Decrease in the efficacy of glucagon-like peptide-1 receptor agonists: what is the reason?

The review deals with the drugs of a group of glucagon-like peptide-1 receptors agonists (GLP-1RA) the action of which is based on the incretin effect. In addition to insulinotropic and glucagonostatic action, GLP-1RA contributes to the improvement of glycemic control, a decrease in body weight, and also reduces cardiovascular effects in diabetic patients. The members of this group are divided into short- and long-acting preparations that is determined by their pharmacodynamic properties. Studies have shown that the long-acting GLP-1RA, which are administered once a week, demonstrate better glycemic control with a similar or less risk of the hypoglycemia and gastrointestinal side effects than their short-acting analogues. However, with long-term use of GLP-1RA, there is a reduction in the hypoglycemic action associated with a decrease in the inhibition of intestinal motility due to the phenomenon of tachyphylaxis (desensitization) of the GLP-1 receptors as a result of the vagus nerve activation. Promising means to overcome this shortcoming are considered, such as the development of modified and combined coagonists of dipeptidyl peptidase 1 receptors, as well as oral forms of GLP-1RA. In addition, we have described possible mechanisms influencing the effectiveness of GLP-1RA due to the production of antibodies to various drugs in this group, and the relationship between the effects of incretin mimetics with the state of the intestinal microbiota. In conclusion, the group of incretin-based drugs provides broad perspectives for use in type 2 diabetic patients, with the possibility of correction of both basal and prandial glycemia, and new efficient and safe forms of drugs of this group are actively creating.

Heterogeneity amongst GLP-1 RA cardiovascular outcome trials results: can definition of established cardiovascular disease be the missing link?

Atherosclerotic cardiovascular diseases are the leading cause of adverse outcomes in patients with type 2 diabetes, and all new anti-diabetic agents are mandated to undergo cardiovascular outcome trials (CVOTs). Glucagon-like peptide-1 receptor agonists (GLP-1 RA) are incretin mimetics that reduce blood glucose levels with a low associated risk of hypoglycaemia. CVOTs with different GLP-1 RAs yielded different results in terms of major cardiovascular composite outcome (MACE), with some trials showing superiority in the treatment arm, whereas other simply displayed non-inferiority. More importantly, the significance of each component of MACE varied between drugs. This begs the question of whether these differences are due to dissimilarities between drugs or other factors, namely trial design, are at the root of these differences. We analyse the trial designs for all CVOTs with GLP-1 RAs and highlight important differences between them, namely in terms of definition of established cardiovascular disease, and discuss how these differences might explain the disparate results of the trials and preclude direct comparisons between them. We conclude that a fair comparison between GLP-1 RA CVOTs would involve post-hoc analysis re-grouping the patients into different cardiovascular risk categories based upon their baseline clinical parameters, in order to even out the criteria used to classify patients.

Isoprenoid Derivatives of Lysophosphatidylcholines Enhance Insulin and GLP-1 Secretion through Lipid-Binding GPCRs

Insulin plays a significant role in carbohydrate homeostasis as the blood glucose lowering hormone. Glucose-induced insulin secretion (GSIS) is augmented by glucagon-like peptide (GLP-1), a gastrointestinal peptide released in response to ingesting nutriments. The secretion of insulin and GLP-1 is mediated by the binding of nutrients to G protein-coupled receptors (GPCRs) expressed by pancreatic β-cells and enteroendocrine cells, respectively. Therefore, insulin secretagogues and incretin mimetics currently serve as antidiabetic treatments. This study demonstrates the potency of synthetic isoprenoid derivatives of lysophosphatidylcholines (LPCs) to stimulate GSIS and GLP-1 release. Murine insulinoma cell line (MIN6) and enteroendocrinal L cells (GLUTag) were incubated with LPCs bearing geranic acid (1-GA-LPC), citronellic acid (1-CA-LPC), 3,7-dimethyl-3-vinyloct-6-enoic acid (GERA-LPC), and (E)-3,7,11-trimethyl- 3-vinyldodeca-6,10-dienoic acid (1-FARA-LPC). Respective free terpene acids were also tested for comparison. Besides their insulin- and GLP-1-secreting capabilities, we also investigated the cytotoxicity of tested compounds, the ability to intracellular calcium ion mobilization, and targeted GPCRs involved in maintaining lipid and carbohydrate homeostasis. We observed the high cytotoxicity of 1-GERA-LPC and 1-FARA-LPC in contrast 1-CA-LPC and 1-GA-LPC. Moreover, 1-CA-LPC and 1-GA-LPC demonstrated the stimulatory effect on GSIS and 1-CA-LPC augmented GLP-1 secretion. Insulin and GLP-1 release appeared to be GPR40-, GPR55-, GPR119- and GPR120-dependent.

