Academic literature on the topic 'GLP-1R agonists'

Abstract Glucagon-like peptide-1 receptor (GLP-1R) agonists are a well-accepted and safe treatment for Type II diabetes. Although GLP-1R agonists mainly act to potentiate insulin and suppress glucagon secretion, recent evidence suggests that GLP-1R signaling also has anti-inflammatory effects. Severe RSV-associated illness is partially caused by type 2-associated immunopathology. We hypothesized that GLP-1R signaling inhibits type 2-mediated immunopathology during infection with RSV 12/12-6, a strain of RSV that was isolated from a hospitalized infant with severe lower respiratory tract infection and bronchiolitis. We show here that GLP-1R agonist treatment decreased airway inflammation, airway reactivity, and airway mucus production in RSV 12/12-6-infected mice. GLP-1R agonist treatment decreased total lung IL-13 and IL-33 levels, with concurrent decreases in lung IL-13-producing group 2 innate lymphoid cell (ILC2), CD4+ Th2 cell, and basophil numbers as well as IL-33-producing epithelial cells. The GLP-1R agonist prevented airway inflammation, and did not impact viral load, anti-viral interferon and antibody production during secondary RSV infection. Relative to the respective mock-infected groups, RSV-infected GLP-1R agonist treated mice did not have increased weight loss compared to vehicle treated mice. A phenome-wide association study (PheWAS) identified a link between GLP-1R signaling and acute bronchitis and bronchiolitis in humans. These studies demonstrate that GLP-1R signaling protects against type 2-mediated immunopathology during RSV infection. GLP-1R agonists are the first known FDA-approved agents to inhibit IL-33 and may represent a novel treatment strategy for RSV bronchiolitis.

The incretin hormone glucagon-like peptide-1 (GLP-1) is an important insulin secretagogue and GLP-1 analogs are used for the treatment of type 2 diabetes. GLP-1 displays antiinflammatory and surfactant-releasing effects. Thus, we hypothesize that treatment with GLP-1 analogs will improve pulmonary function in a mouse model of obstructive lung disease. Female mice were sensitized with injected ovalbumin and treated with GLP-1 receptor (GLP-1R) agonists. Exacerbation was induced with inhalations of ovalbumin and lipopolysaccharide. Lung function was evaluated with a measurement of enhanced pause in a whole-body plethysmograph. mRNA levels of GLP-1R, surfactants (SFTPs), and a number of inflammatory markers were measured. GLP-1R was highly expressed in lung tissue. Mice treated with GLP-1R agonists had a noticeably better clinical appearance than the control group. Enhanced pause increased dramatically at day 17 in all control mice, but the increase was significantly less in the groups of GLP-1R agonist-treated mice (P < .001). Survival proportions were significantly increased in GLP-1R agonist-treated mice (P < .01). SFTPB and SFTPA were down-regulated and the expression of inflammatory cytokines were increased in mice with obstructive lung disease, but levels were largely unaffected by GLP-1R agonist treatment. These results show that GLP-1R agonists have potential therapeutic potential in the treatment of obstructive pulmonary diseases, such as chronic obstructive pulmonary disease, by decreasing the severity of acute exacerbations. The mechanism of action does not seem to be the modulation of inflammation and SFTP expression.

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are important regulators of metabolism, making their receptors (GLP-1R and GIPR) attractive targets in the treatment of type 2 diabetes mellitus (T2DM). GLP-1R agonists are used clinically to treat T2DM but the use of GIPR agonists remains controversial. Recent studies suggest that simultaneous activation of GLP-1R and GIPR with a single peptide provides superior glycemic control with fewer adverse effects than activation of GLP-1R alone. We investigated the signaling properties of a recently reported dual-incretin receptor agonist (P18). GLP-1R, GIPR, and the closely related glucagon receptor (GCGR) were expressed in HEK-293 cells. Activation of adenylate cyclase via Gαs was monitored using a luciferase-linked reporter gene (CRE-Luc) assay. Arrestin recruitment was monitored using a bioluminescence resonance energy transfer (BRET) assay. GLP-1, GIP, and glucagon displayed exquisite selectivity for their receptors in the CRE-Luc assay. P18 activated GLP-1R with similar potency to GLP-1 and GIPR with higher potency than GIP. Interestingly, P18 was less effective than GLP-1 at recruiting arrestin to GLP-1R and was inactive at GCGR. These data suggest that P18 can act as both a dual-incretin receptor agonist, and as a G protein-biased agonist at GLP-1R.

