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Frontiers in Endocrinology 2023Glucagon-like peptide 1 (GLP-1) agonists and sodium-glucose co-transporter-2 (SGLT2) inhibitors are novel drugs which have recently seen rapid uptake in the treatment of... (Review)
Review
AIMS/HYPOTHESIS
Glucagon-like peptide 1 (GLP-1) agonists and sodium-glucose co-transporter-2 (SGLT2) inhibitors are novel drugs which have recently seen rapid uptake in the treatment of type 2 diabetes and obesity. The paucity of data regarding their safety during pregnancy and lactation causes a dilemma for the physician. The aim of the present study was to systematically review all available data on the offspring effects of GLP-1 agonists and SGLT2 inhibitors during pregnancy and lactation.
METHODS
We systematically searched PubMed, clinicaltrials.gov, FDA and EMA product information on GLP-1 agonists and SGLT2 inhibitors in pregnancy and lactation from inception up to 19 April 2022 without language restrictions. We approached both the Netherlands Pharmacovigilance Centre Lareb on January 17 2023 and the Teratology Information Service (TIS) of Switzerland on February 6 2023. Eligible studies investigating the safety (including congenital anomalies, fetal growth, perinatal demise) in animals or humans, or reporting the degree of transfer of these drugs to the fetus, breast milk or breastfed neonate. Two reviewers independently assessed and selected studies for inclusion and subsequently resolved discrepancies by discussion.
RESULTS
We included 39 records (n=9 theoretical; based on drug properties, n=7 human; n=23 animal, including 76 human offspring, and an unknown number of animal offspring as these numbers could not be retrieved from the FDA and EMA product information). In animal studies, GLP1-agonists were associated with reduced fetal weight and/or growth, delayed ossification and skeletal variants, usually associated with a reduction in maternal weight gain and decreased food consumption. Exendin-4 (GLP1-agonist) was not transported across the maternal-fetal placental interface. In human studies, exenatide (GLP1-agonist) showed a fetal-to-maternal peptide concentration ratio of ≤ 0.017 in ex vivo human placental perfusion in a single placenta. Liraglutide (GLP1-agonist) showed no significant maternal to fetal transfer at least 3.5 hours after maternal exposure in a human study with one subject. In animal studies, GLP-1 agonists were excreted in breast milk; human data on excretion were not available. In animal studies, SGLT2 inhibitors were generally safe during the first trimester but exposure during postnatal day 21 to 90 in juvenile rats, a period coinciding with the late second and third trimester of human renal development, caused dilatation of the renal pelvis and tubules. Human data consisted of a pharmaceutical database of inadvertent pregnancies during SGLT2 inhibitor use, which found an increase in miscarriages and congenital malformations. In animal studies SGLT2 inhibitors were excreted in breast milk and affected neonatal growth, but human data are not available.
CONCLUSION/INTERPRETATION
We found evidence for adverse offspring effects of GLP-1 agonists and SGLT2 inhibitors also in human studies. Our findings broadly support the advice to discontinue GLP-1 agonists and SGLT2 inhibitors during pregnancy and lactation, and also support the ongoing registration of pregnancy outcomes in pharmacological databases since the amount of available data is scarce and mostly limited to animal studies.
REGISTRATION
https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=219877.
Topics: Female; Humans; Pregnancy; Rats; Animals; Sodium-Glucose Transporter 2 Inhibitors; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Breast Feeding; Placenta; Exenatide; Liraglutide; Lactation
PubMed: 37881498
DOI: 10.3389/fendo.2023.1215356 -
Biochemical Pharmacology Oct 2020Among the more promising treatments proposed for Alzheimer's disease (AD) and Parkinson's disease (PD) are those reducing brain insulin resistance. The antidiabetics in...
