Peptide drugs are a highly diverse group of therapeutic agents. Over the last decade, more than 40 peptides have been approved for clinical use. They target different structures, ranging from G protein-coupled receptors (GPCRs) to pathogens and are used to treat a variety of indications, including metabolic disorders, genetic diseases, acute illnesses and more. Structurally, peptide therapeutics are a heterogeneous class. This diversity allows them to bridge the gap between small molecules and biologics. However, limited metabolic stability and bioavailability must be addressed. Strategies to improve the half-life include backbone and sequence modification, cyclization and the addition of stabilizing moieties. Great strides have been made in recent years towards achieving sufficient drug uptake for oral application have been achieved within recent years. However, these methods require specialized peptide design or involve permeabilization of the gastrointestinal tract. Consequently, other routes of administration are being explored. One promising approach is the nasal application of peptides. This method can be used for systemic uptake, but also allows for direct nose-to-brain delivery of compounds. While successful nose-to-brain delivery is already used in the clinic, the underlining mechanisms are poorly understood. Strategies for rational optimization are needed to make this method more applicable to a wider range of compounds. Overall, approved peptide therapeutics cover a wide range of applications and have demonstrated a growing and novel potential in recent drug discovery.

Drug delivery technology has emerged as an effective strategy to enhance the anti-tumor potential of camptothecins. In this study, we constructed an enzyme-activated targeted drug release system employing a stable valine-alanine linker in combination with a highly cytotoxic camptothecin derivative, AZ'0132. The prodrug, named HC07, was successfully delivered to the tumor site via eHSP90, where it underwent specific cleavage, thereby enhancing its therapeutic window and reducing ocular toxicity. In order to further improve its metabolic properties, we innovatively combined HC07 with plasma endogenous albumin to construct albumin-binding prodrugs HC08 and HC09 for the first time. These prodrugs demonstrated prolonged circulation times in vivo and significantly improved tumor selectivity and anti-tumor efficacy. This work presents a promising eHSP90-based long-circulating drug delivery system, providing new avenues for the design of future anti-cancer drugs.

Retrospective cohort.

To evaluate the impact of semaglutide treatment for Type 2 Diabetes Mellitus (T2DM) on the risk of short-term (<6 mo) postoperative complications in patients undergoing primary cervical spine decompression and fusion (CSDF).

Semaglutide, a GLP-1 receptor agonist, is gaining popularity as a weekly injectable medication for the treatment of T2DM and obesity. Existing research indicates that higher levels of HbA1c and obesity are linked to fewer positive results after undergoing spine surgery, particularly cervical decompression and fusion. Nevertheless, there is a scarcity of publications evaluating the influence of semaglutide therapy on surgical complications, including surgical site infection, wound complications, and reoperation within 6 months, which were aggregated into a composite measure.

The PearlDiver Database was queried from January 2010 to December 2021 for patients with a primary diagnosis of T2DM who underwent CSDF for degenerative pathology. Patients with semaglutide treatment within 6 months before index surgery were propensity score-matched to patients without the treatment, using age, sex, and Charlson comorbidity index (CCI) as matching covariates. A multivariate regression model was used to investigate the impact of semaglutide treatment on postoperative surgical complications.

The propensity score-matched cohort included 596 patients (semaglutide cohort: 298 and control cohort: 298). There were no statistically significant differences between cohorts in the composite measure of postoperative surgical complications following index CSDF (OR 1.26, 95% CI 0.83-1.93, P =0.331). Similarly, both 30-day (OR 0.83, 95% CI 0.49-1.42, P =0.589) and 90-day readmission rate (OR 0.89, 95% CI 0.56-1.42, P =0.724) were similar between both cohorts.

This study suggests that in patients with T2DM, semaglutide treatment is not associated with higher rates of short-term adverse events after CSDF. The effect of semaglutide use on long-term outcomes remains unknown.

Therapeutic proteins play a crucial role in modern healthcare. However, the rapid clearance of proteins in the circulation system poses a significant threat to their therapeutic efficacy. The generation of anti-drug antibodies expedites drug clearance, resulting in another challenge to overcome in protein delivery. Several methods to increase the circulation half-lives of these proteins and to minimize their immunogenicity have been developed. This Review discusses the causes of protein clearance in the body, evaluates the FDA-approved strategies to prolong protein circulation, and highlights recent progress in the field. Additionally, the strengths and drawbacks of these methods and our perspectives for advancing protein delivery are provided.

Researches have shown that diabetes mellitus (DM) can promote the risk and progression of oral squamous cell carcinoma (OSCC). Semaglutide, a glucagon-like peptide-1 receptor agonist, is currently employed to treat type 2 diabetes mellitus (T2DM) and obesity. This study intends to explore the potential effects and mechanism of Semaglutide on OSCC.

The expression of GLP-1R in OSCC cells and tissues was evaluated by qRT-PCR, western blot and immunohistochemistry assays. Cell proliferation, invasion, migration and apoptosis abilities were determined by relevant experiments. Western blot was employed to verify the expression of relevant proteins and examine the effect of Semaglutide on the MAPK signaling pathway. The xenograft transplantation model of OSCC was established to examine the anti-cancer effects of Semaglutide in vivo and immunohistochemistry assays were performed on tumor tissues.

GLP-1R expression was elevated in OSCC cells and tissues as compared with that in normal. Semaglutide effectively inhibited the proliferation, migration and invasion of OSCC cells while concurrently promoting apoptosis. Moreover, Semaglutide specifically activated the P38 MAPK signaling pathway without significant influence on ERK1/2 or SAPK/JNK, and its pro-apoptotic effects in OSCC cells was related to P38 pathway activation. Animal experiments verified the inhibitory effect of Semaglutide on OSCC tumors in mice.

Semaglutide exerts inhibitory actions on OSCC and may induce apoptosis in OSCC cells via the P38 MAPK signaling pathway. This study has significant implications for the treatment of patients with diabetes who are also afflicted by OSCC.

G protein-coupled receptors (GPCRs) form one of the largest drug target families, reflecting their involvement in numerous pathophysiological processes. In this Review, we analyse drug discovery trends for the GPCR superfamily, covering compounds, targets and indications that have reached regulatory approval or that are being investigated in clinical trials. We find that there are 516 approved drugs targeting GPCRs, making up 36% of all approved drugs. These drugs act on 121 GPCR targets, one-third of all non-sensory GPCRs. Furthermore, 337 agents targeting 133 GPCRs, including 30 novel targets, are being investigated in clinical trials. Notably, 165 of these agents are approved drugs being tested for additional indications and novel agents are increasingly allosteric modulators and biologics. Remarkably, diabetes and obesity drugs targeting GPCRs had sales of nearly US $30 billion in 2023 and the numbers of clinical trials for GPCR modulators in the metabolic diseases, oncology and immunology areas are increasing strongly. Finally, we highlight the potential of untapped target-disease associations and pathway-biased signalling. Overall, this Review provides an up-to-date reference for the drugged and potentially druggable GPCRome to inform future GPCR drug discovery and development.

