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Sydney GI, Do T, West WA, Uwaifo GI. Cystic Fibrosis and Hemochromatosis Carriers May Be Prone to Glucagon-like Peptide-1 Agonist Pancreatitis: 3 Cases. JCEM CASE REPORTS 2025; 3:luaf104. [PMID: 40384889 PMCID: PMC12078934 DOI: 10.1210/jcemcr/luaf104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 02/14/2025] [Indexed: 05/20/2025]
Abstract
Glucagon-like peptide-1 (GLP-1) agonists are widely used in the management of type 2 diabetes and obesity, with their therapeutic scope expanding to address cardiometabolic and cardiorenal conditions. However, their increasing use has been associated with potential adverse effects, including acute pancreatitis (AP). The exact prevalence of GLP-1 agonist-induced AP remains uncertain and reliable predictors for its onset have yet to be identified. We present 3 cases of class-associated predilection for GLP-1 analog-associated AP in patients with carrier states for hemochromatosis (HC) and cystic fibrosis. Case 1 is a heterozygous carrier for the C282Y HC pathogenic variant. Case 2 is a heterozygous carrier of the Delta F508 deletion of the cystic fibrosis transmembrane regulator (CFTR) gene. Case 3 is compound heterozygous carrier of a single CFTR intron 9 poly T allele pathogenic variant (5T/7T/8T), as well as a single pathogenic variant of the C282Y HC gene. Our observation suggests that carrier states for cystic fibrosis and HC may predispose individuals to GLP-1 agonist-associated AP. Genetic testing for these carrier states should be considered among patients with GLP-1 agonist-associated AP to provide more support and data for this as a potential true risk factor.
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Affiliation(s)
- Guy Itzhak Sydney
- Section of Endocrinology, Yale School of Medicine, New Haven, CT 06510, USA
| | - Tammy Do
- Dept of Medicine, Ochsner Medical Center, New Orleans, LA 70121, USA
| | - William Austin West
- Section of Pulmonology and Critical Care, University of Southern California Medical Center, Los Angeles, CA 90333, USA
| | - Gabriel Ikponmosa Uwaifo
- Division of Endocrinology, Department of Medicine, Southern Illinois University School of Medicine, Springfield, IL 62702, USA
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Grobman B, Mansur A, Lu CY. Disparities in heart failure deaths among people with diabetes in the United States: 1999-2020. Diabetes Obes Metab 2025; 27:2977-2984. [PMID: 40019145 DOI: 10.1111/dom.16301] [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: 12/28/2024] [Revised: 02/13/2025] [Accepted: 02/14/2025] [Indexed: 03/01/2025]
Abstract
AIMS Heart failure is a leading cause of mortality in the United States, with significant disparities in its burden, particularly among underserved populations. A similar pattern exists for diabetes, but less is known about the mortality impact of these two comorbid conditions. This study aims to examine the risk of death from heart failure among people with diabetes, focusing on socio-demographic disparities. MATERIALS AND METHODS We analysed data from the Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research Multiple Cause of Death Database, examining patterns of heart failure deaths in which diabetes was a contributing cause. Our analysis was stratified by socio-demographic variables, including race, ethnicity and geography, and we also explored trends over time. RESULTS Between 1999 and 2020, there were 82 617 deaths from heart failure in which diabetes was a contributing cause, with an age-adjusted mortality rate of 32.04 deaths per 1 000 000 individuals. The death rate increased by 2.18% during the study period. Death rates were higher among Black Americans compared with White Americans (age-adjusted mortality rate ratio = 1.51, 95% confidence interval: 1.49-1.53), with disparities growing over time (a 10.75% increase for Black Americans vs. a 1.11% increase for White Americans). CONCLUSIONS Deaths from comorbid heart failure and diabetes are increasing in the United States, with significant and worsening disparities, particularly among minorities. Urgent action is needed to reduce heart failure mortality among people with diabetes, especially in underserved populations.
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Affiliation(s)
| | - Arian Mansur
- Harvard Medical School, Boston, Massachusetts, USA
| | - Christine Y Lu
- Harvard Medical School, Boston, Massachusetts, USA
- Department of Population Medicine, Harvard Pilgrim Health Care Institute, Boston, Massachusetts, USA
- School of Pharmacy, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
- Kolling Institute, Faculty of Medicine and Health, The University of Sydney and the Northern Sydney Local Health District, Sydney, New South Wales, Australia
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Magodoro IM, Kotze LA, Stek CJ, West A, Le Roux A, Sobratee N, Taliep A, Hamada Y, Dave JA, Rangaka MX, Parihar SP, Wilkinson RJ. Clinical, metabolic, and immune interaction between tuberculosis and diabetes mellitus: implications and opportunities for therapies. Expert Opin Pharmacother 2025; 26:1099-1112. [PMID: 40401906 PMCID: PMC7617758 DOI: 10.1080/14656566.2025.2508904] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2025] [Revised: 03/25/2025] [Accepted: 05/16/2025] [Indexed: 05/23/2025]
Abstract
INTRODUCTION Tuberculosis (TB) remains a major infectious threat to global health, while type 2 diabetes mellitus (diabetes) has reached epidemic proportions in many regions of the world. In low- and middle-income countries (LMIC) and among indigenous and minority communities in high-income settings (HIC), these diseases also increasingly overlap, posing new clinical and therapeutic challenges. AREAS COVERED We searched PubMed/CINAHL/Web of Science/Scopus, Google Scholar up to 30 November 2024. Meanwhile, the Immuno-metabolic parallels between TB and Diabetes are underappreciated. Improved understanding of mechanisms may pave the way for novel therapeutic strategies, for example, using antidiabetic medications as adjuvant host-directed therapies (HDT) in active TB. We review the epidemiology of TB, diabetes and their combined comorbidity, their immune and metabolic mechanisms and clinical relevance, as well as potential opportunities for general and targeted therapeutic intervention. EXPERT OPINION Immunometabolic interaction between diabetes and tuberculosis is bidirectional. Underlying this interaction are shared inflammatory mechanisms. It follows that treatments for diabetes and its complication may be beneficial in tuberculosis and that the treatment of both active and latent tuberculosis may improve glycemic control. These interactions are amenable to investigation in experimental models, in human experimental medicine studies and in clinical trials.
