited higher basal C-peptide (1.59 ± 0.36 vs 1.32 ± 0.42 ng/mL, P = 0.006). Following propensity score matching to adjust for basal C-peptide differences, 71 subjects (15 in group A and 56 in group B) were analyzed. No significant differences were observed in demographics, IAsp dosage, or clamp quality. Group B showed significantly higher baseline (4.35 ± 0.21 vs 3.91 ± 0.09 mmol/L, P < 0.001), target (4.13 ± 0.20 vs 3.81 ± 0.08 mmol/L, P < 0.001), and clamped (4.10 ± 0.17 vs 3.80 ± 0.06 mmol/L, P < 0.001) BG levels. Both groups exhibited comparable C-peptide suppression (32.5% ± 10.0% vs 35.6% ± 12.1%, P = 0.370) and similar IAsp activity (AUCGIR, 0-8 h: 1433 ± 400 vs 1440 ± 397 mg/kg, P = 0.952) under nearly equivalent IAsp exposure (AUCIAsp, 0-8 h: 566 ± 51 vs 571 ± 85 ng/mL × h, P = 0.840). CONCLUSION Maintaining BG at 2.5% below a baseline of < 4.00 mmol/L did not compromise the endogenous insulin suppression nor alter the observed pharmacodynamic effects of the study insulin.
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Affiliation(s)
- Hui Liu
- Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
- Clinical Trial Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Ting Li
- Health Management Center, General Practice Medical Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Xin-Lei Chen
- Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Hong-Ling Yu
- Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Ye-Rong Yu
- Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
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Bendtsen KM, Harder MWH, Glendorf T, Kjeldsen TB, Kristensen NR, Refsgaard HHF. Predicting human half-life for insulin analogs: An inter-drug approach. Eur J Pharm Biopharm 2024; 201:114375. [PMID: 38897553 DOI: 10.1016/j.ejpb.2024.114375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 06/14/2024] [Accepted: 06/16/2024] [Indexed: 06/21/2024]
Abstract
An inter-drug approach, applying pharmacokinetic information for insulin analogs in different animal species, rat, dog and pig, performed better compared to allometric scaling for human translation of intra-venous half-life and only required data from a single animal species for reliable predictions. Average fold error (AFE) between 1.2-1.7 were determined for all species and for multispecies allometric scaling AFE was 1.9. A slightly larger prediction error for human half-life was determined from in vitro human insulin receptor affinity data (AFE on 2.3-2.6). The requirements for the inter-drug approach were shown to be a span of at least 2 orders of magnitude in half-life for the included drugs and a shared clearance mechanism. The insulin analogs in this study were the five fatty acid protracted analogs: Insulin degludec, insulin icodec, insulin 320, insulin 338 and insulin 362, as well as the non-acylated analog insulin aspart.
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Affiliation(s)
- Kristian M Bendtsen
- Digital Sciences & Innovation, Research & Early Development, Novo Nordisk, DK-2760 Måløv, Denmark
| | - Magnus W H Harder
- Global Drug Discovery, Research & Early Development, Novo Nordisk, DK-2760 Måløv, Denmark
| | - Tine Glendorf
- Global Research Technologies, Research & Early Development, Novo Nordisk, DK-2760 Måløv, Denmark
| | - Thomas B Kjeldsen
- Global Research Technologies, Research & Early Development, Novo Nordisk, DK-2760 Måløv, Denmark
| | | | - Hanne H F Refsgaard
- Global Drug Discovery, Research & Early Development, Novo Nordisk, DK-2760 Måløv, Denmark.
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Aktas G, Taslamacioglu Duman T. Current usage of long-acting insulin analogs in patients with type 2 diabetes mellitus. Expert Rev Endocrinol Metab 2024; 19:155-161. [PMID: 38375790 DOI: 10.1080/17446651.2024.2320631] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Accepted: 02/15/2024] [Indexed: 02/21/2024]
Abstract
INTRODUCTION Insulin treatment is fundamental to diabetes management. Basal insulin therapy reduces intraday glycemic fluctuations upon reaching a steady state. Besides better blood glucose regulation and achieving target HbA1c values in patients, it also offers protection from diabetes complications. In this review, we aimed to compare basal-acting insulins in light of the literature. AREAS COVERED We reviewed current evidence related to diabetes treatment with basal insulins. This includes discussions on clinical trials and meta-analyses concerning first and second-generation ultra-long-acting basal insulins. Treatment indications for long-acting basal insulins, which have shown benefits and are considered superior or comparable to others in the literature, are derived from current clinical studies and meta-analyses, which form the basis of the recommendations in this review. EXPERT OPINION First and second-generation basal insulins do not show much superiority over each other in terms of blood glucose regulation and reaching the target HbA1c. However, second-generation basal insulins cause fewer hypoglycemic events. We recommend using the appropriate basal insulin in patient-based, individualized treatments. Basal insulin Icodec may become more widely used over time, owing to its association with less hypoglycemia and a reduction in the number of injections.
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Affiliation(s)
- Gulali Aktas
- Department of Internal Medicine, Abant Izzet Baysal University Hospital, Bolu, Turkey
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Liu H, Yu H, Sun L, Qiao J, Li J, Tan H, Yu Y. Effects of Unsuppressed Endogenous Insulin on Pharmacokinetics and/or Pharmacodynamics of Study Insulin in the Healthy: A Retrospective Study. Clin Pharmacol Drug Dev 2022; 11:930-937. [PMID: 35384402 PMCID: PMC9546084 DOI: 10.1002/cpdd.1093] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Accepted: 02/28/2022] [Indexed: 02/05/2023]
Abstract
C‐peptide, a marker of endogenous insulin, should be consistently inhibited during euglycemic clamping, while an elevated postdosing C‐peptide (CPpostdosing) is not an occasional phenomenon. This was a retrospective study that included 33 men who underwent a manual euglycemic clamp with a subcutaneous injection of insulin aspart (IAsp) aiming to describe the effects of insufficient suppression of endogenous insulin on estimates of the pharmacokinetics and pharmacodynamics of injected insulin. The time profiles of whole blood glucose, human insulin, glucose infusion rate (GIR), and C‐peptide were recorded. The subjects were divided into 2 groups at a ratio of 2:1: group A ([CPpostdosing]max>baseline CP [CPbaseline]), group B ([CPpostdosing]max ≤ CPbaseline). The endogenous insulin was approximately equal to the measured value of human insulin or calculated from the C‐peptide. The basal glucose, CPbaseline, basal human insulin, homeostatic model assessment of insulin resistance, IAsp dose, and demographic statistics were all comparable between the 2 groups except the “clamped” glucose. The average clamped glucose was 99.7% (group A) and 94.9% (group B) of baseline. After correction for clamped glucose, GIR area under the concentration‐time curve from time 0 to 8 hours was higher in group A (P < .05) under comparable IAsp exposure. Endogenous insulin area under the concentration‐time curve from time 0 to 8 hours calculated from C‐peptide was different from that measured from human insulin in group A (P < .05), whereas no statistical difference between these measures was observed in group B. Hence, blood glucose should be controlled below the baseline to ensure the inhibition of endogenous insulin. Unsuppressed endogenous insulin may contribute to observed GIR, and the endogenous insulin–corrected pharmacokinetics estimated by C‐peptide may be inaccurate with insufficient endogenous insulin suppression.
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Affiliation(s)
- Hui Liu
- Department of General Practice, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Hongling Yu
- Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Lisi Sun
- Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Jingtao Qiao
- Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Jiaqi Li
- Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Huiwen Tan
- Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yerong Yu
- Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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Characterization of viral insulins reveals white adipose tissue-specific effects in mice. Mol Metab 2020; 44:101121. [PMID: 33220491 PMCID: PMC7770979 DOI: 10.1016/j.molmet.2020.101121] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 11/05/2020] [Accepted: 11/16/2020] [Indexed: 12/11/2022] Open
Abstract
Objective Members of the insulin/insulin-like growth factor (IGF) superfamily are well conserved across the evolutionary tree. We recently showed that four viruses in the Iridoviridae family possess genes that encode proteins highly homologous to human insulin/IGF-1. Using chemically synthesized single-chain (sc), i.e., IGF-1-like, forms of the viral insulin/IGF-1-like peptides (VILPs), we previously showed that they can stimulate human receptors. Because these peptides possess potential cleavage sites to form double chain (dc), i.e., more insulin-like, VILPs, in this study, we have characterized dc forms of VILPs for Grouper iridovirus (GIV), Singapore grouper iridovirus (SGIV) and Lymphocystis disease virus-1 (LCDV-1) for the first time. Methods The dcVILPs were chemically synthesized. Using murine fibroblast cell lines overexpressing insulin receptor (IR-A or IR-B) or IGF1R, we first determined the binding affinity of dcVILPs to the receptors and characterized post-receptor signaling. Further, we used C57BL/6J mice to study the effect of dcVILPs on lowering blood glucose. We designed a 3-h dcVILP in vivo infusion experiment to determine the glucose uptake in different tissues. Results GIV and SGIV dcVILPs bind to both isoforms of human insulin receptor (IR-A and IR-B) and to the IGF1R, and for the latter, show higher affinity than human insulin. These dcVILPs stimulate IR and IGF1R phosphorylation and post-receptor signaling in vitro and in vivo. Both GIV and SGIV dcVILPs stimulate glucose uptake in mice. In vivo infusion experiments revealed that while insulin (0.015 nmol/kg/min) and GIV dcVILP (0.75 nmol/kg/min) stimulated a comparable glucose uptake in heart and skeletal muscle and brown adipose tissue, GIV dcVILP stimulated 2-fold higher glucose uptake in white adipose tissue (WAT) compared to insulin. This was associated with increased Akt phosphorylation and glucose transporter type 4 (GLUT4) gene expression compared to insulin in WAT. Conclusions Our results show that GIV and SGIV dcVILPs are active members of the insulin superfamily with unique characteristics. Elucidating the mechanism of tissue specificity for GIV dcVILP will help us to better understand insulin action, design new analogs that specifically target the tissues and provide new insights into their potential role in disease.
