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Semaglutide-induced loss of skeletal muscle mass is blunted by co-administration of ketone esters.

JCI Insight

Yasser Abuetabh, Mya A Schmidt, Masaaki Naganuma +18 more

While glucagon-like peptide-1 receptor agonists (GLP-1RAs) like semaglutide are effective in treating obesity, up to 45% of the resulting weight loss can be attributed to skeletal muscle loss. Given the critical role of skeletal muscle in health and mobility, this may have long-term adverse consequences. Herein we investigated whether oral ketone ester supplementation could prevent semaglutide-induced muscle loss and explored the underlying molecular mechanisms. Obese, glucose-intolerant mice received vehicle, semaglutide, or semaglutide plus a β-hydroxybutyrate-generating ketone ester for three weeks. Body composition, muscle strength, and endurance were assessed longitudinally. Semaglutide monotherapy reduced lean mass, impaired muscle strength, and suppressed mitochondrial gene expression while elevating atrophy-related genes in skeletal muscle samples. Co-administration with ketone ester preserved skeletal muscle mass and function without compromising fat loss. Mechanistically, ketone ester co-treatment prevented semaglutide-induced changes in mitochondrial and atrophy-related gene expression, suggesting mitochondrial defects and impaired ketone metabolism contribute to GLP-1RA-induced muscle loss. Together, these findings demonstrate that ketone ester supplementation can maintain muscle mass and performance during semaglutide-driven weight loss. These preclinical findings support ketone therapy as a promising strategy to counteract the sarcopenia-promoting effects of GLP-1RAs and warrant clinical evaluation to assess its translational potential.

Association between trajectories of physical activity and depressive symptoms among Chinese older adults with chronic disease: evidence from the Chinese Longitudinal Healthy Longevity Survey.

BMC Geriatr

Jinghong Huang, Xiaojun Liu, Seung Chun Paek

Physical activity (PA) has been associated with depressive symptoms (DS), yet most evidence relies on single time-point assessments and general populations. It remains unclear whether long-term trajectories of PA are associated with the odds of DS among older adults with chronic disease (participants with at least one chronic disease), including those with multimorbidity (participants with two or more chronic diseases). Therefore, this study aimed to examine the association between trajectories of PA and DS with chronic disease.

Risk factors and self-management predictors of activities of daily living in patients with heart failure: A 12-month prospective cohort study.

Medicine (Baltimore)

Meng Ning, Zhiyuan Li, Chong Zhang +2 more

Impaired activities of daily living (ADL) significantly affect the prognosis and quality of life in patients with heart failure (HF). We aimed to identify the key clinical and self-management predictors of ADL 12 months after hospital discharge. This prospective cohort study enrolled 162 hospitalized patients with HF stratified into low-ADL (ADL < 100, n = 66) and high-ADL (ADL = 100, n = 96) groups based on 12 months of follow-up. The baseline characteristics, comorbidities, biomarkers (B-type natriuretic peptide [BNP]), and self-management domains (psychological, drug, dietary, and symptom management) were compared. Logistic regression was used to identify ADL predictors. Subgroup analyses of left ventricular ejection fraction (LVEF) were performed. The low-ADL group had significantly higher rates of valvular heart disease (VHD; 12% vs 3%, P = .025) and diabetes mellitus (29% vs 16%, P = .043), elevated BNP levels (median 474.9 vs 398.0 pg/mL, P = .039), and poorer self-management scores (P < .05). Multivariable analysis confirmed that diabetes (adjusted odds ratio [aOR], 0.33; 95% confidence interval [CI], 0.14-0.80; P = .014) and VHD (aOR, 0.19; 95% CI, 0.04-0.80; P = .024) were independent negative predictors. Symptom management was the strongest positive predictor (crude OR, 12.71; 95% CI, 3.38-47.74; P < .001; aOR, 6.26; 95% CI, 1.44-27.19; P = .014). Stratification by LVEF revealed that diabetes mellitus disproportionately impaired ADL in patients with heart failure with reduced ejection fraction (HFrEF; defined as LVEF < 50%; OR, 0.21; 95% CI, 0.06-0.82). The factors influencing ADL scores changed over the 12-month follow-up period. Diabetes, VHD, and poor symptom management were key predictors of long-term ADL impairment in patients with HF. Targeted interventions addressing symptom management and comorbidity control, particularly in patients with HFrEF, may improve functional outcomes.

