Search Results (752)

Clozapine and olanzapine are important medications in the management of psychiatric conditions such as schizophrenia. However, metabolic disturbances and weight gain are common side effects of these drugs. We aimed to evaluate the effects of GLP-1 RAs treatment for metabolic disturbances and weight gain in patients on clozapine/olanzapine. For this systematic review, searches were conducted in eight different databases. After screening, outcome data was synthesized regarding weight gain and biochemical and clinical indicators of metabolic disturbance, as well as for adverse events/side effects, and any other benefits of GLP-1 RA treatment. A total of 14 studies were included in this medical systematic review, of which four were unique randomized control trials (RCTs), with study contexts including Australia and Denmark. GLP-1 RAs that were utilized include semaglutide, exenatide, and liraglutide. It was consistently demonstrated across studies that, when followed-up, those on GLP-1 RAs had achieved statistically lower levels of weight gain compared to those receiving placebo. A similar effect was seen on fasting glucose levels and glycated haemoglobin levels. Effects on other metabolic parameters were inconsistent. There were minimal gastrointestinal, psychological, cardiac, and other side effects noted across studies. GLP-1 RAs may offer utility in addressing the metabolic side effects of olanzapine/clozapine, but further research is needed. There remains a need to better understand impacts and potential side effects in larger and more diverse populations, as well as a need to better evaluate the long-term outcomes for patients. Full article

Heart failure (HF) is a growing public health concern, driven by the increasing prevalence of obesity, diabetes, and aging. Despite therapeutic advances, HF continues to be associated with high morbidity and mortality. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), originally developed for glycemic control in type 2 diabetes, have demonstrated cardiovascular benefits in clinical trials. Recent studies, including STEP-HFpEF and SUMMIT, have shown improvement in symptoms and weight loss in patients with HF with preserved ejection fraction (HFpEF). GLP-1 RAs are involved in multiple biological pathways relevant to heart failure pathophysiology. These include pathways related to sympathetic nervous system activity, inflammatory cytokine signaling, oxidative stress, calcium handling, natriuretic peptide signaling, and cardiac metabolism. GLP-1 receptor agonists modulate vascular pathways involving nitric oxide signaling, endothelial function, and renal sodium handling, contributing to improved hemodynamics and neurohormonal balance. Together, these actions intersect with key neurohormonal and cellular processes contributing to chronic heart failure progression. This review explores the mechanistic overlap between GLP-1 receptor signaling and heart failure pathophysiology. This mechanistic overlap suggests a plausible role for these agents as adjunctive treatments in heart failure, especially in metabolically driven phenotypes. While direct cardiac effects remain incompletely defined, systemic metabolic and anti-inflammatory actions provide a mechanistic basis for observed clinical benefits. Full article

Dumping Syndrome (DS) is a significant complication following bariatric surgery, particularly Roux-en-Y gastric bypass (RYGB). This condition is characterised by gastrointestinal and vasomotor symptoms resulting from altered anatomy and hormonal dysregulation, notably accelerated gastric emptying and an exaggerated release of gut peptides. Based on the timing of symptom onset after food ingestion, DS is classified as early (EDS) or late (LDS). The critical roles of peptides such as GLP-1, GIP, insulin, and YY peptide are highlighted, along with the involvement of neuroendocrine pathways in symptom manifestation. Diagnosis relies on a combination of clinical evaluation and dynamic testing, with the oral glucose tolerance test (OGTT) often considered a key reference standard for diagnosis. Initial management involves dietary modifications, emphasising the glycaemic index of foods and meal distribution. In cases where nutritional interventions are insufficient, pharmacotherapy with agents such as acarbose, somatostatin analogues (octreotide and pasireotide), GLP-1 receptor agonists (liraglutide), calcium channel blockers (verapamil), and emerging therapies, including herbal medicine, may be considered. For refractory cases, surgical options like bypass reversal or partial pancreatectomy are reserved, although their efficacy can be variable. Despite advancements in understanding and treating DS, further large-scale, randomised controlled trials are essential to validate novel strategies and optimise long-term management. This review provides an updated and comprehensive overview of the aetiology, pathophysiological mechanisms, diagnostic approaches, and current management strategies for DS. Full article