Viral insulin/IGF1-like peptides (VILPs) are microbial members of the insulin superfamily. VILPs bind to human IR and IGF1R and stimulate post-receptor signaling. Grouper iridovirus (GIV) VILP has white adipose tissue (WAT)-specific characteristics. GIV VILP stimulates increased glucose uptake in WAT via increased GLUT4 expression.
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Johansen RF, Søndergaard E, Linnebjerg H, Garhyan P, Lam ECQ, Porksen N, Jacober SJ, Nielsen S. Attenuated suppression of lipolysis explains the increases in triglyceride secretion and concentration associated with basal insulin peglispro relative to insulin glargine treatment in patients with type 1 diabetes. Diabetes Obes Metab 2018; 20:419-426. [PMID: 28817248 DOI: 10.1111/dom.13087] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2017] [Revised: 08/04/2017] [Accepted: 08/12/2017] [Indexed: 01/11/2023]
Abstract
AIMS To test the hypothesis that, as well as lowering weight and increasing plasma triglyceride (TG) levels and hepatic fat compared with insulin glargine (GL) in patients with type 1 diabetes, the attenuated peripheral effects of basal insulin peglispro (BIL) may include increased free fatty acid flux to the liver, causing increased very-low-density lipoprotein (VLDL)-TG secretion and lipid oxidation, and decreased TG adipose tissue deposition. METHODS In this open-label, randomized, 2-period crossover study, 14 patients with type 1 diabetes received once-daily, individualized, stable BIL or GL doses for 3 weeks. Palmitate flux was assessed using [9,10-3 H]palmitate infusion. VLDL-TG secretion, clearance and oxidation rate were assessed using primed-constant infusion of ex vivo labelled [1-14 C]VLDL-TG, while VLDL-TG storage rate was assessed using [9,10-3 H]VLDL-TG bolus injection. RESULTS The VLDL-TG concentration and secretion rate, and palmitate flux were statistically significantly higher during BIL than during GL treatment (58%, 51% and 35%, respectively). The ratios of least squares (LS) geometric means for VLDL-TG clearance and oxidation were 0.92 (95% confidence interval [CI] 0.72, 1.17) and 1.31 (95% CI 0.91, 1.90), respectively. The difference in LS means for VLDL-TG storage rate was -0.36 (95% CI -0.83, 0.12). CONCLUSIONS BIL-treated patients had higher effective lipolysis, VLDL-TG secretion and VLDL-TG concentration compared with GL-treated patients, explaining the increased plasma TG concentrations reported previously. Data support attenuated effects of BIL on lipolysis, in addition to the recently described hepato-preferential glucodynamic effects.
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Affiliation(s)
- Rakel F Johansen
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Esben Søndergaard
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
| | | | | | - Eric C Q Lam
- Formerly of Eli Lilly and Company, Singapore, Singapore
| | - Niels Porksen
- Formerly of Eli Lilly and Company, Indianapolis, Indiana
| | | | - Søren Nielsen
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
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Qu Y, Luo J, Garhyan P, Antalis CJ, Chang AM, Jacober SJ. Dose Unit Establishment for a New Basal Insulin Using Joint Modeling of Insulin Dose and Glycemic Response. J Diabetes Sci Technol 2018; 12:155-162. [PMID: 28466661 PMCID: PMC5761965 DOI: 10.1177/1932296817707542] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND For new insulin analogs with properties that vary from human insulin, defining activity in units of human insulin based on glycemic lowering efficacy may be challenging. Here we present a new method that can be used to quantify a unit dose of an experimental insulin when the traditional euglycemic clamp method is not adequate. METHODS Joint modeling of insulin dose and the glycemic outcome variable hemoglobin A1c (HbA1c), where both were response variables, was used to evaluate insulin unit potency for basal insulin peglispro (BIL). The data were from the Phase 3 program for BIL, which included greater than 5500 patients with type 1 or type 2 diabetes who were treated for 26 or 52 weeks with BIL or a comparator insulin. Both basal-bolus and basal insulin only studies were included, and some type 2 diabetes patients were insulin-naïve. RESULTS The analysis showed that 1 unit of BIL, composed of 9 nmol of active ingredient, had similar or slightly greater potency compared to 1 unit insulin glargine or NPH insulin for all populations. CONCLUSIONS Despite some limitations, the joint modeling of HbA1c and insulin dose provides a reasonable approach to estimate the relative potency of a new basal insulin versus an established basal insulin.
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Affiliation(s)
- Yongming Qu
- Eli Lilly and Company, Indianapolis, IN, USA
| | | | | | | | | | - Scott J. Jacober
- Eli Lilly and Company, Indianapolis, IN, USA
- Scott J. Jacober, DO, Eli Lilly and Company, Lilly Corporate Center, Drop Code 2232, Indianapolis, IN 46285, USA.
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Wronkowitz N, Hartmann T, Görgens SW, Dietze-Schroeder D, Indrakusuma I, Choi IY, Park SH, Lee YM, Kwon SC, Kang Y, Hompesch M, Eckel J. LAPS Insulin115: A novel ultra-long-acting basal insulin with a unique action profile. Diabetes Obes Metab 2017; 19:1722-1731. [PMID: 28497570 DOI: 10.1111/dom.13006] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2017] [Revised: 05/04/2017] [Accepted: 05/08/2017] [Indexed: 12/25/2022]
Abstract
AIMS To conduct a comprehensive pre-clinical study of the novel ultra-long acting insulin analogue LAPS Insulin115. METHODS Pharmacokinetic/pharmacodynamic studies comparing LAPS Insulin115 with other basal insulins were conducted in genetically diabetic (db/db) mice. Insulin signalling in the major target organs was analysed using Western blot after single subcutaneous injection in wild-type male Wistar rats. Using in vitro assays we analysed transendothelial transport, insulin receptor (IR) interaction, and the mitogenic and metabolic properties of LAPS Insulin115. Furthermore, IR downregulation after long-term exposure to high concentrations of LAPS Insulin115 was analysed using an in vitro desensitization/resensitization model. RESULTS The novel Fc-conjugated insulin derivative LAPS Insulin115 showed an extensively prolonged pharmacokinetic and pharmacodynamic profile in rodents. Despite its size of 59 kDa, LAPS Insulin115 passes the vascular endothelial barrier and induces insulin signalling in all major target tissues in rats. In vitro, LAPS Insulin115 showed a very slow onset of action because of its reduced IR affinity; however, after long-term stimulation it was equipotent in respect to its metabolic potency and showed no increased mitogenic action when compared with regular insulin. Remarkably, under conditions of chronic exposure, LAPS Insulin115 does not induce irreversible desensitization of target cells, which is probably attributable to much less prominent IR downregulation. CONCLUSION Thus, LAPS Insulin115 exhibits a unique in vivo and in vitro profile and thereby represents an excellent candidate for a once-weekly insulin analogue.