Type 1 diabetes mellitus (T1D) is a chronic autoimmune disease caused by the immune-mediated destruction of insulin-producing pancreatic beta cells, resulting in the lifelong need for exogenous insulin. Over the last few years, overweight and obesity have recently emerged as growing health issues also afflicting patients with T1D. In this context, the term "double diabetes" has been coined to indicate patients with T1D who have a family history of type 2 diabetes mellitus (T2D) and/or patients with T1D who are affected by insulin resistance and/or overweight/obesity and/or metabolic syndrome. At the same time, the use of second-generation incretin analogs semaglutide and tirzepatide has substantially increased on a global scale over the last few years, given the remarkable clinical benefits of these drugs (in terms of glucose control and weight loss) in patients with T2D and/or overweight/obesity. Although the glucagon-like peptide-1 (GLP-1) receptor agonists and the novel dual GIP (glucose-dependent insulinotropic polypeptide)/GLP-1 receptor agonist tirzepatide are currently not approved for the treatment of T1D, a growing body of evidence over the last few years has shown that these medications may serve as valid add-on treatments to insulin with substantial efficacy in improving glucose control, promoting weight loss, preserving residual beta-cell function and providing other beneficial metabolic effects in patients with T1D, double diabetes and latent autoimmune diabetes in adults (LADA). This manuscript aims to comprehensively review the currently available literature (mostly consisting of real-world studies) regarding the safety and therapeutic use (for different purposes) of semaglutide and tirzepatide in patients with T1D (at different stages of the disease), double diabetes and LADA.

Metabolic diseases like obesity and diabetes are on the rise, and therapies with biomacromolecules (such as proteins, peptides, antibodies, and oligonucleotides) play a crucial role in their treatment. However, these drugs are traditionally injected. For patients with chronic diseases (e.g., metabolic diseases), long-term injections are accompanied by inconvenience and low compliance. Oral administration is preferred, but the delivery of biomacromolecules is challenging due to gastrointestinal barriers. In this article, we introduce the available biomacromolecule drugs for the treatment of metabolic diseases. The gastrointestinal barriers to oral drug delivery and strategies to overcome these barriers are also explored. We then discuss strategies for alleviating metabolic defects, including glucose metabolism, lipid metabolism, and energy metabolism, with oral biomacromolecules such as insulin, glucagon-like peptide-1 receptor agonists, proprotein convertase subtilisin/kexin type 9 inhibitors, fibroblast growth factor 21 analogues, and peptide YY analogues.

Nanobodies (Nbs) hold great promise as next-generation cancer immunotherapies, but their efficacy is hindered by their poor pharmacokinetics and the inability to trigger Fc-mediated immune killing functions. To address these limitations, we designed and synthesized rhamnolipid-modified Nbs as a type of antibody-recruiting molecule by site-specifically conjugating EGFR-targeting Nb 7D12 to a series of rhamnolipid derivatives, and their biological profiles were evaluated in vitro and in vivo. Investigation of the structure-activity relationship revealed that the number of rhamnose (Rha) units and the length of the PEG linker in the conjugates affected anti-tumor activities. Conjugate R5, which contained two Rha units and a PEG2 linker, exhibited the most potent antibody-dependent cell-mediated phagocytosis (ADCP) and complement-dependent cytotoxicity (CDC) activities. In vivo, R5 had a significantly longer half-life because of its ability to bind to serum albumin and endogenous anti-Rha antibodies, and it demonstrated potent in vivo antitumor activity in a xenograft mouse model of A431 tumor. Our findings highlight the potential of rhamnolipidation as a strategy to enhance the efficacy of Nbs in cancer immunotherapy and provide a cost-effective platform for improving the therapeutic efficiency of Nbs.

Semaglutide is a glucagon-like peptide (GLP1) receptor agonist with unprecedented weight-lowering and anti-hyperglycemic properties. Recent clinical trials reported that subcutaneous semaglutide can modulate blood pressure; however, its effect on blood pressure widely varied in different studies and different subgroups of patients.

PubMed, Web of Science, Scopus, and the Cochrane Library were systematically searched from the inception to July 18, 2024. Due to high heterogeneity, a random-effects model was adopted to pool data.

Twenty clinical trials with 15,312 participants in the placebo group and 18,231 participants in the semaglutide group were included in this study. Subcutaneous semaglutide significantly decreased both systolic (WMD - 3.71 mmHg, 95% CI (-4.29, -3.13), I2: 50.2%) and diastolic (WMD - 1.10 mmHg, 95% CI (-1.58, -0.63), I2: 69.7%) blood pressure. Subgroup analyses indicated that the blood pressure-lowering property of subcutaneous semaglutide was greater among patients without diabetes, with lower baseline hemoglobin A1c (HbA1c), baseline body mass index (BMI) greater than 35 kg/m2, dose of semaglutide more than 1 mg/week, baseline systolic blood pressure equal or less than 130 mmHg, weight loss greater than 10 kg, and BMI reduction greater than 3 kg/m2. In addition, a treatment length of 50 to 100 weeks was associated with greater blood pressure-lowering effects in subgroup analysis. After adjusting for other factors, meta-regression revealed that placebo-adjusted weight change was independently correlated with the effect of semaglutide on systolic and diastolic blood pressure.

Subcutaneous semaglutide can significantly decrease systolic and diastolic blood pressure, particularly in selected groups of patients.

Glucagon-like peptide-1 receptor (GLP-1R) agonists have garnered significant attention for their therapeutic potential in addressing the interconnected health challenges of diabetes, obesity, and cancer. The role of GLP-1R in type 2 diabetes mellitus (T2DM) is highlighted, emphasizing its pivotal contribution to glucose homeostasis, promoting β-cell proliferation, and facilitating insulin release. GLP-1R agonists have effectively managed obesity by reducing hunger, moderating food intake, and regulating body weight. Beyond diabetes and obesity, GLP-1R agonists exhibit a multifaceted impact on cancer progression across various malignancies. The mechanisms underlying these effects involve the modulation of signaling pathways associated with cell growth, survival, and metabolism. However, the current literature reveals a lack of in vivo studies on specific GLP-1R agonists such as semaglutide, necessitating further research to elucidate its precise mechanisms and effects, particularly in cancer. While other GLP-1R agonists have shown promising outcomes in mitigating cancer progression, the association between some GLP-1R agonists and an increased risk of cancer remains a topic requiring more profound investigation. This calls for more extensive research to unravel the intricate relationships between the GLP-1R agonist and different cancers, providing valuable insights for clinicians and researchers alike.

