1
|
Khalid SI, Mirpuri P, Massaad E, Wang R, Elsamadicy A, Shin JH, Adogwa O. The impact of semaglutide use for weight loss on transforaminal lumbar interbody fusion outcomes. Clin Neurol Neurosurg 2025; 254:108952. [PMID: 40381509 DOI: 10.1016/j.clineuro.2025.108952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2025] [Revised: 05/04/2025] [Accepted: 05/04/2025] [Indexed: 05/20/2025]
Abstract
INTRODUCTION While glucagon-like peptides 1 receptor agonists (GLP-1RAs) grow in popularity, their potential for presurgical weight optimization in spine surgery remains unclear. We examined the influence of semaglutide prescription on one- to three-level transforaminal lumbar interbody fusion (TLIF) outcomes. METHODS Retrospective analysis of obese, non-diabetic patients was conducted from 2018 to 2022. A 1:1 exact match paired semaglutide users with non-users based on age, gender, surgical levels, and comorbidities. The primary outcome were the rates of surgical and medical complications at 30 days following TLIF. A sub analysis assessed outcomes after stratifying by prescription duration (greater or less than nine months). Kaplan-Meier survival analyses evaluated the need for additional lumbar fusion. The alpha was set to 0.05, but with the Bonferroni correction the significance threshold was set to 0.0045. RESULTS 471 semaglutide users were matched with 471 non-users with no baseline differences. Semaglutide users had higher rates of pneumonia (2.97 % vs 0.85 %, p < 0.05) compared to nonusers. When stratified by prescription duration, patients with longer semaglutide use had a higher incidence of urinary tract infection (4.03 % vs 1.27 %, p < 0.05) and acute kidney injury (3.18 % vs 0.85 %, p < 0.05). The need for additional lumbar fusion was associated with both semaglutide use (17.0 % vs. 6.4 %, p < 0.0001) and duration (28.3 % vs. 4.8 %, p < 0.0001). CONCLUSIONS Semaglutide may adversely affect lumbar fusion outcomes and necessitate additional surgery, possibly secondary to its systemic effects on bone metabolism and weight loss patterns. Further research into optimal drug formulation, dosage, and weight loss protocols will be required before mainstream use.
Collapse
Affiliation(s)
- Syed I Khalid
- Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA; Department of Neurosurgery, University of Illinois at Chicago, Chicago, IL, USA.
| | - Pranav Mirpuri
- Department of Neurology, University of Minnesota, Minneapolis, MN, USA
| | - Elie Massaad
- Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA
| | - Ryan Wang
- Chicago Medical School, Rosalind Franklin University, North Chicago, IL, USA
| | | | - John H Shin
- Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA
| | - Owoicho Adogwa
- Department of Neurosurgery, University of Cincinnati School of Medicine, Cincinnati, OH, USA
| |
Collapse
|
2
|
Abbass NJ, Nahlawi R, Shaia JK, Allan KC, Kaelber DC, Talcott KE, Singh RP. The Effect of Semaglutide and GLP-1 RAs on Risk of Nonarteritic Anterior Ischemic Optic Neuropathy. Am J Ophthalmol 2025; 274:24-31. [PMID: 40015592 DOI: 10.1016/j.ajo.2025.02.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Revised: 02/19/2025] [Accepted: 02/20/2025] [Indexed: 03/01/2025]
Abstract
PURPOSE The association between GLP-1 receptor agonists (GLP-1RA) and nonarteritic anterior ischemic optic neuropathy (NAION) remains unclear. Given the debilitating sequelae of NAION and rapid increase of GLP-1RA use, further research is essential to investigate this potential relationship. This study seeks to determine the risk of NAION and ischemic optic neuropathy (ION) in patients prescribed GLP-1RAs. DESIGN Retrospective matched cohort study. SETTING TriNetX United States collaborative network. PARTICIPANTS Patients ≥12 years old with type 2 diabetes (T2DM) and considered overweight or obese (high BMI), with at least one ophthalmology or neurology visit. Among T2DM patients, approximately 120,000 patients with a semaglutide prescription and 220,000 prescribed any GLP-1RA were compared to matched T2DM controls. Among high BMI patients, approximately 58,000 on semaglutide and 66,000 on any GLP-1RA were compared to matched controls. METHODS Patients prescribed semaglutide or any GLP-1RA were compared with those on non-GLP-1RA medications. Populations were propensity matched (1:1) on various demographic and risk factors to balance baseline cohorts. MAIN OUTCOMES AND MEASURES Cumulative incidence and risk of NAION and ION. Risk ratios (RR) with 95% confidence intervals (CI) were reported, with significance defined as CI <0.9 or > 1.1. RESULTS In T2DM patients prescribed semaglutide, the risk of NAION (RR = 0.7, 95% CI: 0.523-0.937) and ION (RR = 0.788, 95% CI: 0.609-1.102) after 5 years was not significantly increased compared to matched T2DM controls. Similarly, T2DM patients on any GLP-1RA demonstrated no significant difference in the risk of NAION (RR = 0.887, 95% CI: 0.735-1.071) or ION (RR = 0.969, 95% CI: 0.813-1.154) compared to controls. Furthermore, no increased risk of either outcome was found in the high BMI groups prescribed semaglutide or any GLP-1RA. The cumulative 5-year risk of NAION and ION in T2DM patients on semaglutide was 0.065% and 0.08%, respectively. In those with high BMI prescribed semaglutide, the risk of NAION and ION after 2 years was 0.038% and 0.404%, respectively. CONCLUSIONS There was no significant increase in risk of NAION or ION in patients taking semaglutide or GLP-1RAs compared to T2DM or high BMI controls.
Collapse
Affiliation(s)
- Nadia J Abbass
- From the Case Western Reserve University School of Medicine (N.J.A., R.N., J.K.S.), Cleveland, Ohio, USA; Center for Ophthalmic Bioinformatics (N.J.A., R.N., J.K.S., K.E.T., R.P.S.), Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Raya Nahlawi
- From the Case Western Reserve University School of Medicine (N.J.A., R.N., J.K.S.), Cleveland, Ohio, USA; Center for Ophthalmic Bioinformatics (N.J.A., R.N., J.K.S., K.E.T., R.P.S.), Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Jacqueline K Shaia
- From the Case Western Reserve University School of Medicine (N.J.A., R.N., J.K.S.), Cleveland, Ohio, USA; Center for Ophthalmic Bioinformatics (N.J.A., R.N., J.K.S., K.E.T., R.P.S.), Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Kevin C Allan
- Cleveland Clinic Cole Eye Institute (K.C.A., K.E.T., R.P.S.), Cleveland, Ohio, USA
| | - David C Kaelber
- Departments of Internal Medicine, Pediatrics and Population and Quantitative Health Sciences, Case Western Reserve University (D.C.K.), Cleveland, Ohio, USA; The Center for Clinical Informatics Research and Education (D.C.K.), The MetroHealth System, Cleveland, Ohio, USA
| | - Katherine E Talcott
- Center for Ophthalmic Bioinformatics (N.J.A., R.N., J.K.S., K.E.T., R.P.S.), Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, USA; Cleveland Clinic Lerner College of Medicine of Case Western Reserve University (K.E.T., R.P.S.), Cleveland, Ohio, USA; Cleveland Clinic Cole Eye Institute (K.C.A., K.E.T., R.P.S.), Cleveland, Ohio, USA
| | - Rishi P Singh
- Center for Ophthalmic Bioinformatics (N.J.A., R.N., J.K.S., K.E.T., R.P.S.), Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, USA; Cleveland Clinic Lerner College of Medicine of Case Western Reserve University (K.E.T., R.P.S.), Cleveland, Ohio, USA; Cleveland Clinic Cole Eye Institute (K.C.A., K.E.T., R.P.S.), Cleveland, Ohio, USA; Cleveland Clinic Martin Hospitals (R.P.S.), Cleveland Clinic Florida, Stuart, Florida, USA.
| |
Collapse
|
3
|
Wang Y, Duan C, Du X, Zhu Y, Wang L, Hu J, Sun Y. Vagus Nerve and Gut-Brain Communication. Neuroscientist 2025; 31:262-278. [PMID: 39041416 DOI: 10.1177/10738584241259702] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/24/2024]
Abstract
The vagus nerve, as an important component of the gut-brain axis, plays a crucial role in the communication between the gut and brain. It influences food intake, fat metabolism, and emotion by regulating the gut-brain axis, which is closely associated with the development of gastrointestinal, psychiatric, and metabolism-related disorders. In recent years, significant progress has been made in understanding the vagus-mediated regulatory pathway, highlighting its profound implications in the development of many diseases. Here, we summarize the latest advancements in vagus-mediated gut-brain pathways and the novel interventions targeting the vagus nerve. This will provide valuable insights for future research on treatment of obesity and gastrointestinal and depressive disorders based on vagus nerve stimulation.
Collapse
Affiliation(s)
- Yiyang Wang
- Division of Physical Biology, CAS Key Laboratory of Interfacial Physics Technology, Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Chenxi Duan
- Division of Physical Biology, CAS Key Laboratory of Interfacial Physics Technology, Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Xinyi Du
- Institute of Materiobiology, College of Sciences, Shanghai University, Shanghai, China
| | - Ying Zhu
- Division of Physical Biology, CAS Key Laboratory of Interfacial Physics Technology, Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai, China
- Institute of Materiobiology, College of Sciences, Shanghai University, Shanghai, China
| | - Lihua Wang
- Division of Physical Biology, CAS Key Laboratory of Interfacial Physics Technology, Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai, China
- Institute of Materiobiology, College of Sciences, Shanghai University, Shanghai, China
| | - Jun Hu
- Institute of Materiobiology, College of Sciences, Shanghai University, Shanghai, China
- The Interdisciplinary Research Center, Shanghai Synchrotron Radiation Facility, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai, China
| | - Yanhong Sun
- Institute of Materiobiology, College of Sciences, Shanghai University, Shanghai, China
| |
Collapse
|
4
|
Lazarus E. Appropriate use of the fixed-dose, extended-release combination of naltrexone and bupropion as treatment for obesity in primary care. OBESITY PILLARS 2025; 14:100170. [PMID: 40160495 PMCID: PMC11951042 DOI: 10.1016/j.obpill.2025.100170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Revised: 02/24/2025] [Accepted: 02/25/2025] [Indexed: 04/02/2025]
Abstract
Background Obesity is considered a chronic disease and is influenced by biological, environmental, and behavioral factors that can contribute to its progression. Although lifestyle changes are integral to treating obesity and maintaining a healthful weight, weight reduction from behavioral intervention alone is often insufficient because neurophysiologic factors may work against such changes in lifestyle and behavior. Research suggests that the mechanisms underlying food cravings and obesity overlap with dopaminergic signaling in the brain and pathways involved in addiction. As a result, patients who are differentially impacted by food cravings may have better outcomes with treatments targeting neural systems implicated in both homeostatic and hedonic food consumption or addictive behaviors. Methods In this clinical review, we describe the safety and efficacy data for the fixed-dose, extended-release combination of naltrexone and bupropion (NB-ER) compared with its monotherapy constituents (naltrexone and bupropion), as well as discuss the appropriate use of NB-ER to treat patients with obesity. Results NB-ER is approved for the treatment of patients with obesity, with studies showing that patients can achieve significant weight reduction compared with placebo when treatment is combined with a reduced-calorie diet and increased physical activity. Across NB-ER phase 3 trials, responders to treatment had a mean body weight reduction of 11.7 % at 56 weeks. Of note, the unique combination of naltrexone, an opioid receptor antagonist, and bupropion, a norepinephrine-dopamine reuptake inhibitor associated with stimulating pro-opiomelanocortin cells (POMC), in NB-ER may work together to target POMC cells to prevent endogenous negative feedback, thereby decreasing appetite and improving weight-related outcomes. Conclusions Unlike monotherapy with its component drugs, NB-ER is optimized for the treatment of obesity. The appropriate use of NB-ER should consider the specific characteristics and adiposity-related complications of an individual.
Collapse
Affiliation(s)
- Ethan Lazarus
- Clinical Nutrition Center, Greenwood Village, CO, 80111, USA
| |
Collapse
|
5
|
Dodangeh S, Hasani-Ranjbar S. Old and new anti-obesity drugs. J Diabetes Metab Disord 2025; 24:16. [PMID: 39712336 PMCID: PMC11659566 DOI: 10.1007/s40200-024-01512-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Accepted: 11/24/2024] [Indexed: 12/24/2024]
Abstract
Obesity is a pandemic problem that correlates with a cluster of metabolic factors leading to poor cardiovascular outcomes, morbidity, and an increased risk of overall mortality. It is necessary to approach obesity with a comprehensive treatment plan, which may involve lifestyle modifications (diet, exercise, and behavioral therapy) and pharmacological interventions. This article provides an overview of the mechanisms of action, efficacy, and safety of available long-term anti-obesity drugs and introduces other potential agents under investigation.
Collapse
Affiliation(s)
- Salimeh Dodangeh
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Shirin Hasani-Ranjbar
- Obesity and Eating Habits Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| |
Collapse
|
6
|
Zafer M, Tavaglione F, Romero-Gómez M, Loomba R. Review Article: GLP-1 Receptor Agonists and Glucagon/GIP/GLP-1 Receptor Dual or Triple Agonists-Mechanism of Action and Emerging Therapeutic Landscape in MASLD. Aliment Pharmacol Ther 2025; 61:1872-1888. [PMID: 40364529 DOI: 10.1111/apt.70196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2025] [Revised: 04/14/2025] [Accepted: 05/03/2025] [Indexed: 05/15/2025]
Abstract
BACKGROUND Metabolic dysfunction-associated steatotic liver disease (MASLD) is primarily managed through diet and lifestyle modifications. However, these behavioural interventions alone may not achieve disease regression or remission, and maintaining long-term adherence is challenging. Incretin mimetics and other gastrointestinal hormones targeting the pleiotropic pathophysiological pathways underlying MASLD have now emerged as promising disease-modifying therapies. AIMS This is a comprehensive review summarising the role of glucagon-like peptide-1 (GLP-1) receptor agonists and glucagon/glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor dual or triple agonists in the treatment of metabolic dysfunction-associated steatohepatitis (MASH). METHODS Only clinical trials with endpoints assessed by liver histology were included for a robust evaluation of therapeutic efficacy. RESULTS Recent evidence from phase 2 clinical trials for MASH demonstrated that pharmacological agents based on GLP-1 receptor agonism are effective in improving disease activity. Additionally, tirzepatide and survodutide showed potential clinical benefits in reducing fibrosis. Other cardiometabolic benefits observed include weight loss and improvements in glycaemic control and lipid profile. Adherence to treatment may be limited by gastrointestinal side effects, though they were found to be generally mild to moderate in severity. An interim analysis of the semaglutide phase 3 trial confirmed its efficacy in improving steatohepatitis and demonstrated its potential to improve fibrosis. CONCLUSIONS GLP-1 receptor agonists, alone or in combination with GIP and/or glucagon receptor agonists, represent promising, effective pharmacotherapies for the treatment of MASLD/MASH. Larger and longer-duration clinical trials are needed to further evaluate the efficacy and safety of GIP receptor and glucagon receptor agonism.
Collapse
Affiliation(s)
- Maryam Zafer
- MASLD Research Center, Division of Gastroenterology and Hepatology, University of California at San Diego, La Jolla, California, USA
| | - Federica Tavaglione
- MASLD Research Center, Division of Gastroenterology and Hepatology, University of California at San Diego, La Jolla, California, USA
| | - Manuel Romero-Gómez
- UCM Digestive Diseases and Ciberehd, Virgen Del Rocío University Hospital, Institute of Biomedicine of Seville (CSIC/HUVR/US), University of Seville, Seville, Spain
| | - Rohit Loomba
- MASLD Research Center, Division of Gastroenterology and Hepatology, University of California at San Diego, La Jolla, California, USA
- School of Public Health, University of California at San Diego, La Jolla, California, USA
| |
Collapse
|
7
|
Crecca E, Di Giuseppe G, Camplone C, Vigiano Benedetti V, Melaiu O, Mezza T, Cencioni C, Spallotta F. The multifaceted role of agents counteracting metabolic syndrome: A new hope for gastrointestinal cancer therapy. Pharmacol Ther 2025; 270:108847. [PMID: 40216262 DOI: 10.1016/j.pharmthera.2025.108847] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Revised: 01/27/2025] [Accepted: 04/03/2025] [Indexed: 04/24/2025]
Abstract
Metabolic syndrome (MetS) is defined by the presence of at least three of five clinical parameters including abdominal obesity, insulin resistance, elevated triglycerides, reduced high-density lipoprotein (HDL) and hypertension. Major features describing MetS have been recognized risk factors for cancer onset, with an alarming impact on gastrointestinal (GI) tumors. Intriguingly, therapeutic administration of drugs to improve glycemic control and dyslipidemia (including metformin, statins) has been shown to have a preventive role in the development and in prognosis improvement of several cancer types. Overall, these observations highlight the key role of altered metabolism prevalently in cancer risk development and unveil anti-MetS agent repurposing potential beyond their conventional pharmacological action. The objective of this review is to summarize the current knowledge about the antitumor activity of anti-diabetic and anti-lipemic agents in GI cancer onset and progression. Here, pre-clinical evidence of their therapeutic potential and of their integration in novel compelling therapeutic strategies will be discussed. Possible clinical outcomes of these novel therapeutic combined protocols specifically dedicated to GI cancer patients will be put under the spotlight. In the future, these novel therapeutic options should be considered to improve conventional chemotherapy response and prognosis of this group of patients.