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Affiliation(s)
- Itai M Magodoro
- Department of Medicine, University of Cape Town, Observatory, Republic of South Africa
| | | | - Cari J Stek
- Department of Medicine, University of Cape Town, Observatory, Republic of South Africa
- Wellcome Discovery Research Platforms for Infection, Centre for Infectious Diseases Research in Africa, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Observatory, Republic of South Africa
| | - Alexander West
- Wellcome Discovery Research Platforms for Infection, Centre for Infectious Diseases Research in Africa, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Observatory, Republic of South Africa
| | - Andrea Le Roux
- Wellcome Discovery Research Platforms for Infection, Centre for Infectious Diseases Research in Africa, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Observatory, Republic of South Africa
| | - Nadja Sobratee
- Wellcome Discovery Research Platforms for Infection, Centre for Infectious Diseases Research in Africa, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Observatory, Republic of South Africa
| | - Arshad Taliep
- Wellcome Discovery Research Platforms for Infection, Centre for Infectious Diseases Research in Africa, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Observatory, Republic of South Africa
| | - Yohhei Hamada
- MRC Clinical Trials Unit, University College London, London, UK
| | - Joel A Dave
- Department of Medicine, University of Cape Town, Observatory, Republic of South Africa
| | - Molebogeng X Rangaka
- Wellcome Discovery Research Platforms for Infection, Centre for Infectious Diseases Research in Africa, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Observatory, Republic of South Africa
- MRC Clinical Trials Unit, University College London, London, UK
| | - Suraj P Parihar
- Wellcome Discovery Research Platforms for Infection, Centre for Infectious Diseases Research in Africa, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Observatory, Republic of South Africa
- Division of Medical Microbiology, Institute of Infectious Diseases and Molecular Medicine, Department of Pathology, University of Cape Town, Observatory, Republic of South Africa
| | - Robert J Wilkinson
- Department of Medicine, University of Cape Town, Observatory, Republic of South Africa
- Francis Crick Institute, London, UK
- Wellcome Discovery Research Platforms for Infection, Centre for Infectious Diseases Research in Africa, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Observatory, Republic of South Africa
- Department of Infectious Diseases, Imperial College London, London, UK
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Schmidt MR, Ebert ML, Kiechle MA, Zöller K, Laffleur F, Bernkop-Schnürch A. Self-Emulsifying delivery systems for oral administration of exenatide: Hydrophobic ion pairs vs. Dry reverse micelles. Int J Pharm 2025; 678:125711. [PMID: 40360092 DOI: 10.1016/j.ijpharm.2025.125711] [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: 03/14/2025] [Revised: 05/09/2025] [Accepted: 05/09/2025] [Indexed: 05/15/2025]
Abstract
This research provides a comparative analysis of two innovative strategies - hydrophobic ion pairing (HIP) and dry reverse micelles (dRM) - to enhance the oral bioavailability of exenatide, a GLP-1 receptor agonist, as a diabetes treatment. These techniques were integrated into self-emulsifying drug delivery systems (SEDDS) featuring a lipid matrix composed of propylene glycol dilaurate and salicylic acid methyl ester (32.5 %:32.5 %; v/v) with polyethoxylated-35 castor oil (35 %; v/v) as surfactant. HIP enhances the lipophilicity of exenatide through ion-pairing with cationic surfactants, thereby promoting efficient incorporation into the lipid matrix of SEDDS. In contrast, dRM forms stabilized micellar structures using sorbitan monooleate, improving safety and compatibility. The droplet sizes for SEDDS were analyzed via dynamic light scattering and varied from 95 to 110 nm, with a polydispersity index of approximately 0.25, and zeta potentials between -1 mV and -6 mV. The maximum log DSEDDS/AQ values were 2.13 ± 0.31 for exenatide-loaded HIPs (ExeHIP) and 2.05 ± 0.08 for exenatide-loaded dRM (ExedRM), indicating sufficient lipophilicity, which is crucial for effective absorption and bioavailability. Toxicological assessments showed low toxicity levels. In vivo studies indicated a relative bioavailability of 18.08 % for ExeHIP and 17.06 % for ExedRM compared to intravenous injection. Both strategies demonstrated a similar potential in relative bioavailability, reflecting a significant increase in bioavailability compared to the control. Notably, the HIP formulation provided better control over exenatide release and ensured stable GLP-1 levels, while dRMs are preferable for safety reasons as all excipients have GRAS status and are therefore FDA approved.
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Affiliation(s)
- Marlene Ramona Schmidt
- Center for Chemistry and Biomedicine, Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria
| | - Melanie Lena Ebert
- Center for Chemistry and Biomedicine, Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria
| | - Magnus Andre Kiechle
- Center for Chemistry and Biomedicine, Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria
| | - Katrin Zöller
- Center for Chemistry and Biomedicine, Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria
| | - Flavia Laffleur
- Center for Chemistry and Biomedicine, Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria
| | - Andreas Bernkop-Schnürch
- Center for Chemistry and Biomedicine, Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
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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.
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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
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Saran A, Raisinghani R, Paliwal S, Sharma S. GLP-1R agonists: recent advances, current gaps, and future challenges. Mol Divers 2025:10.1007/s11030-025-11195-6. [PMID: 40301134 DOI: 10.1007/s11030-025-11195-6] [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: 02/06/2025] [Accepted: 04/11/2025] [Indexed: 05/01/2025]
Abstract
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) emerged as a promising class of drugs and have been shown to be effective as a key regulator in managing glucose metabolism-associated diseases such as type 2 diabetes mellitus (T2DM), chronic kidney disease (CKD), cardiovascular effects, nephrological complications, diabetes, non-alcoholic fatty liver (NAFLD), as well as to control obesity. A few drugs included in GLP-1RA class are liraglutide, exenatide, and semaglutide. Most recent drug that is available in both oral and subcutaneous forms is semaglutide. Available, withdrawn, and investigational GLP-RAs are listed in this paper. This review article will also explore common side effects and safety profiles of both long-acting and short-acting GLP-1 RAs. Additionally, it will highlight the recent advances and ongoing challenges in the field of drug discovery related to GLP-1 receptor agonists.