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MESH Headings
- Absorption, Physiological
- Animals
- Cell Line
- Cells, Cultured
- Drugs, Investigational/chemistry
- Drugs, Investigational/metabolism
- Drugs, Investigational/pharmacology
- Drugs, Investigational/therapeutic use
- Gene Expression Regulation/drug effects
- Half-Life
- Humans
- Hypoglycemic Agents/chemistry
- Hypoglycemic Agents/metabolism
- Hypoglycemic Agents/pharmacology
- Hypoglycemic Agents/therapeutic use
- Immunoglobulin Fc Fragments/genetics
- Immunoglobulin Fc Fragments/metabolism
- Immunoglobulin Fc Fragments/pharmacology
- Immunoglobulin Fc Fragments/therapeutic use
- Insulin, Long-Acting/genetics
- Insulin, Long-Acting/metabolism
- Insulin, Long-Acting/pharmacology
- Insulin, Long-Acting/therapeutic use
- Intra-Abdominal Fat/drug effects
- Intra-Abdominal Fat/metabolism
- Male
- Mice, Mutant Strains
- Organ Specificity
- Phosphorylation/drug effects
- Protein Processing, Post-Translational/drug effects
- Rats, Wistar
- Receptor, Insulin/agonists
- Receptor, Insulin/antagonists & inhibitors
- Receptor, Insulin/genetics
- Receptor, Insulin/metabolism
- Recombinant Fusion Proteins/chemistry
- Recombinant Fusion Proteins/metabolism
- Recombinant Fusion Proteins/pharmacology
- Recombinant Fusion Proteins/therapeutic use
- Signal Transduction/drug effects
- Toxicity Tests, Chronic
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Affiliation(s)
- Nina Wronkowitz
- Paul-Langerhans-Group, German Diabetes Centre, Düsseldorf, Germany
| | | | | | | | - Ira Indrakusuma
- Paul-Langerhans-Group, German Diabetes Centre, Düsseldorf, Germany
| | | | | | - Young-Mi Lee
- Hanmi Pharmaceutical, Co., Ltd., Seoul, South Korea
| | | | | | | | - Jürgen Eckel
- Paul-Langerhans-Group, German Diabetes Centre, Düsseldorf, Germany
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10
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Moyers JS, Volk CB, Cao JXC, Zhang C, Ding L, Kiselyov VV, Michael MD. Internalization and localization of basal insulin peglispro in cells. Mol Cell Endocrinol 2017; 454:23-38. [PMID: 28576743 DOI: 10.1016/j.mce.2017.05.032] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2017] [Revised: 05/24/2017] [Accepted: 05/27/2017] [Indexed: 01/24/2023]
Abstract
BACKGROUND Basal insulin peglispro (BIL) is a novel, PEGylated insulin lispro that has a large hydrodynamic size compared with insulin lispro. It has a prolonged duration of action, which is related to a delay in insulin absorption and a reduction in clearance. Given the different physical properties of BIL compared with native insulin and insulin lispro, it is important to assess the cellular internalization characteristics of the molecule. METHODS AND MATERIALS Using immunofluorescent confocal imaging, we compared the cellular internalization and localization patterns of BIL, biosynthetic human insulin, and insulin lispro. We assessed the effects of BIL on internalization of the insulin receptor (IR) and studied cellular clearance of BIL. RESULTS Co-localization studies using antibodies to either insulin or PEG, and the early endosomal marker EEA1 showed that the overall internalization and subcellular localization pattern of BIL was similar to that of human insulin and insulin lispro; all were rapidly internalized and co-localized with EEA1. During ligand washout for 4 h, concomitant loss of insulin, PEG methoxy group, and PEG backbone immunostaining was observed for BIL, similar to the loss of insulin immunostaining observed for insulin lispro and human insulin. Co-localization studies using an antibody to the lysosomal marker LAMP1 did not reveal evidence of lysosomal localization for insulin lispro, human insulin, BIL, or PEG using either insulin or PEG immunostaining reagents. BIL and human insulin both induced rapid phosphorylation and internalization of human IR. CONCLUSIONS Our findings show that treatment of cells with BIL stimulates internalization and localization of IR to early endosomes. Both the insulin and PEG moieties of BIL undergo a dynamic cellular process of rapid internalization and transport to early endosomes followed by loss of cellular immunostaining in a manner similar to that of insulin lispro and human insulin. The rate of clearance for the insulin lispro portion of BIL was slower than the rate of clearance for human insulin. In contrast, the PEG moiety of BIL can recycle out of cells.
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Affiliation(s)
- Julie S Moyers
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.
| | - Catherine B Volk
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA
| | - Julia X C Cao
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA
| | - Chen Zhang
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA
| | - Liyun Ding
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA
| | | | - M Dodson Michael
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA
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11
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Harris C, Forst T, Heise T, Plum-Mörschel L, Watkins E, Zhang Q, Fan L, Garhyan P, Porksen N. Hypoglycemia Risk Related to Double Dose Is Markedly Reduced with Basal Insulin Peglispro Versus Insulin Glargine in Patients with Type 2 Diabetes Mellitus in a Randomized Trial: IMAGINE 8. Diabetes Technol Ther 2017; 19:463-470. [PMID: 28817342 PMCID: PMC5567880 DOI: 10.1089/dia.2016.0414] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
BACKGROUND Basal insulin peglispro (BIL) has a peripheral-to-hepatic distribution of action that resembles endogenous insulin and a prolonged duration of action with a flat pharmacokinetic/pharmacodynamic profile at steady state, characteristics that tend to reduce hypoglycemia risk compared to insulin glargine (GL). The primary objective was to demonstrate that clinically significant hypoglycemia (blood glucose ≤54 mg/dL [3.0 mmol/L] or symptoms of severe hypoglycemia) occurred less frequently within 84 h after a double dose (DD) of BIL than a DD of GL. METHODS This was a randomized, double-blind, two-period crossover study in patients with type 2 diabetes (T2D) previously treated with insulin (N = 68). For the first 3 weeks of each of the two crossover periods, patients received an individualized dose of BIL or GL once nightly (stable dose for 2 weeks/period). Then, during a 7-day inpatient stay with frequent blood glucose monitoring and standardized meals, one DD of study insulin was given. Glucose was infused if blood glucose was ≤54 mg/dL (3.0 mmol/L) or for symptoms of severe hypoglycemia. RESULTS Within 84 h after the DD, a significantly smaller proportion of patients experienced clinically significant hypoglycemia with BIL compared to GL (BIL, 6.6%; GL, 35.5%; odds ratio for BIL/GL 0.13 [95% confidence interval 0.04-0.39]; P < 0.001). Adverse event profiles were similar for the two insulins. Serum alanine aminotransferase and triglyceride levels were significantly higher with BIL versus GL. CONCLUSIONS BIL has a markedly lower risk of hypoglycemia than GL when replicating a double-dose error in patients with T2D.
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Affiliation(s)
| | | | | | | | - Elaine Watkins
- Profil Institute for Clinical Research, Chula Vista, California, USA
- Pharmaceutical Product Development, Inc., Wilmington, North Carolina, USA
| | - Qianyi Zhang
- Eli Lilly and Company, Indianapolis, Indiana, USA
| | - Ludi Fan
- Eli Lilly and Company, Indianapolis, Indiana, USA
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12
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Mathieu C, Gillard P, Benhalima K. Insulin analogues in type 1 diabetes mellitus: getting better all the time. Nat Rev Endocrinol 2017; 13:385-399. [PMID: 28429780 DOI: 10.1038/nrendo.2017.39] [Citation(s) in RCA: 153] [Impact Index Per Article: 19.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The treatment of type 1 diabetes mellitus consists of external replacement of the functions of β cells in an attempt to achieve blood levels of glucose as close to the normal range as possible. This approach means that glucose sensing needs to be replaced and levels of insulin need to mimic physiological insulin-action profiles, including basal coverage and changes around meals. Training and educating patients are crucial for the achievement of good glycaemic control, but having insulin preparations with action profiles that provide stable basal insulin coverage and appropriate mealtime insulin peaks helps people with type 1 diabetes mellitus to live active lives without sacrificing tight glycaemic control. Insulin analogues enable patients to achieve this goal, as some have fast action profiles, and some have very slow action profiles, which gives people with type 1 diabetes mellitus the tools to achieve dynamic insulin-action profiles that enable tight glycaemic control with a risk of hypoglycaemia that is lower than that with human short-acting and long-acting insulins. This Review discusses the established and novel insulin analogues that are used to treat patients with type 1 diabetes mellitus and provides insights into the future development of insulin analogues.
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Affiliation(s)
- Chantal Mathieu
- Clinical and Experimental Endocrinology, University of Leuven, Herestraat 49, Leuven 3000, Belgium
| | - Pieter Gillard
- Clinical and Experimental Endocrinology, University of Leuven, Herestraat 49, Leuven 3000, Belgium
| | - Katrien Benhalima
- Clinical and Experimental Endocrinology, University of Leuven, Herestraat 49, Leuven 3000, Belgium
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13
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Muñoz-Garach A, Molina-Vega M, Tinahones FJ. How Can a Good Idea Fail? Basal Insulin Peglispro [LY2605541] for the Treatment of Type 2 Diabetes. Diabetes Ther 2017; 8:9-22. [PMID: 27896568 PMCID: PMC5306113 DOI: 10.1007/s13300-016-0214-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2016] [Indexed: 11/24/2022] Open
Abstract
INTRODUCTION Lack of control in diabetic patients has stimulated the development of new insulin analogues. One of these was basal insulin peglispro (BIL) or LY2605541; it had a large hydrodynamic size, flat pharmacokinetic profile, half life of 2-3 days and acted preferably in the liver. METHODS We reviewed the recent literature examining the pharmacokinetics, pharmacodynamics, efficacy and safety of BIL treatment in type 2 diabetes patients. RESULTS The pharmacodynamic and pharmacokinetic outline of BIL seemed to have an advantage over neutral protamine Hagedorn and glargine insulins. Recently, phase 3 studies suggested BIL was superior to glargine in reducing glucose levels in type 1 and type 2 diabetes patients in addition to causing less weight gain. It showed a different hypoglycaemia rate profile depending on the study population, with less nocturnal hypoglycaemia compared to glargine. Unfortunately, it caused higher transaminase and triglyceride levels, which led the company to discontinue development. The decision came after it had been analysed by the regulatory authorities and other external experts concerning the worse liver profile data from the IMAGINE trials. CONCLUSIONS BIL was an adequate basal insulin analogue with interesting specific properties. Unfortunately the disadvantages as shown in the lipid values and liver function tests led to its failure.
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Affiliation(s)
- Araceli Muñoz-Garach
- Department of Endocrinology and Nutrition, Virgen de la Victoria Universitary Hospital, Malaga, Spain
- Department of Endocrinology and Nutrition, IBIMA foundation, Malaga, Spain
| | - María Molina-Vega
- Department of Endocrinology and Nutrition, Virgen de la Victoria Universitary Hospital, Malaga, Spain
- Department of Endocrinology and Nutrition, IBIMA foundation, Malaga, Spain
| | - Francisco J Tinahones
- Department of Endocrinology and Nutrition, Virgen de la Victoria Universitary Hospital, Malaga, Spain.