Collapse
Affiliation(s)
- Elena Crecca
- Institute of System Analysis and Informatics "Antonio Ruberti", National Research Council (IASI-CNR), 00185 Rome, Italy
| | - Gianfranco Di Giuseppe
- Endocrinology and Diabetology Unit, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy; Department of Translational Medicine, Catholic University of the Sacred Heart, 00168 Rome, Italy
| | - Claudia Camplone
- Department of Biology and Biotechnologies "Charles Darwin", Sapienza University, 00185 Rome, Italy; Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University, 00185 Rome, Italy
| | | | - Ombretta Melaiu
- Department of Clinical Sciences and Translational Medicine, University of Rome "Tor Vergata", Rome, Italy
| | - Teresa Mezza
- Department of Translational Medicine, Catholic University of the Sacred Heart, 00168 Rome, Italy; Pancreas Unit, CEMAD Digestive Diseases Center, Internal Medicine and Gastroenterology Unit, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy
| | - Chiara Cencioni
- Institute of System Analysis and Informatics "Antonio Ruberti", National Research Council (IASI-CNR), 00185 Rome, Italy.
| | - Francesco Spallotta
- Department of Biology and Biotechnologies "Charles Darwin", Sapienza University, 00185 Rome, Italy; Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University, 00185 Rome, Italy.
| |
Collapse
|
8
|
AL-Noshokaty TM, Abdelhamid R, Abdelmaksoud NM, Khaled A, Hossam M, Ahmed R, Saber T, Khaled S, Elshaer SS, Abulsoud AI. Unlocking the multifaceted roles of GLP-1: Physiological functions and therapeutic potential. Toxicol Rep 2025; 14:101895. [PMID: 39911322 PMCID: PMC11795145 DOI: 10.1016/j.toxrep.2025.101895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2024] [Revised: 12/30/2024] [Accepted: 01/03/2025] [Indexed: 02/07/2025] Open
Abstract
Glucagon (GCG) like peptide 1 (GLP-1) has emerged as a powerful player in regulating metabolism and a promising therapeutic target for various chronic diseases. This review delves into the physiological roles of GLP-1, exploring its impact on glucose homeostasis, insulin secretion, and satiety. We examine the compelling evidence supporting GLP-1 receptor agonists (GLP-1RAs) in managing type 2 diabetes (T2D), obesity, and other diseases. The intricate molecular mechanisms underlying GLP-1RAs are explored, including their interactions with pathways like extracellular signal-regulated kinase 1/2 (ERK1/2), activated protein kinase (AMPK), cyclic adenine monophosphate (cAMP), mitogen-activated protein kinase (MAPK), and protein kinase C (PKC). Expanding our understanding, the review investigates the potential role of GLP-1 in cancers. Also, microribonucleic acid (RNA) (miRNAs), critical regulators of gene expression, are introduced as potential modulators of GLP-1 signaling. We delve into the link between miRNAs and T2D obesity and explore specific miRNA examples influencing GLP-1R function. Finally, the review explores the rationale for seeking alternatives to GLP-1RAs and highlights natural products with promising GLP-1 modulatory effects.
Collapse
Affiliation(s)
- Tohada M. AL-Noshokaty
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Rehab Abdelhamid
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | | | - Aya Khaled
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Mariam Hossam
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Razan Ahmed
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Toka Saber
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Shahd Khaled
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Shereen Saeid Elshaer
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Girls), Al-Azhar University, Nasr City, Cairo, Egypt
| | - Ahmed I. Abulsoud
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, Cairo 11231, Egypt
- Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| |
Collapse
|
9
|
Finan B, Douros JD, Goldwater R, Hansen AMK, Hjerpsted JB, Hjøllund KR, Kankam MK, Knerr PJ, Konkar A, Mowery SA, Müller TD, Nielsen JR, Nygård SB, Perez-Tilve D, Raun K, Yang B, Tschöp MH, DiMarchi RD. A once-daily GLP-1/GIP/glucagon receptor tri-agonist (NN1706) lowers body weight in rodents, monkeys and humans. Mol Metab 2025; 96:102129. [PMID: 40139439 PMCID: PMC12051155 DOI: 10.1016/j.molmet.2025.102129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Revised: 03/17/2025] [Accepted: 03/18/2025] [Indexed: 03/29/2025] Open
Abstract
Single molecules that combine complementary modes of action with glucagon-like peptide-1 receptor (GLP-1R) agonism are best-in-class therapeutics for obesity treatment. NN1706 (MAR423, RO6883746) is a fatty-acylated tri-agonist designed for balanced activity at GLP-1R and glucose-dependent insulinotropic peptide receptor (GIPR) with lower relative potency at the glucagon receptor (GcgR). Obese mice, rats and non-human primates dosed with NN1706 showed significant body weight reductions and improved glycemic control. In human participants with overweight or obesity, daily subcutaneous NN1706 treatment resulted in substantial body weight loss in a dose-dependent manner without impairing glycemic control (NCT03095807, NCT03661879). However, increased heart rate was observed across NN1706 treatment cohorts, which challenges further clinical development of NN1706.
Collapse
Affiliation(s)
- Brian Finan
- Novo Nordisk Research Center Indianapolis, Indianapolis, IN, USA.
| | - Jonathan D Douros
- Novo Nordisk Research Center Indianapolis, Indianapolis, IN, USA; Novo Nordisk Research Center Boston, Boston, MA, USA
| | | | | | | | | | | | - Patrick J Knerr
- Novo Nordisk Research Center Indianapolis, Indianapolis, IN, USA
| | - Anish Konkar
- Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland
| | | | - Timo D Müller
- Institute for Diabetes and Obesity, Helmholtz Munich, Neuherberg, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany; Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilians-University Munich (LMU), Germany
| | | | | | - Diego Perez-Tilve
- Department of Pharmacology, Physiology and Neurobiology, University of Cincinnati-College of Medicine, Cincinnati, OH, USA
| | | | - Bin Yang
- Novo Nordisk Research Center Indianapolis, Indianapolis, IN, USA
| | - Matthias H Tschöp
- Division of Metabolic Diseases, Department of Medicine, Technical University of Munich, Munich, Germany; Helmholtz Munich, Neuherberg, Germany
| | | |
Collapse
|
10
|
Baris E, Portakal HS, Aslan A, Firtina Karagonlar Z, Tosun M. Liraglutide modulates cyclooxygenase and α7 acetylcholine receptors: in vitro and in silico insights into its anti-inflammatory role in LPS-induced inflammation in RAW 264.7 macrophages. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-04225-5. [PMID: 40448826 DOI: 10.1007/s00210-025-04225-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Accepted: 04/24/2025] [Indexed: 06/02/2025]
Abstract
Liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, is well-established for its metabolic benefits, including glycemic control and weight loss. Beyond these roles, it exhibits significant anti-inflammatory properties, though the mechanisms remain underexplored. This study investigates the anti-inflammatory effects of liraglutide in lipopolysaccharide (LPS)-stimulated RAW 264.7 murine macrophages. Results demonstrate that increasing concentrations of liraglutide suppresses LPS-elevated prostaglandin E2 (PGE2), 6-keto prostaglandin F1α (6-keto-PGF1α, a stable prostacyclin metabolite) and thromboxane A2 (TXA2), similar to that observed with conventional anti-inflammatory agents, ibuprofen and celecoxib. Mechanistic exploration reveals that liraglutide's anti-inflammatory action is dually-modulated by cyclooxygenase (COX) and nicotinic acetylcholine receptor (nAChR) signaling. The application of non-selective, non-competitive nAChR antagonist or selective and potent α7-nAChR antagonist, mecamylamine (MEC) and methyllycaconitine (MLA), respectively, highlights the involvement of cholinergic pathways in liraglutide's activity. Based on in silico molecular docking analyses, liraglutide exhibits favorable binding affinities to COX-1, COX-2, prostacyclin synthase (PGIS), and α7nAChRs, supporting its potential multi-target anti-inflammatory effects. These findings suggest that the therapeutic potential of liraglutide may go beyond metabolic regulation and may be promising for conditions in which metabolic and inflammatory pathways converge, including inflammation and modulation of cholinergic signaling.
Collapse
Affiliation(s)
- Elif Baris
- Department of Medical Pharmacology, Faculty of Medicine, Izmir University of Economics, Sakarya Cd. 156, 35330, Izmir, Türkiye.
| | - Huseyin Saygin Portakal
- Department of Genetics and Bioengineering, Faculty of Engineering, Izmir University of Economics, Izmir, Türkiye
| | - Arda Aslan
- Department of Genetics and Bioengineering, Faculty of Engineering, Izmir University of Economics, Izmir, Türkiye
| | - Zeynep Firtina Karagonlar
- Department of Genetics and Bioengineering, Faculty of Engineering, Izmir University of Economics, Izmir, Türkiye
| | - Metiner Tosun
- Department of Medical Pharmacology, Faculty of Medicine, Izmir University of Economics, Sakarya Cd. 156, 35330, Izmir, Türkiye
| |
Collapse
|
11
|
Mariscal M, Testai FD. Emerging Treatments for Obesity: the Role of GLP1 Receptor Agonists on Stroke. Curr Neurol Neurosci Rep 2025; 25:36. [PMID: 40397216 PMCID: PMC12095380 DOI: 10.1007/s11910-025-01423-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/01/2025] [Indexed: 05/22/2025]
Abstract
PURPOSE Stroke is a leading cause of disability and mortality worldwide. It has been estimated that more than 90% of the risk of stroke is associated with modifiable factors, including diabetes, hypertension, obesity, and heart disease. Glucagon-like peptide 1 receptor agonists (GLP1RAs) have been shown to have a beneficial effect on these major risk factors. In this review, we discuss the evidence supporting the use of GLP1RAs on brain health, particularly in relation to stroke prevention. RECENT FINDINGS The results of multiple randomized clinical trials demonstrate that, among patients with type 2 diabetes, GLP1RAs reduce body weight and improve glucose levels and lipid metabolism. In high-risk populations, GLP1RAs also reduce the risk of major adverse cardiovascular events, including all stroke and non-fatal stroke. Mechanistically, GLP1RAs have a beneficial effect on different stroke risk factors, support microvascular function, and reduce inflammation and oxidative stress. GLP1RAs are recommended for the primary prevention of stroke in patients with diabetes and elevated cardiovascular risk.
Collapse
Affiliation(s)
- Melissa Mariscal
- Neurology and Rehabilitation, University of Illinois Chicago, 912 S Wood St, Chicago, IL, 60612, USA.
| | - Fernando D Testai
- Neurology and Rehabilitation, University of Illinois Chicago, 912 S Wood St, Chicago, IL, 60612, USA
| |
Collapse
|
12
|
El Nekidy WS, Hasan H, Abidi E, Al Sayegh L, Dajani RZ, El-Kaissi S, Hegazin SB, Mallat J. Comparing the Efficacy of Liraglutide and Semaglutide on Weight Loss: Experience from the Middle East Gulf Region and Literature Review. Hosp Pharm 2025:00185787251340645. [PMID: 40417637 PMCID: PMC12095202 DOI: 10.1177/00185787251340645] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/27/2025]
Abstract
Objective: Available data comparing the efficacy of liraglutide and semaglutide in managing weight loss is limited. The objective of this study was to compare efficacy of both drugs on weight loss. Methods: A retrospective observational cohort study conducted at our quaternary care hospital from June 2018 to July 2022. The study included adults who received either liraglutide or semaglutide during the study period. The primary outcome was weight loss, while secondary outcomes included effects on HbA1c levels and lipid profile. Results: A total of 366 patients were analyzed (122 on liraglutide, 244 on semaglutide). The groups were comparable in mean age (51.00 ± 11.55 vs 51.16 ± 12.35 years, P = 0.521) and baseline mean weight (94.7 ± 19.5 vs 94.6 ± 19.9 kg, P = 0.989). After a median follow-up of 10 (6-17) months for the liraglutide group and 7.5 (6-11) months for the semaglutide group (P < 0.001), the resultant weights were 90.8 ± 19.6 kg for the liraglutide group and 91.1 ± 19.8 kg for the semaglutide group (P < 0.001) when comparing each group to its baseline separately. When comparing the weight loss achieved in each group, liraglutide achieved a median weight loss of -4 (-7 to 0) kg versus -3 (-6 to 0) kg for semaglutide (P = 0.867). The reduction in HbA1c levels with liraglutide was significantly less than with semaglutide: -0.2 (-0.5 to 0.3) versus -0.5 (-1.1 to 0.1), respectively, (P = 0.003). Both drugs significantly lowered LDL and triglycerides. Multivariable linear regression analysis confirmed no significant difference between the drugs [B -0.577, 95% CI -1.87 to 0.7; P = 0.38], while baseline weight, diabetes, and SGLT2 inhibitors were significant factors affecting weight. Conclusion: Both liraglutide and semaglutide were effective in reducing weight, with no significant difference between the two drugs. However, semaglutide was more effective in reducing HbA1c levels.
Collapse
Affiliation(s)
- Wasim S. El Nekidy
- Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates
- Case Western Reserve University, Cleveland, OH, USA
| | - Haneen Hasan
- Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates
| | - Emna Abidi
- Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates
| | | | - Ruba Z. Dajani
- Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates
| | | | | | - Jihad Mallat
- Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates
- Case Western Reserve University, Cleveland, OH, USA
| |
Collapse
|
13
|
Берковская МА, Гурова ОЮ, Суркова ЕВ, Фадеев ВВ. [The history of the pharmacotherapy of obesity]. PROBLEMY ENDOKRINOLOGII 2025; 71:82-92. [PMID: 40411333 PMCID: PMC12117989 DOI: 10.14341/probl13469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 07/03/2024] [Accepted: 07/16/2024] [Indexed: 05/26/2025]
Abstract
The obesity epidemic is a major public health problem nowadays. The pathophysiology of obesity, which underlies its chronic, progressive, self-sustaining course, determines the difficulties in developing effective and safe methods for body weight control. The article is dedicated to the consideration of the evolution of conservative treatment of obesity, in particular, the history of pharmacotherapy of this disease, characterized by many ups and downs, is presented. The paper discusses, in chronological order, the emergence, efficacy, mechanisms of action, and described side effects of drugs that were investigated and used for weight loss at one time or another, as well as the reasons why many of them were subsequently withdrawn from the market. Until recently, long-term effective and safe pharmacotherapy of obesity remained an insurmountable challenge. Only in the last two decades has the understanding of the molecular mechanisms of appetite control reached a level that allows for a more productive search and development of promising drugs aimed at the pathogenetic treatment of obesity. This article discusses the status of currently available drugs for weight loss, as well as the prospects for drug treatment of obesity. The results of clinical trials of advanced therapeutic molecules, including gastrointestinal hormone receptor agonists, reinforce the belief that a breakthrough in the drug treatment of obesity is possible.
Collapse
Affiliation(s)
- М. А. Берковская
- Первый Московский государственный медицинский университет имени И.М. Сеченова
| | - О. Ю. Гурова
- Первый Московский государственный медицинский университет имени И.М. Сеченова
| | - Е. В. Суркова
- Первый Московский государственный медицинский университет имени И.М. Сеченова
| | - В. В. Фадеев
- Первый Московский государственный медицинский университет имени И.М. Сеченова
| |
Collapse
|
14
|
Chen JJ, Hsu CW, Hung CM, Liang CS, Su KP, Carvalho AF, Stubbs B, Chen YW, Chen TY, Lei WT, Zeng BY, Tseng PT. Risk of Hearing Loss in Patients Treated with Exendin-4 Derivatives: A Network Meta-Analysis of Glucagon-like Peptide-1 Receptor Agonists and Sodium-Glucose Cotransporter 2 Inhibitors. Pharmaceuticals (Basel) 2025; 18:735. [PMID: 40430553 PMCID: PMC12115298 DOI: 10.3390/ph18050735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2025] [Revised: 04/30/2025] [Accepted: 05/10/2025] [Indexed: 05/29/2025] Open
Abstract
Background/Objectives: Emerging evidence suggests an association between glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose co-transporter 2 (SGLT2) inhibitors with altered risk of damage in the inner ear system. However, limited research exists on the relationship between these medications and subsequent irreversible hearing loss. We conducted this network meta-analysis (NMA) to evaluate the comparative risk of hearing loss associated with such medications. Methods: In this NMA, we used a confirmatory approach to specifically focus on particular adverse effects of interest (i.e., incidence of hearing loss here) based on the Cochrane recommendation. A Bayesian-based NMA of randomized controlled trials (RCTs) of GLP-1 receptor agonists or SGLT2 inhibitors was conducted. The primary outcome was the hearing loss events. Results: Our NMA of 29 RCTs with 145,895 participants found that only two exendin-4 derivatives-lixisenatide and high-dose efpeglenatide (i.e., 6 mg/week)-showed increased hearing loss events compared to controls. No other GLP-1 receptor agonists or SGLT2 inhibitors demonstrated significantly elevated hearing loss risk. Lixisenatide ranked highest in risk among all investigated regimens. Conclusions: This comprehensive NMA identifies a significant association between exendin-4 derivatives (lixisenatide and efpeglenatide) and potential ototoxicity. Clinicians should carefully consider this potential ototoxicity when prescribing exendin-4 derivatives, particularly in patients with pre-existing hearing loss risk factors.