Perspectives of incretin mimetics in cardiovascular diseases

Introduction: Type 2 Diabetes (DM2) is a chronic conditionassociated with an increased risk of cardiovascular diseases,neuropathies, nephropathies and eye diseases. Incretins (GIPand GLP-1) are hormones important to insulin secretion, andtheir actions are compromised in DM2 patients. Objectives:This review considers the opportunities and challenges ofusing incretin mimetics in the treatment of DM2. Methods:Bibliographic review referring to the period from 2000 to2020, in electronic databases such as Scielo, Lilacs, PubMed,Web of Science. Results: Incretins stimulate insulin secretionby the pancreas in response to nutrient intake, with a lowerpotential to cause hypoglycemia. In addition, they have acardioprotective role, reducing blood pressure, improvingendothelial and myocardial function, and their use has beenassociated with a reduction in the risk of cardiovascularevents, including cardiovascular mortality. Clinical trialswith GLP-1R agonists (GLP-1RA) reduced albuminuria, increasednatriuresis, and decreased oxidative stress. In addition,treatment with incretin mimetics reduced the occurrence ofthe main cardiovascular outcomes related to atherosclerosis,promoted weight loss and improved lipid profile. Conclusion:Studies show the important role of incretin mimetics in thepathophysiology and treatment of DM2, with significanteffects in the cardiovascular system. However, its use must beevaluated in relation to its safety and to in which individualsthe benefits outweigh the risks associated with the treatment.Thus, its clinical relevance depends on studies with long-termfollow-up of patients, with analysis of its impact on mortalityand on the development of micro and macrovascularcomplications.

Incretin Hormones in Obesity and Related Cardiometabolic Disorders: The Clinical Perspective

The prevalence of obesity continues to grow rapidly worldwide, posing many public health challenges of the 21st century. Obese subjects are at major risk for serious diet-related noncommunicable diseases, including type 2 diabetes mellitus, cardiovascular disease, and non-alcoholic fatty liver disease. Understanding the mechanisms underlying obesity pathogenesis is needed for the development of effective treatment strategies. Dysregulation of incretin secretion and actions has been observed in obesity and related metabolic disorders; therefore, incretin-based therapies have been developed to provide new therapeutic options. Incretin mimetics present glucose-lowering properties, together with a reduction of appetite and food intake, resulting in weight loss. In this review, we describe the physiology of two known incretins—glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), and their role in obesity and related cardiometabolic disorders. We also focus on the available and incoming incretin-based medications that can be used in the treatment of the above-mentioned conditions.

Incretin mimetics restore the ER-mitochondrial axis and switch neuronal fate towards survival.

Background and Purpose: Amyotrophic lateral sclerosis with associated frontotemporal dementia, Alzheimer’s disease, Huntington’s disease, and Parkinson’s disease are the major neurodegenerative disorders that afflict more than 7 million people worldwide. There are no disease-modifying or disease-retarding therapeutic agents currently available on the market. All four conditions feature several seemingly-disparate pathological and genetic lesions, which, however, converge into calcium dyshomeostasis and a disturbed function of the axis of the endoplasmic reticulum (ER) and mitochondria. Experimental Approach: Incretin mimetics – traditionally anti-diabetic therapeutic agents – have been repeatedly shown to exert neurotrophic effects in neuroblastoma cells, rodent primary neurones, and murine models of neurodegeneration. Herein, for the very first time, we assess the pharmacological effects of Liraglutide and the dual incretin DA-CH3 in terminally differentiated human neurones under conditions of calcium-dependent chronic ER stress and additionally assess their efficacy in one of the most critical regulatory point for neurones, the mitochondrial respiration and dynamics. Key Results: Liraglutide and DA-CH3 rescue the arrested oxidative phosphorylation and glycolysis. They mitigate the suppressed mitochondrial biogenesis and hyper-polarisation of the mitochondrial membrane, all, to re-establish normalcy of cellular bioenergetics under conditions of chronic ER stress. These effects correlate with a resolution of the unfolded protein response and the autophagic arrest to halt the excessive synaptic and neuronal death, with the dual incretin displaying a superior anti-apoptotic effect. Conclusions: Our findings pave the way for a therapeutic strategy for disorders with a considerable social-economic burden and deepen our understanding of the spectrum of the incretin-signalling functions.