- Department of Endocrinology and Nutrition, IBIMA foundation, Malaga, Spain.
- CIBER Fisiopatologia Obesidad y Nutricion (CIBEROBN), Instituto de Salud Carlos III, Malaga, Spain.
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14
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Blevins T, Pieber TR, Colón Vega G, Zhang S, Bastyr EJ, Chang AM. Randomized double-blind clinical trial comparing basal insulin peglispro and insulin glargine, in combination with prandial insulin lispro, in patients with type 2 diabetes: IMAGINE 4. Diabetes Obes Metab 2016; 18:1072-1080. [PMID: 27234693 PMCID: PMC5096023 DOI: 10.1111/dom.12696] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2016] [Revised: 05/23/2016] [Accepted: 05/24/2016] [Indexed: 12/18/2022]
Abstract
AIMS To evaluate the efficacy and safety of basal insulin peglispro (BIL) with those of insulin glargine, both in combination with prandial insulin lispro, in patients with type 2 diabetes (T2D). METHODS In this phase III, multicentre, double-blind, 26-week study, we randomized patients with T2D [glycated haemoglobin (HbA1c) ≥7 and <12%, on ≥1 insulin injections daily) to BIL (n = 691) or glargine (n = 678), in combination with lispro. RESULTS At week 26, the primary objective of non-inferiority of BIL versus glargine for HbA1c reduction was achieved (least squares mean difference -0.21%; 95% confidence interval -0.31 to -0.11%), with statistical superiority of BIL with multiplicity adjustment (p < 0.001). HbA1c at baseline was 8.4% versus 8.5% for BIL versus glargine and at 26 weeks it was 6.8% versus 7.0%. At 26 weeks, more patients reached HbA1c <7% with BIL than with glargine (63.3% vs 53.3%; p < 0.001), the nocturnal hypoglycaemia rate (≤3.9 mmol/l) was lower with BIL (0.51 vs 0.92 events/30 days; p < 0.001), but the daytime hypoglycaemia rate was higher with BIL (5.47 vs 4.53 events/30 days; p < 0.001). The total hypoglycaemia relative rate was 1.10 (p = 0.053). At 26 weeks, patients in the BIL group had lower fasting serum glucose levels, higher basal insulin dosing, with no statistically significant difference in prandial or total insulin dosing, reduced glucose variability and less weight gain (1.3 kg vs 2.2 kg) compared with the glargine group. The BIL group had higher mean triglyceride and aminotransferase levels. CONCLUSIONS In patients with T2D, BIL with insulin lispro provided greater improvement in glycaemic control with less nocturnal hypoglycaemia, lower glucose variability and less weight gain compared with glargine. The daytime hypoglycaemia rate and mean triglyceride and aminotransferase levels were higher with BIL.
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Affiliation(s)
- T Blevins
- Texas Diabetes and Endocrinology, Austin, TX, USA
| | - T R Pieber
- Division of Endocrinology and Diabetology, Medical University of Graz, Graz, Austria
| | - G Colón Vega
- American Telemedicine Center, San Juan, Puerto Rico
| | - S Zhang
- Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA
| | - E J Bastyr
- Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA
- Division of Endocrinology and Metabolism, Indiana University School of Medicine, Indianapolis, IN, USA
| | - A M Chang
- Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA.
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15
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Morrow LA, Hompesch M, Jacober SJ, Leng Choi S, Qu Y, Sinha VP. Glucodynamics of long-acting basal insulin peglispro compared with insulin glargine at steady state in patients with type 1 diabetes: substudy of a randomized crossover trial. Diabetes Obes Metab 2016; 18:1065-1071. [PMID: 27169522 DOI: 10.1111/dom.12691] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2016] [Revised: 04/29/2016] [Accepted: 05/08/2016] [Indexed: 12/01/2022]
Abstract
AIMS To compare, in an open-label, randomized, crossover phase II substudy, the glucodynamics of insulin glargine and those of basal insulin peglispro (BIL) in patients with type 1 diabetes. METHODS Patients (n = 23) underwent 24-h euglycaemic clamps after 8 weeks of treatment with glargine or with BIL. Clinically-titrated basal insulin doses (BIL group 16-64 U; glargine group 19-60 U) were administered on the morning of the clamp. RESULTS At baseline, the patients' mean ± standard deviation (s.d.) body mass index was 26.78 ± 4.20 kg/m2 and glycated haemoglobin was 7.69 ± 0.99%. The mean ± s.d. endpoint dose for the BIL group was 0.42 ± 0.13 U/kg and for the glargine group was 0.42 ± 0.10. The daily mean ± s.d. blood glucose concentration was 7.7 ± 1.2 in the BIL group and 7.9 ± 1.2 mmol/l in the glargine group (p = 0.641). The mean ± s.d. total and nocturnal hypoglycaemia rates/30 days were 2.7 ± 2.3 and 0.5 ± 0.8, respectively, for the BIL group, and 3.0 ± 2.4 and 0.7 ± 1.1, respectively, for the glargine group (p = 0.112 and 0.428). The mean glucose infusion rate (GIR) normalized to insulin unit was lower for BIL than for glargine. One patient in the glargine group and eight patients in the BIL group had minimal (<0.8 g/kg) GIRs over 24 h. The mean ± s.d. total glucose infused over 24 h (GTOT(0-24) ) was 1.22 ± 0.82 g/kg in the BIL group and 1.90 ± 1.01 g/kg in the glargine group (p = 0.002). The mean ± s.d. total glucose infused during hours 0-6 (GTOT(0-6) ) was 0.21 ± 0.22 in the BIL group and 0.41 ± 0.22 g/kg in the glargine group (p < 0.001), while the mean total glucose infused during hours 18-24 (GTOT(18-24) ) in the BIL group was 0.28 ± 0.18 g/kg and in the glargine group was 0.35 ± 0.23 g/kg (p = 0.198). The peak-to-trough ratio was 1.41 for BIL versus 2.22 for glargine. CONCLUSIONS BIL has a flatter profile than glargine, with potentially more stable metabolic control. The lower GTOT(0-24) observed in the BIL group is consistent with BIL's reduced peripheral action.
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Affiliation(s)
- L A Morrow
- Profil® Institute for Clinical Research, Chula Vista, CA, USA
| | - M Hompesch
- Profil® Institute for Clinical Research, Chula Vista, CA, USA
| | - S J Jacober
- Eli Lilly and Company, Indianapolis, IN, USA.
| | - S Leng Choi
- Lilly-NUS Centre for Pharmacology Pte, Ltd, Singapore
| | - Y Qu
- Eli Lilly and Company, Indianapolis, IN, USA
| | - V P Sinha
- Eli Lilly and Company, Indianapolis, IN, USA
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16
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Bergenstal RM, Lunt H, Franek E, Travert F, Mou J, Qu Y, Antalis CJ, Hartman ML, Rosilio M, Jacober SJ, Bastyr EJ. Randomized, double-blind clinical trial comparing basal insulin peglispro and insulin glargine, in combination with prandial insulin lispro, in patients with type 1 diabetes: IMAGINE 3. Diabetes Obes Metab 2016; 18:1081-1088. [PMID: 27265390 PMCID: PMC5096008 DOI: 10.1111/dom.12698] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2016] [Revised: 03/27/2016] [Accepted: 06/01/2016] [Indexed: 01/07/2023]
Abstract
AIMS To compare the efficacy and safety of basal insulin peglispro (BIL), which has a flat pharmacokinetic and pharmacodynamic profile and a long duration of action, with insulin glargine (GL) in patients with type 1 diabetes. MATERIALS AND METHODS In this phase III, 52-week, blinded study, we randomized 1114 adults with type 1 diabetes in a 3 : 2 distribution to receive either BIL (n = 664) or GL (n = 450) at bedtime, with preprandial insulin lispro, using intensive insulin management. The primary objective was to compare glycated haemoglobin (HbA1c) in the groups at 52 weeks, with a non-inferiority margin of 0.4%. RESULTS At 52 weeks, mean (standard error) HbA1c was 7.38 (0.03)% with BIL and 7.61 (0.04)% with GL {difference -0.22% [95% confidence interval (CI) -0.32, -0.12]; p < 0.001}. At 52 weeks more BIL-treated patients reached HbA1c <7% (35% vs 26%; p < 0.001), the nocturnal hypoglycaemia rate was 47% lower (p < 0.001) and the total hypoglycaemia rate was 11% higher (p = 0.002) than in GL-treated patients, and there was no difference in severe hypoglycaemia rate. Patients receiving BIL lost weight, while those receiving GL gained weight [difference -1.8 kg (95% CI -2.3, -1.3); p < 0.001]. Treatment with BIL compared with GL at 52 weeks was associated with greater increases from baseline in levels of serum triglyceride [difference 0.19 mmol/l (95% CI 0.11, 0.26); p < 0.001] and alanine aminotransferase (ALT) levels [difference 6.5 IU/l (95% CI 4.1, 8.9), p < 0.001], and more frequent injection site reactions. CONCLUSIONS In patients with type 1 diabetes, treatment with BIL compared with GL for 52 weeks resulted in a lower HbA1c, more patients with HbA1c levels <7%, and reduced nocturnal hypoglycaemia, but more total hypoglycaemia and injection site reactions and higher triglyceride and ALT levels.
