The Discovery and Development of Liraglutide and Semaglutide

The discovery of glucagon-like peptide-1 (GLP-1), an incretin hormone with important effects on glycemic control and body weight regulation, led to efforts to extend its half-life and make it therapeutically effective in people with type 2 diabetes (T2D). The development of short- and then long-acting GLP-1 receptor agonists (GLP-1RAs) followed. Our article charts the discovery and development of the long-acting GLP-1 analogs liraglutide and, subsequently, semaglutide. We examine the chemistry employed in designing liraglutide and semaglutide, the human and non-human studies used to investigate their cellular targets and pharmacological effects, and ongoing investigations into new applications and formulations of these drugs. Reversible binding to albumin was used for the systemic protraction of liraglutide and semaglutide, with optimal fatty acid and linker combinations identified to maximize albumin binding while maintaining GLP-1 receptor (GLP-1R) potency. GLP-1RAs mediate their effects via this receptor, which is expressed in the pancreas, gastrointestinal tract, heart, lungs, kidneys, and brain. GLP-1Rs in the pancreas and brain have been shown to account for the respective improvements in glycemic control and body weight that are evident with liraglutide and semaglutide. Both liraglutide and semaglutide also positively affect cardiovascular (CV) outcomes in individuals with T2D, although the precise mechanism is still being explored. Significant weight loss, through an effect to reduce energy intake, led to the approval of liraglutide (3.0 mg) for the treatment of obesity, an indication currently under investigation with semaglutide. Other ongoing investigations with semaglutide include the treatment of non-alcoholic fatty liver disease (NASH) and its use in an oral formulation for the treatment of T2D. In summary, rational design has led to the development of two long-acting GLP-1 analogs, liraglutide and semaglutide, that have made a vast contribution to the management of T2D in terms of improvements in glycemic control, body weight, blood pressure, lipids, beta-cell function, and CV outcomes. Furthermore, the development of an oral formulation for semaglutide may provide individuals with additional benefits in relation to treatment adherence. In addition to T2D, liraglutide is used in the treatment of obesity, while semaglutide is currently under investigation for use in obesity and NASH

Hvad vil der være tilbage til fremtiden? – virksomhedsarkiver i en digital tidsalder

Denne debatartikel ser nærmere på digital bevaring, herunder specielt på danske virksomheders praksis på dette aktuelle område. Forfatterne gør status på, hvordan virksomhederne i dag forholder sig til nogle af de mange udfordringer, som digital bevaring rummer, og der gøres opmærksom på den uensartede digitale bevaring i virksomheder. Problemerne adresseres både i et generelt perspektiv og gennem en række erfaringsbaserede scenarier. De eksisterende digitale tilbud, der i dag står til rådighed for virksomheder med et bevaringsbehov, skitseres kort. Dette leder frem til en diskussion vedrørende de fremtidige udfordringer, som både virksomheder, samfund og historikere vil stå overfor, hvis der ikke snart gøres en aktiv indsats for at gemme mere digital dokumentation for eftertiden. Slutteligt peger vi på mulige løsninger, der kan være relevante at overveje blandt historikere, arkivarer, dokumentationsspecialister og virksomheder.--- What will be left for the Future? Business Archives in the Digital Age Managing the past is a complex and difficult task. In this article we discuss digital preservation by focusing on what Danish companies do to preserve their company history. We examine how companies handle the multiple challenges that are posed by digital preservation and point to the presently uneven and lopsided preservation practices of business records. The problems associated herewith are addressed in a general perspective and through a series of experience based scenarios. Existing commercial as well as non-commercial solutions for companies interested in digital preservation are briefly outlined. This leads to an analysis of future challenges for companies and business historians alike if we do not immediately succeed in preserving more digital information. We conclude by pointing to a number of issues that calls for immediate and careful attention among historians, archivists, records managers and business leaders if we want the past to have a future

Treatment with glucagon-like peptide-1 receptor agonists and incidence of dementia:Data from pooled double-blind randomized controlled trials and nationwide disease and prescription registers