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Affiliation(s)
- Anukriti Saran
- Department of Bioscience and Biotechnology, Banasthali Vidyapith, Banasthali, Rajasthan, 304022, India.
| | - Riya Raisinghani
- Department of Bioscience and Biotechnology, Banasthali Vidyapith, Banasthali, Rajasthan, 304022, India
| | - Sarvesh Paliwal
- Department of Pharmacy, Banasthali Vidyapith, Banasthali, Rajasthan, 304022, India
| | - Swapnil Sharma
- Department of Pharmacy, Banasthali Vidyapith, Banasthali, Rajasthan, 304022, India
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Turkistani Y. Glucagon-like peptide-1 receptor agonists: a review from a cardiovascular perspective. Front Cardiovasc Med 2025; 12:1535134. [PMID: 40342976 PMCID: PMC12060260 DOI: 10.3389/fcvm.2025.1535134] [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: 11/26/2024] [Accepted: 03/28/2025] [Indexed: 05/11/2025] Open
Abstract
Introduction Glucagon-like peptide-1 receptor agonists (GLP-1 RA) are novel agents with proven cardiovascular (CV) benefits. GLP-1 RAs have been used for diabetes and found to improve CV outcomes in diabetic and nondiabetic patients. They are authorized for treating obesity. Our narrative review discussed the CV benefits of GLP-1 RAs in terms of controlling CV risk factors and improving CV outcomes in diabetic and nondiabetic patients regardless of their CV history, and the CV perspectives related to their use in clinical practice. Areas covered Literature was searched with no limits on date or language, using various combinations of keywords. Data on the CV benefits of GLP-1 RAs and their use in clinical practice were summarized. Results Several studies have discussed the CV beneficial effects of GLP-1 RAs in terms of reducing blood pressure, lipid levels, body weight, risk for arrhythmias, reducing the risk of major adverse CV events, and hospital admission for heart failure. Conclusion The cardioprotective effects and low risk of hypoglycemia of GLP-1 RAs make them preferred agents in any multidisciplinary approach aiming to reduce CV disease burden and improve prognosis. Cardiologists are encouraged to strongly consider the CV benefits of GLP-1 RAs in their risk-reduction strategies.
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Affiliation(s)
- Yosra Turkistani
- Department of Medicine, College of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia
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Elsabbagh Z, Haft M, Murali S, Best M, McFarland EG, Srikumaran U. Does use of glucagon-like peptide-1 agonists increase perioperative complications in patients undergoing shoulder arthroplasty? J Shoulder Elbow Surg 2025; 34:997-1006. [PMID: 39322005 DOI: 10.1016/j.jse.2024.07.045] [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: 02/07/2024] [Revised: 07/08/2024] [Accepted: 07/30/2024] [Indexed: 09/27/2024]
Abstract
BACKGROUND Amidst the rising prevalence of type 2 diabetes mellitus (T2DM) and obesity among individuals undergoing total shoulder arthroplasty (TSA), the impact of glucagon-like peptide-1 (GLP-1) therapy on surgical outcomes merits thorough investigation. Though it is known that GLP-1 therapy poses an interesting challenge for anesthesia during the perioperative period, little is known regarding the effects of these medications on surgical outcomes. This study aimed to evaluate the influence of GLP-1 on postoperative outcomes and length of stay (LOS) in patients T2DM undergoing TSA. METHODS A retrospective cohort analysis was performed using a national database to identify primary TSA patients aged 18 and above with T2DM prescribed GLP-1 therapy at the time of surgery. Exclusion criteria included revision surgery, TSA for fracture, type 1 diabetes, steroid-induced diabetes, and contraindications for GLP-1 therapy. A control group of T2DM TSA patients not on GLP-1 therapy was used, and a 1:4 propensity-score match was performed. Incidence rates and odds ratios via multivariable logistic regression were calculated. The primary outcomes were 90 days major medical complications and LOS. Secondary outcomes included 2-year joint-related complications. RESULTS In the 90-day follow-up cohort, 64,567 patients met inclusion criteria, with 8481 (13.1%) on GLP-1 therapy. No significant increase in 90 days major complications, including deep vein thrombosis, cardiac arrest, myocardial infarction, cerebrovascular accident, pneumonia, pulmonary embolism, urinary tract infection, surgical site infection, hypoglycemic event, sepsis, or readmission, was found between GLP-1 and non-GLP-1 cohorts after multivariable logistic regression. In the 2-year follow-up cohort, 47,814 patients were included, with 5969 (12.5%) on GLP-1 therapy. Similarly, 2-year joint-related complications, including all-cause revision, prosthetic joint infection, periprosthetic fracture, and aseptic revision, showed no significant differences between the GLP-1 and non-GLP-1 cohorts. No significant difference was observed in LOS in the 90-day cohort. CONCLUSION This study provides a comprehensive analysis of GLP-1 therapy's impact on TSA outcomes, revealing no significant change in postoperative complications or LOS. The lack of increased postoperative risk underscores the potential of GLP-1 therapy in managing T2DM without adverse effects on TSA recovery. These insights contribute to understanding postoperative management in orthopedic surgery, indicating that we did not note any increased risk with GLP-1 use perioperatively in TSA patients, unlike in other populations like the total knee arthroplasty patients. Future research should focus on prospective analyses to further elucidate the role of GLP-1 therapy in surgical outcomes, aiming to enhance patient care and optimize postoperative strategies for patients with T2DM undergoing TSA.