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Affiliation(s)
| | - H Lunt
- Christchurch Hospital Diabetes Center, Christchurch, New Zealand
| | - E Franek
- Mossakowski Clinical Research Centre, Polish Academy of Science, Warsaw, Poland
| | - F Travert
- Hopital Bichat Claude Bernard, Paris, France
| | - J Mou
- Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA
| | - Y Qu
- Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA
| | - C J Antalis
- Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA
| | - M L Hartman
- Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA
| | - M Rosilio
- Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA
| | - S J Jacober
- Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA
| | - E J Bastyr
- Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA.
- Indiana University School of Medicine, Indianapolis, IN, USA.
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17
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Grunberger G, Chen L, Rodriguez A, Tinahones FJ, Jacober SJ, Bue-Valleskey J. A randomized clinical trial of basal insulin peglispro vs NPH in insulin-naïve patients with type 2 diabetes: the IMAGINE 6 trial. Diabetes Obes Metab 2016; 18 Suppl 2:34-42. [PMID: 27723225 DOI: 10.1111/dom.12743] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2016] [Accepted: 07/11/2016] [Indexed: 12/18/2022]
Abstract
AIMS Basal insulin peglispro (BIL) has a longer duration of action than conventional insulin analogues and a hepato-preferential mechanism of action. This study assessed whether BIL was non-inferior to isophane insulin (NPH) in reducing HbA1c in insulin-naïve patients with type 2 diabetes, when added to pre-study oral anti-hyperglycaemic medications. MATERIALS AND METHODS This was a Phase 3, open-label, treat-to-target (TTT), randomized trial with a 2-week lead-in, 26-week treatment and a 4-week safety follow-up period. Patients were randomized to bedtime (pm) NPH, morning (am) BIL or pm BIL in a 1:1:1 ratio. RESULTS Six hundred and forty-one patients [NPH, n = 213; BIL, n = 428 (am, n = 213; pm, n = 215)] received study drug. BIL was non-inferior to NPH for HbA1c change from baseline at Week 26 with a between-treatment difference (95% confidence interval) of -0.37% (-0.50, -0.23%). HbA1c at baseline was 8.5%, and was lower in BIL- vs NPH-treated patients after 26 weeks of treatment (6.8% vs 7.1%; P < .001). More BIL-treated patients achieved HbA1c <7.0% and HbA1c <7.0% without nocturnal hypoglycaemia. Fasting serum glucose levels and nocturnal hypoglycaemia rates were lower in BIL-treated patients; total hypoglycaemia rates were similar. Treatment-emergent adverse events were similar between groups. Fasting triglycerides decreased from baseline in both groups and to a greater extent with NPH, but were not significantly different between groups at Week 26. Mean alanine aminotransferase (ALT) increased with BIL treatment, but there was no evidence of acute severe hepatotoxicity. CONCLUSIONS In this TTT study, BIL treatment showed clinically relevant improvements in glycaemic control and a significant reduction in nocturnal hypoglycaemia compared to NPH.
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Affiliation(s)
- G Grunberger
- Grunberger Diabetes Institute, Bloomfield Hills, Michigan
| | - L Chen
- Eli Lilly and Company, Indianapolis, Indiana
| | | | | | - S J Jacober
- Eli Lilly and Company, Indianapolis, Indiana
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18
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Jacober SJ, Prince MJ, Beals JM, Hartman ML, Qu Y, Linnebjerg H, Garhyan P, Haupt A. Basal insulin peglispro: Overview of a novel long-acting insulin with reduced peripheral effect resulting in a hepato-preferential action. Diabetes Obes Metab 2016; 18 Suppl 2:3-16. [PMID: 27723228 DOI: 10.1111/dom.12744] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2016] [Accepted: 07/12/2016] [Indexed: 01/04/2023]
Abstract
Basal insulin peglispro (BIL) is a novel basal insulin with a flat, prolonged activity profile. BIL has been demonstrated in a dog model, in healthy men and in patients with type 1 diabetes (T1D) to have significant hepato-preferential action resulting from reduced peripheral activity. In the IMAGINE-Phase 3 clinical trial program, more than 6000 patients were included, of whom ~3900 received BIL. Of the 7 pivotal IMAGINE trials, 3 studies were double-blinded and 3 were in T1D patients. BIL consistently demonstrated a greater HbA1c reduction, less glycaemic variability and a clinically relevant reduction in the rates of nocturnal hypoglycaemia across comparator [glargine and isophane insulin (NPH)] studies. Trials using basal/bolus regimens had higher rates of total hypoglycaemia with BIL due to higher rates of daytime hypoglycaemia. Severe hypoglycaemia rates were similar to comparator among both patients with T1D or type 2 diabetes (T2D). T1D patients lost weight compared with glargine (GL). Patients with T2D tended to gain less weight with BIL than with glargine. Compared to glargine, BIL was associated with higher liver fat, triglycerides and alanine aminotransferase (ALT) levels, including a higher frequency of elevation of ALT ≥3 times the upper limit of normal, but without severe, acute drug-induced liver injury. Injection site reactions, primarily lipohypertrophy, were more frequent with BIL. In conclusion, BIL demonstrated better glycaemic control with reduced glucose variability and nocturnal hypoglycaemia but higher triglycerides, ALT and liver fat relative to conventional comparator insulin. The hepato-preferential action of BIL with reduced peripheral activity may account for these findings.
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Affiliation(s)
- S J Jacober
- Eli Lilly and Company, Indianapolis, Indiana.
| | - M J Prince
- Eli Lilly and Company, Indianapolis, Indiana
| | - J M Beals
- Eli Lilly and Company, Indianapolis, Indiana
| | - M L Hartman
- Eli Lilly and Company, Indianapolis, Indiana
| | - Y Qu
- Eli Lilly and Company, Indianapolis, Indiana
| | | | - P Garhyan
- Eli Lilly and Company, Indianapolis, Indiana
| | - A Haupt
- Eli Lilly and Company, Indianapolis, Indiana
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19
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Cusi K, Sanyal AJ, Zhang S, Hoogwerf BJ, Chang AM, Jacober SJ, Bue-Valleskey JM, Higdon AN, Bastyr EJ, Haupt A, Hartman ML. Different effects of basal insulin peglispro and insulin glargine on liver enzymes and liver fat content in patients with type 1 and type 2 diabetes. Diabetes Obes Metab 2016; 18 Suppl 2:50-58. [PMID: 27723227 DOI: 10.1111/dom.12751] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2016] [Accepted: 07/20/2016] [Indexed: 12/15/2022]
Abstract
AIMS To compare effects of basal insulin peglispro (BIL), a hepatopreferential insulin, to insulin glargine (glargine) on aminotransferases and liver fat content (LFC) in patients with type 1 and type 2 diabetes (T1D, T2D). MATERIALS AND METHODS Data from two Phase 2 and five Phase 3 randomized trials comparing BIL and glargine in 1709 T1D and 3662 T2D patients were integrated for analysis of liver laboratory tests. LFC, measured by magnetic resonance imaging (MRI) at baseline, 26 and 52 weeks, was analyzed in 182 T1D patients, 176 insulin-naïve T2D patients and 163 T2D patients previously treated with basal insulin. RESULTS Alanine aminotransferase (ALT) increased in patients treated with BIL, was higher than in glargine-treated patients at 4-78 weeks (difference at 52 weeks in both T1D and T2D: 7 international units/litre (IU/L), P < .001), and decreased after discontinuation of BIL. More BIL patients had ALT ≥3× upper limit of normal (ULN) than glargine. No patient had ALT ≥3× ULN with bilirubin ≥2× ULN that was considered causally related to BIL. In insulin-naїve T2D patients, LFC decreased with glargine but was unchanged with BIL. In T1D and T2D patients previously treated with basal insulin, LFC was unchanged with glargine but increased with BIL. In all three populations, LFC was higher after treatment with BIL vs glargine (difference at 52 weeks: 2.2% to 5.3%, all P < .01). CONCLUSIONS Compared to glargine, patients treated with BIL had higher ALT and LFC at 52-78 weeks. No severe drug-induced liver injury was apparent with BIL treatment for up to 78 weeks.
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Affiliation(s)
- K Cusi
- Division of Endocrinology, Diabetes and Metabolism, University of Florida College of Medicine, Gainesville, FL, USA
| | - A J Sanyal
- Division of Gastroenterology and Hepatology, Department of Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - S Zhang
- Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA
| | - B J Hoogwerf
- Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA
| | - A M Chang
- Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA
| | - S J Jacober
- Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA
| | - J M Bue-Valleskey
- Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA
| | - A N Higdon
- Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA
| | - E J Bastyr
- Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA
- Indiana University School of Medicine, Indianapolis, IN, USA
| | - A Haupt
- Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA
| | - M L Hartman
- Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA.