Glucagon-like peptide-1 (GLP-1) is produced by and released from the small intestine following ingestion of nutrients. GLP-1 receptor (GLP-1R) agonists applied peripherally or centrally decrease food intake and increase glucose-stimulated insulin secretion. These effects make the GLP-1 system an attractive target for the treatment of type 2 diabetes mellitus and obesity. In addition to these more frequently studied effects of GLP-1R stimulation, previous reports indicate that GLP-1R agonists suppress water intake. The present experiments were designed to provide greater temporal resolution and site specificity for the effect of GLP-1 and the long-acting GLP-1R agonists, exendin-4 and liraglutide, on unstimulated water intake when food was and was not available. All three GLP-1R ligands suppressed water intake after peripheral intraperitoneal administration, both in the presence of and the absence of food; however, the magnitude and time frame of water intake suppression varied by drug. GLP-1 had an immediate, but transient, hypodipsic effect when administered peripherally, whereas the water intake suppression by IP exendin-4 and liraglutide was much more persistent. Additionally, intracerebroventricular administration of GLP-1R agonists suppressed water intake when food was absent, but the suppression of intake showed modest differences depending on whether the drug was administered to the lateral or fourth ventricle. To the best of our knowledge, this is the first demonstration of GLP-1 receptor agonists affecting unstimulated, overnight intake in the absence of food, the first test for antidipsogenic effects of hindbrain application of GLP-1 receptor agonists, and the first test of a central effect (forebrain or hindbrain) of liraglutide on water intake. Overall, these results show that GLP-1R agonists have a hypodipsic effect that is independent of GLP-1R-mediated effects on food intake, and this occurs, in part, through central nervous system GLP-1R activation.

The proglucagon gene gives rise to multiple peptides that play diverse roles in the control of energy intake, gut motility, and nutrient disposal. Glucagon-like peptide-1 (GLP-1), a 30-amino-acid peptide regulates glucose homeostasis via control of insulin and glucagon secretion and by inhibition of gastric emptying and food intake. Oxyntomodulin (OXM) a 37-amino-acid peptide also derived from the proglucagon gene, binds to both the glucagon and GLP-1 receptor (GLP-1R); however, a separate OXM receptor has not yet been identified. Here we show that OXM, like other GLP-1R agonists, stimulates cAMP formation and lowers blood glucose after both oral and ip glucose administration, actions that require a functional GLP-1R. OXM also directly stimulates insulin secretion from murine islets and INS-1 cells in a glucose- and GLP-1R-dependent manner. Moreover, OXM ameliorates hyperglycemia and significantly reduces apoptosis in murine β-cells after streptozotocin administration and directly reduces apoptosis in thapsigargin-treated INS-1 cells. Unexpectedly, OXM, but not the GLP-1R agonist exendin-4, increased plasma levels of insulin after oral glucose administration. Moreover, OXM administered at doses that potently lower blood glucose had no effect on inhibition of gastric emptying but reduced food intake in WT mice. Taken together, these findings illustrate that although structurally distinct proglucagon-derived peptides such as GLP-1 and OXM engage the GLP-1R, OXM mimics some but not all of the actions of GLP-1R agonists in vivo. These findings may have implications for therapeutic efforts using OXM as a long-acting GLP-1R agonist for the treatment of metabolic disorders.