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Affiliation(s)
- Zaid Elsabbagh
- Department of Orthopaedic Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
| | - Mark Haft
- Department of Orthopaedic Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Sudarsan Murali
- Department of Orthopaedic Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Matthew Best
- Department of Orthopaedic Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Edward George McFarland
- Department of Orthopaedic Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Uma Srikumaran
- Department of Orthopaedic Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Mostafa MEA, Alrasheed T. Improvement of irritable bowel syndrome with glucagon like peptide-1 receptor agonists: a systematic review and meta-analysis. Front Endocrinol (Lausanne) 2025; 16:1548346. [PMID: 40134805 PMCID: PMC11932899 DOI: 10.3389/fendo.2025.1548346] [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: 12/19/2024] [Accepted: 02/10/2025] [Indexed: 03/27/2025] Open
Abstract
Introduction Irritable bowel syndrome (IBS) is a severe gastrointestinal condition with symptoms like pain, bloating, diarrhea, and constipation. Glucagon-like peptide-1 (GLP-1) receptors, expressed in the central nervous system and peripheral tissues, have been found to affect gut motility. GLP-1 and its analog ROSE-010 have been shown to inhibit the migrating motor complex and decrease gastrointestinal motility in IBS patients. Aim This systematic review and meta-analysis aim to assess the efficacy and safety of GLP-1 receptor agonists in providing pain and symptom relief for individuals with IBS. Methods The study conducted extensive searches across various databases, including Cochrane Library, Web of Science, PubMed, Google Scholar, and Science Direct, to identify studies on IBS and related drugs. A search strategy using keywords and medical subject heading terms (MeSH) was developed to ensure inclusivity. Exclusion criteria included non-English language studies, books, conference papers, case reports, in vitro studies, animal studies, and non-original articles. Results The study found that ROSE-010 (100 µg) significantly lowered pain intensity in IBS patients compared to a placebo, with an overall odds ratio of 2.30, 95% CI: 1.53-3.46. ROSE-010 (300 µg) is more effective than a placebo for all irritable bowel syndrome subtypes, with consistent effects across trials. ROSE-010 is linked to a greater incidence of nausea, vomiting, and headache than placebo. Conclusion ROSE-010, a glucagon-like peptide-1 receptor agonist, has been shown to reduce pain in individuals with IBS. However, its higher frequency of nausea, vomiting, and headache suggests the need for close monitoring and individualized treatment plans. Further investigation is needed to understand its impact on different IBS subtypes and long-term effects. Systematic review registration https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42024613545.
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Affiliation(s)
- Mohamed E. A. Mostafa
- Department of Anatomy, Faculty of Medicine, University of Tabuk, Tabuk, Saudi Arabia
| | - Tariq Alrasheed
- Department of Internal Medicine, Faculty of Medicine, University of Tabuk, Tabuk, Saudi Arabia
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Li JX, Hsu TJ, Lin HJ, Hsu SB, Lu CR, Chung WH, Liang SJ, Tsai FJ, Chang KC. Combination of Glucagon-Like Peptide 1 Receptor Agonist and Thiazolidinedione for Mortality and Cardiovascular Outcomes in Patients With Type 2 Diabetes. JAMA Netw Open 2025; 8:e252577. [PMID: 40163115 PMCID: PMC11959443 DOI: 10.1001/jamanetworkopen.2025.2577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2024] [Accepted: 12/26/2024] [Indexed: 04/02/2025] Open
Abstract
Importance Combination therapy has emerged as a critical area of interest in managing diabetes; however, the association of combination therapy with a glucagon-like peptide 1 receptor agonist (GLP-1RA) and thiazolidinedione and the risk of diabetes-related complications remains incompletely understood. Objective To compare the hazards of cardiovascular-related morbidities and mortality among patients with type 2 diabetes receiving combination therapy with a GLP-1RA plus thiazolidinedione, those receiving monotherapy with a GLP-1RA or thiazolidinedione, and nonusers. Design, Setting, and Participants This retrospective cohort study used nationwide data obtained from Taiwan's National Health Insurance Research Database. Patients older than 20 years with type 2 diabetes who received a GLP-1RA or thiazolidinedione between January 1, 2011, and December 31, 2020, were enrolled. The data analysis was performed from May 1 to May 22, 2024. Main Outcomes and Measures This study investigated the hazards of all-cause mortality, major adverse cardiovascular events, cardiovascular mortality, cardiovascular complications, and hypoglycemia in GLP-1RA and thiazolidinedione combination or monotherapy users compared with nonusers. Results A total of 110 411 patients were enrolled (mean [SD] age, 58.3 [11.9] years; 45.5% female; 47 526 GLP-1RA users, 32 203 thiazolidinedione users, and 30 682 GLP-1RA plus thiazolidinedione users), along with a propensity score-matched group of patients who did not use a GLP-1RA or thiazolidinedione, for a total cohort size of 220 822. Patients receiving GLP-1RA and thiazolidinedione dual therapy had significantly lower risk of all-cause mortality (adjusted hazard ratio [AHR], 0.20; 95% CI, 0.19-0.21; P < .001), major adverse cardiovascular events (AHR, 0.85; 95% CI, 0.82-0.89; P < .001), and cardiovascular mortality (AHR, 0.20; 95% CI, 0.18-0.23; P < .001) than those who did not receive a GLP-1RA or thiazolidinedione. However, a higher risk of hypoglycemia was seen in those receiving combination therapy (AHR, 1.61; 95% CI, 1.43-1.82; P < .001) and those receiving thiazolidinedione monotherapy (AHR, 1.69; 95% CI, 1.51-1.90; P < .001) compared with nonuse. This risk was mitigated with prolonged use. Thiazolidinedione monotherapy users had a significantly higher risk of all-cause mortality (AHR, 1.29; 95% CI, 1.24-1.34; P < .001) and cardiovascular mortality (AHR, 1.28; 95% CI, 1.13-1.45; P < .001) than GLP-1RA monotherapy users. Several sensitivity analyses further supported the robustness of these findings. Conclusions and Relevance In this cohort study of patients with type 2 diabetes, combination therapy with a GLP-1RA plus thiazolidinedione was associated with significantly lower hazards of mortality and cardiovascular complications compared with nonuse. The findings suggest that GLP-1RAs may mitigate the adverse cardiovascular effects of thiazolidinedione.