Astrocytes are the most common type of glial cell in the central nervous system (CNS). They have many different functions that go beyond just supporting other cells. Astrocytes were once thought of as passive parts of the CNS. However, now they are known to be active regulators of homeostasis and active participants in both neurodevelopmental and neurodegenerative processes. This article looks at the both sides of astrocytic function: how they safeguard synaptic integrity, ion and neurotransmitter balance, and blood-brain barrier (BBB) stability, as well as how astrocytes can become activated and participate in the immune response by releasing cytokines, upregulating interferons, and modulating the blood–brain barrier and inflammation disease condition. Astrocytes affect and influence neuronal function through the tripartite synapse, gliotransmission, and the glymphatic system. When someone is suffering from neurological disorders, reactive astrocytes become activated after being triggered by factors such as pro-inflammatory cytokines, chemokines, and inflammatory mediators, these reactive astrocytes, which have higher levels of glial fibrillary acidic protein (GFAP), can cause neuroinflammation, scar formation, and the loss of neurons. This review describes how astrocytes are involved in important CNS illnesses such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis, and ischemia. It also emphasizes how these cells can change from neuroprotective to neurotoxic states depending on the situation. Researchers look at important biochemical pathways, such as those involving toll-like receptors, GLP-1 receptors, and TREM2, to see if they can change how astrocytes respond. Astrocyte-derived substances, including BDNF, GDNF, and IL-10, are also essential for protecting and repairing neurons. Astrocytes interact with other CNS cells, especially microglia and endothelial cells, thereby altering the neuroimmune environment. Learning about the molecular processes that control astrocytic plasticity opens up new ways to treat glial dysfunction. This review focuses on the importance of astrocytes in the normal and abnormal functioning of the CNS, which has a significant impact on the development of neurotherapeutics that focus on glia. Full article

Diabetes and cardiovascular diseases (CVDs) are two strongly associated conditions that mutually influence each other. This review aims to follow the historical timeline of their association by highlighting the changing paradigm in CV risk management and treatment strategies in type 2 diabetes (T2D). While the discovery of insulin was a breakthrough in reducing life-threatening complications like diabetic ketoacidosis, patients with diabetes still faced a poor prognosis in terms of macrovascular outcomes, especially CVDs. Initial efforts in improving outcomes by tightly controlling glycemia proved insufficient, highlighting the complex relationship between the two diseases. After decades of focusing solely on glucose-lowering strategies, rosiglitazone, a promising new drug was developed, ultimately raising the flag about the potential higher risk of CV complications like myocardial infarction associated with its use. This turning point shifted the focus towards CV safety of novel glucose-lowering drugs, mandating for the development of cardiovascular outcome trials. Several drug classes, like sodium-glucose co-transporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs), exceeded expectations by not only providing safety but also benefits in patients with T2D and CVDs and becoming the new standard of care in T2D management. The historical evidence linking T2D and CVDs has shaped regulatory requirements for cardiovascular outcome trials, guideline recommendations, and current therapeutic strategies. These insights highlight the importance of early interventions and a multidisciplinary approach to optimize patient outcomes. Full article

Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, is widely used to reduce appetite and promote weight loss in patients with type 2 diabetes. However, individual variability may lead to paradoxical responses. We describe a 60-year-old woman with type 2 diabetes who experienced progressive weight gain and increased appetite during 12 months of semaglutide therapy, despite previous successful weight loss with sodium-glucose cotransporter 2 (SGLT2) inhibitors. Her body mass index (BMI) rose from 31.6 to 34.6 kg/m², accompanied by worsening glycemic control. Eating behavior assessment with the Dutch Eating Behavior Questionnaire revealed a maximum score for emotional eating, suggesting a strong psychological barrier to treatment efficacy. Genetic factors, such as GLP-1 receptor polymorphisms, may also contribute to reduced responsiveness. This case highlights the possible influence of both emotional and genetic factors on treatment outcomes and emphasizes the need for personalized approaches in the management of obesity and type 2 diabetes. Full article