Semaglutide showed limited improvements in patients with Alzheimer's disease: Revisiting the evoke and evoke + clinical trials.

J Alzheimers Dis

Christian Hölscher

BackgroundSemaglutide is a glucagon-like peptide-1 analog that is on the market to treat type 2 diabetes and weight loss (Ozempic, Wegovy). Two phase 3 clinical trials have been conducted, Evoke and Evoke+, testing the drug in patients with Alzheimer's disease. The trial management presented results of the intermediate readout at week 104 of the CDR-SB scores, which were negative. On the basis of that, the management decided to declare the trials a failure. However, data from week 130 and 156 had not been statistically analyzed.ObjectiveWhen evaluating time points 130 and 156, several results show a separation between drug group and placebo group with semaglutide showing better results.MethodsUsing the means, converting the SEMs to SDs and numbers of patients per group, I analyzed the results using the Welch T-test (two-tailed), which does not assume equal SD.ResultsThe ADCS-ADL-MCI test, Evoke trial, week 130, did show a significant difference, p = 0.0039. Other test such as the ADAS-cog-13 results show trends towards improvement by semaglutide at week 156. Cerebrospinal fluid biomarker analyses showed significant differences in some AD markers, too.ConclusionsThe results did show some limited drug effects at later time points of the trials. However, Semaglutide has been designed to stay in the blood for a long time and therefore does not cross the blood-brain barrier readily. Novel GLP-1 type drugs that can cross the blood-brain barrier easily may show superior protective effects in AD patients.

Elecoglipron, an oral small molecule GLP-1 receptor agonist in adults with type 2 diabetes (SOLSTICE): a multicentre, phase 2b, randomised, placebo-controlled trial.

Lancet

Vanita R Aroda, Melanie J Davies, Jill Maaske +10 more

Elecoglipron is an oral, small molecule glucagon-like peptide (GLP)-1 receptor agonist currently in development for the management of type 2 diabetes. Elecoglipron is orally administered once daily with no food or fluid restrictions. SOLSTICE, a phase 2b study, evaluated the efficacy, safety, and tolerability of elecoglipron versus placebo in participants with type 2 diabetes.

Risk of Age-Related Ocular Diseases in Non-Diabetic Adults With Obesity Using Glucagon-Like Peptide 1 Receptor Agonists.

Diabetes Obes Metab

Kuo-En Chen, Po-Chun Wang, Hui-An Lin +1 more

To assess whether glucagon-like peptide-1 receptor agonists (GLP-1RAs) are associated with a lower incidence of age-related ocular diseases in non-diabetic older adults with overweight or obesity.

Differential impact of glucagon-like peptide-1 (GLP-1) receptor agonists for weight loss in the type 2 diabetic and non-diabetic populations.

Surg Endosc

Iwanger-I-Ter T Jia, Grace C Bloomfield, Mike Y Chen +8 more

Glucagon-like peptide-1 (GLP-1) receptor agonists have emerged as a cornerstone therapy for obesity management, yet long-term comparative effectiveness across diabetes status, adherence, and specific agents remains unclear. This study evaluates multi-year weight-loss outcomes associated with GLP-1 therapy and characterizes medication- and phenotype-specific differences.

Optic Ischaemic Neuropathy in Incretin-Based Therapy: A Comparative Analysis of Real-World Safety Data.

Diabetes Obes Metab

Ashish Kumar Kakkar, Shuvasree Payra, Aarzoo Charaya

Non-arteritic anterior ischemic optic neuropathy (NAION) has emerged as a safety concern with semaglutide, prompting formal regulatory review and action by the European Medicines Agency. However, its occurrence across the broader class of incretin-based therapies is insufficiently characterised. This study used the FDA Adverse Event Reporting System to evaluate and compare pharmacovigilance signals for optic ischaemic neuropathy across six incretin-based therapies.

Health insurance, healthcare access, and their roles in the association between blood lead levels and epigenetic aging in United States adults.