Role of Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists in Hypoglycemia

A relatively recent addition to the arsenal of antidiabetic drugs used for the treatment of type 2 diabetes mellitus (T2DM) has been the “incretin mimetics,” a group of drugs that work on the glucagon-like peptide-1 (GLP-1) receptor and enhance insulin secretion from the pancreatic β-cells in a glucose-dependent manner, more potently in hyperglycemic conditions, while suppressing glucagon secretion at the same time. Therefore, it was assumed that this class of drugs would have a lower risk of hypoglycemia than insulin secretagogues like sulphonylureas. However, GLP-1 receptor agonists have been proposed to cause hypoglycemia in healthy normoglycemic subjects implying that their action is not as glucose-dependent as once thought. Other studies concluded that they might not induce hypoglycemia and the risk is dependent on other individual factors. However, the FDA announced that the 12 GLP-1 receptor agonists currently available on the market had potential safety signs and evaluated the need for regulatory action. This review provides an overview of the studies that investigated the possible hypoglycemic effect of GLP-1 receptor agonists. In addition, the current review describes other adverse effects of GLP-1 receptor agonist treatment.

Efficacy and Cardiovascular Safety of GLP-1 Receptor Analogues

Abstract:: Glucagon like peptide- 1 receptor analogs (GLP-1RAs) are incretin mimetics with potent glucose-dependent insulinotropic action that translates to glycemic control in people with type-2 diabetes mellitus (T2DM). These agents potentially have the ability to stimulate proliferation or prevent apoptosis of pancreatic β-cells, induce weight-loss and provide vascular benefits in patients with T2DM. Newer GLP-1RA, semaglutide has shown robust reduction in HbA1c up to 1.5 - 1.8%. However individual differences do exist between the different GLP-1RAs, in terms of efficacy, pharmacokinetics, tolerability, and vascular protection. The potential of vascular protection offered by newer anti-diabetic agents has generated a lot of excitement in the field of diabetes, and to a large extent is now driving treatment decisions. So far, six cardiovascular outcome trials of GLP-1 RAs have been published, analyzing lixisenatide (ELIXA), liraglutide (LEADER), semaglutide (SUSTAIN-6), long-acting exenatide (EXSCEL), dulaglutide (REWIND), and oral semaglutide (PIONEER 6) with a follow-up duration of 2-4 years. LEADER, REWIND and SUSTAIN-6 trials have demonstrated reduction in rates of major adverse cardiovascular events with active GLP-1 RA treatment but ELIXA, PIONEER 6 and EXSCEL have been neutral. In this review, we discuss the available evidence from randomized controlled trials (RCTs) analyzing the cardiovascular effects of various GLP-1 RAs with the aim of comparing individual drugs. We have also summarized the general aspects of GLP-1RAs that can be applied in clinical practice.

Morphological features of pancreatic endocrinicytes in rats with type 2 diabetes mellitus receiving the incretin mimetic therapy of different duration