The long-acting glucagon-like peptide-1 receptor (GLP-1R) agonists, exendin-4 and liraglutide, suppress food intake and body weight. The mediating site(s) of action for the anorectic effects produced by peripheral administration of these GLP-1R agonists are not known. Experiments addressed whether food intake suppression after ip delivery of exendin-4 and liraglutide is mediated exclusively by peripheral GLP-1R or also involves direct central nervous system (CNS) GLP-1R activation. Results showed that CNS delivery [third intracerebroventricular (3rd ICV)] of the GLP-1R antagonist exendin-(9–39) (100 μg), attenuated the intake suppression by ip liraglutide (10 μg) and exendin-4 (3 μg), particularly at 6 h and 24 h. Control experiments show that these findings appear to be based neither on the GLP-1R antagonist acting as a nonspecific competing orexigenic signal nor on blockade of peripheral GLP-1R via efflux of exendin-(9–39) to the periphery. To assess the contribution of GLP-1R expressed on subdiaphragmatic vagal afferents to the anorectic effects of liraglutide and exendin-4, food intake was compared in rats with complete subdiaphragmatic vagal deafferentation and surgical controls after ip delivery of the agonists. Both liraglutide and exendin-4 suppressed food intake at 3 h, 6 h, and 24 h for controls; for subdiaphragmatic vagal deafferentation rats higher doses of the GLP-1R agonists were needed for significant food intake suppression, which was observed at 6 h and 24 h after liraglutide and at 24 h after exendin-4. Conclusion: Food intake suppression after peripheral administration of exendin-4 and liraglutide is mediated by activation of GLP-1R expressed on vagal afferents as well as direct CNS GLP-1R activation.

DPP4 inhibitors and GLP-1 receptor agonists used in incretin-based strategies treat Type 2 diabetes with different modes of action. The pharmacological blood GLP-1R agonist concentration targets pancreatic and some extrapancreatic GLP-1R, whereas DPP4i favors the physiological activation of the gut-brain-periphery axis that could allow clinicians to adapt the management of Type 2 diabetes, according to the patient's pathophysiological characteristics.

IntroductionThe insulinotropic capacity of exogenous glucagon like peptide-1 (GLP-1) is reduced in type 2 diabetes and the insulin-resistant obese. We have tested the hypothesis that this response is the consequence of a reduced pancreatic GLP-1 receptor (GLP-1r) density in insulin-resistant obese animals.Research design and methodsGLP-1r density was measured in lean and insulin-resistant adult miniature pigs after the administration of a 68Ga-labeled GLP-1r agonist. The effect of hyperinsulinemia on GLP-1r was assessed using sequential positron emission tomography (PET), both in the fasted state and during a clamp. The impact of tissue perfusion, which could account for changes in GLP-1r agonist uptake, was also investigated using 68Ga-DOTA imaging.ResultsGLP-1r binding potential in the obese pancreas was reduced by 75% compared with lean animals. Similar reductions were evident for fat tissue, but not for the duodenum. In the lean group, induced hyperinsulinemia reduced pancreatic GLP-1r density to a level comparable with that of the obese group. The reduction in blood to tissue transfer of the GLP-1r ligand paralleled that of tissue perfusion estimated using 68Ga-DOTA.ConclusionsThese observations establish that a reduction in abdominal tissue perfusion and a lower GLP-1r density account for the diminished insulinotropic effect of GLP-1 agonists in type 2 diabetes.

Objective: GLP-1R (glucagon-like peptide-1 receptor) agonists are increasingly used for the treatment of hyperglycemia in type 2 diabetes, with additional body weight reducing effects. Long-term administration of GLP-1R agonists has demonstrated cardioprotective effects, but the mechanism of cardiovascular protection is not currently known. Several studies in humans and animal models have shown suppression of intestinal CM (chylomicron) secretion and plasma TG (triglyceride) levels by pharmacological doses of GLP-1R agonists. The objective of this study was to assess the physiological role of endogenously secreted GLP-1 on CM secretion in rats. Approach and Results: Lymph flow, TG concentration, and TG output were assessed in mesenteric lymph duct-cannulated rats in response to an intraduodenal lipid bolus, preceded by an intraperitoneal injection of GLP-1R antagonist Ex (9–39; exendin 9–39) or vehicle. TG output was significantly enhanced in the presence of Ex (9–39) compared with vehicle over a 4-hour period post-lipid bolus ( P =0.007). Total lymph volume ( P =0.005) and TG mass ( P <0.0001) cumulatively collected by the end of the 4-hour period were significantly increased by GLP-1R antagonist. Conclusions: GLP-1R antagonism enhanced intestinal TG output in rats through stimulation of lymph flow and increased lymph TG concentration. Endogenously secreted GLP-1 after a lipid bolus is sufficient to modulate CM secretion in the rat, with GLP-1 physiologically restraining CM secretion through the GLP-1R. It remains to be determined whether the lipid lowering actions of GLP-1R agonists play a role in the cardiovascular protective effects of these therapeutic agents.