Background/Objectives: Bioactive peptides derived from animal venoms, toxins, and secretions demonstrate considerable pharmacological potential for use in the management of diabetes mellitus—a highly prevalent metabolic disorder of substantial global health significance. This integrative review systematically evaluated the current evidence regarding the pharmacological mechanisms underlying the antidiabetic properties of these bioactive peptides. Methods: This study was guided by the research question “What are the mechanisms of action of peptides derived from animal venoms in modulating parameters associated with diabetes?” developed using the PECo framework. A comprehensive literature search was executed across Scopus, PubMed, and Web of Science, focusing on studies from the last five years. Out of 190 identified articles, 17 satisfied the inclusion criteria. Results: Twenty-eight distinct peptides were characterized, exhibiting structural diversity with 7–115 amino acid residues and molecular weights of 900–13,000 Da. These compounds were sourced from venomous taxa including sea anemones, marine snails, spiders, centipedes, scorpions, and snakes. Their antidiabetic mechanisms encompassed glucagon-like peptide-1 (GLP-1) receptor agonism, insulin receptor activation, potassium channel inhibition, glucose transporter type 4 (GLUT4) upregulation, and α-amylase inhibition. Sequence analyses revealed substantial homology among peptides with analogous mechanisms—notably Con-Ins and ILP-Ap04, plus SpTx1 and SsTx-4—suggesting that structural determinants underlie their functional characteristics. Toxicological evaluations of nine peptides demonstrated low-toxicity profiles despite originating from toxic venom, crucial for therapeutic development. Conclusions: These peptides exhibited exceptional pharmacological potency with effective doses in nanogram-to-nanomole per kilogram ranges. Collectively, our findings underscore the therapeutic potential of venom-derived peptides as innovative candidates for use in diabetes management. Full article

Glucagon-like peptide-1 (GLP-1) receptor agonists now serve as therapeutic agents for cardiovascular diseases (CVDs) beyond their original use for treating type 2 diabetes mellitus (T2DM). This review combines molecular mechanisms with clinical evidence to demonstrate how GLP-1 agonists help lower cardiovascular risk for conditions, including atherosclerosis, heart failure, stroke, and vascular dementia. These agents produce multiple beneficial effects, which include anti-inflammatory action along with anti-atherogenic effects, endothelial-protective benefits, and cardioprotective actions to minimize major adverse cardiovascular events (MACEs). GLP-1 agonists achieved substantial reductions in myocardial infarction, stroke, cardiovascular mortality, and heart failure events according to major cardiovascular outcome trials (CVOTs). Recent research, notably the pivotal SELECT trial, has confirmed their suitability for non-diabetic subjects with obesity and established CVD. New drug delivery methods and dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) agonists demonstrate potent efficacy, with tirzepatide showing significant MACE reduction in its own CVOT. However, significant challenges related to high cost, long-term safety uncertainties, and implementation barriers remain, requiring a balanced perspective. The review presents both mechanistic data and clinical evidence to demonstrate how GLP-1 agonists function as vital cardiovascular medications and outlines future research directions to address critical evidence gaps and maximize their therapeutic effectiveness. Full article

The management of type 2 diabetes in patients with intraductal papillary mucinous neoplasms (IPMNs) presents a growing clinical dilemma. As glucagon-like peptide-1 receptor agonists (GLP-1RAs) become first-line therapies for diabetes and obesity, their safety in patients with premalignant pancreatic lesions remains uncertain. This viewpoint examines current evidence through three critical lenses: molecular mechanisms linking incretin signaling to IPMN progression, clinical outcomes from large-scale pharmacovigilance studies, and practical management considerations. We propose a risk-stratified approach that balances the proven metabolic benefits of GLP-1RAs against theoretical oncogenic risks, emphasizing the need for shared decision-making and enhanced surveillance protocols. Full article

To evaluate the effect of sodium–glucose cotransporter-2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1RAs), and their combination on atrial fibrillation (AF) recurrence after catheter ablation in patients with type 2 diabetes mellitus (T2DM). In a prospective cohort study, patients with T2DM undergoing AF ablation were stratified into three groups: SGLT2i-users, GLP-1RAs-users, and combined SGLT2i/GLP-1RAs users. Diabetics under SGLT2i/GLP-1RAs therapy had worse glycemic control (HbA1c > 7%). AF recurrence was assessed over 12 months using implantable continuous monitoring (ICM). Secondary outcomes included the inflammatory/oxidative stress markers measured at the 12-month follow-up. At the follow-up end, patients treated with SGLT2i/GLP-1RAs versus monotherapy patients showed significantly lower AF recurrence and serum inflammatory/oxidative stress markers, despite having higher HbA1c levels (p < 0.05). Combined SGLT2i/GLP-1RAs therapy reduced AF recurrence following catheter ablation and inflammatory/oxidative stress in T2DM patients. Full article