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Affiliation(s)
- Jing-Xing Li
- Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
- School of Medicine, China Medical University, Taichung, Taiwan
- Graduate Institute of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei, Taiwan
| | - Tzu-Ju Hsu
- Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan
| | - Heng-Jun Lin
- Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan
| | - Shu-Bai Hsu
- Department of Nursing, China Medical University Hospital, Taichung, Taiwan
| | - Chiung-Ray Lu
- School of Medicine, China Medical University, Taichung, Taiwan
- Division of Cardiovascular Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Wei-Hsin Chung
- Division of Cardiovascular Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Shinn-Jye Liang
- Division of Pulmonary and Critical Care, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
- School of Chinese Medicine, China Medical University, Taichung, Taiwan
| | - Fuu-Jen Tsai
- School of Chinese Medicine, China Medical University, Taichung, Taiwan
- Department of Medical Research, China Medical University Hospital, Taichung, Taiwan
- Division of Medical Genetics, China Medical University Children’s Hospital, Taichung, Taiwan
- Department of Biotechnology and Bioinformatics, Asia University, Taichung, Taiwan
| | - Kuan-Cheng Chang
- Division of Cardiovascular Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
- Cardiovascular Research Laboratory, China Medical University Hospital, Taichung, Taiwan
- Graduate Institute of Biomedical Science, China Medical University, Taichung, Taiwan
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11
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Abi Zeid Daou C, Aboul Hosn O, Ghzayel L, Mourad M. Exploring Connections Between Weight-Loss Medications and Thyroid Cancer: A Look at the FDA Adverse Event Reporting System Database. Endocrinol Diabetes Metab 2025; 8:e70038. [PMID: 40055991 PMCID: PMC11889434 DOI: 10.1002/edm2.70038] [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] [Received: 10/25/2024] [Revised: 02/08/2025] [Accepted: 02/15/2025] [Indexed: 05/13/2025] Open
Abstract
AIMS GLP-1 receptor agonists, such as semaglutide (Ozempic) and tirzepatide (Monjaro), have gained significant popularity for obesity management, but concerns have arisen about their potential link to thyroid cancer. This study investigates the association between thyroid cancer and weight-loss medications. MATERIALS AND METHODS A disproportionality analysis was conducted using data from the FDA Adverse Event Reporting System (FAERS) from 2004 to Q1 2024. Reporting odds ratios (RORs) were used to identify associations between thyroid cancer and weight-loss drugs, including anti-diabetic medications. RESULTS Significant positive associations with thyroid cancer were found for GLP-1 receptor agonists: semaglutide (ROR = 7.61, 95% CI: 6.37-9.08), dulaglutide (ROR = 3.59, 95% CI: 3.03-4.27), liraglutide (ROR = 15.59, 95% CI: 13.94-17.44) and tirzepatide (ROR = 2.09, 95% CI: 1.51-2.89). A weak inverse association was observed for metformin (ROR = 0.58, 95% CI: 0.36-0.93). No significant associations were found for other drugs, such as topiramate, dapagliflozin and insulin glargine. CONCLUSION The study, based on data from the FAERS database, suggests a potential association between GLP-1 receptor agonists and an increased thyroid cancer risk. These findings underscore the importance of further research and continuous safety monitoring when prescribing these medications for obesity management.
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Affiliation(s)
- Christophe Abi Zeid Daou
- Department of Otolaryngology and Head and Neck SurgeryAmerican University of Beirut Medical CenterBeirutLebanon
| | - Omar Aboul Hosn
- Department of Otolaryngology and Head and Neck SurgeryAmerican University of Beirut Medical CenterBeirutLebanon
| | - Lana Ghzayel
- Department of Otolaryngology and Head and Neck SurgeryAmerican University of Beirut Medical CenterBeirutLebanon
| | - Marc Mourad
- Department of Otolaryngology and Head and Neck SurgeryAmerican University of Beirut Medical CenterBeirutLebanon
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12
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Doyle EA. Medical treatment of type 2 diabetes in children and adolescents: A changing landscape. Nurse Pract 2025; 50:23-29. [PMID: 39994855 DOI: 10.1097/01.npr.0000000000000281] [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: 02/26/2025]
Abstract
ABSTRACT Over the last 20 years, the incidence of type 2 diabetes (T2D) has increased among the pediatric population. This increase is of great concern, as T2D tends to be far more aggressive when diagnosed at an earlier age. This article reviews the incidence, prevalence, diagnosis, and management of T2D in children and adolescents. Implications for NP practice are also discussed.
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Affiliation(s)
- Elizabeth A Doyle
- Elizabeth A. Doyle is an associate professor in the Yale School of Nursing at Yale University in Orange, Conn., and a pediatric NP in the Pediatric Diabetes Program at Yale New Haven Children's Hospital in New Haven, Conn
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13
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Lin CP, Chung CH, Lu CH, Su SC, Kuo FC, Liu JS, Li PF, Huang CL, Ho LJ, Chen KC, Chang CY, Lin MS, Liu YC, Cheng AC, Lin HH, Kuo SW, Lee CH, Hsieh CH, Hung YJ, Liu HY, Guo LY, Chien WC. Glucagon-like peptide-1 receptor agonists therapy to attenuate the risk of knee osteoarthritis and total knee replacement in type 2 diabetes mellitus: A nation-wide population-based cohort study. Medicine (Baltimore) 2025; 104:e41243. [PMID: 39928811 PMCID: PMC11813052 DOI: 10.1097/md.0000000000041243] [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: 01/17/2024] [Revised: 12/12/2024] [Accepted: 12/19/2024] [Indexed: 02/12/2025] Open
Abstract
Type 2 diabetes mellitus (T2DM) is an independent risk factor of knee osteoarthritis (KOA). This study was mainly based on data from the Taiwan National Health Insurance Database. Using big data analysis, we showed that glucagon-like peptide-1 receptor agonist (GLP-1RA) treatment is helpful for patients with T2DM who have a lower risk of KOA or total knee replacement (TKR). A total of 35,762 patients with T2DM were included in this study. We divided these patients into 988 patients with T2DM without KOA and 372 patients with T2DM with KOA who received GLP-1RA treatment and those who did not receive GLP-1RA treatment. The patients were matched for sex, age, and inclusion date by 1:1 propensity score, which was included in the control group. Cox proportional hazards analyses were performed to compare KOA risk and TKR rate during a maximum follow-up period of 5 years. There were 1976/744 patients with T2DM without/with KOA who received and did not receive GLP-1RA treatment, including 1052/322 men (53.24/43.28%) and 924/422 women (46.76/56.72%). At the end of follow-up, there were 46/39 (4.66/10.48%) patients with T2DM without/with KOA who received GLP-1RA treatment and underwent KOA/TKR were lower than those without GLP-1RA treatment 87/70 (8.81/18.82%). Cox proportional hazard regression analysis showed a lower rate of KOA/TKR among patients with GLP-1RA treatment (adjusted hazard ratio [HR] = .852; 95% confidence interval [CI] = .784-.930, P < .001/ adjusted HR = .913; 95% CI = .885-.977, P = .015, respectively). Kaplan-Meier analysis showed that the cumulative risk of KOA/TKR in patient with/without GLP-1RA was significantly different (log-rank test, P < .001/P < .001, respectively). This study aimed to provide clinicians with the option of GLP-1RA as a treatment for patients with T2DM with or without KOA to reduce the risk of KOA or TKR among such patients.
