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      Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

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          Abstract

          The cardiovascular effect of liraglutide, a glucagon-like peptide 1 analogue, when added to standard care in patients with type 2 diabetes, remains unknown.

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          Most cited references 12

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          Glucagon-like Peptide-1 receptor agonists activate rodent thyroid C-cells causing calcitonin release and C-cell proliferation.

          Liraglutide is a glucagon-like peptide-1 (GLP-1) analog developed for type 2 diabetes. Long-term liraglutide exposure in rodents was associated with thyroid C-cell hyperplasia and tumors. Here, we report data supporting a GLP-1 receptor-mediated mechanism for these changes in rodents. The GLP-1 receptor was localized to rodent C-cells. GLP-1 receptor agonists stimulated calcitonin release, up-regulation of calcitonin gene expression, and subsequently C-cell hyperplasia in rats and, to a lesser extent, in mice. In contrast, humans and/or cynomolgus monkeys had low GLP-1 receptor expression in thyroid C-cells, and GLP-1 receptor agonists did not activate adenylate cyclase or generate calcitonin release in primates. Moreover, 20 months of liraglutide treatment (at >60 times human exposure levels) did not lead to C-cell hyperplasia in monkeys. Mean calcitonin levels in patients exposed to liraglutide for 2 yr remained at the lower end of the normal range, and there was no difference in the proportion of patients with calcitonin levels increasing above the clinically relevant cutoff level of 20 pg/ml. Our findings delineate important species-specific differences in GLP-1 receptor expression and action in the thyroid. Nevertheless, the long-term consequences of sustained GLP-1 receptor activation in the human thyroid remain unknown and merit further investigation.
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            Incretin therapies: highlighting common features and differences in the modes of action of glucagon‐like peptide‐1 receptor agonists and dipeptidyl peptidase‐4 inhibitors

             M. Nauck (2016)
            Over the last few years, incretin‐based therapies have emerged as important agents in the treatment of type 2 diabetes (T2D). These agents exert their effect via the incretin system, specifically targeting the receptor for the incretin hormone glucagon‐like peptide 1 (GLP‐1), which is partly responsible for augmenting glucose‐dependent insulin secretion in response to nutrient intake (the ‘incretin effect’). In patients with T2D, pharmacological doses/concentrations of GLP‐1 can compensate for the inability of diabetic β cells to respond to the main incretin hormone glucose‐dependent insulinotropic polypeptide, and this is therefore a suitable parent compound for incretin‐based glucose‐lowering medications. Two classes of incretin‐based therapies are available: GLP‐1 receptor agonists (GLP‐1RAs) and dipeptidyl peptidase‐4 (DPP‐4) inhibitors. GLP‐1RAs promote GLP‐1 receptor (GLP‐1R) signalling by providing GLP‐1R stimulation through ‘incretin mimetics’ circulating at pharmacological concentrations, whereas DPP‐4 inhibitors prevent the degradation of endogenously released GLP‐1. Both agents produce reductions in plasma glucose and, as a result of their glucose‐dependent mode of action, this is associated with low rates of hypoglycaemia; however, there are distinct modes of action resulting in differing efficacy and tolerability profiles. Furthermore, as their actions are not restricted to stimulating insulin secretion, these agents have also been associated with additional non‐glycaemic benefits such as weight loss, improvements in β‐cell function and cardiovascular risk markers. These attributes have made incretin therapies attractive treatments for the management of T2D and have presented physicians with an opportunity to tailor treatment plans. This review endeavours to outline the commonalities and differences among incretin‐based therapies and to provide guidance regarding agents most suitable for treating T2D in individual patients.
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              Cardiovascular actions of incretin-based therapies.

              Glucagon-like peptide-1 receptor (GLP-1R) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors represent 2 distinct classes of incretin-based therapies used for the treatment of type 2 diabetes mellitus. Activation of GLP-1R signaling or inhibition of DPP-4 activity produces a broad range of overlapping and unique cardiovascular actions. Native GLP-1 regulates cardiovascular biology via activation of the classical GLP-1R, or through GLP-1(9-36), a cardioactive metabolite generated by DPP-4-mediated cleavage. In contrast, clinically approved GLP-1R agonists are not cleaved to GLP-1(9-36) and produce the majority of their actions through the classical GLP-1R. The cardiovascular mechanisms engaged by DPP-4 inhibition are more complex, encompassing increased levels of intact GLP-1, reduced levels of GLP-1(9-36), and changes in levels of numerous cardioactive peptides. Herein we review recent experimental and clinical advances that reveal how GLP-1R agonists and DPP-4 inhibitors affect the normal and diabetic heart and coronary vasculature, often independent of changes in blood glucose. Improved understanding of the complex science of incretin-based therapies is required to optimize the selection of these therapeutic agents for the treatment of diabetic patients with cardiovascular disease. © 2014 American Heart Association, Inc.
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                Author and article information

                Journal
                New England Journal of Medicine
                N Engl J Med
                Massachusetts Medical Society
                0028-4793
                1533-4406
                July 28 2016
                July 28 2016
                : 375
                : 4
                : 311-322
                Article
                10.1056/NEJMoa1603827
                27295427
                © 2016
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