A growing number of studies show that the diabetes drug Semaglutide is neuroprotective in Alzheimer's disease (AD) animal models, but its mode of action is not fully understood. In order to explore the mechanism of Semaglutide, 7-month-old APP/PS1/tau transgenic (3xTg) mice and wild-type (WT) mice were randomly divided into four groups: control group (WT + PBS), AD model group (3xTg + PBS), Semaglutide control group (WT + Semaglutide) and Semaglutide treatment group (3xTg + Semaglutide). Semaglutide (25 nmol/kg) or PBS was administered intraperitoneally once every two days for 30 days, followed by behavioral and molecular experiments. The results show that Semaglutide can improve working memory and spatial reference memory of 3xTg-AD mice, promote the release of anti-inflammatory factors and inhibit the production of pro-inflammatory factors in the cortex and hippocampus, and reduce Aβ deposition in the hippocampal CA1 region of 3xTg mice. Semaglutide can inhibit the apoptosis of BV2 cells induced by Aβ1-42 in a dose-dependent manner and promote the transformation of microglia from M1 to M2, thereby exerting anti-inflammatory and neuroprotective effects. Therefore, we speculate that Semaglutide shows an anti-inflammatory effect by promoting the transformation of microglia from M1 to M2 type in the brain of 3xTg mice, and thus exerts a neuroprotective effect.

Diabetes is a global disease that can lead to a range of complications. Currently, the treatment of type 2 diabetes focuses on oral hypoglycemic drugs and insulin analogues. Studies have shown that drugs such as oral metformin are useful in the treatment of diabetes but can limit the liver's ability to release sugar. The development of glucose-lowering peptides has provided new options for the treatment of type 2 diabetes. Peptide drugs have low oral utilization due to their easy degradation, short half-life, and difficulty passing through the intestinal mucosa. Therefore, improving the oral utilization of peptide drugs remains an urgent problem. This paper reviews the research progress of peptide drugs in the treatment of diabetes mellitus and proposes that different types of nano-formulation carriers, such as liposomes, self-emulsifying drug delivery systems, and polymer particles, should be combined with peptide drugs for oral administration to improve their absorption in the gastrointestinal tract.

Semaglutide, a glucagon-like peptide 1 receptor agonist (GLP1RA), is available in both parenteral and oral preparations. Studies of injectable preparations have convincingly demonstrated its beneficial effect on major adverse cardiac events (MACE). This predictive analysis was undertaken to forecast early termination of the SOUL trial (oral semaglutide) as well as the primary events.

SOUL is a multicenter, double-blind, placebo-controlled randomized controlled trial (RCT) evaluating the reduction in MACE associated with oral semaglutide versus placebo in patients with type 2 diabetes (T2D) and cardiovascular (CV) disease. A sample of 9642 participants will be followed for 5 years and 5 months. A random-effects model meta-analysis, pooling hazard ratios from previous RCTs, was conducted using R software to inform the predictive model. The background CV event rates from the placebo arms of previous RCTs with semaglutide were matched with the pre-adjudicated assumptions of the SOUL trial to create the predictive model. The truncated trial duration, MACE, and its individual components in the intervention and placebo arms were estimated. The predicted difference between the two groups was estimated using the chi-squared test.

A pooled analysis of 10,013 patients revealed a significant reduction in the number of MACEs associated with semaglutide (HR 0.79, 95% CI 0.69-0.91). Predictive analysis indicated that 1225 events would be achieved by 3.78 years, suggesting premature termination.

The mathematical model based on the meta-analysis predicts that the SOUL study on oral semaglutide will be terminated early, with oral semaglutide showing benefits in terms of MACE compared to placebo. If the SOUL study corroborates the findings of this model, it may not only form the basis for the calculation of power but also define the duration of such studies, reducing costs and easing the process of designing cardiovascular outcome trials (CVOTs).

INPLASY202460061.

The glucagon-like peptide-1 (GLP-1) receptor, known as GLP-1R, is a vital component of the G protein-coupled receptor (GPCR) family and is found primarily on the surfaces of various cell types within the human body. This receptor specifically interacts with GLP-1, a key hormone that plays an integral role in regulating blood glucose levels, lipid metabolism, and several other crucial biological functions. In recent years, GLP-1 medications have become a focal point in the medical community due to their innovative treatment mechanisms, significant therapeutic efficacy, and broad development prospects. This article thoroughly traces the developmental milestones of GLP-1 drugs, from their initial discovery to their clinical application, detailing the evolution of diverse GLP-1 medications along with their distinct pharmacological properties. Additionally, this paper explores the potential applications of GLP-1 receptor agonists (GLP-1RAs) in fields such as neuroprotection, anti-infection measures, the reduction of various types of inflammation, and the enhancement of cardiovascular function. It provides an in-depth assessment of the effectiveness of GLP-1RAs across multiple body systems-including the nervous, cardiovascular, musculoskeletal, and digestive systems. This includes integrating the latest clinical trial data and delving into potential signaling pathways and pharmacological mechanisms. The primary goal of this article is to emphasize the extensive benefits of using GLP-1RAs in treating a broad spectrum of diseases, such as obesity, cardiovascular diseases, non-alcoholic fatty liver disease (NAFLD), neurodegenerative diseases, musculoskeletal inflammation, and various forms of cancer. The ongoing development of new indications for GLP-1 drugs offers promising prospects for further expanding therapeutic interventions, showcasing their significant potential in the medical field.

A global obesity pandemic is one of the most significant health threats worldwide owing to its close association with numerous comorbidities such as type 2 diabetes mellitus, arterial hypertension, dyslipidemia, heart failure, cancer and many others. Obesity and its comorbidities lead to a higher rate of cardiovascular complications, heart failure and increased cardiovascular and overall mortality. Bariatric surgery is at present the most potent therapy for obesity, inducing a significant weight loss in the majority of patients. In the long-term, a substantial proportion of patients after bariatric surgery experience a gradual weight regain that may, in some, reach up to a presurgical body weight. As a result, anti-obesity pharmacotherapy may be needed in some patients after bariatric surgery to prevent the weight regain or to further potentiate weight loss. This article provides an overview of the use of anti-obesity medications as an augmentation to bariatric surgery for obesity. Despite relatively limited published data, it can be concluded that anti-obesity medication can serve as an effective adjunct therapy to bariatric surgery to help boost post-bariatric weight loss or prevent weight regain.

This study aimed to develop an effective oral formulation of semaglutide, a glucagon-like peptide-1 receptor agonist, using an organometallic phyllosilicate-based colonic delivery system. The core nanocomplex (AMP-Sema) of 3-aminopropyl-functionalized magnesium phyllosilicate (AMP) and semaglutide was prepared via electrostatic interactions. Subsequently, AMP-Sema was coated with a polymer showing pH-dependent solubility (Eudragit® S100) for preferential colonic delivery. The surface-coated nanoparticles (EAMP-Sema) showed a narrow size distribution, and the encapsulated semaglutide maintained its conformational stability. The pH-dependent drug release property of EAMP-Sema yielded around 20% and 62% drug release at pH 1.2 and 7.4, respectively. The nanoparticles exhibited significantly decreased size and surface charge at pH 7.4, which indicated the pH-dependent dissolution of the coating layer. Furthermore, EAMP-Sema effectively improved the membrane permeability and metabolic stability of semaglutide in the gastrointestinal tract. It protected the encapsulated drugs from proteolysis in simulated intestinal fluids and increased drug transport by 2.5-fold in Caco-2 cells. Consequently, orally administered EAMP-Sema (equivalent to 8 mg/kg of semaglutide) showed significant therapeutic benefits, yielding effective glycemic control and weight loss in high-fat diet/streptozotocin (40 mg/kg)-induced type 2 diabetic rats. These results demonstrate that EAMP-Sema could improve the efficacy of orally administered semaglutide by enhancing the GI stability and cellular uptake of protein drugs.

