GLP-1

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron loss and profound systemic metabolic dysfunction, including hypermetabolism, weight loss, insulin resistance, and altered glucose and lipid homeostasis. Increasing recognition of these metabolic abnormalities has driven interest in repurposing antidiabetic therapies, particularly glucagon-like peptide-1 (GLP-1) and GLP-1 receptor agonists (GLP-1RAs), for ALS. Beyond their established metabolic actions, GLP-1RAs exert pleiotropic effects relevant to neurodegeneration, including modulation of neuroinflammation, mitochondrial function, oxidative stress, excitotoxicity, and cell-survival signaling, with selected agents demonstrating central nervous system penetration. This narrative review summarizes current knowledge on metabolic impairment in ALS and critically evaluates the mechanistic rationale, preclinical evidence, and emerging clinical data supporting or opposing the use of GLP-1-based therapies in this disease. Preclinical studies suggest that GLP-1 signaling can provide neuroprotective and neurotrophic effects in ALS models, although findings are heterogeneous and highly dependent on compound selection, delivery strategy, and experimental design. In contrast, available clinical evidence is limited and does not demonstrate therapeutic benefit in ALS, while raising important safety concerns, particularly related to weight loss, lean mass reduction, and altered glucose regulation, factors associated with a worse prognosis in ALS. Collectively, current data indicate that although GLP-1-based therapies may have compelling biological plausibility and beneficial effects in other neurodegenerative disorders (NDGs), their role in ALS remains uncertain and potentially harmful. Well-designed, ALS-specific clinical studies are required to clarify safety, efficacy, and patient selection before GLP-1RAs can be considered for therapeutic use in this vulnerable population.

Abstract

Obesity results from an imbalance between energy intake and energy expenditure (EE). Glucagon-like peptide-1 receptor (GLP-1R) agonists, reduce weight through appetite suppression but exert minimal influence on EE, potentially limiting long-term efficacy due to adaptive declines in metabolic rate. In contrast, glucagon, traditionally regarded as a glucose counter-regulatory hormone, has emerged as a potent catabolic signal with actions on lipid oxidation, substrate mobilization, and EE. These properties position glucagon receptor (GCGR) agonists as complements to GLP-1R agonism, with the potential to close the EE gap in obesity pharmacotherapy.

Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are considered safe, effective medications for type 2 diabetes (T2D) and weight loss, used by millions worldwide. While their cardiometabolic benefits are well established, emerging observations suggest a potential association between GLP-1RA use and new-onset nonarteritic anterior ischemic optic neuropathy (NAION).

Abstract

Over the past 2 decades, treatment for type 2 diabetes (T2D) has evolved with the introduction of medications that offer greater simplicity. The Simplicity of Diabetes Treatment Questionnaire (Sim-Q™) was developed to assess the simplicity or complexity of treatment for T2D. This study assessed the psychometric properties of the Sim-Q.

Abstract

Hypothalamic obesity (HO) is a rare, complex disorder characterized by disruption of brain pathways regulating energy intake, expenditure, autonomic function, and hormonal signaling. It occurs in rare monogenic obesity syndromes affecting central leptin-melanocortin pathways or can be acquired (aHO) as a consequence of hypothalamic injury due to a tumor (e.g., craniopharyngioma), its treatment, or trauma. In this narrative review, we focus on aHO. Damage to specific hypothalamic nuclei leads to hyperphagia, central insulin and leptin resistance, decreased sympathetic activity, reduced energy expenditure, and rapid weight gain. Traditional obesity treatments, including lifestyle interventions, often fail to achieve sustained weight loss in patients with aHO. Recent advances in pharmacotherapy show promise by targeting the distinct pathophysiology of aHO. Effective treatment requires personalized approaches due to the heterogeneity of hypothalamic dysfunction and associated comorbidities. Early intervention may improve outcomes, as rapid postoperative weight gain frequently occurs. Emerging therapies target mechanisms of disturbed energy homeostasis pathways. These agents include stimulants, incretin-based therapies (e.g., glucagon-like peptide-1 receptor agonists), insulin modulators, and melanocortin receptor agonists such as setmelanotide. While monotherapies often fail in long-term treatment, combination therapies hold potential to restore energy balance and reduce or eliminate the need for bariatric surgery. Future research should focus on identifying clinical and biomarker profiles of aHO subtypes and evaluating combination therapies. Although challenging, aHO is no longer untreatable. Patients should be referred and managed at specialized centers, with pharmacological treatment preferably conducted within research settings to optimize and personalize care, and to develop evidence-based protocols for this debilitating condition.