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20
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Mudaliar S, Henry RR, Ciaraldi TP, Armstrong DA, Burke PM, Pettus JH, Garhyan P, Choi SL, Knadler MP, Lam ECQ, Prince MJ, Bose N, Porksen NK, Sinha VP, Linnebjerg H, Jacober SJ. Reduced peripheral activity leading to hepato-preferential action of basal insulin peglispro compared with insulin glargine in patients with type 1 diabetes. Diabetes Obes Metab 2016; 18 Suppl 2:17-24. [PMID: 27723226 DOI: 10.1111/dom.12753] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2016] [Accepted: 07/27/2016] [Indexed: 01/05/2023]
Abstract
AIMS Basal insulin peglispro (BIL), a novel PEGylated basal insulin with a large hydrodynamic size, has a delayed absorption and reduced clearance that prolongs the duration of action. The current study compared the effects of BIL and insulin glargine (GL) on endogenous glucose production (EGP), glucose disposal rate (GDR) and lipolysis in patients with type 1 diabetes. MATERIALS AND METHODS This was a randomized, open-label, four-period, crossover study. Patients received intravenous infusions of BIL and GL, each at two dose levels selected for partial and maximal suppression of EGP, during an 8 to 10 h euglycemic clamp procedure with d-[3-3 H] glucose. RESULTS Following correction for equivalent human insulin concentrations (EHIC), low-dose GL infusion resulted in similar EGP at the end of the clamp compared to low-dose BIL infusion (GL/BIL ratio of 1.03) but a higher GDR (GL/BIL ratio of 2.42), indicating similar hepatic activity but attenuated peripheral activity of BIL. Consistent with this, the EHIC-corrected GDR/EGP at the end of the clamp was 1.72-fold greater for GL than BIL following low-dose administration. At the lower dose of BIL and GL (concentrations in the therapeutic range), BIL produced less suppression of lipolysis compared with GL as indicated by free fatty acid and glycerol levels at the end of the clamp. CONCLUSIONS Compared with GL, BIL restored the hepato-peripheral insulin action gradient seen in normal physiology via its peripherally restricted action on target tissues related to carbohydrate and lipid metabolism.
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Affiliation(s)
- S Mudaliar
- Veterans Affairs San Diego Healthcare System, San Diego, CA, USA
- Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, CA, USA
| | - R R Henry
- Veterans Affairs San Diego Healthcare System, San Diego, CA, USA
- Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, CA, USA
| | - T P Ciaraldi
- Veterans Affairs San Diego Healthcare System, San Diego, CA, USA
- Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, CA, USA
| | - D A Armstrong
- Veterans Affairs San Diego Healthcare System, San Diego, CA, USA
| | - P M Burke
- Veterans Affairs San Diego Healthcare System, San Diego, CA, USA
| | - J H Pettus
- Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, CA, USA
| | - P Garhyan
- Eli Lilly and Company, Indianapolis, IN, USA
| | - S L Choi
- Eli Lilly and Company, Singapore, Singapore
| | - M P Knadler
- Eli Lilly and Company, Indianapolis, IN, USA
| | - E C Q Lam
- Eli Lilly and Company, Singapore, Singapore
| | - M J Prince
- Eli Lilly and Company, Indianapolis, IN, USA
| | - N Bose
- Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, CA, USA
| | - N K Porksen
- Eli Lilly and Company, Indianapolis, IN, USA
| | - V P Sinha
- Eli Lilly and Company, Indianapolis, IN, USA
| | | | - S J Jacober
- Eli Lilly and Company, Indianapolis, IN, USA.
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21
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Garg S, Dreyer M, Jinnouchi H, Mou J, Qu Y, Hartman ML, Rosilio M, Jacober SJ, Bastyr EJ. A randomized clinical trial comparing basal insulin peglispro and insulin glargine, in combination with prandial insulin lispro, in patients with type 1 diabetes: IMAGINE 1. Diabetes Obes Metab 2016; 18 Suppl 2:25-33. [PMID: 27393697 DOI: 10.1111/dom.12738] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2016] [Accepted: 06/29/2016] [Indexed: 12/28/2022]
Abstract
AIMS The primary objective was to demonstrate that basal insulin peglispro (BIL) was non-inferior compared with insulin glargine (GL) for haemoglobin A1c (HbA1c) at 26 weeks with a non-inferiority margin of 0.4%. MATERIALS AND METHODS IMAGINE 1 was a Phase 3, open-label, parallel-arm study conducted in nine countries. Adults with type 1 diabetes (n = 455) were randomized (2:1) to bedtime BIL or GL in combination with prandial insulin lispro for 78 weeks, with a primary endpoint of 26 weeks. An electronic diary facilitated data capture and insulin dosing calculations for intensive insulin management. RESULTS At 26 weeks, mean HbA1c was 7.06% ± 0.04% and 7.43% ± 0.06% for patients assigned to BIL (N = 295) and GL (N = 160), respectively (difference -0.37% [95% CI: -0.50 to -0.23], P < .001); more patients on BIL achieved HbA1c <7% (44.9% vs 27.5%, P < .001). Compared with GL, patients using BIL lost weight, with lower fasting serum glucose and between-day fasting blood glucose variability, and 36% less nocturnal hypoglycemia, 29% more total hypoglycemia and more severe hypoglycemia. Total and prandial insulin doses were lower with BIL; basal insulin doses were higher. Alanine aminotransferase increased with BIL, with more patients having elevations ≥3 × ULN. BIL treatment was associated with more frequent injection site reactions and an increase from baseline in serum triglycerides. CONCLUSIONS In patients with type 1 diabetes, treatment with BIL compared to GL for 26 weeks was associated with lower HbA1c, less nocturnal hypoglycemia, lower glucose variability and weight loss. Increases in total and severe hypoglycemia, triglycerides, aminotransferases and injection site reactions were also noted.
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Affiliation(s)
- S Garg
- Barbara Davis Center for Diabetes, University of Colorado Health Sciences Center, Aurora, USA.
| | - M Dreyer
- Wuxi Mingci Cardiovascular Hospital, Wuxi, China
| | - H Jinnouchi
- Diabetes Care Center, Jinnouchi Hospital, Kumamoto, Japan
| | - J Mou
- Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA
| | - Y Qu
- Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA
| | - M L Hartman
- Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA
| | - M Rosilio
- Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA
| | - S J Jacober
- Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA
| | - E J Bastyr
- Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA
- Division of Endocrinology and Metabolism, Indiana University School of Medicine, Indianapolis, USA
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22
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Garg S, Selam JL, Bhargava A, Schloot N, Luo J, Zhang Q, Jacobson JG, Hoogwerf BJ. Similar HbA1c reduction and hypoglycaemia with variable- vs fixed-time dosing of basal insulin peglispro in type 1 diabetes: IMAGINE 7 study. Diabetes Obes Metab 2016; 18 Suppl 2:43-49. [PMID: 27393722 DOI: 10.1111/dom.12740] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Accepted: 07/03/2016] [Indexed: 11/26/2022]
Abstract
AIMS To compare 24-hour fixed-time basal insulin peglispro (BIL) dosing with 8- to 40-hour variable-time BIL dosing for glycaemic control and safety in patients with type 1 diabetes. Primary outcome was non-inferiority of BIL variable-time dosing compared with fixed-time dosing for glycated haemoglobin (HbA1c) change after 12-week treatment (margin = 0.4%). MATERIALS AND METHODS This Phase 3, open-label, randomized, cross-over study (N = 212) was conducted at 20 centres in the United States. During the 12-week lead-in phase, patients received BIL daily at fixed-times. Two 12-week randomized cross-over treatment phases followed, where patients received BIL dosed at either fixed- or variable-times. During the 4-week safety follow-up, patients received conventional insulins. RESULTS During the lead-in period, least-squares mean HbA1c decreased from 7.5% to 6.8%. For BIL, variable-time dosing was non-inferior to fixed-time dosing for HbA1c change [least-squares mean difference = 0.06%, 95% confidence interval (-0.01, 0.13)]. In both regimens, HbA1c increased slightly during the cross-over periods, but remained significantly below baseline. Variable- and fixed-time dosing regimens had similar rates of total hypoglycaemia (10.4 ± 0.62 and 10.5 ± 0.67 events/patient/30 days, P = .947) and nocturnal hypoglycaemia (1.3 ± 0.11 and 1.5 ± 0.13 events/patient/30days, P = .060). Comparable proportions of patients achieved HbA1c < 7.0% with variable- [91 (54.5%)] and fixed-time dosing [101 (60.5%)]. CONCLUSIONS Treatment with BIL allows patients to use flexible dosing intervals from 8 to 40 hours. Glycaemic efficacy (HbA1c), glycaemic variability and hypoglycaemia are similar to fixed-time dosing, suggesting that BIL could potentially provide flexibility in dosing for patients who miss their daily basal insulin.