Hypoxic-ischaemic encephalopathy (HIE) arises from diminished blood flow and oxygen to the neonatal brain during labor, leading to infant mortality or severe brain damage, with a global incidence of 1.5 per 1000 live births. Glucagon-like Peptide 1 Receptor (GLP1-R) agonists, used in type 2 diabetes treatment, exhibit neuroprotective effects in various brain injury models, including HIE. In this study, we observed enhanced neurological outcomes in post-natal day 10 mice with surgically induced hypoxic-ischaemic (HI) brain injury after immediate systemic administration of exendin-4 or semaglutide. Short- and long-term assessments revealed improved neuropathology, survival rates, and locomotor function. We explored the mechanisms by which GLP1-R agonists trigger neuroprotection and reduce inflammation following oxygen-glucose deprivation and HI in neonatal mice, highlighting the upregulation of the PI3/AKT signalling pathway and increased cAMP levels. These findings shed light on the neuroprotective and anti-inflammatory effects of GLP1-R agonists in HIE, potentially extending to other neurological conditions, supporting their potential clinical use in treating infants with HIE.

Epilepsy is one of the most widespread and complex diseases in the central nervous system (CNS), affecting approximately 65 million people globally, an important factor resulting in neurological disability-adjusted life year (DALY) and progressive cognitive dysfunction. Medication is the most essential treatment. The currently used drugs have shown drug resistance in some patients and only control symptoms; the development of novel and more efficacious pharmacotherapy is imminent. Increasing evidence suggests neuroinflammation is involved in the occurrence and development of epilepsy, and high expression of NLRP3 inflammasome has been observed in the temporal lobe epilepsy (TLE) brain tissue of patients and animal models. The inflammasome is a crucial cause of neuroinflammation by activating IL-1β and IL-18. Many preclinical studies have confirmed that regulating NLRP3 inflammasome pathway can prevent the development of epilepsy, reduce the severity of epilepsy, and play a neuroprotective role. Therefore, regulating NLRP3 inflammasome could be a potential target for epilepsy treatment. In summary, this review describes the priming and activation of inflammasome and its biological function in the progression of epilepsy. In addition, we reviewes the current pharmacological researches for epilepsy based on the regulation of NLRP3 inflammasome, aiming to provide a basis and reference for developing novel antiepileptic drugs.

Cardiovascular diseases remain the main cause of death and disability worldwide. Despite the tremendous improvement in pharmacological, minimally invasive and rehabilitative strategies, global deaths due to cardiovascular diseases are still increasing. Additional risk factors have been recently proposed, and thanks to scientific progress, novel drugs for the control of the main risk factors focusing on the cardiometabolic pathways have been identified. Glucagon-like peptide-1 (GLP-1) receptor agonists represent an innovative step in the management of patients affected by type 2 diabetes mellitus. In addition to their significant efficacy on glycemic homeostasis, some members of this class of drugs have indications in the treatment of obesity. Furthermore, accumulated evidence in the literature has finally suggested a protective role in cardiovascular health. The possible role of GLP-1R agonist drugs (GLP-1RAs) on the mechanisms underlying chronic inflammation and the almost ubiquitous distribution of GLP-1 receptors could explain the enormous versatility of these drugs. Semaglutide is a GLP-1RA recently proven to be effective in cardiovascular outcomes. In the present article, we will review the available data on semaglutide in light of the most recent publications to better characterize the target population achieving cardiovascular benefits.

Since we aim to test new options to find medication for cognitive disorders, we have begun to assess the effect of semaglutide and to conduct a review gathering studies that have attempted this purpose. This systematic review focuses on the cognitive effects of semaglutide, a glucagon-like peptide 1 receptor agonist (GLP-1 RA), in the context of neurological and cognitive impairment. Semaglutide, a synthetic GLP-1 analog, showcased neuroprotective effects beyond metabolic regulation. It mitigated apoptosis and improved cognitive dysfunction in cerebrovascular disease, suggesting broader implications for neurological well-being. Also, studies highlighted GLP-1 RAs' positive impact on olfactory function in obese individuals with type 2 diabetes, on neurodegenerative disorders, multiple sclerosis, and endotoxemia. In order to analyze current studies that assess the impact of semaglutide on cognitive function, a literature search was conducted up to February 2024 on two online databases, MEDLINE (via PubMed) and Web of Science Core Collection, as well as various websites. Fifteen studies on mice populations and two studies on cell lines were included, analyzed, and assessed with bias-specific tools. The neuroprotective and anti-apoptotic properties of GLP-1 and its analogs were emphasized, with animal models and cell line studies demonstrating enhanced cognitive function. While promising, limitations include fewer studies, highlighting the need for extensive research, particularly in the human population. Even though this medication seems promising, there are significant limitations, one of which is the lack of studies on human subjects. Therefore, this review aims to gather current evidence.

As new antidiabetic drugs, tirzepatide (Tir) and semaglutide (Sem) are progressively applied in clinical practice. However, their efficacy and safety profiles have not been comprehensively assessed. Therefore, a Bayesian network meta-analysis was used to evaluate and compare the efficacy and safety of Tir and Sem in treating type 2 diabetes mellitus (T2DM).

PubMed, EMBASE, Web of Science, Cochrane Library and ClinicalTrials.gov were systematically searched from inception to April 3rd, 2023. Randomized clinical trials (RCTs) comparing the efficacy and safety of Tir and Sem with placebo or the other antidiabetic drugs in treating T2DM were included. The efficacy outcomes included changes in glycated hemoglobin (HbA1c), body weight (BW), body mass index (BMI), and the proportion of participants with HbA1c< 7 %. The safety outcome was the proportion of participants experiencing gastrointestinal adverse events (GIAEs).