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Affiliation(s)
- Chih-Ping Lin
- Department of Internal Medicine, Division of Endocrinology and Metabolism, Zuoying Armed Forces General Hospital, Kaohsiung, Taiwan, ROC
- Department of Internal Medicine, Division of Endocrinology and Metabolism, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Chi-Hsiang Chung
- School of Public Health, National Defense Medical Center, Taipei, Taiwan, ROC
- Taiwanese Injury Prevention and Safety Promotion Association, Taipei, Taiwan, ROC
| | - Chieh-Hua Lu
- Department of Internal Medicine, Division of Endocrinology and Metabolism, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Sheng-Chiang Su
- Department of Internal Medicine, Division of Endocrinology and Metabolism, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Feng-Chih Kuo
- Department of Internal Medicine, Division of Endocrinology and Metabolism, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Jhih-Syuan Liu
- Department of Internal Medicine, Division of Endocrinology and Metabolism, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Peng-Fei Li
- Department of Internal Medicine, Division of Endocrinology and Metabolism, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Chia-Luen Huang
- Department of Internal Medicine, Division of Endocrinology and Metabolism, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Li-Ju Ho
- Department of Internal Medicine, Division of Endocrinology and Metabolism, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Kuan-Chan Chen
- Department of Internal Medicine, Division of Endocrinology and Metabolism, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Chun-Yung Chang
- Department of Internal Medicine, Division of Endocrinology and Metabolism, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan, ROC
- Department of Internal Medicine, Division of Endocrinology and Metabolism, Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan, ROC
| | - Ming-Shiun Lin
- Department of Internal Medicine, Division of Endocrinology and Metabolism, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Yi-Chen Liu
- Department of Internal Medicine, Division of Endocrinology and Metabolism, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan, ROC
| | - An-Che Cheng
- Department of Internal Medicine, Division of Endocrinology and Metabolism, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Hong-Han Lin
- Department of Internal Medicine, Division of Endocrinology and Metabolism, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Shi-Wen Kuo
- Department of Internal Medicine, Division of Endocrinology and Metabolism, Taipei Tzu Chi Hospital, Taipei, Taiwan, ROC
| | - Chien-Hsing Lee
- Department of Internal Medicine, Division of Endocrinology and Metabolism, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Chang-Hsun Hsieh
- Department of Internal Medicine, Division of Endocrinology and Metabolism, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Yi-Jen Hung
- Department of Internal Medicine, Division of Endocrinology and Metabolism, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Hsin-Ya Liu
- BeYoung Research Institute, Taipei, Taiwan, ROC
| | - Lan-Yuen Guo
- Department of Sports Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC
| | - Wu-Chien Chien
- School of Public Health, National Defense Medical Center, Taipei, Taiwan, ROC
- Department of Medical Research, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC
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14
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Urbanik LA, Booth JL, Acharya NK, Evans BB, Grigson PS. Effect of acute treatment with the glucagon-like peptide-1 receptor agonist, liraglutide, and estrus phase on cue- and drug-induced fentanyl seeking in female rats. Behav Pharmacol 2025; 36:16-29. [PMID: 39718042 PMCID: PMC12013456 DOI: 10.1097/fbp.0000000000000805] [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] [Indexed: 12/25/2024]
Abstract
Opioid use disorder (OUD) is a crisis in the USA. Despite advances with medications for OUD, overdose deaths have continued to rise and are largely driven by fentanyl. We have previously found that male rats readily self-administer fentanyl, with evident individual differences in fentanyl taking, seeking, and reinstatement behaviors. We also have shown that acute treatment with the glucagon-like peptide-1 receptor (GLP-1R) agonist, liraglutide, can reduce fentanyl seeking behavior in male rats. However, given that females are significantly more vulnerable to drug-related cues, drug cravings, and to the development of OUD compared to males, it is imperative that we investigate the biological risk factors on fentanyl use disorder. Further, preclinical models report that females in estrus have increased fentanyl intake, more rapid development of OUD, and enhanced relapse vulnerability compared to those in a non-estrus phase. Thus, we aimed here to understand the effect of estrus phase on our model of OUD and on the effectiveness of acute liraglutide treatment. Herein, we show that female rats readily self-administer fentanyl (1.85 μg/infusion) intravenously, with marked individual differences in fentanyl taking behavior. Additionally, rats in the estrus phase exhibited greater fentanyl intake compared with those in a non-estrus phase, greater cue-induced fentanyl seeking, and greater drug-induced reinstatement of fentanyl seeking. Finally, acute liraglutide treatment (0.3 mg/kg s.c.) reduced cue-induced fentanyl seeking and blocked drug-induced reinstatement of fentanyl seeking, particularly when tested in estrus. Overall, these data support the broad effectiveness of acute GLP-1R agonists as a promising non-opioid treatment for OUD.
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Affiliation(s)
| | - Jennifer L Booth
- Department of Comparative Medicine, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA
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15
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Gul U, Aung T, Martin M, Farrukh DN, Shah PC, Lovely ZS, Marroquín León E, Alansaari M, Maini S, Fariduddin MM, Ullah A, Nazir Z. A Comprehensive Review of the Role of GLP-1 Agonists in Weight Management and Their Effect on Metabolic Parameters Such as Blood Glucose, Cholesterol, and Blood Pressure. Cureus 2024; 16:e76519. [PMID: 39872560 PMCID: PMC11771532 DOI: 10.7759/cureus.76519] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/27/2024] [Indexed: 01/30/2025] Open
Abstract
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been developed to manage type 2 diabetes mellitus. Although, in the last 10 years, the use of GLP-1 RAs, especially semaglutide and liraglutide, has increased, its clinical implications and how it affects metabolic parameters have yet to be fully consolidated. This narrative review explores the metabolic effects of GLP-1 RAs in weight management, blood glucose, cardiovascular health, lipid profiles, and blood pressure. Data were collected by comparing GLP-1 RAs, such as semaglutide, liraglutide, tripeptide, and exenatide, as well as comparing them to a baseline treatment group. GLP-1 RAs have shown consistent results in managing blood glucose levels by lowering HbA1c with minimal hypoglycemic risk and increasing insulin production and synthesis. GLP-1 RAs have been found to improve overall cardiovascular health and reduce major adverse cardiovascular events (MACE) by improving the endothelial function of the vasculature and lowering ANP (atrial natriuretic peptide) production, leading to reduced blood pressure. In addition to the cardiovascular benefits, GLP-1 RAs have a varying effect on lipid profiles, finding statistically significant results for low-density lipoprotein cholesterol levels. In conjunction with all the effects, GLP-1 RAs have been found to lower weight and aid in weight management.