Abstract

Obesity, type 2 diabetes (T2D), cardiovascular disease (CVD), and chronic kidney disease (CKD) are overlapping conditions that drive premature morbidity and mortality worldwide. Care remains siloed and reactive despite shared risk factors and strong evidence for early intervention. To support integrated disease management, the American Heart Association (AHA) recently introduced the concept of cardiovascular-kidney-metabolic (CKM) syndrome, recognizing the bidirectional links between metabolic, kidney, and cardiovascular health. Kuwait faces one of the highest burdens of CKM-related diseases globally. Three-quarters of adults are overweight or have obesity, and 28% have diabetes, both of which are leading causes of mortality and health system strain. Yet multidisciplinary care remains limited, and innovative pharmacotherapies, including glucagon-like peptide-1 receptor agonists (GLP-1 RAs), are underused. A panel of Kuwaiti endocrinologists, cardiologists, and nephrologists convened to assess barriers to optimal CKM care and define practical recommendations. Discussions focused on current gaps in screening, care coordination, provider education, and access to therapies. Evidence on GLP-1 RAs was reviewed, considering the demonstrated benefits for weight loss, glycemic control, cardiovascular outcomes, and CKD progression. The expert group agreed that multidisciplinary, risk-stratified, and patient-centered approaches are urgently needed. Recommendations include earlier screening and diagnosis, improved integration across specialties, healthcare provider upskilling, public awareness campaigns, and broader access to GLP-1 RAs. Semaglutide was highlighted as a clinically valuable option owing to its broad efficacy and safety profile. Adopting a CKM care model tailored to Kuwait's specific challenges, with appropriate use of GLP-1 RAs, can reduce disease burden, improve outcomes, and increase healthcare system efficiency. The local implementation of evidence-based, cross-specialty strategies is key to altering the trajectory of CKM syndrome in high-risk populations.

Abstract

Use of glucagon-like peptide-1 receptor agonists (GLP1-RA) for weight loss is increasing; implications in breast cancer (BC) survivors remain unclear.This retrospective cohort study evaluated treatment patterns, weight loss, and outcomes in BC survivors at an academic institution receiving GLP1-RA. We evaluated patients with non-metastatic (ductal carcinoma in situ (DCIS), stage 1-3) BC who received GLP1-RA (2005 - 2024). Linear regression models estimated associations between weight change and clinical factors. After excluding DCIS, propensity score matching (1:2) was used to match patients who received GLP1-RA with patients who did not, based on confounding covariates. Kaplan-Meier estimates and log-rank tests compared disease-free survival (DFS) and overall survival (OS) between GLP1-RA users versus non-users in the subgroup with invasive disease. We identified 1,022 patients; 79% had DM2. Median weight and body mass index at GLP1-RA initiation were 86.8 kg (47.2-175.0 kg) and 33.5 kg/m2 (18.9-61.8 kg/m2). In semaglutide or tirzepatide users (442, 43.2%), median weight change at 3, 6, and 12 months after GLP1-RA initiation was -1.9% (-13.2%-14.9%), -3.1% (-20.2%-19.0%), and -2.6% (-27.8%-11.5%), respectively. Endocrine therapy and metformin use were associated with weight gain and loss, respectively; invasive disease stage was linked to greater weight loss. GLP1-RA was not associated with DFS, but OS significantly differed between GLP1-RA users (n=810) and non-users (n=1620) (HR 0.37, 95% CI: 0.27-0.53, p<0.0001). In conclusion, in this real-world study in BC survivors, GLP1-RA was associated with modest weight loss and improved all-cause survival. Clinical trials are warranted to study GLP1-RA in this population.