Collapse
Affiliation(s)
- Jiann-Jy Chen
- Prospect Clinic for Otorhinolaryngology & Neurology, Kaohsiung 81166, Taiwan; (J.-J.C.); (Y.-W.C.)
- Department of Otorhinolaryngology, E-Da Cancer Hospital, I-Shou University, Kaohsiung 82445, Taiwan
| | - Chih-Wei Hsu
- Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan;
| | - Chao-Ming Hung
- Division of General Surgery, Department of Surgery, E-Da Cancer Hospital, I-Shou University, Kaohsiung 82445, Taiwan;
- School of Medicine, College of Medicine, I-Shou University, Kaohsiung 84001, Taiwan
| | - Chih-Sung Liang
- Department of Psychiatry, Beitou Branch, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei 112003, Taiwan;
- Department of Psychiatry, National Defense Medical Center, Taipei 11490, Taiwan
| | - Kuan-Pin Su
- Department of Psychiatry & Mind-Body Interface Laboratory (MBI-Lab), China Medical University Hospital, Taichung 404328, Taiwan;
- College of Medicine, China Medical University, Taichung 404328, Taiwan
- An-Nan Hospital, China Medical University, Tainan 709, Taiwan
| | - Andre F. Carvalho
- Innovation in Mental and Physical Health and Clinical Treatment (IMPACT) Strategic Research Centre, School of Medicine, Barwon Health, Deakin University, Geelong, VIC 3220, Australia;
| | - Brendon Stubbs
- Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London WC2R 2LS, UK;
- Department of Sport, University of Vienna, 1010 Vienna, Austria
| | - Yen-Wen Chen
- Prospect Clinic for Otorhinolaryngology & Neurology, Kaohsiung 81166, Taiwan; (J.-J.C.); (Y.-W.C.)
| | - Tien-Yu Chen
- Department of Psychiatry, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei 114, Taiwan;
- Institute of Brain Science, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
| | - Wei-Te Lei
- Section of Immunology, Rheumatology, and Allergy Department of Pediatrics, Municipal MacKay Children’s Hospital, Hsinchu 300046, Taiwan;
- Department of Medicine, MacKay Medical College, New Taipei 25245, Taiwan
| | - Bing-Yan Zeng
- Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung 804201, Taiwan
- Department of Internal Medicine, E-Da Dachang Hospital, I-Shou University, Kaohsiung 807, Taiwan
| | - Ping-Tao Tseng
- Prospect Clinic for Otorhinolaryngology & Neurology, Kaohsiung 81166, Taiwan; (J.-J.C.); (Y.-W.C.)
- Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung 804201, Taiwan
- Institute of Precision Medicine, National Sun Yat-sen University, Kaohsiung 804201, Taiwan
| |
Collapse
|
15
|
Shalitin S, Phillip M, Yackobovitch-Gavan M. Real -world experience with anti-obesity medications treatment in children and adolescents with overweight and obesity in Israel. Int J Obes (Lond) 2025:10.1038/s41366-025-01801-w. [PMID: 40374727 DOI: 10.1038/s41366-025-01801-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2025] [Revised: 04/18/2025] [Accepted: 04/28/2025] [Indexed: 05/18/2025]
Abstract
BACKGROUND Childhood obesity is a major public health concern, associated with early-onset comorbidities and a high likelihood of persisting into adulthood. Anti-obesity medications (AOMs) may serve as an adjunct to lifestyle modifications for managing pediatric obesity. OBJECTIVE To evaluate prescribing patterns, weight outcomes, and cardiometabolic impacts of AOMs among children and adolescents aged 10-18 years within Clalit Health Services (CHS), the largest health maintenance organization in Israel. SUBJECTS/METHODS This retrospective observational study analyzed data from CHS's electronic database (2017-2024). The study cohort included 307 208 children with BMI measurements exceeding World Health Organization (WHO)-defined thresholds for overweight or obesity. Among these, 2236 (0.7%) were prescribed AOMs (metformin, GLP-1 receptor agonist, or orlistat). A secondary analysis assessed longitudinal changes in BMI z-scores and cardiometabolic parameters among individuals who purchased at list two prescriptions of AOMs. RESULTS AOMs prescriptions were more common among females, younger patients, those with higher BMI z-scores, and medium-to-high socioeconomic position (SEP) levels. Children prescribed AOMs exhibited a higher prevalence of obesity-related comorbidities and greater engagement with dietitians and endocrine specialists. Metformin was the most commonly prescribed medication (73.8%), followed by GLP-1 receptor agonist (24.5%) and orlistat (1.7%). Females demonstrated higher rates of medication adherence and longer treatment durations than males. Among the 1717 participants with ≥2 AOMs purchases, BMI z-scores significantly declined during treatment, accompanied by reductions in blood glucose, HbA1c, triglycerides, and total cholesterol, and increases in HDL cholesterol. BMI z-scores and cardiometabolic parameters partially regressed after treatment cessation but remained improved compared to baseline. CONCLUSIONS AOMs demonstrate potential for weight management and cardiometabolic improvement in children with obesity, particularly among those with severe obesity and comorbidities, within real-world settings. However, the modest utilization rate highlights the need for improved accessibility and further real-world evidence to optimize treatment strategies for pediatric obesity.
Collapse
Affiliation(s)
- Shlomit Shalitin
- The Jesse Z. and Sara Lea Shafer Institute of Endocrinology and Diabetes, National Center for Childhood Diabetes Schneider Children's Medical Center of Israel, Petah Tikva, Israel.
- Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel.
| | - Moshe Phillip
- The Jesse Z. and Sara Lea Shafer Institute of Endocrinology and Diabetes, National Center for Childhood Diabetes Schneider Children's Medical Center of Israel, Petah Tikva, Israel
- Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Michal Yackobovitch-Gavan
- The Jesse Z. and Sara Lea Shafer Institute of Endocrinology and Diabetes, National Center for Childhood Diabetes Schneider Children's Medical Center of Israel, Petah Tikva, Israel
- Dept. of Epidemiology and Preventive Medicine, School of Public Health, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| |
Collapse
|
16
|
Gatto A, Liu K, Milan N, Wong S. The Effects of GLP-1 Agonists on Musculoskeletal Health and Orthopedic Care. Curr Rev Musculoskelet Med 2025:10.1007/s12178-025-09978-3. [PMID: 40372699 DOI: 10.1007/s12178-025-09978-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/02/2025] [Indexed: 05/16/2025]
Abstract
PURPOSE OF REVIEW The global rise in obesity and type 2 diabetes mellitus (T2DM) presents significant challenges in musculoskeletal care, contributing to increased perioperative complications, impaired bone health, and compromised muscle function. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), initially developed for glycemic control in T2DM, have demonstrated substantial benefits in weight reduction and metabolic regulation. The purpose of this review is to understand the musculoskeletal biologic and clinical implications of GLP-1RAs. RECENT FINDINGS Evidence suggests that GLP-1RAs may impact musculoskeletal health through anti-inflammatory effects, bone metabolism modulation, and alterations in muscle composition. GLP-1RAs may promote osteoblastogenesis while dampening osteoclast activity to maintain bone mineral density. The result on fracture risk is unclear. Additionally, while GLP-1RAs cause lean mass loss, GLP-1RAs appear to preserve skeletal muscle, reduce fatty infiltration, and enhance fiber formation and function. Further, GLP-1Rs are present in synovial tissue and cartilage, demonstrating downregulation of inflammatory molecules and chondrocyte apoptotic pathways, though clinical studies show variable effects in the setting of osteoarthritis. Overall, the heterogeneity in findings underscores the need for further research to delineate the long-term musculoskeletal effects of GLP-1RAs. Understanding the musculoskeletal impact of GLP-1RAs is critical for optimizing their integration into orthopedic practice. This review explores the orthopedic implications of GLP-1RAs, highlighting their biologic mechanisms and clinical effects on obesity-related joint inflammation and arthropathy, bone mineral density and fracture risk, and skeletal muscle preservation.
Collapse
Affiliation(s)
- Andrew Gatto
- Department of Orthopaedic Surgery, University of California San Francisco, San Francisco, CA, USA.
| | - Kevin Liu
- Department of Orthopaedic Surgery, University of California San Francisco, San Francisco, CA, USA
| | - Nesa Milan
- Department of Orthopaedic Surgery, University of California San Francisco, San Francisco, CA, USA
| | - Stephanie Wong
- Department of Orthopaedic Surgery, University of California San Francisco, San Francisco, CA, USA
| |
Collapse
|
17
|
Carbone F, Després JP, Ioannidis JPA, Neeland IJ, Garruti G, Busetto L, Liberale L, Ministrini S, Vilahur G, Schindler TH, Macedo MP, Di Ciaula A, Krawczyk M, Geier A, Baffy G, Faienza MF, Farella I, Santoro N, Frühbeck G, Yárnoz-Esquiroz P, Gómez-Ambrosi J, Chávez-Manzanera E, Vázquez-Velázquez V, Oppert JM, Kiortsis DN, Sbraccia P, Zoccali C, Portincasa P, Montecucco F. Bridging the gap in obesity research: A consensus statement from the European Society for Clinical Investigation. Eur J Clin Invest 2025:e70059. [PMID: 40371883 DOI: 10.1111/eci.70059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Accepted: 04/12/2025] [Indexed: 05/16/2025]
Abstract
BACKGROUND Most forms of obesity are associated with chronic diseases that remain a global public health challenge. AIMS Despite significant advancements in understanding its pathophysiology, effective management of obesity is hindered by the persistence of knowledge gaps in epidemiology, phenotypic heterogeneity and policy implementation. MATERIALS AND METHODS This consensus statement by the European Society for Clinical Investigation identifies eight critical areas requiring urgent attention. Key gaps include insufficient long-term data on obesity trends, the inadequacy of body mass index (BMI) as a sole diagnostic measure, and insufficient recognition of phenotypic diversity in obesity-related cardiometabolic risks. Moreover, the socio-economic drivers of obesity and its transition across phenotypes remain poorly understood. RESULTS The syndemic nature of obesity, exacerbated by globalization and environmental changes, necessitates a holistic approach integrating global frameworks and community-level interventions. This statement advocates for leveraging emerging technologies, such as artificial intelligence, to refine predictive models and address phenotypic variability. It underscores the importance of collaborative efforts among scientists, policymakers, and stakeholders to create tailored interventions and enduring policies. DISCUSSION The consensus highlights the need for harmonizing anthropometric and biochemical markers, fostering inclusive public health narratives and combating stigma associated with obesity. By addressing these gaps, this initiative aims to advance research, improve prevention strategies and optimize care delivery for people living with obesity. CONCLUSION This collaborative effort marks a decisive step towards mitigating the obesity epidemic and its profound impact on global health systems. Ultimately, obesity should be considered as being largely the consequence of a socio-economic model not compatible with optimal human health.
Collapse
Affiliation(s)
- Federico Carbone
- Department of Internal Medicine, University of Genoa, Genoa, Italy
- IRCCS Ospedale Policlinico San Martino, Genoa, Genoa, Italy
| | - Jean-Pierre Després
- Institut Universitaire de Cardiologie et de Pneumologie de Québec - Université Laval, Québec, Québec, Canada
- VITAM - Centre de Recherche en santé Durable, Centre intégré Universitaire de santé et de Services Sociaux de la Capitale-Nationale, Québec, Québec, Canada
| | - John P A Ioannidis
- Department of Medicine, Stanford Cardiovascular Institute, and Meta-Research Innovation Center at Stanford (METRICS), Stanford University, Stanford, California, USA
- Department of Epidemiology and Population Health, Stanford Cardiovascular Institute, and Meta-Research Innovation Center at Stanford (METRICS), Stanford University, Stanford, California, USA
- Department of Biomedical Science, Stanford Cardiovascular Institute, and Meta-Research Innovation Center at Stanford (METRICS), Stanford University, Stanford, California, USA
| | - Ian J Neeland
- Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
- Department of Cardiovascular Disease, Harrington Heart and Vascular Institute, Cleveland, Ohio, USA
| | - Gabriella Garruti
- Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University of Bari "Aldo Moro", Bari, Italy
| | - Luca Busetto
- Department of Medicine, University of Padua, Padua, Italy
| | - Luca Liberale
- Department of Internal Medicine, University of Genoa, Genoa, Italy
- IRCCS Ospedale Policlinico San Martino, Genoa, Genoa, Italy
| | - Stefano Ministrini
- Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland
- Cardiology Department, Luzerner Kantonspital, Lucerne, Switzerland
| | - Gemma Vilahur
- Research Institute, Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, IIB-Sant Pau, Barcelona, Spain
- CiberCV, Institute Carlos III, Madrid, Spain
| | - Thomas H Schindler
- Washington University in St. Louis, Mallinckrodt Institute of Radiology, Division of Nuclear Medicine, Cardiovascular Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Maria Paula Macedo
- APDP - Diabetes Portugal, Education and Research Center, Lisbon, Portugal
- iNOVA4Health, NOVA Medical School | Faculdade de Ciências Médicas, NMS | FCM, Universidade Nova de Lisboa, Lisbon, Portugal
| | - Agostino Di Ciaula
- Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University of Bari "Aldo Moro", Bari, Italy
| | - Marcin Krawczyk
- Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, Essen, Germany
- Laboratory of Metabolic Liver Diseases, Department of General, Transplant and Liver Surgery, Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland
| | - Andreas Geier
- Interdisciplinary Amyloidosis Center of Northern Bavaria, University Hospital of Würzburg, Würzburg, Germany
- Department of Internal Medicine II, Hepatology, University Hospital of Würzburg, Würzburg, Germany
| | - Gyorgy Baffy
- Department of Medicine, VA Boston Healthcare System, Harvard Medical School, Boston, Massachusetts, USA
| | - Maria Felicia Faienza
- Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University of Bari "Aldo Moro", Bari, Italy
| | - Ilaria Farella
- Department of Medicine and Surgery, LUM University, Casamassima, Italy
| | - Nicola Santoro
- Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, USA
- Department of Medicine and Health Sciences, "V. Tiberio" University of Molise, Campobasso, Italy
| | - Gema Frühbeck
- Department of Endocrinology and Nutrition, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
- IdiSNA (Instituto de Investigación en la Salud de Navarra), Pamplona, Spain
- CIBERObn (CIBER Fisiopatología de la Obesidad y Nutrición), Instituto de Salud Carlos III, Madrid, Spain
| | - Patricia Yárnoz-Esquiroz
- Department of Endocrinology and Nutrition, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
- IdiSNA (Instituto de Investigación en la Salud de Navarra), Pamplona, Spain
- CIBERObn (CIBER Fisiopatología de la Obesidad y Nutrición), Instituto de Salud Carlos III, Madrid, Spain
| | - Javier Gómez-Ambrosi
- Department of Endocrinology and Nutrition, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
- IdiSNA (Instituto de Investigación en la Salud de Navarra), Pamplona, Spain
- CIBERObn (CIBER Fisiopatología de la Obesidad y Nutrición), Instituto de Salud Carlos III, Madrid, Spain
| | - Emma Chávez-Manzanera
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | | | - Jean-Michel Oppert
- Department of Nutrition, Pitié-Salpêtrière Hospital (AP-HP), Human Nutrition Research Center Ile-de-France (CRNH IdF), Sorbonne University, Paris, France
| | - Dimitrios N Kiortsis
- Atherothrombosis Research Centre, Faculty of Medicine, University of Ioannina, Ioannina, Greece
| | - Paolo Sbraccia
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Carmine Zoccali
- Renal Research Institute, New York, New York, USA
- Institute of Molecular Biology and Genetics (Biogem), Ariano Irpino, Italy
- Associazione Ipertensione Nefrologia Trapianto Renale (IPNET), c/o Nefrologia, Grande Ospedale Metropolitano, Reggio Calabria, Italy
| | - Piero Portincasa
- Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University of Bari "Aldo Moro", Bari, Italy
| | - Fabrizio Montecucco
- Department of Internal Medicine, University of Genoa, Genoa, Italy
- IRCCS Ospedale Policlinico San Martino, Genoa, Genoa, Italy
| |
Collapse
|
18
|
Sardà H, Genua I, Miñambres I. GLP-1 receptor agonists in obesity treatment: Effects on cardiometabolic variables and cardiovascular disease. Med Clin (Barc) 2025; 165:106951. [PMID: 40378625 DOI: 10.1016/j.medcli.2025.106951] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Revised: 03/19/2025] [Accepted: 03/20/2025] [Indexed: 05/19/2025]
Abstract
Obesity is associated with an increased cardiovascular risk. Drugs with glucagon-like peptide-1 receptor agonist (arGLP-1) action for overweight/obesity, such as liraglutide, semaglutide, and tirzepatide, have shown improvements in weight and body composition, as well as in parameters related to glucose metabolism, hypertension, dyslipidemia (reduction of triglycerides and increase in HDL cholesterol), and metabolic dysfunction-associated steatotic liver disease. Additionally, semaglutide 2.4mg sc has shown a reduction in cardiovascular mortality, non-fatal myocardial infarction or stroke, and symptoms of heart failure, while tirzepatide has demonstrated a reduction in cardiovascular mortality and heart failure symptoms in patients with obesity and heart failure. The availability of these new drugs with arGLP-1 action represents a paradigm shift in the treatment of obesity, as they achieve greater weight loss and improvements in cardiometabolic comorbidities.