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Affiliation(s)
- Ushna Gul
- Internal Medicine, Khyber Medical College, Peshawar, PAK
| | - Thandar Aung
- Accident and Emergency, St. Ann's Bay Hospital, St. Ann's Bay, JAM
| | - Mehwish Martin
- Internal Medicine, Icahn School of Medicine at Mount Sinai, New York, USA
| | | | - Pari C Shah
- Family Medicine, Northeast Ohio Medical University, Xenia, USA
| | - Zeenia S Lovely
- Emergency, Kerala University of Health and Sciences, Cochin, IND
| | | | - Mohamed Alansaari
- Internal Medicine, Royal College of Surgeons in Ireland (RCSI) University of Medicine and Health Sciences, Dublin, IRL
| | - Shriya Maini
- Internal Medicine, Dayanand Medical College and Hospital, Punjab, IND
| | | | | | - Zahra Nazir
- Internal Medicine, Combined Military Hospital, Quetta, PAK
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16
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Hsieh YY, Hou WC, Hsu SJ, Liaw CC, Huang C, Shih MCM, Shen YC, Chen YF, Lee CK, Lee OK, Wu CC, Lee IJ, Cheng JJ, Hou YC, Liu HK. Consumption of carotenoid-rich Momordica cochinchinensis (Gac) aril improves glycemic control in type 2 diabetic mice partially through taste receptor type 1 mediated glucagon-like peptide 1 secretion. Food Funct 2024; 15:11415-11431. [PMID: 39535879 DOI: 10.1039/d4fo04316b] [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: 11/16/2024]
Abstract
Incretin-based therapies are widely used to improve glycemic control and β cell dysfunction in the treatment of type 2 diabetes. Momordica cochinchinensis (Gac fruit), a nutritious melon cultivated in many regions, has underexplored health benefits, particular its edible aril. This study comprehensively investigates the stimulatory effect of Gac aril on glucagon-like peptide 1 (GLP-1) secretion, identifies the responsible active constituents, and explores the underlying mechanisms related to its anti-diabetic effects. GLP-1-secreting STC-1 intestinal L cells were used to assess bioactivity and molecular mechanisms. Additionally, the in vivo anti-diabetic effects of Gac aril consumption were evaluated using type 2 diabetic mice induced by a high fat diet and streptozotocin injection, with or without GLP-1 receptor expression. The results demonstrated that Gac pulp and aril stimulated GLP-1 secretion, while Gac seeds did not. β-Carotene, a major constituent of Gac aril, was identified as the key mediator of GLP-1 secretion via sweet taste receptor-mediated signaling in STC-1 cells. Dietary intake of Gac aril significantly improved fasting blood glucose, glucose tolerance, insulin sensitivity, β-cell function, and hemoglobin A1c in type 2 diabetic mice. GLP-1 levels increased 2-fold, and decreased levels of ghrelin and adiponectin were restored. The anti-diabetic effects were partially diminished in GLP-1 receptor knockout mice, suggesting Gac aril's effects are mediated, in part, through GLP-1. In conclusion, Gac aril consumption may provide health benefits for managing type 2 diabetes, partially by enhancing endogenous GLP-1 levels.
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Affiliation(s)
- Ying-Ying Hsieh
- Ph.D. Program in Clinical Drug Development of Herbal Medicine, College of Pharmacy, Taipei Medical University, Taipei 11042, Taiwan.
| | - Wen-Chi Hou
- Ph.D. Program in Clinical Drug Development of Herbal Medicine, College of Pharmacy, Taipei Medical University, Taipei 11042, Taiwan.
- Graduate Institute of Pharmacognosy, Taipei Medical University, Taipei 11042, Taiwan.
| | - Su-Jung Hsu
- School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 11042, Taiwan.
| | - Chia-Ching Liaw
- Division of Chinese Materia Medica Development, National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei, Taiwan.
| | - Cheng Huang
- Department of Biotechnology and Laboratory Science in Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan, Republic of China.
| | - Meng-Chun Monica Shih
- National Laboratory Animal Center, National Applied Research Laboratories, Taipei City, Taipei 115021, Taiwan.
| | - Yuh-Chiang Shen
- Division of Clinical Chinese Medicine, National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei 11221, Taiwan.
| | - Ying-Fang Chen
- Taitung District Agriculture Research and Extension Station, Ministry of Agriculture, Taitung County 950244, Taiwan.
| | - Ching-Kuo Lee
- Ph.D. Program in Clinical Drug Development of Herbal Medicine, College of Pharmacy, Taipei Medical University, Taipei 11042, Taiwan.
- Graduate Institute of Pharmacognosy, Taipei Medical University, Taipei 11042, Taiwan.
- School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 11042, Taiwan.
| | - Oscar K Lee
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan.
- Biomedical Industry Ph.D. Program, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan, Republic of China.
| | - Chia-Chune Wu
- Biomedical Industry Ph.D. Program, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan, Republic of China.
| | - I-Jung Lee
- Herbal Medicine Department, Yokohama University of Pharmacy, Yokohama, Kanagawa, Japan.
| | - Jing-Jy Cheng
- Division of Basic Chinese Medicine, National Research Institute of Chinese Medicine, Ministry of Health and Welfare, 155-1 Li-Nong Street, Section 2, Taipei 11221, Taiwan.
| | - Yu-Chang Hou
- Department of Chinese Medicine, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan, Taiwan.
- Department of Bioscience Technology, Chung Yuan Christian University, Taoyuan 330, Taiwan
- Department of Health Care Management, National Taipei University of Nursing and Health Sciences, Taipei 112303, Taiwan
- School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan 333323, Taiwan
| | - Hui-Kang Liu
- Ph.D. Program in Clinical Drug Development of Herbal Medicine, College of Pharmacy, Taipei Medical University, Taipei 11042, Taiwan.
- Division of Basic Chinese Medicine, National Research Institute of Chinese Medicine, Ministry of Health and Welfare, 155-1 Li-Nong Street, Section 2, Taipei 11221, Taiwan.