A total of 38 studies involving 34,166 participants were included. Compared to 1 mg of subcutaneous Sem (Sem SC), 5 mg, 10 mg and 15 mg of Tir demonstrated superior efficacy in reducing HbA1c (mean difference (MD), [95 % CI], -0.22 [-0.40, -0.03] %, -0.42 [-0.60, -0.24] % and -0.53 [-0.71, -0.35] %, respectively) and BW (MD [95 % CI], -1.48 [-2.53, -0.43] kg, -4.00 [-5.05, -2.95] kg and -5.71 [-6.73, -4.68] kg, respectively). Conversely, 7 mg and 14 mg of oral Sem (Sem PO) displayed inferior efficacy in reducing HbA1c (MD [95 % CI], 0.47 [0.26, 0.68] % and 0.35 [0.16, 0.54] %, respectively) and BW (MD [95 % CI], 2.36 [1.24, 3.48] kg and 1.11 [0.10, 2.13] kg). However, 20 mg and 40 mg of Sem PO were non-inferior in reducing HbA1c (MD [95 % CI], 0.13 [-0.29, 0.55] % and 0.01 [-0.38, 0.40] %, respectively) and BW (MD [95 % CI], -0.41 [-2.71, 1.90] kg and -1.32 [-3.58, 0.92] kg). In terms of safety, compared to 1 mg of Sem SC, 5 mg, 10 mg and 15 mg of Tir did not significantly increase the incidence of GIAEs (odd ratio (OR) [95 % CI], 0.70 [0.42, 1.10], 0.87 [0.52, 1.36] and 0.99 [0.60, 1.54], respectively), while 7 mg of Sem PO showed a lower incidence of GIAEs (OR [95 % CI], 0.48 [0.25, 0.83]). Compared to insulin, 0.5 mg of Sem SC, 1 mg of Sem SC, 5 mg of Tir, 10 mg of Tir and 15 mg of Tir displayed better efficacy in lowering HbA1c (MD [95 % CI], -0.40 [-0.63, -0.18] %, -0.69 [-0.90, -0.48] %, -0.91 [-1.10, -0.72] %, -1.11 [-1.30, -0.92] % and -1.22 [-1.41, -1.03] %, respectively) and BW (MD [95 % CI], -5.34[-6.60, -4.09] kg, -6.70 [-7.90,-5.51] kg, -8.18 [-9.27, -7.10] kg, -10.70 [-11.79, -9.61] kg and -12.41 [-13.49,-11.33] kg, respectively). According to the surface under the cumulative ranking curve (SUCRA) value, among all the included interventions, 15 mg of Tir exhibited the most potent effect in reducing HbA1c (99.81 %) and BW (99.98 %), followed by 10 mg of Tir (96.83 % and 95.72 %), 5 mg of Tir (92.88 % and 86.04 %), 1 mg of Sem SC (85.85 % and 74.97 %), 40 mg of Sem PO (83.66 % and 84.31 %), 20 mg of Sem PO (76.98 % and 77.12 %), 300 mg of Can (49.93 % and 60.89 %), insulin (36.38 % and 0.22 %) and 100 mg of Sit (12.28 % and 18.51 %) respectively. Meanwhile, 5 mg, 10 mg, and 15 mg of Tir (48.32 %, 30.96 %, and 21.07 %, respectively), 0.5 mg and 1 mg of Sem SC (33.54 % and 24.77 %, respectively) significantly increased the incidence of GIAEs.

Both Tir and Sem demonstrated favorable antidiabetic effects and were particularly suitable for T2DM patients who were obese or overweight. Despite a high incidence of GIAEs, their safety profile was deemed acceptable. Tir was the best option among all the included interventions.

An endogenous transporter protein called albumin interacts with the Fc receptor to provide it with multiple substrate-binding domains, cell membrane receptor activation, and an extended circulating half-life. Albumin has the remarkable ability to bind with receptors viz. secreted protein acidic and rich in cysteine (SPARC) and scavenger protein-A (SR-A) that are overexpressed during rheumatoid arthritis (RA), enabling active targeting of the disease site instead of requiring specialized substrates to be added to the nanocarrier. RA, a chronic autoimmune illness, is characterized by the presence of a severe inflammatory response. RA patients have low serum albumin concentration, which signifies the high uptake of albumin at the inflammatory sites, giving a rationale to use albumin as a drug carrier for RA therapy. Albumin has the capacity for both passive and active targeting. It is an abundantly available protein in the bloodstream showing excellent cellular compatibility, degradability in biological tissues, nonantigenicity, and safety. There are three strategies of albumin mediated drug delivery as encapsulating therapeutics in albumin nanoparticles, chemically conjugating drugs with functional proteins, and albumin itself which is used as a targeting ligand to deliver drugs specifically to cells or tissues that express albumin-binding receptors. In the current review, an attempt has been made to highlight the significant evidence of albumin as a drug delivery carrier for the safe and effective management of RA. Evidence has been provided in the form of recent research advances, clinical trials, and patents. Additionally, this review will outline the prospective for the potential utilization of albumin as a drug vehicle for RA and suggest possible future avenues to provide the perspective for subsequent studies.

Diabetes mellitus (DM) and obesity are associated with total knee arthroplasty (TKA) complications. Semaglutide, a medication for DM and weight loss, can potentially affect TKA outcomes. This study investigated whether semaglutide use during TKA demonstrates fewer: (1) medical complications; (2) implant-related complications; (3) readmissions; and (4) costs.

A retrospective query was performed using a National database to 2021. Patients undergoing TKA for osteoarthritis with DM and semaglutide use were successfully propensity score-matched to controls semaglutide = 7,051; control = 34,524. Outcomes included 90-day postoperative medical complications, 2-year implant-related complications, 90-day readmissions, in-hospital lengths of stay, and costs. Multivariate logistical regressions calculated odds ratios (ORs), 95% confidence intervals, and P values (P < .003 as significance threshold after Bonferroni correction).

Semaglutide cohorts had higher incidence and odds of myocardial infarction (1.0 versus 0.7%; OR 1.49; P = .003), acute kidney injury (4.9 versus 3.9%; OR 1.28; P < .001), pneumonia (2.8 versus 1.7%; OR 1.67; P < .001), and hypoglycemic events (1.9 versus 1.2%; OR 1.55; P < .001), but lower odds of sepsis (0 versus 0.4%; OR 0.23; P < .001). Semaglutide cohorts also had lower odds of prosthetic joint infections (2.1 versus 3.0%; OR 0.70; P < .001) and readmission (7.0 versus 9.4%; OR 0.71; P < .001), and trended toward lower odds of revisions (4.0 versus 4.5%; OR 0.86; P = .02) and 90-day costs ($15,291.66 versus $16,798.46; P = .012).

Semaglutide use during TKA decreased risk for sepsis, prosthetic joint infections, and readmissions, but also increased risk for myocardial infarction, acute kidney injury, pneumonia, and hypoglycemic events.