Collapse
Affiliation(s)
- Helena Sardà
- Servicio de Endocrinología y Nutrición, Hospital de la Santa Creu i Sant Pau, Barcelona, España; Departamento de Medicina, Universitat Autònoma de Barcelona, Barcelona, España; Institut de Recerca de Sant Pau (IIB Sant Pau), Barcelona, España
| | - Idoia Genua
- Servicio de Endocrinología y Nutrición, Hospital de la Santa Creu i Sant Pau, Barcelona, España; Departamento de Medicina, Universitat Autònoma de Barcelona, Barcelona, España; Institut de Recerca de Sant Pau (IIB Sant Pau), Barcelona, España; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, España
| | - Inka Miñambres
- Servicio de Endocrinología y Nutrición, Hospital de la Santa Creu i Sant Pau, Barcelona, España; Departamento de Medicina, Universitat Autònoma de Barcelona, Barcelona, España; Institut de Recerca de Sant Pau (IIB Sant Pau), Barcelona, España; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, España.
| |
Collapse
|
19
|
Wooster M, Chen L, Accordino MK, Sathe C, Wright JD, Hershman DL. Utilization of weight management treatment and subsequent cardiovascular events among patients with breast cancer. Breast Cancer Res Treat 2025:10.1007/s10549-025-07714-6. [PMID: 40360855 DOI: 10.1007/s10549-025-07714-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2025] [Accepted: 05/01/2025] [Indexed: 05/15/2025]
Abstract
PURPOSE Overweight and obese breast cancer (BC) survivors face higher risks of recurrence and all-cause mortality, including from cardiovascular disease (CVD). Weight management therapy (WMT) may reduce cardiovascular events (CVE). We assessed trends in WMT in BC survivors and evaluated rates of CVE. METHODS We conducted a retrospective cohort study using the MarketScan Database, including overweight and obese patients (18-95 years) with invasive BC (2009 -2021), who underwent breast surgery. Exclusions were prior bariatric surgery or secondary cancers. Patients were categorized by weight status and by WMT, including nutrition counseling, medications, and bariatric surgery. We utilized descriptive statistics, univariate analysis for factors associated with WMT receipt and rates of CVE, and a multivariable logistic regression model to determine WMT-associated factors. RESULTS We identified 35,206 patients: 18.8% overweight, 53.7% obese class I/II/unspecified, and 27.4% obese class III. WMT was utilized by 5.3%, 6.4%, and 9.6%, respectively (p < 0.001). Among 2,484 patients who received WMT, 72.7% had nutrition counseling, 26.7% received weight loss medication, and 4.9% underwent bariatric surgery. From 2009 to 2021, WMT use increased from 3.7% to 11.3% (p < 0.001), and use of weight loss medication increased from 0.3% to 5.1% (p < 0.001). Factors associated with receipt of WMT included younger age, greater degree of obesity, more recent year of surgery, lumpectomy, higher comorbidity score, and prior WMT. CVE incidence was lower in WMT recipients (0.8% vs.1.3%, p = 0.02). CONCLUSION In patients with BC, WMT has increased over time, and most markedly weight loss medication use. WMT is associated with lower incidence of CVE.
Collapse
Affiliation(s)
- Margaux Wooster
- Department of Medicine, Division of Hematology and Oncology, Columbia University Irving Medical Center, New York, NY, USA.
| | - Ling Chen
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA
| | - Melissa K Accordino
- Department of Medicine, Division of Hematology and Oncology, Columbia University Irving Medical Center, New York, NY, USA
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA
| | - Claire Sathe
- Department of Medicine, Division of Hematology and Oncology, Columbia University Irving Medical Center, New York, NY, USA
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA
| | - Jason D Wright
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA
| | - Dawn L Hershman
- Department of Medicine, Division of Hematology and Oncology, Columbia University Irving Medical Center, New York, NY, USA
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA
| |
Collapse
|
20
|
Welling MS, van Rossum EFC, van den Akker ELT. Antiobesity Pharmacotherapy for Patients With Genetic Obesity Due to Defects in the Leptin-Melanocortin Pathway. Endocr Rev 2025; 46:418-446. [PMID: 39929239 PMCID: PMC12063102 DOI: 10.1210/endrev/bnaf004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Indexed: 05/10/2025]
Abstract
Lifestyle interventions are the cornerstone of obesity treatment. However, insufficient long-term effects are observed in patients with genetic obesity disorders, as their hyperphagia remains untreated. Hence, patients with genetic obesity often require additional pharmacotherapy to effectively manage and treat their hyperphagia and obesity. Recent advancements in antiobesity pharmacotherapy have expanded the range of available antiobesity medications (AOM). This includes the targeted AOM setmelanotide, approved for specific genetic obesity disorders, as well as nontargeted AOMs such as naltrexone-bupropion and glucagon-like peptide-1 analogues. Targeted AOMs have demonstrated significant weight loss, reduced obesity-related comorbidities, and improved hyperphagia and quality of life in patients with specific genetic obesity disorders. Small observational studies have shown that similar benefits from nontargeted AOMs or off-label pharmacotherapies can be achieved in patients with specific genetic obesity disorders, compared to common multifactorial obesity. In the future, novel and innovative pharmacotherapeutical options, including combination therapies and possibly gene therapy, will emerge, offering promising effects on body weight, hyperphagia, and, most importantly, quality of life for patients with a variety of genetic obesity disorders.
Collapse
Affiliation(s)
- Mila S Welling
- Obesity Center CGG, Erasmus MC, University Medical Center Rotterdam, Rotterdam 3015 GD, The Netherlands
- Department of Internal Medicine, Division of Endocrinology, Erasmus MC, University Medical Center Rotterdam, Rotterdam 3015 GD, The Netherlands
- Department of Pediatrics, Division of Endocrinology, Erasmus MC-Sophia Children's Hospital, University of Medical Center Rotterdam, Rotterdam 3015 GD, The Netherlands
| | - Elisabeth F C van Rossum
- Obesity Center CGG, Erasmus MC, University Medical Center Rotterdam, Rotterdam 3015 GD, The Netherlands
- Department of Internal Medicine, Division of Endocrinology, Erasmus MC, University Medical Center Rotterdam, Rotterdam 3015 GD, The Netherlands
| | - Erica L T van den Akker
- Obesity Center CGG, Erasmus MC, University Medical Center Rotterdam, Rotterdam 3015 GD, The Netherlands
- Department of Pediatrics, Division of Endocrinology, Erasmus MC-Sophia Children's Hospital, University of Medical Center Rotterdam, Rotterdam 3015 GD, The Netherlands
| |
Collapse
|
21
|
Gómez-Martín M, Canfell OJ, Chai LK, Jansson AK, Littlewood R, Sullivan C, Power D, Clarke ED, Ells L, De Vlieger N, Burrows TL, Collins CE. What is the Role of Primary Prevention of Obesity in an Age of Effective Pharmaceuticals? Curr Obes Rep 2025; 14:39. [PMID: 40332727 PMCID: PMC12058953 DOI: 10.1007/s13679-025-00632-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/24/2025] [Indexed: 05/08/2025]
Abstract
PURPOSE OF REVIEW To examine the evidence and continuing role of strategies for the primary prevention and treatment of obesity in the context of effective obesity pharmacotherapies, through a narrative review. RECENT FINDINGS Global policies to improve nutritional labelling and reduce sugar-sweetened beverages consumption have been implemented worldwide (> 45 countries) with some success which varies by population and environment. Tailored behavioural interventions are effective and essential to reduce individual risk of progression from preclinical to clinical obesity. Pharmacotherapies are powerful treatment agents for clinical obesity but must consider nutritional and metabolic risks of use and discontinuation. The obesogenic environment continues to undermine individual agency to adopt healthier dietary and physical activity patterns. Population health informatics tools could inform tailored interventions based on real-time risk and contribute to obesity prevention and treatment. Efforts to rebalance investment towards obesity prevention must continue to improve population health and reduce healthcare burden.
Collapse
Affiliation(s)
- María Gómez-Martín
- School of Health Sciences, College of Health, Medicine and Wellbeing, The University of Newcastle, Callaghan, NSW, 2308, Australia
- Food and Nutrition Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW, 2305, Australia
| | - Oliver J Canfell
- Department of Nutritional Sciences, School of Life Course and Population Sciences, Faculty of Life Sciences & Medicine, King's College London, London, UK
| | - Li Kheng Chai
- Health and Wellbeing Queensland, Queensland Government, Brisbane, QLD, Australia
| | - Anna K Jansson
- School of Health Sciences, College of Health, Medicine and Wellbeing, The University of Newcastle, Callaghan, NSW, 2308, Australia
- Food and Nutrition Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW, 2305, Australia
| | - Robyn Littlewood
- Health and Wellbeing Queensland, Queensland Government, Brisbane, QLD, Australia
| | - Clair Sullivan
- Queensland Digital Health Centre, Centre for Health Services Research, The University of Queensland, Saint Lucia, QLD, Australia
- Metro North Hospital and Health Service, Queensland Health, Herston, QLD, Australia
| | - Dawn Power
- School of Health, Obesity Institute, Leeds Beckett University, Leeds, UK
| | - Erin D Clarke
- School of Health Sciences, College of Health, Medicine and Wellbeing, The University of Newcastle, Callaghan, NSW, 2308, Australia
- Food and Nutrition Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW, 2305, Australia
| | - Louisa Ells
- School of Health, Obesity Institute, Leeds Beckett University, Leeds, UK
| | - Nienke De Vlieger
- Food and Nutrition Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW, 2305, Australia
- School of Environmental and Life Sciences, College of Engineering, Science and Environment, The University of Newcastle, Ourimbah, NSW, 2258, Australia
| | - Tracy L Burrows
- School of Health Sciences, College of Health, Medicine and Wellbeing, The University of Newcastle, Callaghan, NSW, 2308, Australia
- Food and Nutrition Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW, 2305, Australia
| | - Clare E Collins
- School of Health Sciences, College of Health, Medicine and Wellbeing, The University of Newcastle, Callaghan, NSW, 2308, Australia.
- Food and Nutrition Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW, 2305, Australia.
| |
Collapse
|
22
|
Savarese G, Schiattarella GG, Lindberg F, Anker MS, Bayes-Genis A, Bäck M, Braunschweig F, Bucciarelli-Ducci C, Butler J, Cannata A, Capone F, Chioncel O, D'Elia E, González A, Filippatos G, Girerd N, Hulot JS, Lam CSP, Lund LH, Maack C, Moura B, Petrie MC, Piepoli M, Shehab A, Yilmaz MB, Seferovic P, Tocchetti CG, Rosano GMC, Metra M. Heart failure and obesity: Translational approaches and therapeutic perspectives. A scientific statement of the Heart Failure Association of the ESC. Eur J Heart Fail 2025. [PMID: 40328668 DOI: 10.1002/ejhf.3676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Revised: 04/02/2025] [Accepted: 04/08/2025] [Indexed: 05/08/2025] Open
Abstract
Obesity and heart failure (HF) represent two growing pandemics. In the general population, obesity affects one in eight adults and is linked with an increased risk for HF. Obesity is even more common in patients with HF, where it complicates the diagnosis of HF and is linked with worse symptoms and impaired exercise capacity. Over the past few years, new evidence on the mechanisms linking obesity with HF has been reported, particularly in relation to HF with preserved ejection fraction. Novel therapies inducing weight loss appear to have favourable effects on health status and cardiovascular risk. Against the backdrop of this rapidly evolving evidence landscape, HF clinicians are increasingly required to tailor their preventive, diagnostic, and therapeutic approaches to HF in the presence of obesity. This scientific statement by the Heart Failure Association of the European Society of Cardiology provides an up-to-date summary on obesity in HF, covering key areas such as epidemiology, translational aspects, diagnostic challenges, therapeutic approaches, and trial design.
Collapse
Affiliation(s)
- Gianluigi Savarese
- Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden
| | - Gabriele G Schiattarella
- Max Rubner Center for Cardiovascular Metabolic Renal Research (MRC), Deutsches Herzzentrum der Charité (DHZC), Charité - Universitätsmedizin Berlin, Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany
- Translational Approaches in Heart Failure and Cardiometabolic Disease, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
- Division of Cardiology, Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy
| | - Felix Lindberg
- Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden
| | - Markus S Anker
- Department of Cardiology CBF German Heart Center Charité, DZHK, BCRT, University Medicine Berlin FU and HU, Berlin, Germany
| | - Antoni Bayes-Genis
- Heart Institute, Hospital Universitari Germasn Trias I Pujol, CIBERCV, Badalona, Spain
| | - Magnus Bäck
- Université de Lorraine, INSERM, Centre d'Investigations Cliniques Plurithématique 1433, Inserm U1116, CHRU de Nancy and F-CRIN INI-CRCT, Nancy, France
- Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
| | | | - Chiara Bucciarelli-Ducci
- Royal Brompton and Harefield Hospitals, Guys' and St Thomas NHS Trust, London, UK
- School of Biomedical Engineering and Imaging Sciences, Faculty of Life Sciences and Medicine, King's College University, London, UK
| | - Javed Butler
- Baylor Scott and White Research Institute, Dallas, TX, USA
- University of Mississippi, Jackson, MS, USA
| | - Antonio Cannata
- British Heart Foundation Centre of Research Excellence, School of Cardiovascular Medicine, Faculty of Life Science, King's College London, London, UK
- Cardiology Department, King's College Hospital NHS Foundation Trust, London, UK
| | - Federico Capone
- Max Rubner Center for Cardiovascular Metabolic Renal Research (MRC), Deutsches Herzzentrum der Charité (DHZC), Charité - Universitätsmedizin Berlin, Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany
- Translational Approaches in Heart Failure and Cardiometabolic Disease, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
- Unit of Internal Medicine III, Department of Medicine (DIMED), Padua University Hospital, University of Padua, Padova, Italy
- Department of Biomedical Sciences, University of Padua, Padova, Italy
| | - Ovidiu Chioncel
- Emergency Institute for Cardiovascular Diseases 'Prof. C.C. Iliescu', University of Medicine Carol Davila, Bucharest, Romania
| | - Emilia D'Elia
- Cardiovascular Department, Papa Giovanni XXIII Hospital, Bergamo, Italy
- School of Medicine and Surgery, University Milano-Bicocca, Milan, Italy
| | - Arantxa González
- Program of Cardiovascular Diseases, CIMA Universidad de Navarra, Department of Cardiology and Cardiac Surgery, Clínica Universidad de Navarra and IdiSNA, Pamplona, Spain
- CIBERCV, Carlos III Institute of Health, Madrid, Spain
| | - Gerasimos Filippatos
- Department of Cardiology, University Hospital Attikon, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
| | - Nicolas Girerd
- Université de Lorraine, INSERM, Centre d'Investigations Cliniques Plurithématique 1433, Inserm U1116, CHRU de Nancy and F-CRIN INI-CRCT, Nancy, France
| | - Jean-Sébastien Hulot
- Université Paris Cité, INSERM, PARCC, Paris, France
- CIC1418 and DMU CARTE, AP-HP, Hôpital Européen Georges-Pompidou, Paris, France
| | - Carolyn S P Lam
- National Heart Centre Singapore & Duke-National University of Singapore, Singapore
| | - Lars H Lund
- Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
| | - Christoph Maack
- Department of Translational Research, Comprehensive Heart Failure Center, University Clinic Würzburg, Würzburg, Germany
- Medical Clinic 1, University Clinic Würzburg, Würzburg, Germany
| | - Brenda Moura
- Department of Cardiology, Armed Forces Hospital, Porto, Portugal
- Faculty of Medicine, University of Porto, Porto, Portugal
| | - Mark C Petrie
- School of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
| | - Massimo Piepoli
- Clinical Cardiology, IRCCS Policlinico San Donato, Milan, Italy
- Department of Preventive Cardiology, University of Wroclaw, Wroclaw, Poland
| | - Abdullah Shehab
- Department of Cardiology, Royal Burjeel Hospital, UAE University, Al Ain, UAE
| | - Mehmet B Yilmaz
- Department of Cardiology, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey
| | - Peter Seferovic
- Faculty of Medicine, University of Belgrade, and Serbian Academy of Sciences and Arts, Belgrade, Serbia
- University of Belgrade, Belgrade, Serbia
| | - Carlo G Tocchetti
- Cardio-Oncology Unit, Department of Translational Medical Sciences (DISMET), Center for Basic and Clinical Immunology Research (CISI), Interdepartmental Center of Clinical and Translational Sciences (CIRCET), Interdepartmental Hypertension Research Center (CIRIAPA), Federico II University, Naples, Italy
| | - Giuseppe M C Rosano
- Department of Human Sciences and Promotion of Quality of Life, San Raffaele Open University of Rome, Rome, Italy
- Cardiology, San Raffaele Cassino Hospital, Cassino, Italy
| | - Marco Metra
- Cardiology and Cardiac Catheterization Laboratory, Cardio-Thoracic Department, Civil Hospitals, Brescia, Italy
- Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, Brescia, Italy
| |
Collapse
|
23
|
Liu Y, He L, Han S, Ping F, Li W, Xu L, Zhang H, Li Y. Glucagon-Like Peptide-1 Receptor Agonists and Risk of Venous Thromboembolism: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. J Am Heart Assoc 2025; 14:e039446. [PMID: 40314346 DOI: 10.1161/jaha.124.039446] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Accepted: 03/13/2025] [Indexed: 05/03/2025]
Abstract
BACKGROUND Limited data exist on the association of glucagon-like peptide 1 receptor agonists (GLP-1RAs) with the risk of venous thromboembolism. This meta-analysis aimed to investigate the association between GLP-1RAs and the risk of venous thromboembolism including deep vein thrombosis (DVT) and pulmonary embolism. METHODS AND RESULTS A systematic search of PubMed, Web of Science, EMBASE, and Cochrane library was conducted from inception until July 3, 2024, to identify randomized controlled trials comparing GLP-1RAs with placebo or other anti-iabetic drugs, with reported data on DVT and pulmonary embolism. The primary outcome was venous thromboembolism, and secondary outcomes included DVT and pulmonary embolism. Pooled odds ratios (ORs) were calculated using fixed-effects models with Mantel-Haenszel method and treatment arm continuity correction for zero-event trials. A total of 39 randomized controlled trials involving 70 499 participants were included. A nonsignificant upward trend in the risk of venous thromboembolism was observed among participants using GLP-1RAs (OR, 1.19 [95% CI, 0.94-1.50]). GLP-1RAs were significantly associated with an increased risk of DVT (OR, 1.64 [95% CI, 1.14-2.36]); risk difference 25 (5-52) more events per 10 000 person-years). Subgroup analyses revealed that increased risk of DVT was particularly prominent in randomized controlled trials with treatment duration >1.5 years (OR, 2.32 [95% CI, 1.49-3.60]) and in cardiovascular outcome trials (OR, 2.18 [95% CI, 1.36-3.49]). No significant association was observed between GLP-1RAs and risk of pulmonary embolism. CONCLUSIONS GLP-1RAs might increase the risk of DVT, especially for long-term use of GLP-1RAs. Clinicians should be aware of this potential risk when prescribing GLP-1RAs.