Among the more promising treatments proposed for Alzheimer's disease (AD) and Parkinson's disease (PD) are those reducing brain insulin resistance. The antidiabetics in the class of incretin receptor agonists (IRAs) reduce symptoms and brain pathology in animal models of AD and PD, as well as glucose utilization in AD cases and clinical symptoms in PD cases after their systemic administration. At least 9 different IRAs are showing promise as AD and PD therapeutics, but we still lack quantitative data on their relative ability to cross the blood-brain barrier (BBB) reaching the brain parenchyma. We consequently compared brain uptake pharmacokinetics of intravenous I-labeled IRAs in adult CD-1 mice over the course of 60 min. We tested single IRAs (exendin-4, liraglutide, lixisenatide, and semaglutide), which bind receptors for one incretin (glucagon-like peptide-1 [GLP-1]), and dual IRAs, which bind receptors for two incretins (GLP-1 and glucose-dependent insulinotropic polypeptide [GIP]), including unbranched, acylated, PEGylated, or C-terminally modified forms (Finan/Ma Peptides 17, 18, and 20 and Hölscher peptides DA3-CH and DA-JC4). The non-acylated and non-PEGylated IRAs (exendin-4, lixisenatide, Peptide 17, DA3-CH and DA-JC4) had significant rates of blood-to-brain influx (Ki), but the acylated IRAs (liraglutide, semaglutide, and Peptide 18) did not measurably cross the BBB. The brain influx of the non-acylated, non-PEGylated IRAs were not saturable up to 1 μg of these drugs and was most likely mediated by adsorptive transcytosis across brain endothelial cells, as observed for exendin-4. Of the non-acylated, non-PEGylated IRAs tested, exendin-4 and DA-JC4 were best able to cross the BBB based on their rate of brain influx, percentage reaching the brain that accumulated in brain parenchyma, and percentage of the systemic dose taken up per gram of brain tissue. Exendin-4 and DA-JC4 thus merit special attention as IRAs well-suited to enter the central nervous system (CNS), thus reaching areas pathologic in AD and PD.
Topics: Alzheimer Disease; Amino Acid Sequence; Animals; Blood-Brain Barrier; Brain; Exenatide; Humans; Incretins; Male; Mice; Parkinson Disease
PubMed: 32755557
DOI: 10.1016/j.bcp.2020.114187 -
Nutrients Dec 2022Depression is a frequent and serious comorbidity associated with diabetes which adversely affects prognosis and quality of life. Glucagon-like peptide-1 receptor...
Depression is a frequent and serious comorbidity associated with diabetes which adversely affects prognosis and quality of life. Glucagon-like peptide-1 receptor (GLP-1R) agonists, widely used in the treatment of diabetes, are reported to exert neuroprotective effects in the central nervous system. Thus, we aim to evaluate whether GLP-1R agonist exendin-4 (EX-4) could alleviate depression-like behaviors in diabetic mice and to explore its underlying mechanism. The antidepressant effects of EX-4 were evaluated using behavioral tests in / mice. The effects of EX-4 on microglial pyroptosis and neuroinflammation were assessed in N9 microglial cells. EX-4 administration alleviated depression-like behaviors in diabetic / mice. GLP-1R activation by EX-4 significantly suppressed microglial pyroptosis and neuroinflammation by downregulation of gasdermin D (GSDMD) and interleukin (IL)-1β in diabetic mice and lipopolysaccharide (LPS)-primed N9 microglia. Mechanistically, GLP-1R activation improved mitochondrial function and promoted mitophagy by decreasing the accumulation of mitochondrial reactive oxygen species (mtROS) and intracellular ROS production. EX-4 exhibits antidepressant effects in depression associated with diabetes in diabetic mice, which may be mediated by inhibiting microglial pyroptisis via promoting mitophagy. It is supposed that GLP-1R agonists may be a promising therapy in depression associated with diabetes.