Obesity is a major public health concern linked to health risks such as hypertension, hyperlipidemia, type 2 diabetes mellitus (T2DM), stroke, metabolic syndrome, asthma, and cancer. It is among the leading causes of morbidity and mortality worldwide caused by an unhealthy diet and lack of physical activity, but genetic or hormonal factors may also contribute. Over a third of adults in the United States are obese. Pharmacological agents have been designed to reduce weight gain caused by excessive calorie intake and low physical activity. They work by inhibiting the absorption of dietary fat or stimulating the secretion of satiety hormones. These drugs include lipase inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists. However, the current weight-loss strategies do not effectively treat genetic-related diseases, such as generalized lipodystrophy, Bardet-Biedl syndrome, and proopiomelanocortin (POMC) deficiency. Emerging therapies for these gene mutations have been developed targeting leptin and melanocortin-4 receptors (MC4Rs), restoring the normal function of leptin or melanocortin-4 receptors regulating energy balance and appetite. Leptin analogs and MC4R agonists are novel therapies that target genetic or hormonal causes of obesity. This article provides a comprehensive review of anti-obesity medications (AOMs). In this review, we discuss the clinical trials, efficacy, United States FDA-approved indication, contraindications, and serious side effects of different classes of drugs, including lipase inhibitors, GLP-1 agonists, leptin analogs, and MC4R agonists.

While the prevalence of obesity has rapidly increased worldwide, there has also been a notable decline in semen parameters over the last several decades. While obesity can negatively impact reproductive hormones, many studies have sought a link between rising obesity and decreased male fertility potential. Nonetheless, few data support a direct link between the two. The focus on obesity as a causative factor in male infertility can potentially result in patient harm through delayed fertility treatment and missed diagnoses. This review investigates the associations between obesity and male infertility and why a potential direct link has been elusive and may not exist. Additionally, indirect mechanisms that may link the two will be reviewed and treatment options for obese infertile men presenting for evaluation will briefly be discussed.

Obesity is a complex metabolic condition that can have a negative impact on one's health and even result in mortality. The management of obesity has been addressed in a number of ways, including lifestyle changes, medication using appetite suppressants and thermogenics, and bariatric surgery for individuals who are severely obese. Liraglutide and semaglutide are two of the five Food and Drug Administration (FDA)-approved anti-obesity drugs that are FDA-approved agents for the treatment of type 2 diabetes mellitus (T2DM) patients. In order to highlight the positive effects of these drugs as anti-obesity treatments, we analyzed the weight loss effects of T2DM agents that have demonstrated weight loss effects in this study by evaluating clinical studies that were published for each agent. Many clinical studies have revealed that some antihyperglycemic medications can help people lose weight, while others either cause weight gain or neutral results. Acarbose has mild weight loss effects and metformin and sodium-dependent glucose cotransporter proteins-2 (SGLT-2) inhibitors have modest weight loss effects; however, some glucagon-like peptide-1 (GLP-1) receptor agonists had the greatest impact on weight loss. Dipeptidyl peptidase 4 (DPP-4) inhibitors showed a neutral or mild weight loss effect. To sum up, some of the GLP-1 agonist drugs show promise as weight-loss treatments.

Weight loss achieved with standard doses of glucagon-like peptide-1 (GLP-1) agonists among real-world patients with type 2 diabetes has not been determined. This study sought to describe the percent change in body weight 72 weeks after starting a GLP-1 agonist.

A retrospective cohort study of nonpregnant adults who were first dispensed a GLP-1 agonist between 2011 and 2018 was conducted using electronic health record data from patients receiving care at a large health system. Linear mixed models were used, with a person-level random intercept controlling for baseline variables associated with missing weight data to estimate percent body weight change during follow-up.

The cohort included 2405 patients (mean [SD] age 48 [10] years, 53% female), with a mean BMI of 37 (8) kg/m2 and a mean baseline weight of 238 (54) lb. Mean percent weight loss significantly increased from 1.1% (95% CI: 0.6%-1.6%) 8 weeks after GLP-1-agonist dispensing to 2.2% (95% CI: 1.7%-2.6%) 72 weeks after GLP-1-agonist dispensing (p value for quadratic trend < 0.001). One-third of patients lost ≥5% body weight at 72 weeks.

In this real-world study of more than 2400 patients with overweight or obesity and type 2 diabetes, starting a GLP-1 agonist at standard glycemic control doses was associated with modest weight loss through 72 weeks.

Insulin desensitization has been observed in the brains of patients with Parkinson's disease (PD), which is a progressive neurodegenerative disorder for which there is no cure. Semaglutide is a novel long-actingglucagon-likepeptide-1 (GLP-1) receptor agonist that is on the market as a treatment for type 2 diabetes. It is in a phase II clinical trial in patients with PD. Two previous phase II trials in PD patients showed good effects with the older GLP-1 receptor agonists, exendin-4 and liraglutide. We have developed a dual GLP-1/GIP receptor agonist (DA5-CH) that can cross the blood-brain barrier (BBB) at a higher rate than semaglutide. We tested semaglutide and DA5-CH in the 6-OHDA-lesion rat model of PD. Treatment was semaglutide or DA5-CH (25 nmol/kg, i.p.) daily for 30 days postlesion. Both drugs reduced the apomorphine-induced rotational behavior and alleviated dopamine depletion and the inflammation response in the lesioned striatum as shown in reduced IL-1β and TNF-α levels, with DA5-CH being more effective. In addition, both drugs protected dopaminergic neurons and increased TH expression in the substantia nigra. Furthermore, the level of monomer and aggregated α-synuclein was reduced by the drugs, and insulin resistance as shown in reduced pIRS-1ser312 phosphorylation was also attenuated after drug treatment, with DA5-CH being more effective. Therefore, while semaglutide showed good effects in this PD model, DA5-CH was superior and may be a better therapeutic drug for neurodegenerative disorders such as PD than GLP-1 receptor agonists that do not easily cross the BBB.

Infantile neuroaxonal dystrophy (INAD) is a rare paediatric neurodegenerative condition caused by mutations in the PLA2G6 gene, which is also the causative gene for PARK14-linked young adult-onset dystonia parkinsonism. INAD patients usually die within their first decade of life, and there are currently no effective treatments available. GLP1 receptor (GLP-1R) agonists are licensed for treating type 2 diabetes mellitus but have also demonstrated neuroprotective properties in a clinical trial for Parkinson's disease. Therefore, we evaluated the therapeutic efficacy of a new recently licensed GLP-1R agonist diabetes drug in a mouse model of INAD. Systemically administered high-dose semaglutide delivered weekly to juvenile INAD mice improved locomotor function and extended the lifespan. An investigation into the mechanisms underlying these therapeutic effects revealed that semaglutide significantly increased levels of key neuroprotective molecules while decreasing those involved in pro-neurodegenerative pathways. The expression of mediators in both the apoptotic and necroptotic pathways were also significantly reduced in semaglutide treated mice. A reduction of neuronal loss and neuroinflammation was observed. Finally, there was no obvious inflammatory response in wild-type mice associated with the repeated high doses of semaglutide used in this study.