Obesity is a multifactorial chronic disease resulting from complex genetic, molecular, environmental, and behavioral interactions. Its prevalence rises worldwide, affecting cardiovascular, metabolic, oncological, hepatic, respiratory, and skeletal health. Beyond caloric excess, genetic predisposition, epigenetic modifications, gut microbiota dysbiosis, endocrine-disrupting agents, circadian misalignment, and intergenerational and prenatal influences are critical determinants of obesity risk. Core pathophysiological mechanisms include insulin resistance, dyslipidemia, chronic low-grade inflammation, and neuroendocrine dysregulation of appetite and energy balance. These processes are linked to comorbidities such as type 2 diabetes, hypertension, atherosclerosis, fatty liver disease, sleep apnea, osteoporosis, and cancer. Advances in molecular profiling, metabolic phenotyping, and body composition analysis are refining obesity classification and enabling precise risk stratification. Current therapeutic strategies include behavioral interventions addressing stress-related mechanisms, pharmacological therapies such as GLP-1 receptor agonists, emerging gene therapy approaches, and bariatric surgery. Gut-derived hormones (leptin, ghrelin, GLP-1, PYY, CCK) are recognized as pivotal regulators of appetite and weight. Preventive strategies increasingly emphasize circadian alignment, while epigenetic inheritance and prenatal exposures such as maternal obesity or smoking highlight early-life programming in future metabolic health. Additionally, artificial intelligence-based platforms and personalized nutrition provide innovative opportunities for individualized prevention and management. This review synthesizes contemporary evidence on the biological basis, systemic consequences, preventive strategies, and evolving therapeutic modalities of obesity, affirming its recognition as a complex chronic disease requiring personalized, multidisciplinary care. Full article

The Farnesoid-X-receptor (FXR) is a bile sensor involved in the regulation of bile acid homeostasis, fibrosis, inflammation, and metabolism. Obeticholic acid (OCA), a semisynthetic derivative of chenodeoxycholic acid (CDCA), initially named 6-ethyl-CDCA or INT-747, is the first in a class of FXR ligands that have been approved for clinical use for the treatment of patients with primary biliary cholangitis (PBC) who are unresponsive or intolerant to ursodeoxycholic acid. In this narrative review, we will examine the current status and future perspective of clinical use of OCA. Based on results from phase 2 and 3 clinical trials, OCA received a conditional market approval for its use as a second-line treatment for the management of PBC in 2016. However, concerns over drug (OCA)-induced liver injury (DILI), including hepatic decompensation in cirrhotic and non-cirrhotic PBC patients, have led to discontinuation of OCA commercialization in the EU, but not in North America and the UK, in 2024. Based on positive results from preclinical models, OCA has been investigated also for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). Results from phase 2 and 3 trials, however, have shown that while OCA reduces liver fibrosis, the beneficial effects on steatosis are marginal, thus preventing its clinical approval under the current regulatory guidelines. Here, we review potential applications of OCA in PBC patients in the context of a highly competitive therapeutic landscape, generated by the approval for clinical use of safer and effective second-line therapies, including PPARs agonists such as elafibranor and seladelapar and increased off-label use of fibrates. The current status of development of second-generation FXR agonists such as cilofexor, tropifexor, and vonafexor and their potential in the treatment of liver fibrosis in MASH will be discussed and compared to recently approved therapies, resmetirom, and semaglutide, a GLP-1 agonist. Finally, since some of the novel candidates for treating MASH, have shown limited efficacy on liver fibrosis, we suggest that development of combinatorial therapies based on FXR ligands and agents acting on different molecular targets might offer the opportunity for the repositioning of drug candidates whose development has been abandoned for insufficient efficacy, minimizing/recovering costs linked to drug development. Full article