Topics: Mice; Animals; Microglia; Glucagon-Like Peptide-1 Receptor; Pyroptosis; Diabetes Mellitus, Experimental; Depression; Neuroinflammatory Diseases; Mitophagy; Quality of Life; Exenatide; Glucagon-Like Peptide 1; Antidepressive Agents
PubMed: 36615696
DOI: 10.3390/nu15010038 -
Diabetes, Obesity & Metabolism Sep 2018To assess the effect of baseline body mass index (BMI) and the occurrence of nausea and/or vomiting on weight loss induced by semalgutide, a once-weekly glucagon-like... (Randomized Controlled Trial)
Randomized Controlled Trial
AIMS
To assess the effect of baseline body mass index (BMI) and the occurrence of nausea and/or vomiting on weight loss induced by semalgutide, a once-weekly glucagon-like peptide 1 analogue for the treatment of type 2 diabetes. Semaglutide demonstrated superior reductions in HbA1c and superior weight loss (by 2.3-6.3 kg) versus different comparators across the SUSTAIN 1 to 5 trials; the contributing factors to weight loss are not established.
MATERIALS AND METHODS
Subjects with inadequately controlled type 2 diabetes (drug-naïve or on background treatment) were randomized to subcutaneous semaglutide 0.5 mg (excluding SUSTAIN 3), 1.0 mg (all trials), or comparator (placebo, sitagliptin, exenatide extended release or insulin glargine). Subjects were subdivided by baseline BMI and reporting (yes/no) of any nausea and/or vomiting. Change from baseline in body weight was assessed within each trial and subgroup. A mediation analysis separated weight loss into direct or indirect (mediated by nausea or vomiting) effects.
RESULTS
Clinically relevant weight-loss differences were observed across all BMI subgroups, with a trend towards higher absolute weight loss with higher baseline BMI. Overall, 15.2% to 24.0% and 21.5% to 27.2% of subjects experienced nausea or vomiting with semaglutide 0.5 and 1.0 mg, respectively, versus 6.0% to 14.1% with comparators. Only 0.07 to 0.5 kg of the treatment difference between semaglutide and comparators was mediated by nausea or vomiting (indirect effects).
CONCLUSIONS
In SUSTAIN 1 to 5, semaglutide-induced weight loss was consistently greater versus comparators, regardless of baseline BMI. The contribution of nausea or vomiting to this weight loss was minor.
Topics: Adult; Aged; Body Mass Index; Diabetes Mellitus, Type 2; Exenatide; Female; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Insulin Glargine; Male; Middle Aged; Nausea; Sitagliptin Phosphate; Treatment Outcome; Vomiting; Weight Loss
PubMed: 29766634
DOI: 10.1111/dom.13353 -
EBioMedicine Jul 2023Glucagon-like peptide1 receptor (GLP-1R) agonists have been found to reduce alcohol drinking in rodents and overweight patients with alcohol use disorder (AUD). However,...
BACKGROUND
Glucagon-like peptide1 receptor (GLP-1R) agonists have been found to reduce alcohol drinking in rodents and overweight patients with alcohol use disorder (AUD). However, the probability of low semaglutide doses, an agonist with higher potency and affinity for GLP-1R, to attenuate alcohol-related responses in rodents and the underlying neuronal mechanisms is unknown.
METHODS
In the intermittent access model, we examined the ability of semaglutide to decrease alcohol intake and block relapse-like drinking, as well as imaging the binding of fluorescently marked semaglutide to nucleus accumbens (NAc) in both male and female rats. The suppressive effect of semaglutide on alcohol-induced locomotor stimulation and in vivo dopamine release in NAc was tested in male mice. We evaluated effect of semaglutide on the in vivo release of dopamine metabolites (DOPAC and HVA) and gene expression of enzymes metabolising dopamine (MAOA and COMT) in male mice.
FINDINGS
In male and female rats, acute and repeated semaglutide administration reduced alcohol intake and prevented relapse-like drinking. Moreover, fluorescently labelled semaglutide was detected in NAc of alcohol-drinking male and female rats. Further, semaglutide attenuated the ability of alcohol to cause hyperlocomotion and to elevate dopamine in NAc in male mice. As further shown in male mice, semaglutide enhanced DOPAC and HVA in NAc when alcohol was onboard and increased the gene expression of COMT and MAOA.