Collapse
Affiliation(s)
- Yiwen Liu
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences Beijing China
| | - Liyun He
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences Beijing China
| | - Shumeng Han
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences Beijing China
| | - Fan Ping
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences Beijing China
| | - Wei Li
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences Beijing China
| | - Lingling Xu
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences Beijing China
| | - Huabing Zhang
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences Beijing China
| | - Yuxiu Li
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences Beijing China
| |
Collapse
|
24
|
Zhao L, Tao F, Cheng Z, Lu Y, Liu M, Chen H, Zhang M, Yang Y, Song X, Sun Y, Ma X, Si S, Zhang H, Li X. Predicting 10-year risk of type 2 diabetes in Chinese people with overweight or obesity treated with Tirzepatide: Post hoc analysis of SURMOUNT-CN trial. Diabetes Obes Metab 2025. [PMID: 40329666 DOI: 10.1111/dom.16439] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Revised: 04/22/2025] [Accepted: 04/23/2025] [Indexed: 05/08/2025]
Abstract
AIM To assess the association of tirzepatide use with a 10-year predicted risk of type 2 diabetes (T2D) among Chinese participants with obesity or overweight from the SURMOUNT-CN trial. MATERIALS AND METHODS In this post hoc analysis, the QDiabetes-2018 risk engine was used to calculate the 10-year predicted T2D risk at baseline, week 24 and week 52 among SURMOUNT-CN participants randomized to receive tirzepatide 10 mg, 15 mg or placebo. A mixed model for repeated measures was used to compare mean predicted risk changes from baseline to weeks 24 and 52 between tirzepatide and placebo. Subgroup analyses were conducted by baseline body weight mass index (BMI) status and baseline prediabetes status. RESULTS Demographic and baseline clinical characteristics were similar among tirzepatide10 mg (n = 59), 15 mg (n = 53) and placebo (n = 57). From baseline to week 52, the least square (LS) mean predicted T2D risk changed from 5.3% to 1.2% for tirzepatide 10 mg, from 4.9% to 1.0% for tirzepatide 15 mg and from 5.8% to 4.5% for placebo. The difference in LS mean risk change from baseline to week 52 was significant between both tirzepatide 10 mg (-3.2%, 95% confidence interval [CI]: -4.2%, -2.2%) and 15 mg (-3.4%, 95% CI: -4.4%, -2.4%) and placebo. Significantly greater predicted risk reductions for tirzepatide than placebo were observed in all subgroups. CONCLUSION Tirzepatide was associated with significantly reduced predicted 10-year risk of T2D among SURMOUNT-CN participants with obesity or overweight, irrespective of baseline BMI and prediabetes status.
Collapse
Affiliation(s)
- Lin Zhao
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Feng Tao
- Department of Endocrinology, Shanghai Traditional Chinese Medicine Hospital, Shanghai, China
| | - Zhifeng Cheng
- Department of Endocrinology, Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yibing Lu
- Department of Endocrinology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Ming Liu
- Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, China
| | - Hong Chen
- Department of Endocrinology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Min Zhang
- Department of Endocrinology and Metabolism, Qingpu Branch of Zhongshan Hospital Affiliated with Fudan University, Shanghai, China
| | - Yang Yang
- Eli Lilly and Company, Shanghai, China
| | | | - Yuzi Sun
- Eli Lilly and Company, Shanghai, China
| | - Xiao Ma
- Eli Lilly and Company, Shanghai, China
| | - Si Si
- Eli Lilly and Company, Shanghai, China
| | | | - Xiaoying Li
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
| |
Collapse
|
25
|
Parker CH, Slattery C, Brennan DJ, le Roux CW. Glucagon-like peptide 1 (GLP-1) receptor agonists' use during pregnancy: Safety data from regulatory clinical trials. Diabetes Obes Metab 2025. [PMID: 40329607 DOI: 10.1111/dom.16437] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2025] [Revised: 04/19/2025] [Accepted: 04/22/2025] [Indexed: 05/08/2025]
Abstract
AIMS The prevalence of diabetes and obesity continues to rise in women of reproductive age, with significant implications for both mother and foetus. Glucagon-like peptide-1 receptor agonists are effective treatments of diabetes and obesity. However, no Glucagon-like peptide-1 receptor agonists are currently approved for use during pregnancy. We describe the outcomes of unplanned pregnancies during regulatory clinical trials of Glucagon-like peptide-1 receptor agonists submitted to the Food and Drug Administration and European Medicines Agency. MATERIALS AND METHODS A search was conducted of the regulatory documentation published by the European Medicines Agency and the Food and Drug Administration on unplanned pregnancies during regulatory clinical trials of Glucagon-like peptide-1 receptor agonists. Clinical and Medical Reviews published by the Center for Drug Evaluation and Research at the Food and Drug Administration for every Glucagon-like peptide-1 receptor agonist prior to market authorisation were assessed to gather information on unplanned pregnancies that occurred while females were partaking in the clinical development programmes of such drugs. RESULTS Evidence in women having planned pregnancies is lacking, and the only evidence thus far relies on pregnancies occurring inadvertently during Glucagon-like peptide-1 receptor agonist trials. The incidence of congenital abnormalities in humans appears relatively low following Glucagon-like peptide-1 receptor agonist use during pregnancy. CONCLUSIONS Key knowledge gaps must be addressed before the introduction of the Glucagon-like peptide-1 receptor agonist class of drugs for pregnant women. Currently, Glucagon-like peptide-1 receptor agonists should be stopped as soon as the patient becomes aware of a pregnancy. The establishment of patient registries designed to capture data relating to cases of Glucagon-like peptide-1 receptor agonist exposure during pregnancy is a high priority, and where data already exist, the findings need to be published.
Collapse
Affiliation(s)
- Claire H Parker
- Renaissance School of Medicine at Stony Brook University, Stony Brook, New York, USA
| | - Craig Slattery
- School of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland
| | - Donal J Brennan
- University College Dublin School of Medicine, Catherine McCauley Research Centre, Mater Misericoridiae University Hospital, Dublin, Ireland
| | - Carel W le Roux
- Diabetes Complications Research Centre, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland
| |
Collapse
|
26
|
Wang W, Green D, Ibrahim R, Abdelnabi M, Pham HN, Forst B, Allam M, Sarkis P, Bcharah G, Farina J, Ayoub C, Sorajja D, Arsanjani R. Navigating Sarcopenia Risks in GLP-1RA Therapy for Advanced Heart Failure. Biomedicines 2025; 13:1108. [PMID: 40426935 PMCID: PMC12109496 DOI: 10.3390/biomedicines13051108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2025] [Revised: 04/16/2025] [Accepted: 04/29/2025] [Indexed: 05/29/2025] Open
Abstract
Cardiac cachexia (CC) is a severe complication of advanced heart failure (HF), characterized by involuntary weight loss and muscle wasting, leading to poor outcomes and higher mortality. Despite its severity, CC remains under-recognized and undertreated, lacking targeted therapies specifically addressing its pathophysiology. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), though beneficial in reducing cardiovascular risk in patients with HF, may exacerbate muscle wasting in cachectic patients, necessitating further investigation. Non-pharmacological strategies, including tailored nutritional support and exercise programs, have shown positive effects on body composition and quality of life in patients with CC. However, there remains a gap in recommendations tailored to preventive strategies and pharmacologic therapies for patients with CC and concomitant GLP-1RA use. This review highlights the multifactorial mechanisms underlying CC and current and emerging therapeutic approaches for mitigating HF-related sarcopenia while on GLP-1RAs.
Collapse
Affiliation(s)
- Winston Wang
- Department of Medicine, Mayo Clinic, Phoenix, AZ 85054, USA; (W.W.); (D.G.)
| | - Danielle Green
- Department of Medicine, Mayo Clinic, Phoenix, AZ 85054, USA; (W.W.); (D.G.)
| | - Ramzi Ibrahim
- Department of Cardiovascular Medicine, Mayo Clinic, Scottsdale, AZ 85259, USA; (M.A.); (B.F.); (M.A.); (P.S.); (J.F.); (C.A.); (D.S.); (R.A.)
| | - Mahmoud Abdelnabi
- Department of Cardiovascular Medicine, Mayo Clinic, Scottsdale, AZ 85259, USA; (M.A.); (B.F.); (M.A.); (P.S.); (J.F.); (C.A.); (D.S.); (R.A.)
| | - Hoang Nhat Pham
- Department of Medicine, University of Arizona, Tucson, AZ 85724, USA;
| | - Beani Forst
- Department of Cardiovascular Medicine, Mayo Clinic, Scottsdale, AZ 85259, USA; (M.A.); (B.F.); (M.A.); (P.S.); (J.F.); (C.A.); (D.S.); (R.A.)
| | - Mohamed Allam
- Department of Cardiovascular Medicine, Mayo Clinic, Scottsdale, AZ 85259, USA; (M.A.); (B.F.); (M.A.); (P.S.); (J.F.); (C.A.); (D.S.); (R.A.)
| | - Patrick Sarkis
- Department of Cardiovascular Medicine, Mayo Clinic, Scottsdale, AZ 85259, USA; (M.A.); (B.F.); (M.A.); (P.S.); (J.F.); (C.A.); (D.S.); (R.A.)
| | - George Bcharah
- Mayo Clinic Alix School of Medicine, Phoenix, AZ 85054, USA;
| | - Juan Farina
- Department of Cardiovascular Medicine, Mayo Clinic, Scottsdale, AZ 85259, USA; (M.A.); (B.F.); (M.A.); (P.S.); (J.F.); (C.A.); (D.S.); (R.A.)
| | - Chadi Ayoub
- Department of Cardiovascular Medicine, Mayo Clinic, Scottsdale, AZ 85259, USA; (M.A.); (B.F.); (M.A.); (P.S.); (J.F.); (C.A.); (D.S.); (R.A.)
| | - Dan Sorajja
- Department of Cardiovascular Medicine, Mayo Clinic, Scottsdale, AZ 85259, USA; (M.A.); (B.F.); (M.A.); (P.S.); (J.F.); (C.A.); (D.S.); (R.A.)
| | - Reza Arsanjani
- Department of Cardiovascular Medicine, Mayo Clinic, Scottsdale, AZ 85259, USA; (M.A.); (B.F.); (M.A.); (P.S.); (J.F.); (C.A.); (D.S.); (R.A.)
| |
Collapse
|
27
|
Arredouani A. GLP-1 receptor agonists, are we witnessing the emergence of a paradigm shift for neuro-cardio-metabolic disorders? Pharmacol Ther 2025; 269:108824. [PMID: 39983843 DOI: 10.1016/j.pharmthera.2025.108824] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 02/07/2025] [Accepted: 02/14/2025] [Indexed: 02/23/2025]
Abstract
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as groundbreaking therapeutic agents in managing a spectrum of metabolic disorders, demonstrating remarkable efficacy across multiple organ systems and disease states. These compounds are not only well-established in the treatment of type 2 diabetes (T2D) and obesity-conditions for which they have received widespread approval-but also exhibit promising potential in addressing cardiovascular disease (CVD) and Metabolic dysfunction-associated steatotic liver disease (MASLD). Recent investigations have begun to illuminate the utility of GLP-1RAs in the management of type 1 diabetes (T1D), as well as neurodegenerative disorders such as Alzheimer's and Parkinson's disease and various behavioral disorders. A plethora of clinical trials have consistently validated the capacity of GLP-1RAs to improve glycemic control, promote weight loss, and mitigate cardiovascular risk factors in individuals with T2D and obesity. While their application in T1D remains limited due to safety concerns-particularly regarding the risks of hypoglycemia and hyperglycemic ketoacidosis-emerging data suggest that GLP-1RAs may offer hepatoprotective benefits, potentially reducing liver fat content and decelerating the progression of MASLD. The neuroprotective attributes of GLP-1 RAs have garnered significant interest, with research indicating their potential to alleviate cognitive decline associated with neurodegenerative diseases. Furthermore, preliminary findings highlight the role of GLP-1 RAs in addressing behavioral disorders, emphasizing their extensive therapeutic promise. This comprehensive review synthesizes the current evidence supporting the diverse therapeutic applications of GLP-1RAs, positioning them as "magic drug" therapies for metabolic and neurological disorders. As ongoing research continues to explore innovative applications and combinations of GLP-1RAs, the landscape of disease management in metabolic and neurological contexts is poised for transformative advancements. This review will also critically assess safety considerations and underscore the need for personalized treatment strategies to optimize patient outcomes in these complex and often comorbid conditions.
Collapse
Affiliation(s)
- Abdelilah Arredouani
- Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha, Qatar; College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation, Qatar.
| |
Collapse
|
28
|
Hu C. Prevention of cardiovascular disease for healthy aging and longevity: A new scoring system and related "mechanisms-hallmarks-biomarkers". Ageing Res Rev 2025; 107:102727. [PMID: 40096912 DOI: 10.1016/j.arr.2025.102727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Accepted: 03/05/2025] [Indexed: 03/19/2025]
Abstract
Healthy "environment-sleep-emotion-exercise-diet" intervention [E(e)SEEDi] lifestyle can improve the quality of life, prolong aging and promote longevity due to improvement of human immunity and prevention of cardiovascular diseases (CVD). Here, the author reviewed the associations between these core elements with CVD and cardiovascular aging, and developed a new scoring system based on the healthy E(e)SEEDi lifestyle for prediction and evaluation of life expectancy. These core factors are assigned 20 points each (120 points in total), and a higher score predicts healthier aging and longevity. The E(e)SEEDi represents "a tree of life" bearing the fruits of longevity as well as "a rocket of anti-ageing" carrying people around the world on a journey of longevity. In conclusion, the E(e)SEEDi can delay aging and increase the life expectancy due to the role of a series of cellular and molecular "mechanisms-hallmarks-biomarkers". It's believed that the novel scoring system has a huge potential and beautiful prospects.
Collapse
Affiliation(s)
- Chunsong Hu
- Department of Cardiovascular Medicine, Nanchang University, Hospital of Nanchang University, Jiangxi Academy of Medical Science, No. 461 Bayi Ave, Nanchang, Jiangxi 330006, China.
| |
Collapse
|
29
|
Lawand JJ, Tansey PJ, Ghali A, Tye C, Hantouly A, Fares MY, Khan AZ, Somerson JS, Abboud JA. Glucagon-like peptide-1 receptor agonist use is associated with increased risk of perioperative complication and readmission following shoulder arthroplasty. J Shoulder Elbow Surg 2025; 34:1152-1157. [PMID: 39528042 DOI: 10.1016/j.jse.2024.09.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 08/15/2024] [Accepted: 09/01/2024] [Indexed: 11/16/2024]
Abstract
BACKGROUND Glucagon-like peptide-1 (GLP-1) receptor agonists, increasingly used for diabetes management and weight loss, have been linked to lower readmission rates after knee and hip arthroplasty. However, their impact on total shoulder arthroplasty (TSA) outcomes remains unclear. This study investigates the effects of GLP-1 receptor agonists on major complications and revisions following TSA. METHODS A retrospective query of the TriNetX database from 2010 to 2023 was performed to identify patients who underwent anatomic or reverse TSA and were prescribed GLP-1 receptor agonists. GLP-1 receptor agonist users were 1:1 propensity score-matched to controls for demographic factors and comorbidities, yielding 1259 patients in each group. Outcomes included 90-day postoperative medical complications and readmission and revision surgery at 2 years. Odds ratios (ORs), 95% confidence intervals, and P values were calculated. After Bonferroni correction, P < .005 was considered significant. RESULTS GLP-1 receptor agonist users (n = 1259) experienced significantly higher rates of deep vein thrombosis (1.6% vs. 0.9%; OR 3.0; P = .001), myocardial infarction (1.60% vs. 0.9%; OR 2.84; P = .003), pneumonia (3.34% vs. 1.50%; OR 2.25; P = .003), transfusion (7.1% vs. 4.3%; OR 1.7; P = .003), and readmission (8.1% vs. 5.2%; OR 1.6; P = .004) in the 90-day postoperative period compared to patients not taking GLP-1 receptor agonists. There were no differences in the rates of stroke, pulmonary embolism, postoperative anemia, or renal failure. In patients with a minimum 2-year follow-up (n = 776), there was no difference in revision rate (3.2% vs. 1.8%; OR 1.8; P = .07). CONCLUSION GLP-1 receptor agonist use during TSA was associated with an increased risk of deep vein thrombosis, myocardial infarction, pneumonia, need for transfusion, and readmission. Further investigation into the perioperative risk assessment and medical optimization of patients utilizing GLP-1 receptor agonists may be warranted.
