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Frontiers in Endocrinology 2021The glucagon-like peptide-1 receptor agonist (GLP-1RA) semaglutide is the most recently approved agent of this drug class, and the only GLP-1RA currently available as... (Review)
Review
The glucagon-like peptide-1 receptor agonist (GLP-1RA) semaglutide is the most recently approved agent of this drug class, and the only GLP-1RA currently available as both subcutaneous and oral formulation. While GLP-1RAs effectively improve glycemic control and cause weight loss, potential safety concerns have arisen over the years. For semaglutide, such concerns have been addressed in the extensive phase 3 registration trials including cardiovascular outcome trials for both subcutaneous (SUSTAIN: Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes) and oral (PIONEER: Peptide InnOvatioN for the Early diabEtes tReatment) semaglutide and are being studied in further trials and registries, including real world data studies. In the current review we discuss the occurrence of adverse events associated with semaglutide focusing on hypoglycemia, gastrointestinal side effects, pancreatic safety (pancreatitis and pancreatic cancer), thyroid cancer, gallbladder events, cardiovascular aspects, acute kidney injury, diabetic retinopathy (DRP) complications and injection-site and allergic reactions and where available, we highlight potential underlying mechanisms. Furthermore, we discuss whether effects are specific for semaglutide or a class effect. We conclude that semaglutide induces mostly mild-to-moderate and transient gastrointestinal disturbances and increases the risk of biliary disease (cholelithiasis). No unexpected safety issues have arisen to date, and the established safety profile for semaglutide is similar to that of other GLP-1RAs where definitive conclusions for pancreatic and thyroid cancer cannot be drawn at this point due to low incidence of these conditions. Due to its potent glucose-lowering effect, patients at risk for deterioration of existing DRP should be carefully monitored if treated with semaglutide, particularly if also treated with insulin. Given the beneficial metabolic and cardiovascular actions of semaglutide, and the low risk for severe adverse events, semaglutide has an overall favorable risk/benefit profile for patient with type 2 diabetes.
Topics: Acute Kidney Injury; Animals; Blood Glucose; Body Weight; Cardiovascular System; Cholelithiasis; Clinical Trials as Topic; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Gallbladder; Gastrointestinal Tract; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Insulin; Nausea; Pancreas; Pancreatic Neoplasms; Pancreatitis; Patient Safety; Peptides; Thyroid Neoplasms; Time Factors
PubMed: 34305810
DOI: 10.3389/fendo.2021.645563 -
Physiological Reviews Jan 2015Magnesium (Mg(2+)) is an essential ion to the human body, playing an instrumental role in supporting and sustaining health and life. As the second most abundant... (Review)
Review
Magnesium (Mg(2+)) is an essential ion to the human body, playing an instrumental role in supporting and sustaining health and life. As the second most abundant intracellular cation after potassium, it is involved in over 600 enzymatic reactions including energy metabolism and protein synthesis. Although Mg(2+) availability has been proven to be disturbed during several clinical situations, serum Mg(2+) values are not generally determined in patients. This review aims to provide an overview of the function of Mg(2+) in human health and disease. In short, Mg(2+) plays an important physiological role particularly in the brain, heart, and skeletal muscles. Moreover, Mg(2+) supplementation has been shown to be beneficial in treatment of, among others, preeclampsia, migraine, depression, coronary artery disease, and asthma. Over the last decade, several hereditary forms of hypomagnesemia have been deciphered, including mutations in transient receptor potential melastatin type 6 (TRPM6), claudin 16, and cyclin M2 (CNNM2). Recently, mutations in Mg(2+) transporter 1 (MagT1) were linked to T-cell deficiency underlining the important role of Mg(2+) in cell viability. Moreover, hypomagnesemia can be the consequence of the use of certain types of drugs, such as diuretics, epidermal growth factor receptor inhibitors, calcineurin inhibitors, and proton pump inhibitors. This review provides an extensive and comprehensive overview of Mg(2+) research over the last few decades, focusing on the regulation of Mg(2+) homeostasis in the intestine, kidney, and bone and disturbances which may result in hypomagnesemia.