Группа препаратов, основанных на инкретиновых эффектах (аналоги глюкагоноподобного пептида-1 аГПП1) и ингибиторы дипептидилпептидазы-4, иДПП4), обладают способностью увеличивать репликацию β -клеток и ингибировать апоптоз. Инкретиномиметики способны влиять на функцию α-клеток, восстанавливая физиологическую регуляцию уровня глюкагона. При этом эффекты инкретиномиметиков на пролиферацию/апоптоз α-клеток изучены недостаточно. В единичных исследованиях отмечено увеличение пролиферации α-клеток, но факторы, определяющие выраженность этих изменений, не установлены. Цель - оценка влияния терапии инкретиномиметиками разной продолжительности на морфологические и функциональные особенности α- и β-клеток поджелудочной железы крыс (12 мес) с сахарным диабетом 2-го типа (СД 2-го типа). Методика. У крыс (возраст 12 мес), находящихся на высокожировой диете, моделировали стрептозотоцин-никотинамид-индуцированный СД 2-го типа. Животные получали инкретиномиметки: агонист рецепторов ГПП1 (лираглутид) или ингибитор ДПП4 (вилдаглиптин) в течение 4,10 и 24 нед. Макроскопически оценивали наличие/отсутствие видимых изменений поджелудочной железы. Парафиновые срезы поджелудочной железы окрашивали гематоксилином и эозином для оценки микроструктуры ткани. Проводили иммуногистохимическое (ИГХ) исследование с применением антител (Abcam) к глюкагону, инсулину в аппарате для ИГХ «Thermo Autostainer 720». После процедуры ИГХ ядра доокрашивали гематоксилином в аппарате для окраски гистологических микропрепаратов LeicaST5020. Результаты. Показано, что без лечения сахарный диабет приводил к снижению числа α- и β- клеток на всех сроках наблюдения. Лечение диабета лираглутидом и вилдаглиптином приводило к восстановлению пула как α-, так и β- клеток. При сравнении групп, получавших терапию и без терапии, с группой контроля значимые отличия сохранялись по количеству как α-, так и β-клеток во все сроки наблюдения. Через 4 нед в группах, получавших лираглутид, количество α-клеток стало сопоставимым с таковым в группе контроля, но количество β-клеток оставалось сниженным. После 10 и 24 нед терапии статистически значимой разницы между группой контроля и животными, получавшими терапию лиралутидом, по количеству как β-, так и α- клеток не выявлено. Заключение. Полученные данные свидетельствуют в пользу того, что терапия инкретиномиметиками способствует восстановлению пула как α-, так и β-клеток поджелудочной железы. Drugs based on incretin effects, including analogs of glucagon-like peptide-1 (GLP1) and dipeptidyl peptidase-4 inhibitors (DPP4), increase replication and inhibit apoptosis of β-cells. Incretin mimetics can influence the function of α-cells thereby restoring physiological regulation of glucagon. However, effects of incretin mimetics on proliferation and apoptosis of α-cells are understudied. A few studies reported increased α-cell proliferation, but the factors determining the degree of these changes were not established. Aim. To evaluate the effect of incretin mimetic treatment of different duration on morphological and functional features of pancreatic α- and β-cells of 12-month-old rats with type 2 diabetes mellitus. Method. Streptozotocin-nicotinamide-induced type 2 diabetes mellitus was modeled in 12-month-old rats receiving a high-fat diet. The rats were treated with incretin mimetics, a GLP-1 receptor antagonist (Liraglutide) or a DPP-4 inhibitor (Vildagliptin) for 4, 10 or 24 weeks. Paraffin sections of the pancreas were stained with hematoxylin-eosin to evaluate the tissue microstructure. An immunohistochemical (IHC) study was performed using glucagon and insulin antibodies (Abcam) with a Thermo Autostainer 720 IHC instrument. After the IHC procedure, nuclei were additionally stained with hematoxylin using a Leica ST5020 stainer for histological micropreparations. Results. Untreated diabetes mellitus resulted in decreased numbers of α- and β-cells at all timepoints of observation. The treatments with Liraglutide and Vildagliptin recovered the pools of α- and β-cells. Significant differences of both treated and untreated diabetic groups from the control group in the number of α- and β-cells remained at all timepoints of observation. In the Liraglutide group at 4 weeks, the number of α-cells became comparable with the control group, but the number of β-cells remained lower. At 10 and 24 weeks of treatment, statistically significant differences between the control group and the Liraglutide or Vildagliptin treatment groups in the number of α- and β-cells were not observed. Conclusion. The results of the study suggested that the incretin mimetic therapy provided recovery of both α and β-cell pools in the pancreas.