Collapse
Affiliation(s)
- Jad J Lawand
- John Sealy School of Medicine, The University of Texas Medical Branch, Galveston, TX, USA.
| | - Patrick J Tansey
- Department of Orthopaedic Surgery and Rehabilitation, The University of Texas Medical Branch, Galveston, TX, USA
| | - Abdullah Ghali
- Department of Orthopaedics, Baylor College of Medicine, Houston, TX, USA
| | - Cooper Tye
- Department of Orthopaedic Surgery, John Peter Smith Hospital, Fort Worth, TX, USA
| | - Ashraf Hantouly
- Department of Orthopedic Surgery, Hamad Medical Corporation, Doha, Qatar
| | - Mohamad Y Fares
- Division of Shoulder and Elbow Surgery, Rothman Orthopaedic Institute, Philadelphia, PA, USA
| | - Adam Z Khan
- Department of Orthopaedic Surgery, Southern California Permanente Medical Group, Panorama City, CA, USA
| | - Jeremy S Somerson
- Department of Orthopaedic Surgery and Rehabilitation, The University of Texas Medical Branch, Galveston, TX, USA
| | - Joseph A Abboud
- Division of Shoulder and Elbow Surgery, Rothman Orthopaedic Institute, Philadelphia, PA, USA
| |
Collapse
|
30
|
Park JS, Kim KS, Choi HJ. Glucagon-Like Peptide-1 and Hypothalamic Regulation of Satiation: Cognitive and Neural Insights from Human and Animal Studies. Diabetes Metab J 2025; 49:333-347. [PMID: 40367985 PMCID: PMC12086555 DOI: 10.4093/dmj.2025.0106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2025] [Accepted: 04/16/2025] [Indexed: 05/16/2025] Open
Abstract
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as blockbuster drugs for treating metabolic diseases. Glucagon-like peptide-1 (GLP-1) plays a pivotal role in glucose homeostasis by enhancing insulin secretion, suppressing glucagon release, delaying gastric emptying, and acting on the central nervous system to regulate satiation and satiety. This review summarizes the discovery of GLP-1 and the development of GLP-1RAs, with a particular focus on their central mechanisms of action. Human neuroimaging studies demonstrate that GLP-1RAs influence brain activity during food cognition, supporting a role in pre-ingestive satiation. Animal studies on hypothalamic feed-forward regulation of hunger suggest that cognitive hypothalamic mechanisms may also contribute to satiation control. We highlight the brain mechanisms of GLP-1RA-induced satiation and satiety, including cognitive impacts, with an emphasis on animal studies of hypothalamic glucagon-like peptide-1 receptor (GLP-1R) and GLP-1R-expressing neurons. Actions in non-hypothalamic regions are also discussed. Additionally, we review emerging combination drugs and oral GLP-1RA formulations aimed at improving efficacy and patient adherence. In conclusion, the dorsomedial hypothalamus (DMH)-a key GLP-1RA target-mediates pre-ingestive cognitive satiation, while other hypothalamic GLP-1R neurons regulate diverse aspects of feeding behavior, offering potential therapeutic targets for obesity treatment.
Collapse
Affiliation(s)
- Joon Seok Park
- Department of Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Kyu Sik Kim
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea
| | - Hyung Jin Choi
- Department of Medicine, Seoul National University College of Medicine, Seoul, Korea
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea
- Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul, Korea
- Neuroscience Research Institute, Seoul National University College of Medicine, Seoul, Korea
- Wide River Institute of Immunology, Seoul National University, Hongcheon, Korea
- Department of Brain and Cognitive Sciences, Seoul National University, Seoul, Korea
| |
Collapse
|
31
|
Price SAL, Nankervis A. Considering the use of GLP-1 receptor agonists in women with obesity prior to pregnancy: a narrative review. Arch Gynecol Obstet 2025; 311:1241-1247. [PMID: 39762582 PMCID: PMC12033171 DOI: 10.1007/s00404-024-07849-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Accepted: 11/16/2024] [Indexed: 04/29/2025]
Abstract
PURPOSE Metabolic disease, including obesity and type 2 diabetes, are amongst the most significant health issues facing women of reproductive age. To date, no antenatal weight management tools have reduced the risk of adverse health outcomes for women with obesity and their offspring, resulting in a shift in focus to the pre-conception period. Although not yet recognised in most international weight management guidelines, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are being increasingly used for weight management prior to conception. METHODS A literature search of PubMed, Medline, and Embase databases identified relevant articles describing the use of GLP-1 RAs prior to and during pregnancy. Papers were selected based on relevance and originality, with clinical trials, large observational studies and meta-analyses being preferentially included. RESULTS This narrative review summarises the mechanism of action of GLP-1 RAs and the clinical effects observed in non-pregnant adults. It synthesises the available data from human and animal studies regarding the safety and efficacy of GLP-1 RAs prior to pregnancy, and the consequences of inadvertent drug exposure in early pregnancy. In considering the need to balance the risks of metabolic disease with the risks posed by inadvertent drug exposure, it highlights the areas where further research is needed to guide clinical decision-making. CONCLUSION GLP-1 RAs may have a role in facilitating weight loss and improving the metabolic health of women prior to pregnancy. However, there is currently insufficient evidence to demonstrate that the use of this class of drugs prior to pregnancy improves pregnancy outcomes.
Collapse
Affiliation(s)
- Sarah A L Price
- Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Grattan St, Parkville, VIC, 3050, Australia.
- Department of Obstetric Medicine, Royal Women's Hospital, Flemington Rd, Parkville, VIC, Australia.
- Department of Diabetes and Endocrinology, Royal Melbourne Hospital, Grattan St, Parkville, VIC, Australia.
| | - Alison Nankervis
- Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Grattan St, Parkville, VIC, 3050, Australia
- Department of Obstetric Medicine, Royal Women's Hospital, Flemington Rd, Parkville, VIC, Australia
- Department of Diabetes and Endocrinology, Royal Melbourne Hospital, Grattan St, Parkville, VIC, Australia
| |
Collapse
|
32
|
Blüher M. [Pharmacotherapy of obesity in Germany]. INNERE MEDIZIN (HEIDELBERG, GERMANY) 2025; 66:475-484. [PMID: 40278869 DOI: 10.1007/s00108-025-01897-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 03/31/2025] [Indexed: 04/26/2025]
Abstract
Pharmacotherapy is part of a comprehensive guideline-conform treatment concept for people with obesity. The foundation of obesity treatment is initially a conservative multimodal basic treatment and consists of a low-energy diet, increased physical activity and behavioral changes. If the individual treatment goals are not achieved with this approach, medications can support the basic treatment. The concept is that drugs should not only achieve weight reduction and stabilization of the reduced body weight but also provide better long-term treatment for the chronic multisystem disease obesity. The incretin-based pharmacotherapy with liraglutide, semaglutide and tirzepatide, which have been introduced in recent years, have not only pronounced weight-reducing but also beneficial cardiometabolic effects. These include improvements in obesity-related comorbidities, such as type 2 diabetes, hypertension, fatty liver disease, obstructive sleep apnea, cardiovascular risk factors, chronic kidney disease and others. In contrast, incretin-based pharmacotherapy is typically associated with mild to moderate gastrointestinal side effects. With the marketing launch of setmelanotide, a medication became available for the treatment of rare monogenic forms of obesity. In addition, numerous incretin-based active agents and new substance classes are in advanced phases of clinical development. Due to their favorable efficacy and side effect profiles and also with respect to the positive cardiometabolic effects, the new drugs have the potential to significantly increase the importance of pharmacotherapy of obesity in Germany.
Collapse
Affiliation(s)
- Matthias Blüher
- Helmholtz-Institut für Metabolismus‑, Adipositas- und Gefäßforschung (HI-MAG), Helmholtz Zentrum München an der Universität Leipzig und dem Universitätsklinikum Leipzig AöR, Philipp-Rosenthal-Straße 27, 04103, Leipzig, Deutschland.
- Klinik und Poliklinik für Endokrinologie, Nephrologie und Rheumatologie, Bereich Endokrinologie, Universität Leipzig, Leipzig, Deutschland.
| |
Collapse
|
33
|
Danielak A, Magierowski M. Obesity and mitochondrial uncoupling - an opportunity for the carbon monoxide-based pharmacology of metabolic diseases. Pharmacol Res 2025; 215:107741. [PMID: 40252782 DOI: 10.1016/j.phrs.2025.107741] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Revised: 04/16/2025] [Accepted: 04/16/2025] [Indexed: 04/21/2025]
Abstract
Obesity, a chronic and progressive disease with a complex etiology, remains a significant global health challenge. Despite advancements in lifestyle interventions, pharmacological therapies, and bariatric surgery, substantial barriers to effective and sustained obesity management persist. Resistance to weight loss and gradual weight regain are commonly reported, limiting the long-term success of both non-pharmacological and pharmacological strategies. A possible contributor is metabolic adaptation, a phenomenon characterized by reduced metabolic rate and energy expenditure following weight loss, which hinders therapeutic efficacy. To address these challenges, increasing attention has been directed toward strategies that counteract maladaptive mechanisms by modulating metabolic rate and enhancing energy expenditure. One promising approach involves mitochondrial uncoupling, where electron transport and oxygen consumption are disconnected from ATP synthesis, promoting energy dissipation. Preclinical studies have demonstrated the potential of various chemical compounds with uncoupling activity as anti-obesity agents. Additionally, carbon monoxide (CO) has emerged as a significant gaseous signaling molecule in human physiology, with anti-inflammatory, antioxidative, and cytoprotective properties. Advances in CO-based pharmacology have led to the development of controlled-release CO donors, enabling precise therapeutic application. Experimental studies suggest that CO modulates mitochondrial bioenergetics, induces mild mitochondrial uncoupling, and regulates mitochondrial biogenesis. By integrating these findings, this review uniquely connects scientific threads, offering a comprehensive synthesis of current knowledge while proposing innovative directions in mitochondrial, metabolic and CO-based pharmacological research. It highlights the potential of CO-based pharmacology to regulate metabolic rate, support weight loss, and address obesity-related dysfunctions, thus suggesting novel pathways for advancing obesity treatment.
Collapse
Affiliation(s)
- Aleksandra Danielak
- Center for Biomedicine and Interdisciplinary Sciences, Jagiellonian University - Medical College, Krakow, Poland; Doctoral School of Medical and Health Sciences, Jagiellonian University - Medical College, Krakow, Poland
| | - Marcin Magierowski
- Center for Biomedicine and Interdisciplinary Sciences, Jagiellonian University - Medical College, Krakow, Poland.
| |
Collapse
|
34
|
Kim SE, Yoo BS. Obesity and heart failure with preserved ejection fraction: focus on new drugs and future direction in medical treatment. Korean J Intern Med 2025; 40:357-370. [PMID: 40360219 PMCID: PMC12081111 DOI: 10.3904/kjim.2024.387] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Revised: 01/02/2025] [Accepted: 02/12/2025] [Indexed: 05/15/2025] Open
Abstract
Obesity is a major risk factor for heart failure with preserved ejection fraction (HFpEF) and contributes through multiple pathophysiological pathways, including systemic inflammation, neurohormonal activation, and mechanical inhibition. The treatment of obesity has shown significant potential for improving HFpEF outcomes. Sodium-glucose cotransporter 2 inhibitors have emerged as effective treatments for improving symptoms and quality of life in patients with HFpEF while aiding in weight control. Furthermore, a recent demonstration of the clinical benefits of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in HFpEF showed promising results in reducing weight loss, and improving symptoms and clinical outcomes. In this review article, we discuss the association between HFpEF and obesity, the emerging role of GLP-1 RAs, and future directions for medical therapies targeting obesity-associated HFpEF.
Collapse
Affiliation(s)
- Se-Eun Kim
- Division of Cardiology, Department of Internal Medicine, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Byung-Su Yoo
- Division of Cardiology, Department of Internal Medicine, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Korea
| |
Collapse
|
35
|
Wee CC, Arbaje AI, Bering H, Blount L, Joseph JJ, Kahan S, Apovian CM, White-Faines A. Unifying Efforts to Empower Equitable Obesity Care: Synopsis of an American College of Physicians and Council of Subspecialty Societies Summit. Ann Intern Med 2025; 178:725-736. [PMID: 40163876 DOI: 10.7326/annals-25-00675] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/02/2025] Open
Abstract
Obesity is a leading cause of morbidity and mortality with health consequences that crosscut most medical specialties. Despite the emergence of effective and promising new therapies, many impediments to comprehensive obesity care remain. As part of their commitment to improving obesity care, the American College of Physicians (ACP) and its Council of Subspecialty Societies (CSS) held a summit on 24 October 2023 to identify barriers to and opportunities for collaborative action in the domains of physician education, health care policy and care delivery, and addressing weight bias. This report summarizes the summit proceedings and provides a postsummit synthesis from ACP and CSS. Key themes were centered on knowledge, advocacy, action, and compassion, including the need for culture change, paradigm shifts, and stakeholder engagement and collaboration; a focus on empowerment of both clinicians and patients; the importance of knowing patients as people to help address social determinants of health; the need to address learned helplessness; and the importance of embracing artificial intelligence and technology as disruptive innovations. Recommendations for next steps for collaborative action include leveraging and improving already available educational and clinical resources, developing obesity education and care standards that incorporate patients' perspectives and address social determinants of health, developing community and public-private partnerships to improve access and public awareness, and coordinating messaging and policy advocacy efforts that align with mitigating the longstanding obesity epidemic.
Collapse
Affiliation(s)
- Christina C Wee
- American College of Physicians, Philadelphia, Pennsylvania (C.C.W., A.W-F.)
| | - Alicia I Arbaje
- Division of Geriatric Medicine and Gerontology, Johns Hopkins University School of Medicine, and Department of Health Policy and Management, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland (A.I.A.)
| | | | - Linda Blount
- Black Women's Health Imperative, Washington, DC (L.B.)
| | - Joshua J Joseph
- Division of Endocrinology, Diabetes and Metabolism, The Ohio State University College of Medicine, Columbus, Ohio (J.J.J.)
| | - Scott Kahan
- National Center for Weight and Wellness, Chevy Chase, Maryland, and George Washington University School of Medicine, Washington, DC (S.K.)
| | - Caroline M Apovian
- Center for Weight Management and Wellness, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts (C.M.A.)
| | | |
Collapse
|
36
|
Arrowaili A. Efficacy and Safety of GLP- 1 Receptor Agonists in the Management of Weight Recurrence or Suboptimal Clinical Response after Undergoing Metabolic Bariatric Surgeries: A Meta-Analysis. Obes Surg 2025; 35:1947-1960. [PMID: 40237975 DOI: 10.1007/s11695-025-07856-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 03/31/2025] [Accepted: 04/04/2025] [Indexed: 04/18/2025]
Abstract
BACKGROUND There is a pressing requirement to formulate innovative approaches for addressing inadequate weight loss or recurrence in individuals following metabolic bariatric surgery (MBS). Glucagon-like peptide- 1 (GLP- 1) analogues such as liraglutide and semaglutide have been formulated for treating type 2 diabetes or managing obesity. In this systematic review and meta-analysis, we aimed to pool the results from all available studies on GLP- 1 agonists to assess the efficacy of these drugs in weight recurrence or suboptimal clinical response of patients who underwent MBS. METHODS We searched PubMed, Scopus, and Web of Science from inception till October 2024 for articles that fulfil our eligibility to be included in the systematic review and meta-analysis investigating the use of GLP- 1 agonists in the management of weight recurrence or suboptimal clinical response in patients who underwent MBS. The search strategy was as follows: "Liraglutide" OR "Semaglutide" OR "Tirzepatide" OR "GLP- 1" OR "Glucagon like peptide" AND "Weight" AND "Bariatric" OR "Sleeve" OR "Banding" OR "Roux-en-Y bypass. We used the mean difference (MD) to compare between continuous variables at a confidence interval (CI) of 95%, and p-value of 0.05. RESULTS The use of GLP- 1 agonists (liraglutide, semaglutide, and tirzepatide) was associated with a statistically significant decrease in the weight of the included patients showing an overall MD = 8.07 kg (95%CI: 5.5, 10.64, p < 0.00001) and I2 = 44%, p = 0.04. Moreover, these drugs (liraglutide, and semaglutide) showed significantly reduced body mass index (BMI) after treatment with overall MD = 4.42 kg/m2 (95%CI: 3.42, 5.42, p < 0.00001), and I2 = 67%, p = 0.0005. Compared with control group, the use of GLP- 1 agonists was associated with reduced weight with MD = - 9.19% (95%CI: - 10.81, - 7.58, p < 0.00001) and I2 = 0%. However, no difference was observed between both groups regarding BMI change with MD = - 1.97% (95%CI: - 4.65, 0.71, p = 0.15). CONCLUSION GLP- 1 agonists such as liraglutide and semaglutide effectively lower body weight and BMI in patients who suffer from weight recurrence or suboptimal clinical response after undergoing MBS. However, future studies are still warranted to investigate the most appropriate protocols for management.