Type 2 diabetes mellitus (T2D) and cardiovascular disease (CVD) are not merely coexisting epidemics but co-evolving manifestations of a shared cardiometabolic continuum. Despite advances in glycemic, lipid, and blood pressure control, residual cardiovascular risk remains high, underscoring the limitations of siloed approaches. In this perspective, we argue for reframing T2D and CVD as interconnected conditions driven by inflammation, adipose tissue dysfunction, and organ crosstalk. Beyond metformin, which remains foundational, several glucose-lowering drug classes are now evaluated not only for glycemic control but also for their cardiovascular and renal impact. Landmark trials and recent meta-analyses confirm that sodium-glucose co-transporter 2 inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists improve cardiorenal outcomes. More recently, tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist, has shown unprecedented efficacy in weight and glucose management, with potential to further transform cardiometabolic risk reduction. Yet enthusiasm for these therapies must be tempered by heterogeneity of response, treatment costs, and inequitable access. Integrated care models, supported by multidisciplinary teams, digital health tools, and value-based reimbursement, are essential to close the gap between trial efficacy and real-world outcomes. Attention to sex, age, ethnicity, and comorbidity profiles is critical to ensure equity, as is the adaptation of strategies to low- and middle-income countries where the burden of cardiometabolic disease is rapidly rising. Ultimately, advancing cardiometabolic medicine requires not only novel therapies but also a unifying framework that integrates biology, behavior, economics, and health systems to deliver the right treatment to the right patient at the right time. Full article

Background: Diabetes mellitus (DM), periodontal disease (PD), and cardiovascular disease (CVD) are highly prevalent global health conditions with overlapping pathophysiological mechanisms. Emerging evidence suggests a bidirectional and synergistic relationship among them, driven by chronic inflammation, immune dysregulation, oxidative stress, and microbial dysbiosis. Objective: This review synthesizes current literature on the interconnectedness of DM, PD, and CVD, emphasizing shared molecular pathways, clinical implications, and opportunities for integrated management. Methods: A systematic review and narrative synthesis of recent clinical trials, observational studies, and multi-omics investigations was conducted to explore the mechanisms linking these three conditions. A structured literature search was performed across PubMed, Scopus, and Web of Science from database inception until 30 June 2025. Key findings were contextualized within systems biology, precision medicine, and real-world clinical strategies. Results: DM exacerbates periodontal inflammation and accelerates tissue destruction via hyperglycemia-induced inflammatory mediators, while periodontitis worsens glycemic control and insulin resistance. Both conditions independently elevate cardiovascular risk, and their co-occurrence significantly amplifies the incidence of adverse cardiovascular events. Shared biomarkers such as Interleukin (IL)-6, Tumor Necrosis Factor (TNF)-α, and CRP, as well as overlapping genetic and epigenetic signatures, underscore a common inflammatory axis. Periodontal therapy has demonstrated modest but meaningful benefits on glycemic control and endothelial function, while cardiometabolic therapies (e.g., statins, Glucagon-Like Peptide (GLP-1) receptor agonists, SGLT2 inhibitors) show potential to improve periodontal outcomes. Probiotics, microbiome-targeted therapies, and AI-based risk models are emerging as future tools. Conclusions: DM, PD, and CVD form a mutually reinforcing triad mediated by systemic inflammation and metabolic dysregulation. Integrated, multidisciplinary care models and precision health strategies are essential to address this inflammatory burden and improve long-term outcomes. Further large-scale interventional trials and mechanistic human studies are needed to establish causal links and optimize combined therapeutic approaches. Full article

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used in the management of type 2 diabetes and obesity due to their metabolic benefits. Beyond weight loss and glycemic control, emerging evidence suggests they may also exert cardioprotective effects. In the context of heart failure (HF), particularly HF with preserved ejection fraction (HFpEF), GLP-1RAs have been associated with improvement in symptoms, physical capacity, biomarkers, and structural cardiac remodeling. These benefits appear to be independent of weight loss, suggesting additional mechanisms including anti-inflammatory effects, improved myocardial metabolism or modulation of epicardial adipose tissue. However, current data largely come from non-HF dedicated trials, with limited standardization of the HF phenotype. Results are overall inconsistent and may suggest potential harm in some cases, particularly in HF with reduced ejection fraction (HFrEF). This review aims to summarize the current evidence on the role of GLP-1RAs in heart failure, explore possible underlying mechanisms and highlight key gaps in knowledge. Full article