Abstract

Second-generation antipsychotics (SGA) are well known to frequently cause weight gain, increasing cardiometabolic risk, and reducing medication adherence. Glucagon-like peptide-1 receptor agonists (GLP-1RA) mitigate weight gain in controlled settings, but their real-world impact on SGA adherence remains unexplored. This study evaluated the role of adjuvant GLP-1RA treatment in improving SGA adherence among nondiabetic adults.

Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are approved for treating type 2 diabetes and obesity and are under investigation as potential treatments for substance use disorders (SUD). GLP-1 RA-induced weight loss is thought to arise from both peripheral effects on gastrointestinal function and central modulation of appetite and reward circuits, though the exact mechanisms are unclear. Functional magnetic resonance imaging (fMRI) studies examining brain responses to reward-related cues can help clarify the central mechanisms through which GLP-1 RAs influence reward-seeking behavior. We systematically reviewed the fMRI literature examining how GLP-1 RAs affect brain responses to reward-related cues. We identified 1,209 records through a comprehensive literature search. After screening, only 11 studies met eligibility criteria. The vast majority assessed reactivity to food-related cues, with only one examining drug-related cues (alcohol), leaving neural mechanisms relevant to SUD largely unexplored. None included non-food emotional stimuli as control conditions. Several methodological limitations emerged. Most studies enrolled 20 or fewer participants per group, limiting statistical power. Treatment protocols varied substantially, with some assessing cue responses after single-dose administration and others after chronic treatment. Heterogeneity in medications used further confounds interpretation. The limited evidence tentatively suggests that acute GLP-1 RA administration may reduce brain reactivity to food cues in appetite and reward regions. However, effects appear inconsistent and may attenuate over time. Future studies should recruit larger samples, standardize agents and dosing, and assess responses to diverse motivationally relevant stimuli.

Abstract

The aim of this research is to evaluate the clinical and economic benefits of semaglutide in patients with type 2 diabetes mellitus (T2DM) in real-world setting in tertiary hospital in Saudi Arabia.

Abstract

Patients with obesity undergoing spine surgery are at increased risk for postoperative complications. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are widely used for diabetes and weight management, but their perioperative impact in spine procedures is not well defined. This study evaluated whether long-term preoperative GLP-1 RA therapy is associated with improved postoperative outcomes after elective laminectomy in overweight adults.

Abstract

With the rise of glucagon-like peptide-1 receptor agonists for obesity, rigorous long-term data on surgical outcomes are essential to establish benchmarks and inform future comparative effectiveness studies.

Abstract

Semaglutide (SEM) is a glucagon-like peptide-1 (GLP-1) receptor agonist formulated for oral delivery with the absorption enhancer salcaprozate sodium (SNAC). Although oral SEM achieves 0.4-1% bioavailability through gastric epithelial uptake, gastrointestinal (GI) adverse events remain a major cause of therapy discontinuation. This study examined the effects of SEM (0.74 mg/kg/day), SNAC (22 mg/kg/day), and combined SEM-SNAC (1:33 w/w) treatments on microbiota and metabolic function, in healthy Sprague Dawley rats over 21 days. Whilst microbial α-diversity remained stable, SNAC significantly altered β-diversity (PERMANOVA, p < 0.05) and depleted primary fermenters in Muribaculaceae (-62%) and Bacteroidaceae (-77%) compared to the control group. These compositional changes correlated with reduced predicted saccharolytic enzyme abundance and fecal butyrate concentrations (-77% SNAC, -75% SEM-SNAC). Plasma cytokine analysis showed elevated tumor necrosis factor-α (TNF-α, 70%) and suppressed brain-derived neurotrophic factor (BDNF, 85%), consistent with changes in circulating inflammatory and neurotrophic markers from SNAC monotherapy. SNAC-treated animals also exhibited increased liver weight and reduced caecum mass, occurring alongside microbiota compositional changes and altered fermentation-associated markers. Spearman correlations linked Muribaculaceae and Bacteroidaceae loss with decreased saccharolytic enzyme abundance, lower SCFA levels, and increased TNF-α. While these findings are associative and require mechanistic validation, they indicate that chronic SNAC exposure is linked to concurrent microbial, metabolic, and inflammatory marker changes in healthy rats, highlighting the potential need for alternative, microbiota-safe strategies for oral peptide delivery.