INTERPRETATION
Altogether, this indicates that semaglutide reduces alcohol drinking behaviours, possibly via a reduction in alcohol-induced reward and NAc dependent mechanisms. As semaglutide also decreased body weight of alcohol-drinking rats of both sexes, upcoming clinical studies should test the plausibility that semaglutide reduces alcohol intake and body weight in overweight AUD patients.
FUNDING
Swedish Research Council (2019-01676), LUA/ALF (723941) from the Sahlgrenska University Hospital and the Swedish brain foundation.
Topics: Female; Rats; Mice; Male; Animals; Exenatide; Dopamine; 3,4-Dihydroxyphenylacetic Acid; Overweight; Ethanol; Alcoholism; Alcohol Drinking; Recurrence
PubMed: 37295046
DOI: 10.1016/j.ebiom.2023.104642 -
Journal of Neuroinflammation Nov 2019Preserving the integrity of the blood-brain barrier (BBB) is beneficial to avoid further brain damage after acute ischemic stroke (AIS). Astrocytes, an important...
BACKGROUND
Preserving the integrity of the blood-brain barrier (BBB) is beneficial to avoid further brain damage after acute ischemic stroke (AIS). Astrocytes, an important component of the BBB, promote BBB breakdown in subjects with AIS by secreting inflammatory factors. The glucagon-like peptide-1 receptor (GLP-1R) agonist exendin-4 (Ex-4) protects the BBB and reduces brain inflammation from cerebral ischemia, and GLP-1R is expressed on astrocytes. However, the effect of Ex-4 on astrocytes in subjects with AIS remains unclear.
METHODS
In the present study, we investigated the effect of Ex-4 on astrocytes cultured under oxygen-glucose deprivation (OGD) plus reoxygenation conditions and determined whether the effect influences bEnd.3 cells. We used various methods, including permeability assays, western blotting, immunofluorescence staining, and gelatin zymography, in vitro and in vivo.
RESULTS
Ex-4 reduced OGD-induced astrocyte-derived vascular endothelial growth factor (VEGF-A), matrix metalloproteinase-9 (MMP-9), chemokine monocyte chemoattractant protein-1 (MCP-1), and chemokine C-X-C motif ligand 1 (CXCL-1). The reduction in astrocyte-derived VEGF-A and MMP-9 was related to the increased expression of tight junction proteins (TJPs) in bEnd.3 cells. Ex-4 improved neurologic deficit scores, reduced the infarct area, and ameliorated BBB breakdown as well as decreased astrocyte-derived VEGF-A, MMP-9, CXCL-1, and MCP-1 levels in ischemic brain tissues from rats subjected to middle cerebral artery occlusion. Ex-4 reduced the activation of the JAK2/STAT3 signaling pathway in astrocytes following OGD.
CONCLUSION
Based on these findings, ischemia-induced inflammation and BBB breakdown can be improved by Ex-4 through an astrocyte-dependent manner.
Topics: Animals; Astrocytes; Blood-Brain Barrier; Chemokine CCL2; Chemokine CXCL1; Exenatide; Glucagon-Like Peptide-1 Receptor; Infarction, Middle Cerebral Artery; Inflammation; Male; Matrix Metalloproteinase 9; Rats; Rats, Sprague-Dawley; Stroke; Vascular Endothelial Growth Factor A
PubMed: 31779652
DOI: 10.1186/s12974-019-1638-6 -
Molecular Medicine (Cambridge, Mass.) Dec 2022The T helper 17 (Th17)/T regulatory (Treg) cell imbalance is involved in the course of obesity and type 2 diabetes mellitus (T2DM). In the current study, the exact role...
BACKGROUND
The T helper 17 (Th17)/T regulatory (Treg) cell imbalance is involved in the course of obesity and type 2 diabetes mellitus (T2DM). In the current study, the exact role of glucagon-like peptide-1 receptor agonist (GLP-1RA) exenatide on regulating the Th17/Treg balance and the underlying molecular mechanisms are investigated in obese diabetic mice model.