The glucagon-like peptide-1 receptor (GLP-1R) plays a key role in metabolism and is an important therapeutic target in diabetes and obesity. Recent studies in experimental animals have shown that certain subsets of T cells express functional GLP-1R, indicating an immune regulatory role of GLP-1. In contrast, less is known about the expression and function of the GLP-1R in human T cells. Here, we provide evidence that activated human T cells express GLP-1R. The expressed GLP-1R was functional, as stimulation with a GLP-1R agonist triggered an increase in intracellular cAMP, which was abrogated by a GLP-1R antagonist. Analysis of CD4+ T cells activated under T helper (Th) 1, Th2, Th17 and regulatory T (Treg) cell differentiation conditions indicated that GLP-1R expression was most pronounced in induced Treg (iTreg) cells. Through multimodal single-cell CITE- and TCR-sequencing, we detected GLP-1R expression in 29–34% of the FoxP3+CD25+CD127- iTreg cells. GLP-1R+ cells showed no difference in their TCR-gene usage nor CDR3 lengths. Finally, we demonstrated the presence of GLP-1R+CD4+ T cells in skin from patients with allergic contact dermatitis. Taken together, the present data demonstrate that T cell activation triggers the expression of functional GLP-1R in human CD4+ T cells. Given the high induction of GLP-1R in human iTreg cells, we hypothesize that GLP-1R+ iTreg cells play a key role in the anti-inflammatory effects ascribed to GLP-1R agonists in humans.

Relatório de Estágio do Mestrado Integrado em Ciências Farmacêuticas apresentado à Faculdade de Farmácia
O presente documento inclui a monografia intitulada “A incidência de neoplasias no tratamento com agonistas do GLP-1R” e os relatórios dos estágios realizados em farmácia comunitária e INFARMED, I.P..Os agonistas dos recetores do GLP-1 (GLP-1RA), são uma das mais recentes terapêuticas com indicação para a Diabetes Mellitus (DM) tipo 2. Diferenciam-se dos demais por possuírem um efeito glucose dependente, impedindo a ocorrência de hipoglicémia.Os doentes com DM tipo 2 apresentam resistência à insulina, uma redução de 50% na capacidade de resposta a incretinas e uma atividade aumentada da dipeptidil peptidase-4 (DPP-4). Estas características têm tornado os GLP-1RA numa terapêutica em expansão.Estão atualmente aprovados diversos GLP-1RA, uns de longa e outros de curta duração de ação. Sendo que o que se pretende é obter moléculas que permitam o menor número de administrações possível.Vários efeitos adversos têm sido reportados, quer pela FDA quer pela EMA, tendo sido gerados alertas de segurança por se acreditar que o tratamento com GLP-1RA poderia estar relacionado com o aumento da incidência de diversas neoplasias, como cancro do pâncreas e da tiroide.Têm surgido vários ensaios clínicos com o intuito de avaliar esta correlação, no entanto, até ao momento não há prova de que a incidência de neoplasias possa estar aumentada em doentes tratados com GLP-1RA, permanecendo assim a necessidade de mais estudos.No que respeita aos relatórios de estágio, estes foram realizados segundo uma análise SWOT, na qual tive oportunidade de expor os pontos fortes, os pontos fracos, as oportunidades e as ameaças de cada um deles.
This document includes the monograph entitled "The incidence of neoplasms in the treatment with GLP-1R agonists" and the reports of the placements performed in pharmacy and INFARMED, I.P .. GLP-1 receptor agonists (GLP-1RA) are one of the most recent therapies for type 2 diabetes mellitus (DM). They differ from others because they have a glucose-dependent effect, preventing the occurrence of hypoglycaemia. Patients with type 2 DM exhibit insulin resistance, a 50% reduction in incretin responsiveness, and increased dipeptidyl peptidase-4 (DPP-4) activity. These characteristics have made GLP-1RA an expanding therapy. Several GLP-1RA are currently approved, some long-acting and others short-acting. The aim is to obtain molecules that allow the smallest number of administrations possible.Several adverse effects have been reported by both the FDA and EMA, and safety alerts have been generated because it is believed that GLP-1RA treatment could be related to the increased incidence of various neoplasms, such as pancreatic and thyroid cancer.Clinical trials have often been conducted to assess this correlation, however, it is not yet possible to prove that the incidence of neoplasms is increased in patients treated with GLP-1RA, thus requiring further studies. As regards the traineeship reports, they were carried out according to a SWOT analysis, in which I was able to present the strengths, weaknesses, opportunities and threats of each of them.

