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      Lixisenatide as add-on therapy to basal insulin

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          Abstract

          Many patients with type 2 diabetes mellitus do not achieve target glycosylated hemoglobin A 1c levels despite optimally titrated basal insulin and satisfactory fasting plasma glucose levels. Current evidence suggests that HbA 1c levels are dictated by both basal glucose and postprandial glucose levels. This has led to a consensus that postprandial glucose excursions contribute to poor glycemic control in these patients. Lixisenatide is a once-daily, prandial glucagon-like peptide 1 (GLP-1) receptor agonist with a four-fold affinity for the GLP-1 receptor compared with native GLP-1. Importantly, lixisenatide causes a significant delay in gastric emptying time, an important determinant of the once-daily dosing regimen. An exendin-4 mimetic with six lysine residues removed at the C-terminal, lixisenatide has pronounced postprandial glucose-lowering effects, making it a novel incretin agent for use in combination with optimally titrated basal insulin. Lixisenatide exerts profound effects on postprandial glucose through established mechanisms of glucose-dependent insulin secretion and glucagon suppression in combination with delayed gastric emptying. This review discusses the likely place that lixisenatide will occupy in clinical practice, given its profound effects on postprandial glucose and potential to reduce glycemic variability.

          Most cited references70

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

          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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            Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients: variations with increasing levels of HbA(1c).

            The exact contributions of postprandial and fasting glucose increments to overall hyperglycemia remain controversial. The discrepancies between the data published previously might be caused by the interference of several factors. To test the effect of overall glycemic control itself, we analyzed the diurnal glycemic profiles of type 2 diabetic patients investigated at different levels of HbA(1c). In 290 non-insulin- and non-acarbose-using patients with type 2 diabetes, plasma glucose (PG) concentrations were determined at fasting (8:00 A.M.) and during postprandial and postabsorptive periods (at 11:00 A.M., 2:00 P.M., and 5:00 P.M.). The areas under the curve above fasting PG concentrations (AUC(1)) and >6.1 mmol/l (AUC(2)) were calculated for further evaluation of the relative contributions of postprandial (AUC(1)/AUC(2), %) and fasting [(AUC(2) - AUC(1))/AUC(2), %] PG increments to the overall diurnal hyperglycemia. The data were compared over quintiles of HbA(1c). The relative contribution of postprandial glucose decreased progressively from the lowest (69.7%) to the highest quintile of HbA(1c) (30.5%, P < 0.001), whereas the relative contribution of fasting glucose increased gradually with increasing levels of HbA(1c): 30.3% in the lowest vs. 69.5% in the highest quintile (P < 0.001). The relative contribution of postprandial glucose excursions is predominant in fairly controlled patients, whereas the contribution of fasting hyperglycemia increases gradually with diabetes worsening. These results could therefore provide a unifying explanation for the discrepancies as observed in previous studies.
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              Effect of glycemic exposure on the risk of microvascular complications in the diabetes control and complications trial--revisited.

              The Diabetes Control and Complications Trial (Diabetes 44:968-983, 1995) presented statistical models suggesting that subjects with similar A1C levels had a higher risk of retinopathy progression in the conventional treatment group than in the intensive treatment group. That analysis has been cited to support the hypothesis that specific patterns of glucose variation, in particular postprandial hyperglycemia, contribute uniquely to an increased risk of microvascular complications above and beyond that explained by the A1C level. We performed statistical evaluations of these models and additional analyses to assess whether the original analyses were flawed. Statistically, we show that the original results are an artifact of the assumptions of the statistical model used. Additional analyses show that virtually all (96%) of the beneficial effect of intensive versus conventional therapy on progression of retinopathy is explained by the reductions in the mean A1C levels, similarly for other outcomes. Furthermore, subjects within the intensive and conventional treatment groups with similar A1C levels over time have similar risks of retinopathy progression, especially after adjusting for factors in which they differ. A1C explains virtually all of the difference in risk of complications between the intensive and conventional groups, and a given A1C level has similar effects within the two treatment groups. While other components of hyperglycemia, such as glucose variation, may contribute to the risk of complications, such factors can only explain a small part of the differences in risk between intensive and conventional therapy over time.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2014
                13 December 2013
                : 8
                : 25-38
                Affiliations
                Diabetes Department, University Hospital Llandough, Cardiff, UK
                Author notes
                Correspondence: Dominique Xavier Brown, Diabetes Department, University Hospital Llandough, Cardiff, CF64 2XX, UK, Tel +44 29 2115 5725, Email browndx@ 123456cf.ac.uk
                Article
                dddt-8-025
                10.2147/DDDT.S45108
                3865973
                24363554
                a495beda-4b26-490e-9be7-9616413468b9
                © 2014 Brown et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                History
                Categories
                Review

                Pharmacology & Pharmaceutical medicine
                add-on therapy,insulin,glp-1 receptor agonist,lixisenatide,postprandial glucose,pharmacodynamics

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