METHODS
Metabolic parameters were monitored in db/db mice treated with/without exenatide during 8-week study period. The frequencies of Th17 and Treg cells from peripheral blood and pancreas in db/db mice were assessed. The phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/Forkhead box O1 (FoxO1) pathway in Th17 and Treg cells from the spleens of male C57BL/6J mice was detected by western blotting. In addition, the expression of glucagon-like peptide-1 receptor (GLP-1R) in peripheral blood mononuclear cells (PBMCs) of male C57BL/6J mice was analyzed.
RESULTS
Exenatide treatment improved β-cell function and insulitis in addition to glucose, insulin sensitivity and weight. Increased Th17 and decreased Treg cells in peripheral blood were present as diabetes progressed while exenatide corrected this imbalance. Progressive IL-17 + T cell infiltration of pancreatic islets was alleviated by exenatide intervention. In vitro study showed no significant difference in the level of GLP-1R expression in PBMCs between control and palmitate (PA) groups. In addition, PA could promote Th17 but suppress Treg differentiation along with down-regulating the phosphorylation of PI3K/Akt/FoxO1, which was reversed by exenatide intervention. FoxO1 inhibitor AS1842856 could abrogate all these effects of exenatide against lipid stress.
CONCLUSIONS
Exenatide could restore systemic Th17/Treg balance via regulating FoxO1 pathway with the progression of diabetes in db/db mice. The protection of pancreatic β-cell function may be partially mediated by inhibiting Th17 cell infiltration into pancreatic islets, and the resultant alleviation of islet inflammation.
Topics: Male; Mice; Animals; Phosphatidylinositol 3-Kinase; Exenatide; Proto-Oncogene Proteins c-akt; Phosphatidylinositol 3-Kinases; T-Lymphocytes, Regulatory; Glucagon-Like Peptide-1 Receptor; Diabetes Mellitus, Type 2; Leukocytes, Mononuclear; Diabetes Mellitus, Experimental; Mice, Inbred C57BL; Forkhead Box Protein O1
PubMed: 36463128
DOI: 10.1186/s10020-022-00574-6 -
Diabetologia Jul 2023Wolfram syndrome is a rare autosomal recessive disorder caused by pathogenic variants in the WFS1 gene. It is characterised by insulin-dependent diabetes mellitus, optic...
AIMS/HYPOTHESIS
Wolfram syndrome is a rare autosomal recessive disorder caused by pathogenic variants in the WFS1 gene. It is characterised by insulin-dependent diabetes mellitus, optic nerve atrophy, diabetes insipidus, hearing loss and neurodegeneration. Considering the unmet treatment need for this orphan disease, this study aimed to evaluate the therapeutic potential of glucagon-like peptide 1 receptor (GLP-1R) agonists under wolframin (WFS1) deficiency with a particular focus on human beta cells and neurons.
METHODS
The effect of the GLP-1R agonists dulaglutide and exenatide was examined in Wfs1 knockout mice and in an array of human preclinical models of Wolfram syndrome, including WFS1-deficient human beta cells, human induced pluripotent stem cell (iPSC)-derived beta-like cells and neurons from control individuals and individuals affected by Wolfram syndrome, and humanised mice.
RESULTS
Our study shows that the long-lasting GLP-1R agonist dulaglutide reverses impaired glucose tolerance in WFS1-deficient mice, and that exenatide and dulaglutide improve beta cell function and prevent apoptosis in different human WFS1-deficient models including iPSC-derived beta cells from people with Wolfram syndrome. Exenatide improved mitochondrial function, reduced oxidative stress and prevented apoptosis in Wolfram syndrome iPSC-derived neural precursors and cerebellar neurons.
CONCLUSIONS/INTERPRETATION
Our study provides novel evidence for the beneficial effect of GLP-1R agonists on WFS1-deficient human pancreatic beta cells and neurons, suggesting that these drugs may be considered as a treatment for individuals with Wolfram syndrome.