Geroscience

Jamaji C Nwanaji-Enwerem, Dennis Khodasevich, Nicole Gladish +5 more

Lead exposure remains a significant public health problem, and even within current standards, most individuals have limited means to avoid it. Regulating or removing toxic exposures remains a priority, but complementary nearer-term protections are needed. We previously observed that health insurance coverage attenuated associations of blood lead levels with two DNA methylation-based biomarkers of morbidity and mortality: GrimAge2 and DunedinPoAm. In this study, we evaluated whether healthcare access could account for or modify these relationships. We conducted a cross-sectional analysis of 2,312 adults aged 50-84 years from the 1999-2002 National Health and Nutrition Examination Survey (NHANES). Survey-weighted generalized linear models were used to test effect modification of the lead-epigenetic aging relationship by health insurance and by healthcare access, defined as having a routine place of healthcare. In models adjusted for demographic, socioeconomic, lifestyle, and health factors, insurance significantly modified associations of lead with epigenetic age. Although model estimates remained comparable, interactions were no longer statistically significant after healthcare access was added as a covariate for GrimAge2 (βinsured = 0.08, 95%CIinsured: -0.08, 0.23, βuninsured = 0.60, 95%CIuninsured: -0.10, 1.28, Pinteraction = 0.09) and DunedinPoAm (βinsured = 0.001, 95%CIinsured: -0.002, 0.003, βuninsured = 0.01, 95%CIuninsured: -0.003, 0.02, Pinteraction = 0.09). Healthcare access alone did not significantly modify the associations of lead with either biomarker in models with or without insurance as a covariate. These findings suggest that healthcare access may partially contribute to the attenuation of lead-related epigenetic aging observed among insured adults and a need for further research to better understand these complex relationships.

A discovery-based proteomic approach of epidermal growth factor and growth hormone-releasing peptide-6 in a model of acute ischemic stroke.

Pharmacol Rep

Arielis Rodríguez-Ulloa, Nelvys Subirós-Martínez, Luis Javier González +4 more

Combined therapy with epidermal growth factor (EGF) and growth hormone-releasing peptide 6 (GHRP6) has demonstrated neuroprotective effects in models of global and focal brain ischemia. Clinical studies in ischemic stroke patients have confirmed the safety and preliminary efficacy of this combined treatment. This study aimed to elucidate the molecular mechanisms underlying the effects of EGF+GHRP6 co-administration.

Homer 2 regulates muscle differentiation with NFATc1.

Cells Tissues Organs

Miki Aizawa, Masakazu Kinoshita, Kunihiro Sakuma

Calcineurin-NFAT is an important pathway that regulates skeletal muscle regeneration. Homer 2 that modulates signal transduction in the central nervous system directly binds to NFATc1. However, its role is not fully understood in skeletal muscle regeneration. We aimed to investigate the change of Homer 2 protein levels and expression patterns during muscle regeneration. Male ICR mice (12 weeks) were used in the experiment (n=6/group). Their left TA muscle was damaged via intramuscular injection of 0.5% bupivacaine hydrochloride (100 μL). The TA muscles of both legs were dissected at 2, 4, and 6 days post-injection and were subjected to immunofluorescence staining with Homer 2, NFATc1 and muscle regeneration markers [Pax7 and myogenin]. We calculated their expression frequency by quantifying the immunoreactivity per 500 nuclei. We observed Homer 2 immunoreactivity in TA muscles at 2, 4, and 6 days post-injection. Homer 2 and Pax7, a satellite cell marker, were co-localized in mononuclear cells also in regenerating TA muscles. Many Homer 2-positive mononuclear cells expressed myogenin. The frequency of Homer 2 and NFATc1-positive cells significantly increased at 4 and 6 days rather than 2 days post-injection. Interestingly, co-immunoprecipitation experiments of Homer 2 and NFATc 1 showed markedly increased levels at 4 days. In conclusion, we demonstrated that expression of Homer 2 protein increases in TA muscle regeneration. Homer 2 may act in the muscle regeneration process via the calcineurin-NFAT pathway.

Spinal Implant-Associated Infection in Type 2 and Type 1 Diabetes: Phenotype-Specific Inflammatory Features and Therapeutic Response to Semaglutide.

JOR Spine

Thomas E Olson, Trevor S Lloyd, Christopher D Hamad +14 more

Diabetes mellitus (DM) is a major risk factor for postoperative infection and wound complications in spine surgery, yet distinctions between Type 2 (T2DM) and Type 1 (T1DM) pathophysiology are rarely addressed. This study compares infectious burden, wound healing, and immune response among a murine model of spinal implant-associated infection of T2DM, T1DM, and nondiabetic control mice before and after metabolic intervention with the GLP-1 receptor agonist (GLP-1RA), semaglutide.

Efficacy and safety of novel formulation of semaglutide injection: A multicentre, randomized, comparative, active controlled, phase 3 study in comparison with reference biologic in Indian patients with type 2 diabetes mellitus.