Relatório de Estágio do Mestrado Integrado em Ciências Farmacêuticas apresentado à Faculdade de Farmácia
A doença de Alzheimer é a doença neurodegenerativa mais comum e é caracterizadapela deterioração progressiva e irreversível das funções cognitivas. As principaiscaraterísticas histopatológicas da doença de Alzheimer compreendem a presença de placasamiloides extracelulares e de emaranhados neurofibrilares intracelulares. Apesar doconhecimento sobre a doença ser cada vez maior, ainda carece de uma terapêutica eficaz ecapaz de reverter ou, até mesmo, retardar a progressão da doença, constituindo assim umdesafio para a investigação científica e ganhando impulso nas últimas décadas.Estudos epidemiológicos sugerem que a diabetes mellitus tipo 2 constitui um fator derisco para o desenvolvimento da doença de Alzheimer, provavelmente devido à disfunção dasinalização da insulina e insulinorresistência nos tecidos cerebrais. Nesta perspetiva, tem sidorecentemente sugerido que medicamentos originalmente desenvolvidos para o tratamentoda diabetes mellitus tipo 2 constituam uma abordagem terapêutica eficiente contra odesenvolvimento da doença de Alzheimer. Um crescente número de estudos pré-clínicossugere que os agonistas do recetor do peptídeo 1 semelhante ao glucagon, como oexenatido, o liraglutido e o lixisenatido, sejam potenciais fármacos terapêuticos na doença deAlzheimer.Assim, a presente monografia pretende substanciar o papel da insulina na doença deAlzheimer e analisar a forma como os mais recentes avanços de um potencial terapêuticoafetam a progressão da patologia da doença de Alzheimer: os agonistas do recetor dopeptídeo 1 semelhante ao glucagon.
Alzheimer’s disease is the most common of progressive disorders and is characterized by progressive and irreversible memory loss and cognitive impairments. The two main histological hallmarks of Alzheimer’s disease include extracellular amyloid plaques and intracellular neurofibrillary tangles. Although the knowledge of the disease is now greater there is still lack of effective therapeutics, able to reverse or even delay the advance of the disease, thus constituting a challenge to the scientific investigation and gaining momentum in the last decades. Epidemiological studies have recently discovered that type 2 diabetes mellitus has been identified as a risk factor for developing Alzheimer’s disease, most likely linked to an impairment of insulin in the brain. In view of the similarities and close association between Alzheimer’s disease and defective brain insulin signalling it has been recently hypothesized that efficient drugs against type 2 diabetes mellitus could be also a beneficial therapeutic strategy against Alzheimer’s disease. There is mounting experimental evidence that glucagon-like peptide-1 receptor agonists, including exenatide, liraglutide, lixisenatide ameliorate show promise as potential drug treatments of Alzheimer’s disease. In the present study the effects of insulin in Alzheimer’s disease are explored as well as how the most recent advances of a potential therapeutics affect the progression of the pathology of this disease: the glucagon-like peptide-1 receptor agonists.