Topics: Bone and Bones; Brain; Cardiovascular System; Cell Communication; Cell Proliferation; Digestive System; Humans; Kidney; Lung; Magnesium; Magnesium Deficiency; Muscles; Neoplasms; Signal Transduction
PubMed: 25540137
DOI: 10.1152/physrev.00012.2014 -
Arteriosclerosis, Thrombosis, and... Mar 2020Androgen deprivation therapy is a cornerstone of prostate cancer treatment. Pharmacological androgen deprivation includes gonadotropin-releasing hormone agonism and... (Meta-Analysis)
Meta-Analysis Review
Androgen deprivation therapy is a cornerstone of prostate cancer treatment. Pharmacological androgen deprivation includes gonadotropin-releasing hormone agonism and antagonism, androgen receptor inhibition, and CYP17 (cytochrome P450 17A1) inhibition. Studies in the past decade have raised concerns about the potential for androgen deprivation therapy to increase the risk of adverse cardiovascular events such as myocardial infarction, stroke, and cardiovascular mortality, possibly by exacerbating cardiovascular risk factors. In this review, we summarize existing data on the cardiovascular effects of androgen deprivation therapy. Among the therapies, abiraterone stands out for increasing risk of cardiac events in meta-analyses of both randomized controlled trials and observational studies. We find a divergence between observational studies, which show consistent positive associations between androgen deprivation therapy use and cardiovascular disease, and randomized controlled trials, which do not show these associations reproducibly.
Topics: Androgen Antagonists; Antineoplastic Agents, Hormonal; Cardiotoxicity; Cardiovascular Diseases; Cardiovascular System; Humans; Male; Prostatic Neoplasms; Risk Assessment; Risk Factors; Treatment Outcome
PubMed: 31969015
DOI: 10.1161/ATVBAHA.119.313046 -
Ageing Research Reviews Dec 2022While handgrip strength is associated with all-cause and cause-specific mortality, whether such associations are dose-dependent is largely unknown. Therefore, we... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
While handgrip strength is associated with all-cause and cause-specific mortality, whether such associations are dose-dependent is largely unknown. Therefore, we conducted a systematic review on the dose-response relationship of handgrip strength with all-cause mortality, cancer, and cardiovascular mortality.
METHODS
The data source included three electronic databases (PubMed/MEDLINE, Web of Science and Scopus) from inception to 8 February 2022. Prospective cohort studies of healthy adults with objective measures of handgrip strength were included. Two researchers independently screened studies, extracted data, and assessed risk of bias. We used estimates regarding handgrip strength categories to conduct a random forest model, and a two-stage random-effects hierarchical meta-regression model pooling study-specific estimates for dose-response relationship. Outcomes included all-cause, cancer, and cardiovascular mortality.
REULTS
Forty-eight studies comprising 3,135,473 participants (49.6% women, age range 35-85 years) were included. Random forest models showed a significant inverse association between handgrip strength and all-cause and cause-specific mortality. Dose-response meta-analyses showed that higher levels of handgrip strength significantly reduced the risk of all-cause mortality within 26-50 kg (Higgin´s I =45.7%) in a close-to-linear inverse fashion. Cancer and cardiovascular mortality displayed a trend towards a U-shaped association with a significant risk reduction between 16 and 33 kg (Higgin´s I =77.4%), and a close-to-linear inverse shaped and significant risk reduction ranging from 24 to 40 kg (Higgin´s I =79.7%) respectively.
CONCLUSION
There is strong evidence for an association between lower handgrip strength with higher all-cause, cancer, and cardiovascular mortality risk. The dose-response relationship of handgrip strength substantially varies depending on the cause of mortality.
Topics: Female; Humans; Aged; Aged, 80 and over; Male; Hand Strength; Prospective Studies; Cardiovascular System; Neoplasms; Cardiovascular Diseases
PubMed: 36332759
DOI: 10.1016/j.arr.2022.101778 -
Physiological Reviews Jul 2011New vessel formation (angiogenesis) is an essential physiological process for embryologic development, normal growth, and tissue repair. Angiogenesis is tightly... (Review)
Review
New vessel formation (angiogenesis) is an essential physiological process for embryologic development, normal growth, and tissue repair. Angiogenesis is tightly regulated at the molecular level. Dysregulation of angiogenesis occurs in various pathologies and is one of the hallmarks of cancer. The imbalance of pro- and anti-angiogenic signaling within tumors creates an abnormal vascular network that is characterized by dilated, tortuous, and hyperpermeable vessels. The physiological consequences of these vascular abnormalities include temporal and spatial heterogeneity in tumor blood flow and oxygenation and increased tumor interstitial fluid pressure. These abnormalities and the resultant microenvironment fuel tumor progression, and also lead to a reduction in the efficacy of chemotherapy, radiotherapy, and immunotherapy. With the discovery of vascular endothelial growth factor (VEGF) as a major driver of tumor angiogenesis, efforts have focused on novel therapeutics aimed at inhibiting VEGF activity, with the goal of regressing tumors by starvation. Unfortunately, clinical trials of anti-VEGF monotherapy in patients with solid tumors have been largely negative. Intriguingly, the combination of anti-VEGF therapy with conventional chemotherapy has improved survival in cancer patients compared with chemotherapy alone. These seemingly paradoxical results could be explained by a "normalization" of the tumor vasculature by anti-VEGF therapy. Preclinical studies have shown that anti-VEGF therapy changes tumor vasculature towards a more "mature" or "normal" phenotype. This "vascular normalization" is characterized by attenuation of hyperpermeability, increased vascular pericyte coverage, a more normal basement membrane, and a resultant reduction in tumor hypoxia and interstitial fluid pressure. These in turn can lead to an improvement in the metabolic profile of the tumor microenvironment, the delivery and efficacy of exogenously administered therapeutics, the efficacy of radiotherapy and of effector immune cells, and a reduction in number of metastatic cells shed by tumors into circulation in mice. These findings are consistent with data from clinical trials of anti-VEGF agents in patients with various solid tumors. More recently, genetic and pharmacological approaches have begun to unravel some other key regulators of vascular normalization such as proteins that regulate tissue oxygen sensing (PHD2) and vessel maturation (PDGFRβ, RGS5, Ang1/2, TGF-β). Here, we review the pathophysiology of tumor angiogenesis, the molecular underpinnings and functional consequences of vascular normalization, and the implications for treatment of cancer and nonmalignant diseases.