Several clinical trials have demonstrated that many SGLT-2 inhibitors (SGLT2i) and GLP-1 receptor agonists (GLP-1 RA) can reduce the risk of cardiovascular events in patients with Type 2 diabetes and atherosclerotic cardiovascular disease. Recent reports indicate an underutilization of new cardiometabolic drugs, including SGLT2i and GLP-1 RA. We aimed to evaluate the use of online search volumes to reflect United States prescription rates. A repeated cross-sectional analysis of Google search volumes and corresponding data from the IQVIA National Prescription Audit (NPA) of pharmacy dispensing of newly prescribed drugs was performed. Monthly data for online searches and prescription between January 1, 2016 and December 31, 2021 were collected for selected SGLT2i and GLP-1 RA. Prescription data for drugs classes (SGLT2i and GLP-1 RA) and individual drugs were calculated as the total of queried data for branded drug names. Trends were analyzed for visual and quantitative correlation as well as predictive patterns. Overall, online searches increased by 157.6% (95% CI: 142.2-173.1%) and 295.2% (95% CI: 257.7-332.6%) for SGLT2i and GLP-1RA between 2016 and 2021. Prescription rates raised by 114.6% (95% CI: 110.8-118.4%) and 221.0% (95% CI: 212.1-229.9%) for SGLT2i and GLP-1RA for this period. Correlation coefficients (range 0.86-0.99) were strongest for drugs with growing number of prescriptions, for example dapagliflozin, empagliflozin, ertugliflozin, dulaglutide, and semaglutide. Online searches might represent an additional tool to monitor the utilization trends of cardiometabolic drugs. Associations were strongest for drugs with reported cardioprotective effect. Thus, trends in online searches complement conventionally acquired data to reflect and forecast prescription trends of cardiometabolic drugs.

Testicular torsion is a serious emergency and a well-known cause of male infertility. It represents 10 %-15 % of scrotal diseases in children. Kisspeptin (KISS1) is a hormone secreted from the hypothalamic nuclei and testis, but its role in testis is not fully understood. Semaglutide is a novel antidiabetic glucagon-like peptide 1 (GLP-1) analog. Hence, we designed the current study to elucidate the possible ameliorative effect of semaglutide on ischemia/reperfusion-induced testicular dysfunction in rats and highlight the role of the testicular GLP-1/PCG-1α-PPAR-α-KISS1 signaling pathway. We randomly divided 50 male Sprague Dawley into five equal groups (10 rats each): SHAM, exendin 9-39 -treated (EX), testicular torsion/detorsion (T/D), testicular torsion/detorsion and semaglutide-treated (SEM + T/D), and testicular torsion/detorsion, exendin, and semaglutide-treated (EX + SEM + T/D). We quantified serum follicle-stimulating hormone, luteinizing hormone, total testosterone, testicular oxidative stress markers, testicular gene expression of GLP-1/KISS1 pathway-related genes (KISS1, KISS1R, GLP-1, GLP-1R, PGC-1α, PPAR-α), steroidogenesis pathway-related genes (STAR, CYP11A1, CYP17A1, HSD17B3, CYP19A1), HO-1, Nrf-2, and testicular protein expression of HIF-1α, TNF-α, NF-κβ, Caspase-3, FAS, proliferating cell nuclear antigen, and KISS1 through testicular histopathology and immunohistochemistry assays. Testicular torsion/detorsion markedly elevated proapoptotic, proinflammatory, and oxidative stress marker levels, noticeably downregulating the expression of GLP-1/KISS1 and steroidogenesis pathway-related proteins. Semaglutide administration significantly ameliorated all these deleterious effects. Nevertheless, injecting exendin, a GLP1-R antagonist, before semaglutide abolished all the documented improvements. We concluded that semaglutide ameliorated ischemia/reperfusion-induced testicular dysfunction by modulating the GLP-1/PGC-1α-PPAR-α/KISS1/steroidogenesis signaling pathway, improving testicular oxidative state, and suppressing testicular inflammation and apoptosis.

Type 2 diabetes mellitus and the associated desensitisation of insulin signalling has been identified as a risk factor for progressive neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and others. Glucagon-like peptide 1 (GLP-1) is a hormone that has growth factor-like and neuroprotective properties. Several clinical trials have been conducted, testing GLP-1 receptor agonists in patients with Alzheimer's disease, Parkinson's disease or diabetes-induced memory impairments. The trials showed clear improvements in Alzheimer's disease, Parkinson's disease and diabetic patients. Glucose-dependent insulinotropic polypeptide/gastric inhibitory peptide (GIP) is the 'sister' incretin hormone of GLP-1. GIP analogues have shown neuroprotective effects in animal models of disease and can improve on the effects of GLP-1. Novel dual GLP-1/GIP receptor agonists have been developed that can enter the brain at an enhanced rate. The improved neuroprotective effects of these drugs suggest that they are superior to single GLP-1 receptor agonists and could provide disease-modifying care for Alzheimer's disease and Parkinson's disease patients. LINKED ARTICLES: This article is part of a themed issue on GLP1 receptor ligands (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.4/issuetoc.

Epilepsy comorbidities and anti‑epileptic drugs (AEDs) are currently the main limitations of epilepsy treatment. Semaglutide is a glucagon like peptide‑1 analogue that has entered the market as a new once‑weekly drug for type II diabetes. The aim of the present study was to investigate the functions of semaglutide in epilepsy and inflammation models, in order to investigate its potential mechanism. In vitro, an inflammation model was established using lipopolysaccharide (LPS) and nigericin stimulation in BV2 cells. In vivo, chronic epilepsy model mice were generated using a pentylenetetrazole (PTZ) kindling method. BV2 cell proliferation was assessed using the Cell Counting Kit‑8. The effects of semaglutide on NLR family pyrin domain containing 3 (NLRP3) inflammasome activation and inflammatory cytokine secretion were determined using western blotting (WB) and ELISA. A lactate dehydrogenase (LDH) assay kit was used to detect the effect of semaglutide on LDH release. Electrocorticography and the modified Racine scale were used to assess seizure severity. Cognitive function was evaluated with behavioral assessment. Morphological changes in the hippocampus were observed with Nissl staining. Double immunofluorescence staining for NeuN and Iba‑1, WB and immunofluorescence analysis of apoptosis‑related proteins were used to evaluate neuronal apoptosis. The NLRP3 inflammasome was assessed by reverse transcription‑quantitative PCR, WB and immunofluorescence staining, and inflammatory cytokine release was evaluated by WB analysis in the hippocampus of C57/BL6J model mouse. Semaglutide attenuated the LPS‑ and nigericin‑induced inflammatory response and LDH release by blocking NLRP3 inflammasome activation in BV2 cells. Moreover, semaglutide decreased seizure severity, alleviated hippocampal neuronal apoptosis, ameliorated cognitive dysfunction, blocked NLRP3 inflammasome activation and decreased inflammatory cytokine secretion in PTZ‑kindled mice. These results indicated that semaglutide reduced seizure severity, exerted neuroprotective effects and ameliorated cognitive dysfunction, possibly via inhibition of NLRP3 inflammasome activation and inflammatory cytokine secretion. Semaglutide may therefore be a novel, promising adjuvant therapeutic for epilepsy and its associated comorbidities.