INTRODUCTION: People with type 2 diabetes have increased risk of dementia. Glucagon‐like peptide‐1 (GLP‐1) receptor agonists (RAs) are among the promising therapies for repurposing as a treatment for Alzheimer's disease; a key unanswered question is whether they reduce dementia incidence in people with type 2 diabetes. METHODS: We assessed exposure to GLP‐1 RAs in patients with type 2 diabetes and subsequent diagnosis of dementia in two large data sources with long‐term follow‐up: pooled data from three randomized double‐blind placebo‐controlled cardiovascular outcome trials (15,820 patients) and a nationwide Danish registry‐based cohort (120,054 patients). RESULTS: Dementia rate was lower both in patients randomized to GLP‐1 RAs versus placebo (hazard ratio [HR]: 0.47 (95% confidence interval [CI]: 0.25–0.86) and in the nationwide cohort (HR: 0.89; 95% CI: 0.86–0.93 with yearly increased exposure to GLP‐1 RAs). DISCUSSION: Treatment with GLP‐1 RAs may provide a new opportunity to reduce the incidence of dementia in patients with type 2 diabetes

Semaglutide treatment attenuates vessel remodelling in ApoE-/- mice following vascular injury and blood flow perturbation.

BACKGROUND AND AIMS Randomized clinical studies have shown a reduction in cardiovascular outcomes with glucagon-like peptide 1 receptor agonist (GLP-1RA) treatment with the hypothesized mechanisms being an underlying effect on atherosclerosis. Here, we aimed to assess the pharmacological effects of semaglutide in an atheroprone murine model that recapitulates central mechanisms related to vascular smooth muscle cell (VSMC) phenotypic switching and endothelial dysfunction known to operate within the atherosclerotic plaque. METHODS In study A, we employed an electrical current to the carotid artery in ApoE-/- mice to induce severe VSMC injury and death, after which the arteries were allowed to heal for 4 weeks. In study B, a constrictive cuff was added for 6 h at the site of the healed segment to induce a disturbance in blood flow. RESULTS Compared to vehicle, semaglutide treatment reduced the intimal and medial area by ∼66% (p = 0.007) and ∼11% (p = 0.0002), respectively. Following cuff placement, expression of the pro-inflammatory marker osteopontin and macrophage marker Mac-2 was reduced (p < 0.05) in the semaglutide-treated group compared to vehicle. GLP-1R were not expressed in murine carotid artery and human coronary vessels with and without atherosclerotic plaques, and semaglutide treatment did not affect proliferation of cultured primary human VSMCs. CONCLUSIONS Semaglutide treatment reduced vessel remodelling following electrical injury and blood flow perturbation in an atheroprone mouse model. This effect appears to be driven by anti-inflammatory and -proliferative mechanisms independent of GLP-1 receptor-mediated signalling in the resident vascular cells. This mechanism of action may be important for cardiovascular protection.This study was supported by a grant from the LifePharm Centre of In Vivo Pharmacology.S

Integrated Brain Atlas for Unbiased Mapping of Nervous System Effects Following Liraglutide Treatment

Light Sheet Fluorescence Microscopy (LSFM) of whole organs, in particular the brain, offers a plethora of biological data imaged in 3D. This technique is however often hindered by cumbersome non-Automated analysis methods. Here we describe an approach to fully automate the analysis by integrating with data from the Allen Institute of Brain Science (AIBS), to provide precise assessment of the distribution and action of peptide-based pharmaceuticals in the brain. To illustrate this approach, we examined the acute central nervous system effects of the glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide. Peripherally administered liraglutide accessed the hypothalamus and brainstem, and led to activation in several brain regions of which most were intersected

Incretin-based therapies

Incretin-based therapies have established a foothold in the diabetes armamentarium through the introduction of oral dipeptidyl peptidase-4 inhibitors and the injectable class, the glucagon-like peptide-1 receptor agonists. In 2009, the American Diabetes Association and European Association for the Study of Diabetes authored a revised consensus algorithm for the initiation and adjustment of therapy in Type 2 diabetes (T2D). The revised algorithm accounts for the entry of incretin-based therapies into common clinical practice, especially where control of body weight and hypoglycemia are concerns. The gut-borne incretin hormones have powerful effects on glucose homeostasis, particularly in the postprandial period, when approximately two-thirds of the β-cell response to a given meal is due to the incretin effect. There is also evidence that the incretin effect is attenuated in patients with T2D, whereby the β-cell becomes less responsive to incretin signals. The foundation of incretin-based therapies is to target this previously unrecognized feature of diabetes pathophysiology, resulting in sustained improvements in glycemic control and improved body weight control. In addition, emerging evidence suggests that incretin-based therapies may have a positive impact on inflammation, cardiovascular and hepatic health, sleep, and the central nervous system. In the present article, we discuss the attributes of current and near-future incretin-based therapies