Topics: Angiogenesis Inhibitors; Animals; Blood Vessels; Disease; Disease Progression; Humans; Lymphatic System; Models, Cardiovascular; Neoplasms; Neovascularization, Pathologic; Vascular Endothelial Growth Factor A
PubMed: 21742796
DOI: 10.1152/physrev.00038.2010 -
Nature Reviews. Endocrinology Aug 2011Estrogens mediate profound effects throughout the body and regulate physiological and pathological processes in both women and men. The low prevalence of many diseases... (Review)
Review
Estrogens mediate profound effects throughout the body and regulate physiological and pathological processes in both women and men. The low prevalence of many diseases in premenopausal women is attributed to the presence of 17β-estradiol, the predominant and most potent endogenous estrogen. In addition to endogenous estrogens, several man-made and plant-derived molecules, such as bisphenol A and genistein, also exhibit estrogenic activity. Traditionally, the actions of 17β-estradiol are ascribed to two nuclear estrogen receptors (ERs), ERα and ERβ, which function as ligand-activated transcription factors. However, 17β-estradiol also mediates rapid signaling events via pathways that involve transmembrane ERs, such as G-protein-coupled ER 1 (GPER; formerly known as GPR30). In the past 10 years, GPER has been implicated in both rapid signaling and transcriptional regulation. With the discovery of GPER-selective ligands that can selectively modulate GPER function in vitro and in preclinical studies and with the use of Gper knockout mice, many more potential roles for GPER are being elucidated. This Review highlights the physiological roles of GPER in the reproductive, nervous, endocrine, immune and cardiovascular systems, as well as its pathological roles in a diverse array of disorders including cancer, for which GPER is emerging as a novel therapeutic target and prognostic indicator.
Topics: Animals; Benzhydryl Compounds; Cardiovascular System; Endocrine System; Estradiol; Female; Genistein; Humans; Immune System; Male; Neoplasms; Nervous System; Phenols; Premenopause; Receptors, Estrogen; Receptors, G-Protein-Coupled; Signal Transduction
PubMed: 21844907
DOI: 10.1038/nrendo.2011.122 -
Clinical Science (London, England :... Mar 2012Considerable efforts have been made since the 1950s to better understand the cellular and molecular mechanisms of action of metformin, a potent antihyperglycaemic agent... (Review)
Review
Considerable efforts have been made since the 1950s to better understand the cellular and molecular mechanisms of action of metformin, a potent antihyperglycaemic agent now recommended as the first-line oral therapy for T2D (Type 2 diabetes). The main effect of this drug from the biguanide family is to acutely decrease hepatic glucose production, mostly through a mild and transient inhibition of the mitochondrial respiratory chain complex I. In addition, the resulting decrease in hepatic energy status activates AMPK (AMP-activated protein kinase), a cellular metabolic sensor, providing a generally accepted mechanism for the action of metformin on hepatic gluconeogenesis. The demonstration that respiratory chain complex I, but not AMPK, is the primary target of metformin was recently strengthened by showing that the metabolic effect of the drug is preserved in liver-specific AMPK-deficient mice. Beyond its effect on glucose metabolism, metformin has been reported to restore ovarian function in PCOS (polycystic ovary syndrome), reduce fatty liver, and to lower microvascular and macrovascular complications associated with T2D. Its use has also recently been suggested as an adjuvant treatment for cancer or gestational diabetes and for the prevention in pre-diabetic populations. These emerging new therapeutic areas for metformin will be reviewed together with recent findings from pharmacogenetic studies linking genetic variations to drug response, a promising new step towards personalized medicine in the treatment of T2D.