Glucagon-like peptide 1 receptor agonist (GLP-1 RA) is a class of hypoglycemic medications. Semaglutide once-weekly (QW) and liraglutide once-daily (OD) significantly improved glycemic control compared to placebo. To date, no long-term phase III trials directly comparing semaglutide and liraglutide are available. This network meta-analysis (NMA) aims to compare the long-term efficacy of semaglutide and liraglutide.

PubMed, Embase, and Cochrane Library were searched from inception until June 2019 to identify relevant articles. Nine long-term randomized controlled trials comparing once-weekly semaglutide or liraglutide with placebo or other active comparisons were identified. The outcomes of interest were changes in HbA1c and weight after 52 weeks. A Bayesian framework and NMA were used for data synthesis. This is a sub-study of the protocol registered in PROSPERO (number CRD42018091598).

The data showed significant superiority in HbA1c reduction of semaglutide 1 mg QW over liraglutide 1.2 and 1.8 mg with a treatment difference of 0.47% and 0.3%, respectively. Semaglutide 0.5 mg QW was found to be significantly superior to liraglutide 1.2 mg in HbA1c reduction with a treatment difference of 0.17%. Regarding weight reduction analysis, semaglutide 0.5 and 1 mg QW were significantly associated with a greater reduction than liraglutide 0.6 mg with a treatment difference of 2.42 and 3.06 kg, respectively. However, no significant reduction was found in comparison to liraglutide 1.2 and 1.8 mg.

Semaglutide improved the control of blood glucose and body weight. The capacity of long-term glycemic control and body weight control of semaglutide appears to be more effective than other GLP-1 RAs, including liraglutide. However, considering the number of included studies and potential limitations, more large-scale, head-to-head, well-designed randomized-controlled trials (RCTs) are needed to confirm these findings.

Diabetes mellitus is a chronic disease with an elevated risk of micro- and macrovascular complications, such as fibrosis. To prevent diabetes-associated fibrosis, the symptomatology of diabetes must be controlled, which is commonly done by subcutaneous injection of antidiabetic peptides. To minimize the pain and distress associated with such injections, there is an urgent need for non-invasive oral transmucosal drug delivery strategies. However, orally administered peptide-based drugs are exposed to harsh conditions in the gastrointestinal tract and poorly cross the selective intestinal epithelium. Thus, targeting of drugs to receptors expressed in epithelial cells, such as the neonatal Fc receptor (FcRn), may therefore enhance uptake and transport through mucosal barriers. This review compiles how in-depth studies of FcRn biology and engineering of receptor-binding molecules may pave the way for design of new classes of FcRn-targeted nanosystems. Tailored strategies may open new avenues for oral drug delivery and provide better treatment options for diabetes and, consequently, fibrosis prevention.

Glycemic control and weight gain are two essential considerations in the pharmacological management of type 2 diabetes mellitus. Pharmacological agents are effective in lowering blood glucose levels but may result in significant weight gain. Liraglutideeffectively maintains glycemic control while reducingweight.

This is a real-world study and brief narrative review of the effects of liraglutide on glycemic control and weight in adult patients with type 2 diabetes mellitus. The study uses data extracted from the electronic health record of the Ministry of National Guard-Health Affairs.

In this study of 348 subjects, there was a statistically significant reduction in hemoglobin A1c of 0.9% (P < .0001) and weight of 2.3 kg (P < .0001). The majority (77.3%) were on concomitant insulin.Subjects with a baseline hemoglobin A1c greater than 9% had a significantly greater reduction than those below 9% (-0.7%;P < .0001). Those with a weight more than 100 kg had a significantly greater reduction than those below 100 kg (-0.9 kg;P = .0096).

In this real-world, observational study, liraglutide was shown to be effective in improving glycemic control and reducing weight in adult patients with type 2 diabetes mellitus.

Neurotensin receptor activation augments the biosctivity of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). JMV-449, a C-terminal neurotensin-like fragment with a reduced peptide bond, represents a neurotensin receptor agonist.

The present study assessed the actions of JMV-449 on pancreatic beta-cells alone, and in combination with GIP and GLP-1. Further studies examined the impact of JMV-449 and incretin mimetics on glucose homeostasis and appetite control in mice.

JMV-449 was resistant to plasma enzyme degradation and induced noticeable dose-dependent insulin-releasing actions in BRIN-BD11 beta-cells. In combination with either GIP or GLP-1, JMV-449 augmented (P < 0.05) the insulinotropic actions of both hormones, as well as enhancing (P < 0.001) insulin secretory activity of both incretin peptides. JMV-449 also increased beta-cell proliferation and induced significant benefits on beta-cell survival in response to cytokine-induced apoptosis. JMV-449 (25 nmol/kg) inhibited (P < 0.05-P < 0.001) food intake in overnight fasted lean mice, and enhanced (P < 0.01) the appetite supressing effects of an enzymatically stable GLP-1 mimetic. When injected co-jointly with glucose, JMV-449 evoked glucose lowering actions, but more interestingly significantly augmented (P < 0.05) the glucose lowering effects of established long-acting GIP and GLP-1 receptor mimetics. In terms of glucose-induced insulin secretion, only GIP receptor signalling was associated with increases in insulin concentrations, and this was not enhanced by JMV-449.

JMV-449 is a neurotensin receptor agonist that positively augments key aspects of the biological action profile of GIP and GLP-1.

These observations emphasise the, yet untapped, therapeutic potential of combined neurotensin and incretin receptor signalling for diabetes.

A few randomized controlled trials (RCTs) have assessed the use of liraglutide as a treatment option in patients with non-alcoholic fatty liver disease (NAFLD). We aimed at critically appraising and summarizing these RCTs, providing precise effect estimates regarding the safety and efficacy of liraglutide in NAFLD.

We searched major databases and grey literature from their inception to May 2019, for RCTs comparing liraglutide with placebo or active comparator in patients with NAFLD. We defined as primary efficacy outcomes the observed changes in hepatic fat content (HFC) and alanine aminotransferase levels (ALT). Metabolic outcomes of interest and major safety endpoints were also assessed.

We included five trials with 371 randomised participants in total. Liraglutide produced a non-significant decrease in HFC and ALT levels, compared to control. It induced a significant reduction in body mass index, primarily driven by reduction in patients with type 2 diabetes, while it did not affect significantly glycated hemoglobin levels and Homeostatic Model Assessment of Insulin Resistance. We also showed that liraglutide significantly decreased serum triglyceride levels, also driven by the observed reduction in patients with type 2 diabetes, however it did not significantly affect the rest lipid parameters. Liraglutide was associated with increased incidence of gastrointestinal adverse events, while, no other safety issues were identified.

Our results do not substantiate the use of liraglutide in patients with NAFLD yet, despite its promising role.