Tese de mestrado, Mestrado em Regulação e Avaliação do Medicamento e Produtos de Saúde, Universidade de Lisboa, Faculdade de Farmácia, 2017
Diabetes Mellitus (DM) is one of the most important diseases at public health level around the world. Over the last 25 years there has been a dramatic increase in the number of people with diabetes around the world. In Portugal, in 2014 the estimated prevalence of Diabetes in population with ages between 20 and 79 years was 13.1%, i.e. more than 1 million of Portuguese people in this age range had Diabetes. During the last decade, in Portugal, it has been observed a significant decrease in the number of potential years of life, lost by DM. Diabetes assumes a preponderant role in the causes of death, and it was the cause of 4.0% of deaths occurred in 2014. The treatment of diabetes has come a long way in the last century. Starting with the discovery of insulin in 1921, it has seen also the development of antidiabetic drugs. In recent years, newer drugs have become available, targeting specific components of the spectrum of pathophysiologic abnormalities, regulating glucose input, and also addressing glucose utilization and disposal through impacts on insulin resistance and insulin deficiency. The Glucagon-Like Peptide-1 receptor (GLP-1R) agonists mimic the GLP-1 function in order to enhance insulin secretion after food-intake, restoring the incretin function, while being protected from the DPP-4 deactivation. This is achieved by binding to a GLP-1R that resides in the β-cell. This work focused on drawing a safety profile for GLP-1R agonists and conclude on the need and/or opportunity of adapting their Risk Management Plans (RMPs) for the new markets, taking into account the safety data collected both in EU and U.S. The methodology herein used was based on the comparison nonclinical and clinical data and RMPs for each medicinal product. Following this, it was presented a resume table identifying the risks considered by European Medicines Agency (EMA) and those ones accepted by U.S. Food and Drug Administration (FDA). After that, a comparison of adverse reactions reported both in European Union (EU) and U.S. within each medicinal product was performed. It was concluded that the relevant safety information identified in the nonclinical phase was assessed and observed during the clinical phase. The results obtained from all the nonclinical and clinical studies were resumed in the RMP. When observing the post-marketing data, collected from the public databases of adverse reactions reports, it was realized that, although some exceptions, the risks identified previously were the ones mostly reported. In general, the safety concerns identified were similar to all GLP-1R agonists. Regarding the European and the U.S. data several discrepancies were identified, namely on what concerns to the malignancies occurrence. It became clear that the occurrence of adverse reactions was associated both to the pharmaceutical formulation of the medicinal products and to their mechanism of action. Although there are some areas of special concern which require further and thorough analysis (namely the occurrence of cardiovascular (CV) adverse effects and thyroid or pancreatic cancers), it was concluded that all safety concerns are very well monitored and followed either by the EMA/FDA or by the Marketing Authorisation Holders (MAHs). As final conclusion, it was clear that the safety profile of GLP-1R agonists remain unchanged after this evaluation and no additional minimisation measures, other than those already defined and implemented, seem to be necessary, and, therefore, the RMPs do not need to be updated.
A Diabetes Mellitus (DM) é uma das doenças mais importantes para a saúde a nível mundial. Durante os últimos 25 anos houve um aumento dramático no número de pessoas com diabetes em todo o mundo. Em Portugal, em 2014 a prevalência estimada de Diabetes na população com idades compreendidas entre os 20 e os 79 anos era de 13.1%, isto é, mais de 1 milhão de Portugueses nesta faixa etária tinham Diabetes. Durante a última década, em Portugal, houve uma redução significativa do número de anos de vida, perdidos devido à DM. A Diabetes assume um papel preponderante entre as causas de morte, sendo a responsável por 4% das mortes ocorridas em 2014. O tratamento da diabetes percorreu um longo caminho no século passado. Começando com a descoberta da insulina em 1921, tendo-se também assistido a um grande desenvolvimento de medicamentos antidiabéticos. Nos últimos anos, novos medicamentos ficaram disponíveis, cujos alvos são componentes específicos do espectro das deficiências fisiopatológicas, regulando a entrada de glicose e também a utilização e eliminação de glicose através de ações na resistência à insulina e deficiência de insulina. Os agonistas do recetor do peptídeo-1 semelhantes ao glucagon (GLP-1R) imitam a função do GLP-1 de modo a aumentar a secreção de insulina após a ingestão de alimentos, restaurando a função incretina, enquanto são simultaneamente protegidos da desativação pelo DPP-4. Esta ação é alcançada pela sua ligação ao GLP-1R que se encontra na célula β. Este trabalho focou-se no desenho de um perfil de segurança para os agonistas do GLP-1R com vista a apurar a necessidade de adaptação dos Planos de Gestão de Risco (RMPs) aos novos mercados, tendo em conta os dados de segurança recolhidos na Europa (EU) e nos Estados Unidos (U.S.). A metodologia utilizada baseou-se na comparação dos dados não-clínicos e clínicos com os RMPs para cada medicamento. Apresentou-se em formato tabelar um resumo dos riscos considerados pela Agência Europeia do Medicamento (EMA) e os riscos aceites pela U.S. Food and Drug Administration (FDA). Após esta abordagem, foi realizada uma comparação entre as reações adversas reportadas na EU e nos U.S. para cada um dos medicamentos. Concluiu-se que a informação de segurança relevante identificada na fase não-clínica foi avaliada e observada durante a fase clínica. Os resultados obtidos nos estudos não-clínicos e clínicos foram resumidos no RMP. Pela observação dos dados pós-marketing, obtidos a partir das bases de dados públicas de notificações de reações adversas, concluiu-se que, apesar de algumas exceções, os riscos identificados anteriormente são os mais reportados. Em geral, os problemas de segurança identificados são semelhantes para todos os agonistas GLP-1R. Relativamente aos dados da EU e dos U.S., várias discrepâncias foram detetadas, nomeadamente no que se refere à ocorrência de tumores. Tornou-se evidente que a ocorrência de reações adversas está dependente quer da forma farmacêutica dos medicamentos quer do mecanismo de ação dos mesmos. Embora existam várias áreas de especial atenção que requerem mais e minuciosa análise (nomeadamente a ocorrência de efeitos adversos cardiovasculares (CV) e de cancros da tiroide e pancreáticos), considera-se que todos os problemas de segurança estão bem monitorizados e seguidos tanto pela EMA/FDA como pelos titulares de autorização de introdução no mercado (MAHs). Como conclusão, percebeu-se que o perfil de segurança dos agonistas GLP-1R permaneceu inalterado após esta avaliação. Deste modo, não parece ser necessário propor novas medidas de minimização de risco, para além das já definidas e implementadas, pelo que não é necessário atualizar os RMPs.