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Affiliation(s)
- S Garg
- Barbara Davis Center for Diabetes, University of Colorado Denver, Aurora
| | - J-L Selam
- Diabetes Research Center, Tustin, California
| | - A Bhargava
- Iowa Diabetes and Endocrinology Research Center, Des Moines, Iowa
| | - N Schloot
- Lilly Deutschland GmbH, Bad Homburg, Germany
| | - J Luo
- Eli Lilly and Company, Indianapolis, Indiana
| | - Q Zhang
- Eli Lilly and Company, Indianapolis, Indiana
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23
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Pettus J, Santos Cavaiola T, Tamborlane WV, Edelman S. The past, present, and future of basal insulins. Diabetes Metab Res Rev 2016; 32:478-96. [PMID: 26509843 DOI: 10.1002/dmrr.2763] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2015] [Revised: 07/23/2015] [Accepted: 10/04/2015] [Indexed: 12/14/2022]
Abstract
Insulin production by the pancreas follows a basic pattern where basal levels of insulin are secreted during fasting periods, with prandial increases in insulin associated with food ingestion. The aim of insulin therapy in patients with diabetes is to match the endogenous pattern of insulin secretion as closely as possible without causing hypoglycaemia. There are several optimal pharmacokinetic and pharmacodynamic properties of long-acting basal insulins that can help to achieve this aim, namely, as follows: activity that is flat and as free of peaks as possible, a duration of action of ≥24-h, and as little day-to-day variation as possible. The long-acting basal insulins are a fundamental therapy for patients with type 1 and type 2 diabetes, and those that are currently available have many benefits; however, the development of even longer-acting insulins and improved insulin delivery techniques may lead to better glycemic control for patients in the future. Established long-acting basal insulins available in the United States and Europe include insulin glargine 100 units/mL and insulin detemir, both of which exhibit similar glycemic control to that of the intermediate-acting neutral protamine Hagedorn insulin, but with a reduction in hypoglycaemia. Newer insulin products available include new insulin glargine 300 units/mL (United States and Europe) and the ultra-long-acting insulin degludec (Europe) with basal insulin peglispro currently in development. These new insulins demonstrate different pharmacokinetic/pharmacodynamic profiles and longer durations of action (>24 h) compared with insulin glargine 100 units/mL, which may lead to potential benefits. The introduction of biosimilar insulins may also broaden access to insulins by reducing treatment costs. Copyright © 2015 John Wiley & Sons, Ltd.
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Affiliation(s)
- Jeremy Pettus
- Division of Endocrinology and Metabolism, University of California San Diego, San Diego, CA, USA
| | - Tricia Santos Cavaiola
- Division of Endocrinology and Metabolism, University of California San Diego, San Diego, CA, USA
| | | | - Steven Edelman
- Division of Endocrinology and Metabolism, University of California San Diego, San Diego, CA, USA
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24
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Affiliation(s)
- Eberhard Standl
- Munich Diabetes Research Group e.V. at the Munich Helmholtz Centre, Munich-Neuherberg, Germany
| | - David R Owen
- Diabetes Research Group, Institute of Life Sciences, College of Medicine, Swansea University, Swansea, Wales, U.K
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25
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Owens RA, Hansen RJ, Kahl SD, Zhang C, Ruan X, Koester A, Li S, Qian HR, Farmen MW, Michael MD, Moyers JS, Cutler GB, Vick A, Beals JM. In Vivo and In Vitro Characterization of Basal Insulin Peglispro: A Novel Insulin Analog. J Pharmacol Exp Ther 2016; 357:459-65. [PMID: 27026683 DOI: 10.1124/jpet.115.231035] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Accepted: 03/22/2016] [Indexed: 03/08/2025] Open
Abstract
The aim of this research was to characterize the in vivo and in vitro properties of basal insulin peglispro (BIL), a new basal insulin, wherein insulin lispro was derivatized through the covalent and site-specific attachment of a 20-kDa polyethylene-glycol (PEG; specifically, methoxy-terminated) moiety to lysine B28. Addition of the PEG moiety increased the hydrodynamic size of the insulin lispro molecule. Studies show there is a prolonged duration of action and a reduction in clearance. Given the different physical properties of BIL, it was also important to assess the metabolic and mitogenic activity of the molecule. Streptozotocin (STZ)-treated diabetic rats were used to study the pharmacokinetic and pharmacodynamic characteristics of BIL. Binding affinity and functional characterization of BIL were compared with those of several therapeutic insulins, insulin AspB10, and insulin-like growth factor 1 (IGF-1). BIL exhibited a markedly longer time to maximum concentration after subcutaneous injection, a greater area under the concentration-time curve, and a longer duration of action in the STZ-treated diabetic rat than insulin lispro. BIL exhibited reduced binding affinity and functional potency as compared with insulin lispro and demonstrated greater selectivity for the human insulin receptor (hIR) as compared with the human insulin-like growth factor 1 receptor. Furthermore, BIL showed a more rapid rate of dephosphorylation following maximal hIR stimulation, and reduced mitogenic potential in an IGF-1 receptor-dominant cellular model. PEGylation of insulin lispro with a 20-kDa PEG moiety at lysine B28 alters the absorption, clearance, distribution, and activity profile receptor, but does not alter its selectivity and full agonist receptor properties.
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Affiliation(s)
- Rebecca A Owens
- Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana
| | - Ryan J Hansen
- Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana
| | - Steven D Kahl
- Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana
| | - Chen Zhang
- Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana
| | - Xiaoping Ruan
- Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana
| | - Anja Koester
- Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana
| | - Shun Li
- Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana
| | - Hui-Rong Qian
- Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana
| | - Mark W Farmen
- Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana
| | - M Dodson Michael
- Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana
| | - Julie S Moyers
- Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana
| | - Gordon B Cutler
- Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana
| | - Andrew Vick
- Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana
| | - John M Beals
- Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana
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26
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Hoogwerf BJ, Lincoff AM, Rodriguez A, Chen L, Qu Y. Major adverse cardiovascular events with basal insulin peglispro versus comparator insulins in patients with type 1 or type 2 diabetes: a meta-analysis. Cardiovasc Diabetol 2016; 15:78. [PMID: 27188479 PMCID: PMC4869328 DOI: 10.1186/s12933-016-0393-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2016] [Accepted: 04/29/2016] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND To identify possible differences in cardiovascular (CV) risk among different insulin therapies, we performed pre-specified meta-analyses across the clinical program for basal insulin peglispro (BIL), in patients randomized to treatment with BIL or comparator insulin [glargine (IG) or NPH]. METHODS One phase 2 (12-week) and 6 phase 3 (26 to 78-week) randomized studies of BIL compared to IG or NPH, in patients with type 1 or type 2 diabetes, were included. The participants were diverse with respect to demographics, baseline glycemic control, and concomitant disease or medications, but treatment groups were comparable in each study. For any potential CV or neurovascular event, relevant medical information was provided to a blinded external clinical events committee (C5Research, Cleveland Clinic, Cleveland, OH, USA) for adjudication. Cox regression analysis was used to compare treatment groups. The primary endpoint was a composite of adjudicated MACE+ [CV death, myocardial infarction (MI), stroke, or hospitalization for unstable angina]. RESULTS The pooled population included 5862 patients in the safety evaluation, with randomization to BIL:IG:NPH of 3578:2072:212. Mean age was 54.1 years, 27 % had type 1 diabetes, 56 % were male, and 88 % were white. Baseline demographic and clinical characteristics, including use of statins or other lipid-lowering drugs, were comparable between BIL and comparators. A total of 83 patients experienced at least 1 MACE+ and 70 patients experienced at least 1 MACE (CV death, MI, or stroke). Overall, there were no treatment-associated differences in time to MACE+ [hazard ratio (HR) for BIL versus comparator insulin (95 % CI): 0.82 (0.53-1.27)] or MACE [0.83 (0.51-1.33)]. In 4297 patients with type 2 diabetes, there were 71 MACE+ events [HR: 1.02 (95 % CI: 0.63-1.65), p = 0.94]. In 1565 patients with type 1 diabetes, there were only 12 MACE+ [0.24 (0.07-0.85), p = 0.027]. There were no differences in all-cause death between BIL and comparators. Sub-group analyses did not identify any sub-population with increased risk with BIL versus comparator insulins. CONCLUSIONS Treatment with BIL versus comparator insulin in patients with type 1 diabetes or type 2 diabetes was not associated with increased risk for major CV events in the studies analyzed.
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Affiliation(s)
- Byron J. Hoogwerf
- />Lilly Corporate Center, Eli Lilly and Company, Drop Code 2240, Indianapolis, IN 46285 USA
| | - A. Michael Lincoff
- />Cleveland Clinic Coordinating Center for Clinical Research (C5 Research), Cleveland Clinic, Cleveland, OH USA
| | | | - Lei Chen
- />Lilly Corporate Center, Eli Lilly and Company, Drop Code 2240, Indianapolis, IN 46285 USA
| | - Yongming Qu
- />Lilly Corporate Center, Eli Lilly and Company, Drop Code 2240, Indianapolis, IN 46285 USA
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27
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Abstract
Insulin remains indispensable in the treatment of diabetes, but its use is hampered by its narrow therapeutic index. Although advances in peptide chemistry and recombinant DNA-based macromolecule synthesis have enabled the synthesis of structurally optimized insulin analogues, the growing epidemics of obesity and diabetes have emphasized the need for diabetes therapies that are more efficacious, safe and convenient. Accordingly, a broad set of drug candidates, targeting hyperglycaemia plus other disease abnormalities, is now progressing through the clinic. The development of an insulin therapy that is responsive to glucose concentration remains an ultimate goal, with initial prototypes now reaching the proof-of-concept stage. Simultaneously, the first alternatives to injectable delivery have progressed to registration.