Collapse
Affiliation(s)
- Arief Arrowaili
- Department of Anesthesia and Surgery, Faculty of Medicine, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh, 13317, Saudi Arabia.
| |
Collapse
|
37
|
Ayares G, Diaz LA, Idalsoaga F, Alkhouri N, Noureddin M, Bataller R, Loomba R, Arab JP, Arrese M. MetALD: New Perspectives on an Old Overlooked Disease. Liver Int 2025; 45:e70017. [PMID: 40179033 PMCID: PMC11967760 DOI: 10.1111/liv.70017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 01/02/2025] [Accepted: 01/24/2025] [Indexed: 04/05/2025]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) and alcohol-associated liver disease (ALD) are the major contributors to the liver disease burden globally. The rise in these conditions is linked to obesity, type 2 diabetes, metabolic syndrome and increased alcohol consumption. MASLD and ALD share risk factors, pathophysiology and histological features but differ in their thresholds for alcohol use, and the ALD definition does not require the presence of metabolic dysfunction. A recent multi-society consensus overhauled the nomenclature of liver steatosis and introduced the term MetALD to describe patients with metabolic dysfunction who drink more than those with MASLD and less than those with ALD. This new terminology aims to enhance the understanding and management of liver disease but poses challenges, such as the need to accurately measure alcohol consumption in research and clinical practice settings. Recent studies show that MetALD has significant implications for patient management, as it is associated with increased mortality risks and more severe liver outcomes compared to MASLD alone. MetALD patients face increased risks of liver disease progression, cancer and cardiovascular disease. The diagnosis of MetALD involves the adequate quantification of alcohol use through standardised questionnaires and/or biomarkers as well as proper assessment of liver disease stage and progression risk using non-invasive tools including serologic markers, imaging, elastography techniques and genetic testing. Effective management requires addressing both metabolic and alcohol-related factors to improve outcomes. This review intends to provide a comprehensive overview of MetALD, covering pathogenesis, potential diagnostic approaches, management strategies and emerging therapies.
Collapse
Affiliation(s)
- Gustavo Ayares
- Departamento de GastroenterologíaEscuela de Medicina, Pontificia Universidad Católica de ChileSantiagoChile
- Escuela de Medicina, Universidad Finis TerraeSantiagoChile
| | - Luis Antonio Diaz
- Departamento de GastroenterologíaEscuela de Medicina, Pontificia Universidad Católica de ChileSantiagoChile
- MASLD Research Center, Division of Gastroenterology and HepatologyUniversity of California San DiegoCaliforniaUSA
| | - Francisco Idalsoaga
- Departamento de GastroenterologíaEscuela de Medicina, Pontificia Universidad Católica de ChileSantiagoChile
- Division of Gastroenterology Department of MedicineSchulich School of Medicine, Western University & London Health Sciences CentreLondonOntarioCanada
| | - Naim Alkhouri
- Department of HepatologyArizona Liver HealthChandlerArizonaUSA
| | | | - Ramon Bataller
- Liver UnitHospital Clinic and Institut d'Investigacions Biomediques August Pi I Sunyer (IDIBAPS)BarcelonaSpain
| | - Rohit Loomba
- MASLD Research Center, Division of Gastroenterology and HepatologyUniversity of California San DiegoCaliforniaUSA
| | - Juan Pablo Arab
- Departamento de GastroenterologíaEscuela de Medicina, Pontificia Universidad Católica de ChileSantiagoChile
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Internal MedicineVirginia Commonwealth University School of MedicineVirginiaUSA
| | - Marco Arrese
- Departamento de GastroenterologíaEscuela de Medicina, Pontificia Universidad Católica de ChileSantiagoChile
| |
Collapse
|
38
|
Pierret ACS, Benton M, Sen Gupta P, Ismail K. A qualitative study of the mental health outcomes in people being treated for obesity and type 2 diabetes with glucagon-like peptide-1 receptor agonists. Acta Diabetol 2025; 62:731-742. [PMID: 39520512 PMCID: PMC12116896 DOI: 10.1007/s00592-024-02392-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Accepted: 10/13/2024] [Indexed: 11/16/2024]
Abstract
OBJECTIVE Obesity and type 2 diabetes (T2D) are associated with increased rates of mental disorders, particularly depression, anxiety and binge-eating disorder. GLP-1 receptor agonists are a novel class of pharmacological agents for obesity and T2D. We aimed to describe participants' experiences of GLP-1 receptor agonists on their mental health. METHODS Qualitative, individual, semi-structured interviews were conducted in nine participants who were prescribed GLP-1 receptor agonists for the treatment of obesity and/or T2D. Mental health status was measured at time of GLP-1 receptor agonist initiation and assessed again at 12-16 weeks when the semi-structured interview took place. Data were analysed using reflexive thematic analysis. RESULTS Three main themes were generated from the analysis: (1) acceptance of negative side effects for long term physical health benefits; (2) reflections on the diverse impact on mental health; (3) reduced appetite and increased control of eating behaviours. DISCUSSION Overall, participants with obesity and/or T2D described a positive impact of GLP-1 receptor agonists on their mental health, especially perception of improved control of eating behaviours. This suggests GLP-1 receptor agonists should be further studied for their potential effectiveness for treatment of binge-eating disorder.
Collapse
Affiliation(s)
- Aureliane C S Pierret
- Department of Diabetes, St Thomas' Hospital, Guy's and St Thomas' NHS Foundation Trust, Westminster Bridge Road, London, SE1 7EH, UK.
- Department of Psychological Medicine, King's College London, 16 De Crespigny Park, London, SE5 8AB, UK.
| | - Madeleine Benton
- Department of Psychological Medicine, King's College London, 16 De Crespigny Park, London, SE5 8AB, UK
| | - Piya Sen Gupta
- Department of Diabetes, St Thomas' Hospital, Guy's and St Thomas' NHS Foundation Trust, Westminster Bridge Road, London, SE1 7EH, UK
| | - Khalida Ismail
- Department of Psychological Medicine, King's College London, 16 De Crespigny Park, London, SE5 8AB, UK
| |
Collapse
|
39
|
Liu L, Cui J, Neidecker MV, Nahata MC. Tirzepatide vs semaglutide and liraglutide for weight loss in patients with overweight or obesity without diabetes: A short-term cost-effectiveness analysis in the United States. J Manag Care Spec Pharm 2025; 31:441-450. [PMID: 40298310 PMCID: PMC12039506 DOI: 10.18553/jmcp.2025.31.5.441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/30/2025]
Abstract
BACKGROUND Glucagon-like peptide-1 receptor agonists and their analogues have emerged as effective pharmacotherapies for obesity. OBJECTIVE To assess the short-term cost-effectiveness of subcutaneous tirzepatide, semaglutide, liraglutide, and oral semaglutide for managing obesity or overweight in patients without diabetes. METHODS A decision tree model was developed using a 68-week time window with consideration of serious adverse events and treatment discontinuation from a US payer's perspective. The study population were adults with obesity or overweight with at least 1 weight-related comorbidity but without diabetes. Clinical data were obtained from clinical trials. Model utilities, disutilities, and the costs of serious adverse events were sourced from published literature. Medication costs were assigned from Red Book. All costs were calculated in 2024 US dollars. The incremental cost-effectiveness ratio was calculated based on the cost per quality-adjusted life-year (QALY) gained. A willingness-to-pay threshold of $150,000 per QALY was used. One-way sensitivity analysis and probabilistic sensitivity analysis were performed to assess the effect of parameter uncertainty on the results. RESULTS In the base-case analysis, both subcutaneous tirzepatide and oral semaglutide were cost-effective vs subcutaneous liraglutide and subcutaneous semaglutide. Compared with oral semaglutide, subcutaneous tirzepatide was cost-effective, with an incremental cost-effectiveness ratio of $34,212 per QALY gained. Sensitivity analyses indicated the results were highly sensitive to medication costs and the effectiveness of medications. The probabilistic sensitivity analysis suggested that subcutaneous tirzepatide was most likely to remain cost-effective, with a 98% probability at a willingness to pay of $150,000 per QALY compared with other medications. CONCLUSIONS Subcutaneous tirzepatide and oral semaglutide were cost-effective therapies compared with subcutaneous liraglutide and subcutaneous semaglutide for the short-term management of obesity in adults without diabetes. At or under a willingness-to-pay threshold of $150,000 per QALY, subcutaneous tirzepatide was most cost-effective, surpassing oral semaglutide. These findings provide valuable insights for health care decision-makers in selecting antiobesity medications.
Collapse
Affiliation(s)
- Ligang Liu
- Institute of Therapeutic Innovations and Outcomes, College of Pharmacy, The Ohio State University, Columbus
| | | | | | - Milap C. Nahata
- Institute of Therapeutic Innovations and Outcomes, College of Pharmacy, The Ohio State University, Columbus
- College of Medicine, The Ohio State University, Columbus
| |
Collapse
|
40
|
Kadowaki T, Kiyosue A, Shingaki T, Oura T, Yokote K. Efficacy and safety of once-weekly tirzepatide in Japanese patients with obesity disease (SURMOUNT-J): a multicentre, randomised, double-blind, placebo-controlled phase 3 trial. Lancet Diabetes Endocrinol 2025; 13:384-396. [PMID: 40031941 DOI: 10.1016/s2213-8587(24)00377-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2024] [Revised: 12/01/2024] [Accepted: 12/06/2024] [Indexed: 03/05/2025]
Abstract
BACKGROUND Data on tirzepatide in Asian patients with obesity are limited. This study aimed to gain a better understanding of tirzepatide for treatment of Japanese patients with obesity disease (BMI ≥25 kg/m2 with excessive fat accumulation) as defined by the Japanese Society for the Study of Obesity. METHODS This was a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial of the efficacy and safety of tirzepatide as an adjunct to lifestyle modifications. Japanese adults with obesity disease (BMI ≥27 kg/m2 accompanied by ≥2 obesity-related health disorders or ≥35 kg/m2 accompanied by ≥1 obesity-related health disorders), excluding diabetes, were assigned 1:1:1 via computer-generated random sequence to receive once weekly subcutaneous tirzepatide (10 mg or 15 mg) or placebo. Coprimary endpoints were the mean percent change in bodyweight and the proportion of participants achieving at least 5% bodyweight reduction at week 72, using the efficacy estimand. Efficacy and safety were assessed in the modified intention-to-treat (mITT) population. This study is registered with ClinicalTrials.gov, NCT04844918. FINDINGS Between May 10, 2021, and June 24, 2023, 413 participants were screened, and 267 were randomly assigned. Due to exclusion of one study site, the mITT population was 225 participants (133 [59%] men and 92 [41%] women, mean age 50·8 [SD 10·7] years), with 73 in the tirzepatide 10 mg group, 77 in the tirzepatide 15 mg group, and 75 in the placebo group, of whom 192 (85%) completed both study and treatment. Estimated treatment differences relative to placebo in change in bodyweight at week 72 were -16·1% (95% CI -18·7 to -13·5; p<0·0001) and -21·1% (95% CI -23·6 to -18·5; p<0·0001) following tirzepatide 10 mg and 15 mg, respectively. At week 72, a higher proportion of participants achieved at least 5% bodyweight reduction with tirzepatide 10 mg (67 [94%] of 71) and 15 mg (73 [96%] of 76) compared with placebo (15 [20%] of 75; both p<0·0001). Cardiometabolic and body composition indices were also improved with tirzepatide. Participants treated with tirzepatide experienced treatment-emergent adverse events more frequently (10 mg: n=61 [84%]; 15 mg: n=66 [86%]) than those who received placebo (52 [69%]), most commonly gastrointestinal symptoms. Study discontinuations due to adverse events were infrequent (placebo: n=3 [4%]; tirzepatide 10 mg: n=1 [1%]; tirzepatide 15 mg: n=0). INTERPRETATION In Japanese adults with obesity disease, tirzepatide provided clinically a meaningful reduction in bodyweight compared with placebo over 72 weeks, with a safety profile consistent with that observed in global populations. FUNDING Eli Lilly and Company. TRANSLATION For the Japanese translation of the abstract see Supplementary Materials section.
Collapse
Affiliation(s)
- Takashi Kadowaki
- Toranomon Hospital, Federation of National Public Service Personnel Mutual Aid Associations, Tokyo, Japan
| | - Arihiro Kiyosue
- Moriyama Memorial Hospital, Cardiovascular Center, Tokyo, Japan
| | - Tomotaka Shingaki
- Japan Drug Development and Medical Affairs, Eli Lilly Japan, Kobe, Japan.
| | - Tomonori Oura
- Japan Drug Development and Medical Affairs, Eli Lilly Japan, Kobe, Japan
| | | |
Collapse
|
41
|
Kahwaji J, Hashmi S, Parke CY, Lee R. Safety and Efficacy of Liraglutide and Semaglutide in Kidney Transplant Recipients. KIDNEY360 2025; 6:848-850. [PMID: 39847451 DOI: 10.34067/kid.0000000706] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Accepted: 01/13/2025] [Indexed: 01/24/2025]
Affiliation(s)
- Joseph Kahwaji
- Department of Nephrology, Kaiser Permanente, Los Angeles Medical Center, Los Angeles, California
| | - Sean Hashmi
- Department of Nephrology, Kaiser Permanente, Woodland Hills Medical Center, Los Angeles, California
| | - Chong Young Parke
- Department of Nephrology, Kaiser Permanente, Los Angeles Medical Center, Los Angeles, California
| | - Roland Lee
- Department of Nephrology, Kaiser Permanente, Los Angeles Medical Center, Los Angeles, California
| |
Collapse
|
42
|
Ghanta A, Wilson E, Chao AM. Sex Differences in Obesity and Its Treatment. Curr Psychiatry Rep 2025; 27:278-285. [PMID: 40100584 DOI: 10.1007/s11920-025-01601-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/04/2025] [Indexed: 03/20/2025]
Abstract
PURPOSE OF REVIEW Researchers and clinicians have increasingly recognized the importance of investigating and considering sex differences in obesity treatment. In this narrative review, we first summarized sex differences in select obesity-related conditions that have been the focus of studies of second-generation anti-obesity medications (i.e., semaglutide and tirzepatide) including type 2 diabetes, obstructive sleep apnea, knee osteoarthritis, and heart failure. We next described sex differences related to obesity treatments with a focus on the second-generation anti-obesity medications, semaglutide and tirzepatide. RECENT FINDINGS Type 2 diabetes, obstructive sleep apnea, knee osteoarthritis, and heart failure demonstrated sex-specific pathways influenced by factors such as hormones and body composition. Lifestyle modification, on average, resulted in larger weight losses in males. In contrast, second-generation AOMs produced higher mean weight losses among females. Females reported more adverse events (e.g., nausea, vomiting) with second-generation anti-obesity medications. The few studies that have performed analyses of changes in obesity-related comorbidities stratified by sex have shown consistent improvements between males and females in heart failure and cardiovascular outcomes. Studies are needed to evaluate the effect of sex on the efficacy of anti-obesity medications including on mental health, investigate the mechanisms underlying these effects, and develop interventions to improve the availability and access of these medications.
Collapse
Affiliation(s)
- Aleena Ghanta
- Johns Hopkins University School of Nursing, Baltimore, MD, USA
- University of Pennsylvania School of Nursing, Philadelphia, PA, USA
| | | | - Ariana M Chao
- Johns Hopkins University School of Nursing, Baltimore, MD, USA.
- University of Pennsylvania School of Nursing, Philadelphia, PA, USA.
| |
Collapse
|
43
|
John S, Bhowmick K, Park A, Huang H, Yang X, Mishra L. Recent advances in targeting obesity, with a focus on TGF-β signaling and vagus nerve innervation. Bioelectron Med 2025; 11:10. [PMID: 40301996 PMCID: PMC12042417 DOI: 10.1186/s42234-025-00172-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Accepted: 03/31/2025] [Indexed: 05/01/2025] Open
Abstract
Over a third of the global population is affected by obesity, fatty liver disease (Metabolic Dysfunction-Associated Steatotic Liver Disease, MASLD), and its severe form, MASH (Metabolic Dysfunction-Associated Steatohepatitis), which can ultimately progress to hepatocellular carcinoma (HCC). Recent advancements include therapeutics such as glucagon-like peptide 1 (GLP-1) agonists and neural/vagal modulation strategies for these disorders. Among the many pathways regulating these conditions, emerging insights into transforming growth factor-β (TGF-β) signaling highlight potential future targets through its role in pathophysiological processes such as adipogenesis, inflammation, and fibrosis. Vagus nerve innervation in the gastrointestinal tract is involved in satiety regulation and energy homeostasis, and vagus nerve stimulation has been applied in weight loss and diabetes. This review explores clinical trials in obesity, novel therapeutic targets, and the role of TGF-β signaling and vagus nerve modulation in obesity-related liver diseases and HCC.
