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      The Evolution of Insulin Glargine and its Continuing Contribution to Diabetes Care

      review-article
      Author(s): , , ,
      Publication date (Electronic):
      Journal: Drugs
      Publisher: Springer International Publishing

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          Abstract

          The epoch-making discovery of insulin heralded a new dawn in the management of diabetes. However, the earliest, unmodified soluble insulin preparations were limited by their short duration of action, necessitating multiple daily injections. Initial attempts to protract the duration of action of insulin involved the use of various additives, including vasoconstrictor substances, which met with limited success. The subsequent elucidation of the chemical and three-dimensional structure of insulin and its chemical synthesis and biosynthesis allowed modification of the insulin molecule itself, resulting in insulin analogs that are designed to mimic normal endogenous insulin secretion during both fasting and prandial conditions. Insulin glargine was the first once-daily, long-acting insulin analog to be introduced into clinical practice more than 10 years ago and is specifically designed to provide basal insulin requirements. It has a prolonged duration of action and no distinct insulin peak, making it suitable for once-daily administration and reducing the risk of nocturnal hypoglycemia that is seen with intermediate-acting insulins. Insulin glargine can be used in combination with prandial insulin preparations and non-insulin anti-diabetic agents according to individual requirements.

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          The online version of this article (doi:10.1007/s40265-014-0226-4) contains supplementary material, which is available to authorized users.

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          GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus.

          Juris Meier (2012)
          In healthy humans, the incretin glucagon-like peptide 1 (GLP-1) is secreted after eating and lowers glucose concentrations by augmenting insulin secretion and suppressing glucagon release. Additional effects of GLP-1 include retardation of gastric emptying, suppression of appetite and, potentially, inhibition of β-cell apoptosis. Native GLP-1 is degraded within ~2-3 min in the circulation; various GLP-1 receptor agonists have, therefore, been developed to provide prolonged in vivo actions. These GLP-1 receptor agonists can be categorized as either short-acting compounds, which provide short-lived receptor activation (such as exenatide and lixisenatide) or as long-acting compounds (for example albiglutide, dulaglutide, exenatide long-acting release, and liraglutide), which activate the GLP-1 receptor continuously at their recommended dose. The pharmacokinetic differences between these drugs lead to important differences in their pharmacodynamic profiles. The short-acting GLP-1 receptor agonists primarily lower postprandial blood glucose levels through inhibition of gastric emptying, whereas the long-acting compounds have a stronger effect on fasting glucose levels, which is mediated predominantly through their insulinotropic and glucagonostatic actions. The adverse effect profiles of these compounds also differ. The individual properties of the various GLP-1 receptor agonists might enable incretin-based treatment of type 2 diabetes mellitus to be tailored to the needs of each patient.
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            The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients.

            Matthew C Riddle, Julio Rosenstock, John Gerich (2003)
            To compare the abilities and associated hypoglycemia risks of insulin glargine and human NPH insulin added to oral therapy of type 2 diabetes to achieve 7% HbA(1c). In a randomized, open-label, parallel, 24-week multicenter trial, 756 overweight men and women with inadequate glycemic control (HbA(1c) >7.5%) on one or two oral agents continued prestudy oral agents and received bedtime glargine or NPH once daily, titrated using a simple algorithm seeking a target fasting plasma glucose (FPG)
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              Pharmacokinetics and pharmacodynamics of subcutaneous injection of long-acting human insulin analog glargine, NPH insulin, and ultralente human insulin and continuous subcutaneous infusion of insulin lispro.

              M Lepore, S Pampanelli, C Fanelli … (2000)
              To compare the pharmacokinetics/dynamics of the long-acting insulin analog glargine with NPH, ultralente, and continuous subcutaneous (SC) infusion of insulin lispro (continuous subcutaneous insulin infusion [CSII]), 20 C-peptide-negative type 1 diabetic patients were studied on four occasions during an isoglycemic 24-h clamp. Patients received SC injection of either 0.3 U/kg glargine or NPH insulin (random sequence, crossover design). On two subsequent occasions, they received either an SC injection of ultralente (0.3 U/kg) or CSII (0.3 U x kg(-1) x 24 h(-1)) (random sequence, crossover design). After SC insulin injection or CSII, intravenous (IV) insulin was tapered, and glucose was infused to clamp plasma glucose at 130 mg/dl for 24 h. Onset of action (defined as reduction of IV insulin >50%) was earlier with NPH (0.8 +/- 0.2 h), CSII (0.5 +/- 0.1 h), and ultralente (1 +/- 0.2 h) versus glargine (1.5 +/- 0.3 h) (P 150 mg/dl) occurred later with glargine (22 +/- 4 h) than with NPH (14 +/- 3 h) (P < 0.05) but was similar with ultralente (20 +/- 6 h). NPH and ultralente exhibited a peak concentration and action (at 4.5 +/- 0.5 and 10.1 +/- 1 h, respectively) followed by waning, whereas glargine had no peak but had a flat concentration/action profile mimicking CSII. Interindividual variability (calculated as differences in SD of plasma insulin concentrations and glucose infusion rates in different treatments) was lower with glargine than with NPH and ultralente (P < 0.05) but was similar with glargine and CSII (NS). In conclusion, NPH and ultralente are both peak insulins. Duration of action of ultralente is greater, but intersubject variability is also greater than that of NPH. Glargine is a peakless insulin, it lasts nearly 24 h, it has lower intersubject variability than NPH and ultralente, and it closely mimics CSII, the gold standard of basal insulin replacement.
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                Author and article information

                Contributors
                Rolf Hilgenfeld: +49 451 500 4060 , hilgenfeld@biochem.uni-luebeck.de
                Journal
                Journal ID (nlm-ta): Drugs
                Journal ID (iso-abbrev): Drugs
                Title: Drugs
                Publisher: Springer International Publishing (Cham )
                ISSN (Print): 0012-6667
                ISSN (Electronic): 1179-1950
                Publication date (Electronic): 28 May 2014
                Publication date PMC-release: 28 May 2014
                Publication date (Print): 2014
                Volume: 74
                Pages: 911-927
                Affiliations
                [ ]Institute of Biochemistry, Center for Structural and Cell Biology in Medicine and Center for Brain, Behavior and Metabolism, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany
                [ ]Shanghai Institute of Materia Medica, Shanghai, China
                [ ]Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, Germany
                [ ]Diabetes Research Group, Institute of Life Sciences College of Medicine, Swansea University, Swansea, Wales
                Article
                Publisher ID: 226
                DOI: 10.1007/s40265-014-0226-4
                PMC ID: 4045187
                PubMed ID: 24866023
                SO-VID: d4000d33-e011-4362-8e20-52c6245ee733
                Copyright © © The Author(s) 2014
                License:

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.

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                Subject: Review Article
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                issue-copyright-statement © Springer International Publishing Switzerland 2014

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