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28
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Rosenstock J, Blevins TC, Bergenstal RM, Morrow LA, Qu Y, Jacober SJ. Reduction in short-acting insulin requirement accompanies improved glycemic control with basal insulin peglispro compared with insulin glargine in patients with type 1 diabetes. J Diabetes 2016; 8:166-9. [PMID: 26278063 DOI: 10.1111/1753-0407.12332] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2015] [Revised: 06/25/2015] [Accepted: 08/01/2015] [Indexed: 11/30/2022] Open
Affiliation(s)
- Julio Rosenstock
- Dallas Diabetes and Endocrine Center at Medical City, Dallas, Texas
| | | | | | - Linda A Morrow
- Profil Institute for Clinical Research Inc., Chula Vista, California
| | - Yongming Qu
- Lilly Diabetes, Eli Lilly and Company, Indianapolis, Indiana, USA
| | - Scott J Jacober
- Lilly Diabetes, Eli Lilly and Company, Indianapolis, Indiana, USA
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29
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Gilroy CA, Luginbuhl KM, Chilkoti A. Controlled release of biologics for the treatment of type 2 diabetes. J Control Release 2015; 240:151-164. [PMID: 26655062 DOI: 10.1016/j.jconrel.2015.12.002] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2015] [Revised: 11/28/2015] [Accepted: 12/01/2015] [Indexed: 12/25/2022]
Abstract
Type 2 diabetes is a rapidly growing disease that poses a significant burden to the United States healthcare system. Despite the many available treatments for the disease, close to half of diagnosed type 2 diabetes cases are not properly managed, largely due to inadequate patient adherence to prescribed treatment regimens. Methods for improving delivery - and thereby easing administration - of type 2 drugs have the potential to greatly improve patient health. This review focuses on two peptide drugs - insulin and glucagon-like peptide 1 (GLP-1) - for treatment of type 2 diabetes. Peptide drugs offer the benefits of high potency and specificity but pose a significant delivery challenge due to their inherent instability and short half-life. The development of insulin and GLP-1 analogs highlights the broad spectrum of drug delivery strategies that have been used to solve these problems. Numerous structural modifications and formulations have been introduced to optimize absorption, residence time, stability, route of delivery and frequency of administration. Continual improvements in delivery methods for insulin and GLP-1 receptor agonists are paving the way towards better patient compliance and improved disease management, and thereby enhanced patient quality of life.
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Affiliation(s)
- Caslin A Gilroy
- Department of Biomedical Engineering, 136 Hudson Hall, Box 90281, Duke University, Durham, NC 27708, USA
| | - Kelli M Luginbuhl
- Department of Biomedical Engineering, 136 Hudson Hall, Box 90281, Duke University, Durham, NC 27708, USA
| | - Ashutosh Chilkoti
- Department of Biomedical Engineering, 136 Hudson Hall, Box 90281, Duke University, Durham, NC 27708, USA
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30
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Home PD. Plasma insulin profiles after subcutaneous injection: how close can we get to physiology in people with diabetes? Diabetes Obes Metab 2015; 17:1011-20. [PMID: 26041603 PMCID: PMC4744667 DOI: 10.1111/dom.12501] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2015] [Revised: 05/28/2015] [Accepted: 06/01/2015] [Indexed: 12/29/2022]
Abstract
Many people with diabetes rely on insulin therapy to achieve optimal blood glucose control. A fundamental aim of such therapy is to mimic the pattern of 'normal' physiological insulin secretion, thereby controlling basal and meal-time plasma glucose and fatty acid turnover. In people without diabetes, insulin release is modulated on a time base of 3-10 min, something that is impossible to replicate without intravascular glucose sensing and insulin delivery. Overnight physiological insulin delivery by islet β cells is unchanging, in contrast to requirements once any degree of hyperglycaemia occurs, when diurnal influences are evident. Subcutaneous pumped insulin or injected insulin analogues can approach the physiological profile, but there remains the challenge of responding to day-to-day changes in insulin sensitivity. Physiologically, meal-time insulin release begins rapidly in response to reflex activity and incretins, continuing with the rise in glucose and amino acid concentrations. This rapid response reflects the need to fill the insulin space with maximum concentration as early as 30 min after starting the meal. Current meal-time insulins, by contrast, are associated with a delay after injection before absorption begins, and a delay to peak because of tissue diffusion. While decay from peak for monomeric analogues is not dissimilar to average physiological needs, changes in meal type and, again, in day-to-day insulin sensitivity, are difficult to match. Recent and current developments in insulin depot technology are moving towards establishing flatter basal and closer-to-average physiological meal-time plasma insulin profiles. The present article discusses the ideal physiological insulin profile, how this can be met by available and future insulin therapies and devices, and the challenges faced by healthcare professionals and people with diabetes in trying to achieve an optimum plasma insulin profile.
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Affiliation(s)
- P D Home
- Institute for Cellular Medicine-Diabetes, Newcastle University, Newcastle upon Tyne, UK
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31
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Knadler MP, Ellis BB, Brown-Augsburger PL, Murphy AT, Martin JA, Wroblewski VJ. Disposition of Basal Insulin Peglispro Compared with 20-kDa Polyethylene Glycol in Rats Following a Single Intravenous or Subcutaneous Dose. Drug Metab Dispos 2015; 43:1477-83. [PMID: 26175543 DOI: 10.1124/dmd.115.064337] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2015] [Accepted: 07/14/2015] [Indexed: 02/13/2025] Open
Abstract
Basal insulin peglispro (BIL) comprises insulin lispro covalently bound to a 20-kDa polyethylene glycol (PEG) at lysine B28. The biologic fate of BIL and unconjugated PEG were examined in rats given a single 0.5-mg/kg i.v. or 2-mg/kg s.c. dose of BIL with (14)C label in 20-kDa PEG or (125)I label in lispro. Unconjugated (14)C-labeled 20-kDa PEG was dosed at 10 mg/kg i.v. or s.c. Blood, urine, and feces were collected up to 336 hours after dosing. Radioactivity was measured by scintillation spectrometry, and BIL was quantitated by enzyme-linked immunosorbent assay. Area under the curve and half-life for immunoreactive BIL were lower than those for both (14)C and (125)I after subcutaneous and intravenous administration. The half-lives of (14)C after BIL and PEG dosing were similar. The clearance of immunoreactive BIL was 2.4-fold faster than that of (14)C and 1.6-fold faster than (125)I. After a subcutaneous dose of BIL, immunoreactive BIL accounted for 31% of the circulating (125)I and 16% of the circulating (14)C, indicating extensive catabolism of BIL. Subcutaneous bioavailability of BIL was 23%-29%; bioavailability for unconjugated PEG was 78%. For unconjugated PEG, most of the (14)C dose was recovered in urine. For BIL, ≥86% of (125)I was eliminated in urine and (14)C was eliminated about equally in urine and feces. The major (14)C-labeled catabolism product of BIL in urine was 20-kDa PEG with lysine attached. The attachment of 20-kDa PEG to lispro in BIL led to a different elimination pathway for PEG compared with unconjugated 20-kDa PEG.
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Affiliation(s)
- Mary Pat Knadler
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana
| | - Bernice B Ellis
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana
| | | | - Anthony T Murphy
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana
| | - Jennifer A Martin
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana
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32
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Nuevas insulinas en la diabetes tipo 1. Med Clin (Barc) 2015; 145:70-5. [DOI: 10.1016/j.medcli.2014.04.024] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2014] [Accepted: 04/10/2014] [Indexed: 11/16/2022]
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33
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Røder ME. PEGylated insulin Lispro (LY2605541): clinical overview of a new long-acting basal insulin analog in the treatment of Type 2 diabetes mellitus. Expert Rev Endocrinol Metab 2015; 10:365-374. [PMID: 30293492 DOI: 10.1586/17446651.2015.1043270] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Neutral Protamine Hagedorn insulin with an intermediate action profile has been in use for many years for the treatment of Type 1 diabetes and as an option for Type 2 diabetes. It is efficacious in reducing blood sugars, but shows substantial variability and risk of hypoglycemia. Basal insulin analogs have been developed in recent years to overcome these issues. Three basal insulin analogs are currently in the market in Europe. PEGylated insulin lispro is a new second-generation basal insulin analog which most likely will undergo review in 2016 by the US FDA and EMA in Europe for possible approval for marketing. Phase III trials are finalized, but not yet published. Phase II studies suggest antiglycemic efficacy, possible with a preferential hepato-specific action, a low rate of hypoglycemia, minor weight loss and acceptable tolerability. The benefit-risk profile needs, however, to be established.
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Affiliation(s)
- Michael E Røder
- a Center for Diabetes Research, Department of Medicine F, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
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Abstract
Insulin has classically been considered a treatment of last resort for individuals with type 2 diabetes, delayed until all other efforts by the patient and healthcare provider have failed. Recent treatment guidelines recommend the use of insulin, in particular basal insulin, as part of a treatment regimen earlier in the disease process. Many patients are reticent about initiating insulin, so therapies that allow insulin treatment to be more tailored to individual needs are likely to result in greater acceptance and patient adherence with therapy. To meet this need, a range of insulin products are in development that aim to increase absorption rate or prolong the duration of action, reduce peak variability and weight gain associated with insulin treatment, and offer alternative delivery methods. This review describes insulin products in clinical development, new combination therapies, and new devices for insulin delivery.
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Affiliation(s)
- Christopher Sorli
- Department of Diabetes, Endocrinology and Metabolism, Billings Clinic, Billings, Mont.
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