Collapse
Affiliation(s)
- Sahara John
- Institute for Bioelectronic Medicine, Divisions of Gastroenterology and Hepatology, Department of Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, 11030, USA
| | - Krishanu Bhowmick
- Institute for Bioelectronic Medicine, Divisions of Gastroenterology and Hepatology, Department of Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, 11030, USA
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, 11724, USA
| | - Andrew Park
- Institute for Bioelectronic Medicine, Divisions of Gastroenterology and Hepatology, Department of Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, 11030, USA
| | - Hai Huang
- Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, 11030, USA
| | - Xiaochun Yang
- Institute for Bioelectronic Medicine, Divisions of Gastroenterology and Hepatology, Department of Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, 11030, USA.
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, 11724, USA.
| | - Lopa Mishra
- Institute for Bioelectronic Medicine, Divisions of Gastroenterology and Hepatology, Department of Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, 11030, USA.
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, 11724, USA.
- Department of Surgery, George Washington University, Washington, DC, 20037, USA.
| |
Collapse
|
44
|
Budny A, Janczy A, Mika A. New Approaches to the Treatment of Severe Obesity-Prehabilitation as the Key to Success. Curr Nutr Rep 2025; 14:64. [PMID: 40299104 DOI: 10.1007/s13668-025-00652-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/06/2025] [Indexed: 04/30/2025]
Abstract
PURPOSE OF REVIEW Bariatric surgery (BS) has emerged as a crucial and effective treatment for severe obesity (SO), providing significant and sustained weight loss and improving comorbidities. Optimizing perioperative careparticularly through structured prehabilitation is crucial for improving surgical outcomes and long-term weight management. This review examines the role of prehabilitation, nutrition, psychological support, physical activity, and pharmacologic treatment in improving the effectiveness of BS. RECENT FINDINGS Despite the benefits of prehabilitation, there are significant differences in the way it is implemented in different healthcare centers. Protocols vary widely in terms of duration, components and intensity, leading to inconsistencies in patient preparation and postoperative recovery. Many patients still do not receive multidisciplinary support from dietitians, psychologists or physiotherapists prior to surgery, which can affect long-term outcomes. Barriers to effective prehabilitation include a lack of standardized guidelines, insufficient healthcare resources and limited patient adherence due to lack of awareness, low motivation or logistical constraints. Despite its proven benefits, structured prehabilitation lasting at least 3-6 months is not available to all patients, as access remains unequal and suboptimal in many healthcare settings. Prehabilitation is an important but underutilized component of BS preparation. Standardizing protocols and ensuring multidisciplinary, patient-centered support are essential to maximizing surgical benefit. Overcoming barriers such as healthcare system limitations, patient motivation and knowledge gaps is critical to integrating prehabilitation into routine bariatric care. This review emphasizes the need for evidence-based, multimodal prehabilitation strategies to improve perioperative care and long-term outcomes for BS patients.
Collapse
Affiliation(s)
- Aleksandra Budny
- Division of Hypertension and Diabetology, Medical University of Gdansk, Gdansk, Poland
| | - Agata Janczy
- Division of Food Commodity Science, Faculty of Health Sciences With the Institute of Maritime and Tropical Medicine, Medical University of Gdansk, Gdansk, Poland
| | - Adriana Mika
- Department of Environmental Analytics, Faculty of Chemistry, University of Gdansk, Gdansk, Poland.
- Department of Pharmaceutical Biochemistry, Medical University of Gdansk, Gdansk, Poland.
| |
Collapse
|
45
|
Hurwitz M, Agboola OJ, Gami A, Williams MS, Virani SS, Sharma GV, Patel J. Strategies for the Secondary Prevention of Atherosclerotic Cardiovascular Disease. US CARDIOLOGY REVIEW 2025; 19:e11. [PMID: 40342903 PMCID: PMC12060178 DOI: 10.15420/usc.2024.33] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Accepted: 02/26/2025] [Indexed: 05/11/2025] Open
Abstract
Patients with atherosclerotic cardiovascular disease (ASCVD), such as those with a history of MI or stroke, are at high risk for morbidity and mortality associated with future cardiovascular events. Ideal management of these patients requires a multifactorial strategy for risk factor mitigation and prevention of additional cardiovascular events. Traditional management of secondary prevention patients involves lipid-lowering with statins, blood pressure control, and anti-platelet treatment. Several additional targets have been identified to optimize the secondary prevention of ASCVD, such as further lipid control, inflammation management, lifestyle and weight optimization, strict diabetes control, use of β-blockers, use of renin-angiotensin-aldosterone system inhibitors, vaccinations, and additional considerations of anti-thrombotic therapies. This review will describe the interventions associated with these targets, as well as the relevant research and indications for these therapies.
Collapse
Affiliation(s)
- Madelyn Hurwitz
- School of Medicine, University of VirginiaCharlottesville, VA
| | - Olayinka J Agboola
- Department of Cardiology, Inova Schar Heart and Vascular InstituteFalls Church, VA
| | - Abhishek Gami
- Division of Cardiology, Johns Hopkins University School of MedicineBaltimore, MD
| | - Marlene S Williams
- Division of Cardiology, Johns Hopkins University School of MedicineBaltimore, MD
| | - Salim S Virani
- Department of Medicine, The Aga Khan UniversityKarachi, Pakistan
- Texas Heart Institute and Baylor College of MedicineHouston, TX
| | - Garima V Sharma
- Department of Cardiology, Inova Schar Heart and Vascular InstituteFalls Church, VA
| | - Jaideep Patel
- Division of Cardiology, Johns Hopkins University School of MedicineBaltimore, MD
- Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of MedicineMD
| |
Collapse
|
46
|
Memel Z, Gold SL, Pearlman M, Muratore A, Martindale R. Impact of GLP- 1 Receptor Agonist Therapy in Patients High Risk for Sarcopenia. Curr Nutr Rep 2025; 14:63. [PMID: 40289060 DOI: 10.1007/s13668-025-00649-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/26/2025] [Indexed: 04/29/2025]
Abstract
PURPOSE OF REVIEW Glucagon-like peptide- 1 receptor agonists (GLP- 1 RA) are a rapidly expanding class of medications used to treat many chronic diseases. This review explores factors that may contribute to accelerated muscle loss among higher-risk patient populations and describes tailored interventions to reduce the risk of accelerated sarcopenia and frailty. RECENT FINDINGS While GLP- 1 RA can result in total weight loss upwards of 25%, recent studies show that they can also lead to significant loss of lean body mass, reaching as high as 15-40% of total weight lost. This rapid and significant decline in muscle mass while taking GLP- 1 RA places certain patient populations already predisposed to sarcopenia at higher risk for muscle loss and adverse events. Currently, there is insufficient evidence delving into the impact of GLP- 1 RA on body composition among older adults, patients with chronic kidney disease, liver disease, and inflammatory bowel disease. However, research suggests that a high protein diet and resistance training may help prevent loss of muscle mass during GLP- 1 RA usage. A targeted and individualized nutrition and physical activity regimen should be instituted for each patient with a focus on optimizing protein intake and performing frequent resistance training in order to minimize loss of muscle mass while promoting the loss of fat mass. Future research should evaluate the impact of GLP- 1 RA on sarcopenia in high-risk patient populations.
Collapse
Affiliation(s)
- Zoe Memel
- Department of Gastroenterology, University of California San Francisco, San Francisco, California, USA
| | - Stephanie L Gold
- Department of Gastroenterology, Icahn School of Medicine at Mount Sinai Hospital, New York, NY, USA
| | - Michelle Pearlman
- Gastroenterologist and Obesity Medicine Specialist, Co-Founder Prime Institute, Coral Gables, Florida, USA
| | - Alicia Muratore
- Department of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Robert Martindale
- Department of Surgery, Oregon Health and Science University, Portland, OR, USA.
| |
Collapse
|
47
|
Murray-Thomas T, Dcruz JM, Harder-Lauridsen NM, Olsen AH, Williams R, Major-Pedersen A. Real-world use of liraglutide for weight management according to label in the United Kingdom: A cohort study using the Clinical Practice Research Datalink primary care databases. Diabetes Obes Metab 2025. [PMID: 40292833 DOI: 10.1111/dom.16393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2025] [Revised: 03/27/2025] [Accepted: 03/28/2025] [Indexed: 04/30/2025]
Abstract
AIMS To assess real-world use of Saxenda® (liraglutide 3.0 mg) and off-label use of Victoza® (liraglutide 1.2 mg/1.8 mg) for weight management and Saxenda® posology in the United Kingdom. Their similar doses and formulation pose a risk of inadvertent use due to their use for different indications. MATERIALS AND METHODS This retrospective, non-interventional drug utilization cohort study (DUS), based on anonymized patient data from the Clinical Practice Research Datalink databases (CPRD Aurum, GOLD), included adult liraglutide initiators without prior prescription 12 months before the index date. Descriptive statistics were used to characterize Saxenda® and Victoza® user demographics and drug utilization. RESULTS Totally 604 Saxenda® and 4853 Victoza® patients were included. Approximately half of the Saxenda® initiators (Si's) (N = 306) had available body weight, of which 96.4% initiated treatment according to the weight loss indication. Si's were more likely female than Victoza® initiators (Vi's) (86.4% vs. 52.1%), younger (mean age ± SD: 46.5 ± 11.7 years) versus (57.5 ± 12.0 years) and with shorter duration of follow-up observation (18.8 ± 13.9 months) versus (32.9 ± 15.9 months). N < 5 of 16 patients with 24-weeks body mass index (BMI) data did not adhere to the Saxenda® stopping rule. N < 5 of 92 patients with valid dose used Victoza® outside the diabetes indication. CONCLUSIONS This DUS provides descriptive data for initiators of liraglutide in the initial 5-year period following the launch of Saxenda® in the United Kingdom. Real-world use of Saxenda® and Victoza® raised no new safety concerns. Where assessment was possible, Saxenda® and Victoza® were mostly prescribed by physicians according to their approved indications.
Collapse
Affiliation(s)
- Tarita Murray-Thomas
- Clinical Practice Research Datalink, Medicines and Healthcare Products Regulatory Agency, London
| | | | | | | | - Rachael Williams
- Clinical Practice Research Datalink, Medicines and Healthcare Products Regulatory Agency, London
| | | |
Collapse
|
48
|
Zhang H, Xiong P, Zheng T, Hu Y, Guo P, Shen T, Zhou X. Combination of Berberine and Evodiamine Alleviates Obesity by Promoting Browning in 3T3-L1 Cells and High-Fat Diet-Induced Mice. Int J Mol Sci 2025; 26:4170. [PMID: 40362407 PMCID: PMC12072149 DOI: 10.3390/ijms26094170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2025] [Revised: 04/13/2025] [Accepted: 04/24/2025] [Indexed: 05/15/2025] Open
Abstract
Traditional Chinese medicine has long acknowledged the therapeutic potential of Tetradium ruticarpum (A.Juss.) T.G.Hartley together with Coptis chinensis Franch in managing metabolic disorders. However, their combined anti-obesity effects and the underlying mechanisms remain poorly characterized. This study investigates the synergistic anti-obesity effects and mechanisms of a combined berberine and evodiamine treatment (BBE) in high-fat diet (HFD)-induced C57BL/6J mice and 3T3-L1 cells. In vitro, cell viability was evaluated using the Cell Counting Kit-8 (CCK-8), while lipid accumulation was assessed through Oil Red O staining and triglyceride content determination. Molecular docking simulations performed with AutoDockTools 1.5.6 software Vina predicted interactions between BBE and key proteins. The analysis of genes and proteins involved in browning and thermogenesis was conducted using quantitative reverse transcription polymerase chain reaction and Western blotting. In vivo, HFD-induced mice were assessed for serum lipids profiles, glucose, insulin, adipocytokines, fat tissue morphology (Hematoxylin and eosin staining), mitochondrial activity (flow cytometry), and protein expression (immunofluorescence). Molecular docking analysis revealed strong binding affinities between BBE and key target proteins, including UCP1, PGC-1α, PRDM16, CIDEA, FGF21, and FGFR1c. BBE significantly reduced lipid accumulation in 3T3-L1 cells, upregulated the mRNA expression of Prdm16, Cidea, Ucp1, and Dio2, elevated UCP1 and PGC-1α protein levels, and activated the FGF21/PGC-1α signaling pathway. In HFD-induced mice, BBE administration led to reduced body weight, smaller adipocyte size, increased adipocyte number, and alleviated hepatic steatosis. Furthermore, it lowered serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and levels of triglycerides (TG), while simultaneously increasing concentrations of high-density lipoprotein cholesterol (HDL-C). BBE also improved glucose tolerance, reduced fasting insulin levels, and modulated adipocytokine levels (reduced leptin, increased adiponectin), while promoting browning gene and protein expression. Overall, the combination of berberine and evodiamine mitigates obesity by enhancing browning and activating the FGF21/PGC-1α signaling pathway.
Collapse
Affiliation(s)
| | | | | | | | | | | | - Xin Zhou
- School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; (H.Z.); (P.X.); (T.Z.); (Y.H.); (P.G.); (T.S.)
| |
Collapse
|
49
|
Kong Y, Yang H, Nie R, Zhang X, Zuo F, Zhang H, Nian X. Obesity: pathophysiology and therapeutic interventions. MOLECULAR BIOMEDICINE 2025; 6:25. [PMID: 40278960 PMCID: PMC12031720 DOI: 10.1186/s43556-025-00264-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Revised: 03/15/2025] [Accepted: 03/24/2025] [Indexed: 04/26/2025] Open
Abstract
Over the past few decades, obesity has transitioned from a localized health concern to a pressing global public health crisis affecting over 650 million adults globally, as documented by WHO epidemiological surveys. As a chronic metabolic disorder characterized by pathological adipose tissue expansion, chronic inflammation, and neuroendocrine dysregulation that disrupts systemic homeostasis and impairs physiological functions, obesity is rarely an isolated condition; rather, it is frequently complicated by severe comorbidities that collectively elevate mortality risks. Despite advances in nutritional science and public health initiatives, sustained weight management success rates and prevention in obesity remain limited, underscoring its recognition as a multifactorial disease influenced by genetic, environmental, and behavioral determinants. Notably, the escalating prevalence of obesity and its earlier onset in younger populations have intensified the urgency to develop novel therapeutic agents that simultaneously ensure efficacy and safety. This review aims to elucidate the pathophysiological mechanisms underlying obesity, analyze its major complications-including type 2 diabetes mellitus (T2DM), cardiovascular diseases (CVD), non-alcoholic fatty liver disease (NAFLD), obesity-related respiratory disorders, obesity-related nephropathy (ORN), musculoskeletal impairments, malignancies, and psychological comorbidities-and critically evaluate current anti-obesity strategies. Particular emphasis is placed on emerging pharmacological interventions, exemplified by plant-derived natural compounds such as berberine (BBR), with a focus on their molecular mechanisms, clinical efficacy, and therapeutic advantages. By integrating mechanistic insights with clinical evidence, this review seeks to provide innovative perspectives for developing safe, accessible, and effective obesity treatments.
Collapse
Affiliation(s)
- Yue Kong
- Department of Endocrinology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | | | - Rong Nie
- Department of Endocrinology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Xuxiang Zhang
- Department of Endocrinology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Fan Zuo
- Department of Endocrinology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | | | - Xin Nian
- Department of Endocrinology, The First Affiliated Hospital of Kunming Medical University, Kunming, China.
| |
Collapse
|
50
|
Drucker DJ. GLP-1-based therapies for diabetes, obesity and beyond. Nat Rev Drug Discov 2025:10.1038/s41573-025-01183-8. [PMID: 40281304 DOI: 10.1038/s41573-025-01183-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/13/2025] [Indexed: 04/29/2025]
Abstract
Glucagon-like peptide 1 (GLP-1)-based therapies, such as semaglutide and tirzepatide, represent highly effective treatment options for people with type 2 diabetes and obesity, enabling effective control of glucose and weight loss, while reducing cardiovascular and renal morbidity and mortality. The success of these medicines has spurred development of next-generation GLP-1-based drugs, promising greater weight loss, improved tolerability and additional options for the route and frequency of dosing. This Review profiles established and emerging GLP-1-based medicines, discussing optimization of pharmacokinetics and tolerability, engagement of new therapeutically useful pathways and safety aspects. Structurally unique GLP-1-based medicines that achieve substantially greater and rapid weight loss may impact musculoskeletal health, providing a rationale for therapeutics that more selectively target adipose tissue loss while preserving muscle mass and strength. Ongoing clinical trials in peripheral vascular disease, neuropsychiatric and substance use disorders, metabolic liver disease, arthritis, hypertension and neurodegenerative disorders may broaden indications for GLP-1-based therapeutics.
Collapse
Affiliation(s)
- Daniel J Drucker
- Department of Medicine and Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
| |
Collapse
|