Metabol Open

Prabhat Kumar Sharma, V Viswaprasad, Animesh Choudhary +24 more

Type 2 diabetes mellitus (T2DM) is the most common non-communicable disease affecting over 89.8 million adults in India. Evidence suggests long-acting glucagon-like peptide-1 (GLP-1) receptor agonist improves glycaemic control in the patients with T2DM. This phase 3 trial compared a novel semaglutide injection developed by Zydus Lifesciences Ltd. with the reference biologic in Indian adults with T2DM inadequately controlled on metformin.

Semaglutide and weight loss in obese patients with and without type 2 diabetes.

J Family Med Prim Care

Harish Gupta, Rajeev Verma

Dulaglutide in the era of tirzepatide and semaglutide: reaffirming its role in contemporary cardiometabolic care.

Diabetol Int

Shambo Samrat Samajdar, Shashank Joshi, Banshi Saboo +2 more

The management of type 2 diabetes (T2D) has entered a new era with the advent of advanced incretin-based therapies. Therapeutic agents such as semaglutide and tirzepatide have demonstrated exceptional efficacy in improving glycemic control, inducing substantial weight loss, and reducing cardiometabolic risk, thereby redefining therapeutic expectations. Yet, dulaglutide retains a distinct role supported by its strong cardiovascular evidence base. The REWIND trial remains the only GLP-1 receptor agonist study to show a statistically significant reduction in major adverse cardiovascular events (MACE) in a predominantly primary prevention population, with durable benefit sustained over more than five years of follow-up. Comparative trials highlight that while tirzepatide and semaglutide deliver superior reductions in HbA1c and body weight, dulaglutide offers proven cardiovascular safety, favourable tolerability, and high persistence in real-world analyses. Its once-weekly, fixed-dose regimen requires no titration and is accessible across diverse healthcare systems in low- and middle-income countries, including those constrained by cost or resources. The SURPASS-CVOT established tirzepatide's non-inferiority to dulaglutide for cardiovascular outcomes, reaffirming dulaglutide as an established comparator with robust outcome data. This narrative review collates evidence in this regard and argues that dulaglutide should be viewed not as superseded but as complementary offering a pragmatic balance of efficacy, safety, and accessibility that supports equitable cardiometabolic care worldwide.

Indications, efficacy, and safety of glucagon-like peptide-1 receptor agonists in respiratory diseases: A systematic review.

J Family Med Prim Care

Moudhi N Esmaeel, Nasima N Esmaeel, Reem M Alhouli +7 more

Glucagon-like peptide-1 receptor agonists (GLP-1RA), initially developed to control type 2 diabetes mellitus, have gained recognition for their broad cardiometabolic benefits, including weight loss, and cardiovascular protection. Emerging evidence indicates that these agents may also improve respiratory outcomes through their anti-inflammatory effects, bronchodilation, and weight reduction effects. This systematic review aimed to evaluate the indications, efficacy, and safety of GLP-1RA in respiratory diseases.

A two-tier protection strategy for oral delivery of GLP-1 peptides: lipid-based formulation combined with enteric capsules.

Front Drug Deliv

Camille Dumont, Vanessa Gonzalez, Paula Klatt +6 more

Oral delivery of peptides is a promising alternative to invasive injectable therapies, offering improved patient adherence and convenience. Glucagon-like peptide-1 (GLP-1) analogs, in particular, are highly effective for the management of type 2 diabetes mellitus and obesity, yet their oral bioavailability remains limited by enzymatic degradation and poor intestinal permeability.

A Age Related Vascular Senescence: Mystery of Blood-brain Barrier Dysfunction in Neurodegeneration.

