Lixisenatide, a novel GLP-1 receptor agonist for the treatment of T2D mellitus

Amager Hospital, Department of Internal Medicine, University of Copenhagen, Denmark.
IDrugs: the investigational drugs journal (Impact Factor: 2.33). 09/2009; 12(8):503-13.
Source: PubMed


Lixisenatide, under development by sanofi-aventis, is a novel human glucagon-like peptide-1 receptor (GLP-1R) agonist for the treatment of type 2 diabetes mellitus (T2DM; non-insulin dependent diabetes). The structure of lixisenatide, based on exendin-4(1-39) modified C-terminally with six Lys residues, is able to withstand physiological degradation by dipeptidyl peptidase IV. In vitro, lixisenatide bound to human GLP-1R with a greater affinity than native human GLP-1 (7-36 amide). In various in vitro and in vivo models of T2DM, lixisenatide improved glycemic measures and demonstrated promising pancreatic beta-cell-preserving actions. In patients with T2DM, subcutaneously administered lixisenatide displayed linear pharmacokinetics. In two phase II clinical trials, lixisenatide improved glucose tolerance, resulted in weight loss and lowered HbA1C, thereby causing significantly more patients to achieve target HbA1C levels compared with placebo. Lixisenatide exhibited well-established GLP-1-related gastrointestinal side effects, with mild nausea occurring most frequently; a low frequency of hypoglycemia was also reported. The results of phase III trials are awaited for confirmation of the anticipated effects of lixisenatide on glycemic measures and weight; favorable results would place lixisenatide for consideration among other GLP-1R agonists in the treatment armamentarium for T2DM.

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    • "Amongst the novel GLP-1R agonists, lixisenatide and albiglutide are currently undergoing phase III clinical trials. Lixisenatide is based on exendin-4 (1–39) molecule and has a modified C-terminal with six additional lysine residues that confers a fourfold higher affinity to the GLP-1R than the human GLP-1, together with a half-life of about 3 h (139, 140). Similar to liraglutide, lixisenatide also crosses the BBB into CNS, whereby it has been shown to exert strong neurogenic effects in an AD rodent model (124, 141) (Figure 1), as well as to prevent Aβ-related impaired synaptic plasticity, hippocampal LTP, and spatial learning memory in a PI3K/Akt/GSK-3β-mediated pathway (142). "
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    ABSTRACT: Type 2 diabetes (T2D) and Alzheimer disease (AD) are two major health issues nowadays. T2D is an ever increasing epidemic, affecting millions of elderly people worldwide, with major repercussions in the patients' daily life. This is mostly due to its chronic complications that may affect brain and constitutes a risk factor for AD. T2D principal hallmark is insulin resistance which also occurs in AD, rendering both pathologies more than mere unrelated diseases. This hypothesis has been reinforced in the recent years, with a high number of studies highlighting the existence of several common molecular links. As such, it is not surprising that AD has been considered as the "type 3 diabetes" or a "brain-specific T2D," supporting the idea that a beneficial therapeutic strategy against T2D might be also beneficial against AD. Herewith, we aim to review some of the recent developments on the common features between T2D and AD, namely on insulin signaling and its participation in the regulation of amyloid β (Aβ) plaque and neurofibrillary tangle formation (the two major neuropathological hallmarks of AD). We also critically analyze the promising field that some anti-T2D drugs may protect against dementia and AD, with a special emphasis on the novel incretin/glucagon-like peptide-1 receptor agonists.
    Frontiers in Endocrinology 07/2014; 5:110. DOI:10.3389/fendo.2014.00110
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    • "Additionally, endogenous expression of Glp-1 in murine models of streptozotocin (STZ)induced diabetes has been shown to prevent hyperglycemia and to improve β-cell survival [75] [76] [77]. Clinical trials targeting the GLP-1 pathway by the administration of Lixisenatide have reported encouraging data in terms of novel therapeutic approaches for T2DM, however, if GLP-1 contributes to β-cell regeneration in humans remains to be clarified [78] [79] [80]. Years of research indicate that β-cells retain the capacity to undergo dynamic changes to compensate for both physiological (pregnancy) and pathological (e.g. "
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    Molecular Metabolism 06/2014; 3(3):268-274. DOI:10.1016/j.molmet.2014.01.010
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    • "Les données sont similaires avec la sitagliptine. Pour les analogues du GLP-1 la baisse d'HbA1c peut être très importante, À1,5 à À2 %, chez certains patients très hyperglycémiques au départ (HbA1c > 8,5 à > 10 %) et en fort surpoids (IMC > 35 kg/m 2 ), donc en l'absence de signe de carence insulinique marquée [24] [25] [26] [27]. "
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