Abstract

Glucagon-like peptide-1 (GLP-1), an incretin secreted by intestinal L-cells in response to nutrients, regulates glucose homeostasis by enhancing insulin secretion, suppressing glucagon release, delaying gastric emptying, and reducing appetite via hypothalamic signaling. Beyond these canonical actions, emerging evidence reveals GLP-1's pleiotropic functions across multiple systems, with relevance to metabolic disorders, chronic inflammation, and aging-related pathologies. This review summarizes molecular mechanisms underlying GLP-1's protective roles, highlighting its contributions to metabolic balance, inhibition of NF-κB-mediated inflammation, and attenuation of cellular aging through mitochondrial enhancement and autophagy promotion. GLP-1 also influences immune cell function and alleviates hallmarks of senescence, thereby offering therapeutic potential beyond diabetes. We further critically assess the translational potential of GLP-1 receptor agonists (GLP-1RAs), pharmacological agents with superior pharmacokinetics versus native GLP-1, in treating conditions linked to dysregulated metabolism, persistent inflammation, and accelerated aging. Despite demonstrated efficacy in preclinical models and clinical studies, important challenges persist, including inter-individual variability, off-target risks, and uncertainties regarding long-term safety. We conclude by emphasizing the necessity of integrated strategies to target the metabolic-inflammatory-aging axis and by advocating optimization of GLP-1RA formulations, identification of predictive biomarkers, and expansion of their utility for age-associated diseases.

Abstract

Physical activity helps maintain a healthy stable body weight. One mechanism underlying this beneficial effect could be the improved coupling between energy intake and expenditure, since hunger and satiety are better regulated in active individuals. Whether this enhancement of appetite control by exercise is reflected in overall adaptations in the gut and gut-brain communication remains poorly defined.

Abstract

Intracranial aneurysms (IAs) occur in up to 3% of the population, with rupture leading to substantial morbidity and mortality. Preclinical evidence suggests glucagon-like peptide-1 receptor agonists (GLP-1RAs) may provide vascular protection. Their role in IA rupture prevention has not been readily assessed in large human cohorts.

Abstract

To compare the effects of diet restriction and semaglutide treatment on body composition (BC), energy expenditure (EE), and metabolic adaptation (MA) in Göttingen Minipigs as a model for human obesity.

Abstract

This study aimed to assess the latent threat of depression and suicide/self-injury associated with the combination of glucagon-like peptide-1 agonists (GLP-1RAs) and metformin versus GLP-1RAs monotherapy, through analyzing the data from the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS).

Abstract

To describe the design and rationale of LIGHT 2, a seamless, adaptive phase 2b/3 trial evaluating the efficacy and safety of efsubaglutide alfa for chronic weight management in adults with overweight or obesity.

Abstract

Background and objective Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), especially semaglutide, are commonly used to treat obesity and diabetes. They may influence sebaceous gland activity, hidradenitis suppurativa (HS), and acne via metabolic and anti-inflammatory pathways. This study aimed to assess the effects of semaglutide on acne severity, HS activity, and sebaceous gland function, and to evaluate associations with metabolic improvements. Materials and methods This prospective, observational, single-arm study was conducted at the Department of Dermatology, Hayatabad Medical Complex, Peshawar, from January 2023 to December 2024. Adults with acne, HS, or increased sebaceous gland activity who initiated semaglutide therapy between the ages of 18 and 65 years were included. Sebumetry, HS severity using the Hidradenitis Suppurativa Area and Severity Index - Revised (HASI-R), and acne grading using the Investigator's Global Assessment (IGA) were evaluated at baseline and at three, six, 12, 18, and 24 months. Concurrent measurements of metabolic markers, including BMI, HbA1c, fasting glucose, and insulin, were also obtained. Statistical analyses included Pearson and Spearman correlations, multivariate regression to adjust for confounders, and paired t-tests for pre- and post-treatment comparisons. P-values below 0.05 were considered statistically significant. Results Of the 120 enrolled participants, 110 completed the follow-up (91.7%). Over 24 months, acne severity decreased from 1.92 ± 0.78 to 1.21 ± 0.63, HS activity declined from 11.34 ± 4.56 to 7.45 ± 3.21, and sebaceous gland activity was reduced from 186.45 ± 52.34 to 138.56 ± 42.78 µg/cm². Improvements in BMI, HbA1c, fasting glucose, and insulin were significantly associated with dermatologic improvement (p < 0.05). Adverse events were mild and transient and occurred in 17 participants (15.45%). Conclusions Semaglutide therapy was significantly associated with improvement in acne, HS activity, and sebaceous gland function, independently correlated with metabolic enhancements. These findings indicate a potential dermatologic benefit of GLP-1 agonists, supporting the need for further controlled studies.