Topics: Humans; Animals; Mice; Wolfram Syndrome; Exenatide; Induced Pluripotent Stem Cells; Optic Atrophy; Insulin-Secreting Cells; Mice, Knockout
PubMed: 36995380
DOI: 10.1007/s00125-023-05905-8 -
Medicine Sep 2023Type 2 diabetes mellitus (T2DM) related bone fracture. The effects of glucagon-like peptide-1 receptor analogs for the treatment of T2DM on bone are controversial in... (Randomized Controlled Trial)
Randomized Controlled Trial
Type 2 diabetes mellitus (T2DM) related bone fracture. The effects of glucagon-like peptide-1 receptor analogs for the treatment of T2DM on bone are controversial in human studies. This study aimed to compare the effects of GLP-1 receptor analogs exenatide and insulin glargine treatment on bone turnover marker levels and bone mineral density (BMD) in postmenopausal female patients with T2DM. Thirty female patients with T2DM who were naive to insulin and incretin-based treatments, with spontaneous postmenopause, were randomized to exenatide or insulin glargine arms and were followed up for 24 weeks. BMD was evaluated using dual-energy X-ray absorptiometry and bone turnover markers by serum enzyme-linked immunosorbent assay. The body mass index significantly decreased in the exenatide group compared to the glargine group (P < .001). Receptor activator of nuclear factor kappa-B (RANK) and RANK ligand (RANKL) levels were significantly decreased with exenatide treatment (P = .009 and P = .015, respectively). Osteoprotegerin (OPG) level significantly increased with exenatide treatment (P = .02). OPG, RANK, RANKL levels did not change with insulin glargine treatment. No statistically significant difference was found between the pre- and posttreatment BMD, alkaline phosphatase, bone-specific alkaline phosphatase, and type 1 crosslinked N-telopeptide levels in both treatment arms. Despite significant weight loss with exenatide treatment, BMD did not decrease, OPG increased, and the resorption markers of RANK and RANKL decreased, which may reflect early antiresorptive effects of exenatide via the OPG/RANK/RANKL pathway.
Topics: Humans; Female; Bone Density; Insulin Glargine; Exenatide; Diabetes Mellitus, Type 2; Postmenopause; Alkaline Phosphatase; Osteoprotegerin; Receptor Activator of Nuclear Factor-kappa B; Bone Remodeling; RANK Ligand
PubMed: 37773814
DOI: 10.1097/MD.0000000000035394 -
Acta Neuropathologica Communications Apr 2021Alzheimer's disease (AD) is the most common cause of age-related dementia. Increasing evidence suggests that neuroinflammation mediated by microglia and astrocytes...
Alzheimer's disease (AD) is the most common cause of age-related dementia. Increasing evidence suggests that neuroinflammation mediated by microglia and astrocytes contributes to disease progression and severity in AD and other neurodegenerative disorders. During AD progression, resident microglia undergo proinflammatory activation, resulting in an increased capacity to convert resting astrocytes to reactive astrocytes. Therefore, microglia are a major therapeutic target for AD and blocking microglia-astrocyte activation could limit neurodegeneration in AD. Here we report that NLY01, an engineered exedin-4, glucagon-like peptide-1 receptor (GLP-1R) agonist, selectively blocks β-amyloid (Aβ)-induced activation of microglia through GLP-1R activation and inhibits the formation of reactive astrocytes as well as preserves neurons in AD models. In two transgenic AD mouse models (5xFAD and 3xTg-AD), repeated subcutaneous administration of NLY01 blocked microglia-mediated reactive astrocyte conversion and preserved neuronal viability, resulting in improved spatial learning and memory. Our study indicates that the GLP-1 pathway plays a critical role in microglia-reactive astrocyte associated neuroinflammation in AD and the effects of NLY01 are primarily mediated through a direct action on Aβ-induced GLP-1R microglia, contributing to the inhibition of astrocyte reactivity. These results show that targeting upregulated GLP-1R in microglia is a viable therapy for AD and other neurodegenerative disorders.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Astrocytes; Cells, Cultured; Exenatide; Glucagon-Like Peptide-1 Receptor; Humans; Male; Maze Learning; Mice; Mice, Transgenic; Microglia; Neuroprotection; Neuroprotective Agents; Peptide Fragments
PubMed: 33902708
DOI: 10.1186/s40478-021-01180-z