Incretin hormones are gut peptides secreted in response to nutrient ingestion, which play a key role in the regulation of islet function and blood glucose levels. In humans, the major incretin hormones are glucagon-like peptide (GLP)-1 and glucose- dependent insulinotropic polypeptide (GIP), and together they fully account for the incretin effect which is defined as the phenomenon whereby orally ingested glucose elicits a much greater insulin response than that obtained when glucose is infused intravenously to give identical blood glucose levels. there is evidence to suggest that impairments in secretion and/or action of incretin hormones arise secondarily to the development of insulin resistance, glucose intolerance, and/or increases in body weight rather than being causative factors. In separate studies, insulin sensitivity, glucose tolerance, and body mass index (BMI) have all been identified as independent factors associated with reductions in GLP-1 secretion and an impaired incretin effect. In patients with type 2 diabetes, the incretin effect is clearly reduced, which results in an inappropriately low insulin response to the ingestion of nutrients. Several early studies indicated that the reduced incretin effect could, at least in part, be related to impaired secretion of GLP- 1 (whereas secretion of GIP is generally found to be unaltered). Impaired meal-stimulated GLP-1 levels have been reported in some studies of patients with type 2 diabetes.  incretins exert antidiabetic actions in a glucose-dependent manner  Glucagon-like peptide 1 receptor (GLP-1r) agonists, but not dipeptidyl peptidase-4 (DPP-4) inhibitors, inhibit gastric emptying and might cause weight loss  DPP-4 inhibitors can be administered orally and are well tolerated  GLP-1r agonists must be administered by subcutaneous injection and commonly cause nausea. Key words: Incretin, Diabetes Mellitus..