Abstract

To evaluate the association between glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and intestinal cancers and to explore the risk factors for these associations.

Abstract

The phenomenon where excessive activation of branched-chain amino acid (BCAA) degrading enzymes caused by high concentrations of leucine (Leu) leads to a decrease in the overall concentration of BCAA [including isoleucine (Ile) and valine (Val)] is called BCAA antagonism. Although this phenomenon has long been widely studied, the specific mechanism of its occurrence is still poorly understood. In this study, we investigated the specific mechanism by which Val and Ile alleviate the antagonistic effect caused by high concentrations of Leu through influencing insulin function. First, the ratios of Ile and Val in the low-protein diet were adjusted up and down by 15% to observe the metabolic status of broilers at the end of the experiment (the experiment period was from 0 to 42 d). Subsequently, the physiological and biochemical changes related to antagonism were determined using transcriptome and lipid metabolome analyses.

Abstract

We aimed to analyse trends and demographic and clinical profiles in initial prescriptions of semaglutide ("Ozempic") by general practitioners in New South Wales between 2020 and 2023.

Abstract

Metabolic disorders have been recognized as a major contributor to the occurrence and progression of osteoarthritis (OA). Identifying novel therapeutic agents to ameliorate the progression of OA with metabolic disorder is crucial. In this study, we demonstrate that semaglutide (SG), a glucagon-like peptide-1 receptor (GLP-1R) agonist, exhibits strong chondroprotective effects in an OA mouse model with obesity, as evidenced by reduced pathological changes, including cartilage degeneration, osteophyte formation, synovial lesion, and pain sensitivity. A randomized pilot clinical study (ChiCTR2200066291) further supports these findings. By designing a precise diet-controlled setting to rule out the effect of appetite suppression and weight loss induced by SG, we demonstrate a weight loss-independent mechanism. Through regulating the "GLP-1R-AMPK-PFKFB3" axis, the SG reprograms chondrocyte metabolism profile from glycolysis to oxidative phosphorylation under inflammatory conditions, resulting in cartilage restoration.

Abstract

Semaglutide, a glucagon-like peptide-1 receptor agonist, has gained increasing popularity for managing both type 2 diabetes mellitus and obesity. However, as its use increases, new adverse events are emerging. This case report presents a 70-year-old patient who developed pleural and pericardial effusions likely related to semaglutide use.

Abstract

Obesity adversely affects atrial fibrillation (AF) outcomes and is associated with higher recurrence after catheter ablation. Glucagon-like peptide-1 receptor agonists (GLP-1RA) promote weight loss and improve metabolic inflammation, but their role as adjuncts to ablation has not been completely defined. This study investigated the impact of semaglutide on post-ablation rhythm outcomes in obese patients with AF.

Abstract

As endometrial cancer (EC) incidence rises, particularly among individuals with obesity and metabolic disorders, effective strategies targeting hormonal and metabolic risks are needed.

Abstract

GLP-1RAs are increasingly prescribed to older adults with type 2 diabetes for their metabolic and cardiovascular benefits, but their effects on bone health in this high-risk population are not well established. The aim of this study was to assess the risk of fragility fractures associated with glucagon-like peptide 1 receptor agonist (GLP-1RA) therapy compared to sodium-glucose cotransporter-2 inhibitors or dipeptidyl peptidase-4 inhibitors in older adults with type 2 diabetes.

Abstract

The cardiovascular and renal benefits of sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) are well established among patients with type 2 diabetes (T2D). However, comparative evidence regarding cancer risk remains limited.