Mol Neurobiol

Tapan Behl, Karthikeyan Jayabalan, Suhas Ballal +6 more

The pathophysiology of neurodegenerative illnesses is increasingly understood to be influenced by vascular aging, with blood-brain barrier (BBB) disruption emerging as a crucial mechanistic connection. Comprising endothelial cells, pericytes, astrocytes, and microglia, the BBB is a complex neurovascular unit (NVU) that strictly regulates molecular trafficking and shields neural tissue from circulating toxins and immune cells, therefore maintaining central nervous system homeostasis. The integrity of the BBB is compromised as people age due to structural and functional changes in the cerebrovasculature, such as endothelial senescence, pericyte loss, mitochondrial dysfunction, and persistent low-grade inflammation. These alterations speed up neuronal damage and encourage the development of classical proteinopathies like tau aggregation and amyloid-β by making it easier for neurotoxic proteins, immunological mediators, and metabolic waste to enter the brain parenchyma. BBB disruption is both an early occurrence and a factor in the development of neurodegenerative diseases including Alzheimer's disease, cerebral amyloid angiopathy, and vascular dementia. It exacerbates neuroinflammation, hinders clearance processes, and contributes to cognitive decline. Recent developments in single-cell omics, fluid biomarkers, and molecular imaging have made it possible to identify and characterize BBB failure in preclinical and clinical contexts, creating new opportunities for early diagnosis and treatment. Restoring BBB function and addressing vascular aging are two viable approaches to alter the course of neurodegenerative illnesses and enhance their prognoses. The processes, effects, and translational potential of vascular aging and BBB degradation in neurodegeneration are summarized in this review, which also identifies new treatment targets and research objectives for the future.

Reviving Brain Waste Clearance: A Pharmacological Perspective on Glymphatic Dysfunction and AQP4 Modulation.

Curr Neuropharmacol

Souvik Banerjee, Shareen Singh, Thakur Gurjeet Singh

The glymphatic system is a brain-wide clearance pathway that maintains CNS homeostasis by eliminating interstitial solutes, including neurotoxic proteins such as amyloid-ß and tau. This process depends on CSF movement through perivascular spaces, where it exchanges with ISF before draining via perivenous routes. Aquaporin-4 (AQP4) fluid channels localized at astrocytic endfeet are central to glymphatic transport, with their polarization being critical for efficiency. Glymphatic activity peaks during sleep but declines with aging, vascular stiffening, and neuroinflammation. Impaired clearance has been linked to the progression of neurodegeneration. Dysregulation of signaling pathways, including NF-kB, Nrf2/keap1, and NLRP3 inflammasome, contributes to AQP4 mislocalization, glial activation, and disrupted fluid dynamics. These alterations promote neuroinflammation and oxidative stress, accelerating neurodegeneration. Pharmacological interventions that restore AQP4 polarization, together with antioxidant and anti-inflammatory therapies, have demonstrated potential in enhancing glymphatic clearance. In addition, recent advances in imaging and drug delivery technologies, such as nanocarriers and non-invasive nose-to-brain systems, provide new opportunities to modulate glymphatic function and improve neuroprotection. However, significant challenges remain in achieving isoform-selective AQP4 modulation, ensuring long-term safety, and translating findings from rodent models to humans. Overall, targeting AQP4 and associated molecular pathways represents a promising adjunctive strategy to enhance waste removal, reduce neuroinflammation, and delay neurodegenerative disease progression.

The interplay of sleep architecture and exercise in executive function of middle-aged and older adults.

Front Neurol

WenHui Zheng, LiYing Huang, Mian Wu +1 more

Executive function decline in middle-aged and older adults is a significant public health concern, with sleep disturbances and physical inactivity being two major modifiable risk factors. Existing evidence suggests bidirectional associations between sleep and exercise, with both factors potentially influencing cognitive function. This review synthesizes current evidence on the interplay among exercise, sleep architecture, and executive function in aging populations. We first discuss the noradrenergic and adenosinergic systems as shared neuromodulatory substrates underlying the reciprocal regulation of sleep and exercise. We then review evidence linking slow-wave sleep (SWS) to exercise-induced neuroplasticity and sleep spindles to memory consolidation. The glymphatic system is presented as a sleep-dominant clearance mechanism that may interact with exercise. At the brain network level, we summarize how sleep and exercise are, respectively, associated with the dynamic balance between the central executive network and the default mode network. Furthermore, subcomponent-specific associations are examined: SWS duration correlates with inhibitory control and working memory, whereas REM sleep is linked to cognitive flexibility, and resistance or mind-body exercises show selective benefits for distinct executive domains. Nonlinear dose-timing effects are also considered, such as the optimal moderate-intensity aerobic exercise for preserving SWS and the morning exercise preference for aligning with circadian rhythms in older adults. Collectively, this review provides a theoretical basis for understanding how physical activity and sleep architecture jointly influence executive function in middle-aged and older adults. It highlights convergent physiological pathways-ranging from molecular neuromodulators and glymphatic clearance to large-scale brain network dynamics-that may guide future mechanistic studies and intervention strategies for age-related cognitive decline.