Topics: Animals; Cardiovascular System; Circadian Clocks; Diabetic Nephropathies; Female; Humans; Hypoglycemic Agents; Metformin; Neoplasms; Polycystic Ovary Syndrome
PubMed: 22117616
DOI: 10.1042/CS20110386 -
Indian Heart Journal 2023Having established the significance of cardiovascular side-effects of anti-neoplastic drugs, present day cardio-oncology has forayed into newer territories buoyed by... (Review)
Review
Having established the significance of cardiovascular side-effects of anti-neoplastic drugs, present day cardio-oncology has forayed into newer territories buoyed by research into the multiple connections that exist between cardiovascular disease and cancer. An emerging concept of reverse cardio-oncology focuses on the heightened risk of cancer in patients with cardiovascular disease. Common mechanistics of cancer and heart failure (HF) like chronic inflammation and clonal haematopoesis as well as common predisposing factors like obesity and diabetes underline the relation between both cardiovascular disease and various cancers.This review discusses the potential magnitude of the problem, the underlying pathophysiological mechanisms and classification of this novel subject.
Topics: Humans; Cardiovascular Diseases; Cardio-Oncology; Neoplasms; Heart Failure; Cardiovascular System
PubMed: 37774949
DOI: 10.1016/j.ihj.2023.09.004 -
Annals of the New York Academy of... Nov 2019Chromogranin A (CgA)-the index member of the chromogranin/secretogranin secretory protein family-is ubiquitously distributed in endocrine, neuroendocrine, and immune... (Review)
Review
Chromogranin A (CgA)-the index member of the chromogranin/secretogranin secretory protein family-is ubiquitously distributed in endocrine, neuroendocrine, and immune cells. Elevated levels of CgA-related polypeptides, consisting of full-length molecules and fragments, are detected in the blood of patients suffering from neuroendocrine tumors, heart failure, renal failure, hypertension, rheumatoid arthritis, and inflammatory bowel disease. Full-length CgA and various CgA-derived peptides, including vasostatin-1, pancreastatin, catestatin, and serpinin, are expressed at different relative levels in normal and pathological conditions and exert diverse, and sometime opposite, biological functions. For example, CgA is overexpressed in genetic hypertension, whereas catestatin is diminished. In rodents, the administration of catestatin decreases hypertension, cardiac contractility, obesity, atherosclerosis, and inflammation, and it improves insulin sensitivity. By contrast, pancreastatin is elevated in diabetic patients, and the administration of this peptide to obese mice decreases insulin sensitivity and increases inflammation. CgA and the N-terminal fragment of vasostatin-1 can enhance the endothelial barrier function, exert antiangiogenic effects, and inhibit tumor growth in animal models, whereas CgA fragments lacking the CgA C-terminal region promote angiogenesis and tumor growth. Overall, the CgA system, consisting of full-length CgA and its fragments, is emerging as an important and complex player in cardiovascular, immunometabolic, and cancer regulation.
Topics: Animals; Cardiovascular System; Chromogranin A; Humans; Inflammation; Neoplasms; Peptide Fragments
PubMed: 31588572
DOI: 10.1111/nyas.14249 -
Journal of Molecular and Cellular... Jun 2022As the number of cancer survivors has increased significantly over the last decades due to aging of population and development of effective cancer therapies, side... (Review)
Review
As the number of cancer survivors has increased significantly over the last decades due to aging of population and development of effective cancer therapies, side effects from cancer therapies have been increasingly recognized. High-dose anthracyclines, immunotherapies, and concurrent radiation, as well as traditional cardiovascular risk factors such as smoking, hypertension, diabetes, hyperlipidemia, and obesity increase risks for unintended cardiovascular toxicity. However, these factors do not fully explain why only a subset of patients develop adverse cardiovascular sequelae from cancer therapies. Recent studies demonstrate that genetics play a substantial role in susceptibility to development of cardiovascular toxicities from cancer therapies. Common single nucleotide polymorphisms in multiple genes involved in various cellular pathways including membrane transport, stress response, and sarcomeres are recognized to increase risks for these toxicities. Pathogenic variants in the genes encoding proteins that comprise sarcomeres also contribute to cardiomyopathy following cancer therapies. Furthermore, genetic manipulations of model systems indicate mechanisms by which cardiotoxicities emerge following cancer immunomodulatory therapies. Continued efforts are needed to enable insights into cardiovascular responsiveness to these multi-targeted therapies, improve risk stratification of patients, and enable therapeutic interventions that limit these unintended adverse consequences from life-saving cancer treatments.
Topics: Anthracyclines; Antineoplastic Agents; Cardiotoxicity; Cardiovascular System; Heart Diseases; Humans; Neoplasms
PubMed: 35358500
DOI: 10.1016/j.yjmcc.2022.03.010