- Traditional Herbal Medicine Research Center, Taipei Medical University Hospital, Taipei 11042, Taiwan
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17
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Docimo S, Shah J, Warren G, Ganam S, Sujka J, DuCoin C. A cost comparison of GLP-1 receptor agonists and bariatric surgery: what is the break even point? Surg Endosc 2024; 38:6560-6565. [PMID: 39285034 DOI: 10.1007/s00464-024-11191-1] [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: 05/13/2024] [Accepted: 08/17/2024] [Indexed: 11/01/2024]
Abstract
BACKGROUND With the prevalence of obesity rising in the US, medical management is of increasing importance. Two popular options for the treatment of obesity are bariatric surgery (e.g. sleeve gastrectomy and Roux-en-Y gastric bypass) and the increasingly popular GLP-1 Receptor Agonists (GLP-1 s). This study examines the initial and long-term costs of GLP-1 s compared to bariatric surgery. STUDY DESIGN We compared average 2023 national retail prices for GLP-1 s to surgical cost estimates from 2015 adjusted for inflation. We then plotted the cumulative medication cost over time against the flat cost of each surgery, thus calculating "break-even points" (when medication costs equal surgery costs). The findings revealed a crucial insight, for some GLP-1 s like Saxenda and Wegovy, the high cost of ongoing use surpasses the cost of RYGB in less than a year and sleeve gastrectomy within nine months. Even the most affordable option, Byetta, becomes costlier than surgery after around 1.5 years. RESULTS This highlights the importance of looking beyond the initial financial investment when considering cost-effectiveness. Additionally, while not directly assessed, this study acknowledges that GLP-1 s take time to reach full effectiveness, potentially delaying weight loss while accumulating costs. Concerns also exist about weight regain after discontinuing the medication. CONCLUSION This study is limited by the real-world variation for individual treatment costs (e.g. insurance), a limited evaluation of long-term costs associated with either treatment modality and their co-morbidities, and the reality of patient preference providing subjective value to either modality. Overall, the study offers insights into the financial trade-offs between GLP-1 s and bariatric surgery.
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Affiliation(s)
- Salvatore Docimo
- Division of Gastrointestinal Surgery, Tampa General Hospital, Horatio Street, Tampa, FL, 33609, USA.
| | - Jay Shah
- Morsani College of Medicine, University of South Florida, Horatio Street, Tampa, FL, 33609, USA
| | - Gus Warren
- Morsani College of Medicine, University of South Florida, Horatio Street, Tampa, FL, 33609, USA
| | - Samer Ganam
- Morsani College of Medicine, University of South Florida, Horatio Street, Tampa, FL, 33609, USA
- Division of Gastrointestinal Surgery, Tampa General Hospital, Horatio Street, Tampa, FL, 33609, USA
| | - Joseph Sujka
- Division of Gastrointestinal Surgery, Tampa General Hospital, Horatio Street, Tampa, FL, 33609, USA
| | - Christopher DuCoin
- Division of Gastrointestinal Surgery, Tampa General Hospital, Horatio Street, Tampa, FL, 33609, USA
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Joshi N, Qasim MZ, Kanumilli S, Shaukat F, Kumar A, Mahek F, Khalid S, Zeeshan M, Shaik MY, Nishat SM, Gandhi F, Belletieri C. Exploring the clinical effectiveness of glucagon-like peptide-1 receptor agonists in managing cardiovascular complications: an updated comprehensive review and future directives. Ann Med Surg (Lond) 2024; 86:5947-5956. [PMID: 39359798 PMCID: PMC11444620 DOI: 10.1097/ms9.0000000000002494] [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: 04/22/2024] [Accepted: 08/09/2024] [Indexed: 10/04/2024] Open
Abstract
The possible cardiovascular advantages of glucagon-like peptide-1 receptor agonists (GLP-1RAs), a class of drugs predominantly used to treat type 2 diabetes (T2D), have garnered increasing attention in recent years. Clinical trials have looked into the possibility that GLP-1RAs have extra cardioprotective benefits in addition to their ability to manage T2D, demonstrating significant major adverse cardiovascular events (MACE) reduction and a favorable safety profile. GLP-1 RAs improve cardiovascular outcomes, especially in those with existing cardiovascular disease. MACE has been steadily declining with this class of drugs, which results in a noticeable rise in cardiovascular outcome trials (CVOTs). GLP-1 RAs have a variety of impacts on the cardiovascular system beyond their function in glycemic control. They offer direct cardioprotection, vasodilation, promotion of salt excretion, reduction of weight, improved lipid profile, and anti-inflammatory qualities through a variety of mechanisms. Thus, this review focuses on GLP-1RAs, its mechanism of action, its clinical effectiveness in CVOTs, the mechanism behind its cardiovascular benefits, its potential role in heart failure, cardiovascular outcomes, its underutilization, and future directives. In conclusion, GLP-1 RAs shows potential in controlling T2D while also lowering cardiovascular risk, but warrants further study into long-term results and real-world data to optimize treatment regimens, ultimately increasing patient outcomes and lowering the burden of cardiovascular disease in T2D populations.
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Affiliation(s)
- Nandan Joshi
- Department of Internal Medicine, Surat Municipal Institute of Medical Education and Research, Surat
| | | | - Srilakshmidevi Kanumilli
- Department of Internal Medicine, GSL Medical College, Rajamahendravaram, Jagannadhapuram Agraharam, Andhra Pradesh
| | - Faiza Shaukat
- Department of Internal Medicine, Akhtar Saeed Medical and Dental College, Lahore
| | - Ateesh Kumar
- Department of Internal Medicine, Dow Medical College, Karachi
| | - Fnu Mahek
- Department of Internal Medicine, Peoples University of Medical and Health Sciences, Nawabshah, Pakistan
| | - Saif Khalid
- Department of Internal Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Mohd Zeeshan
- Department of Internal Medicine, Career Institute of Medical Sciences and Hospital, Lucknow
| | - Mahboob Younus Shaik
- Department of Internal Medicine, Deccan College of Medical Sciences, Hyderabad, India
| | - Syeed Mahmud Nishat
- Department of Internal Medicine, Shaheed Suhrawardy Medical College, Dhaka, Bangladesh
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19
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Gangemi CG, Janovjak H. Optogenetics in Pancreatic Islets: Actuators and Effects. Diabetes 2024; 73:1566-1582. [PMID: 38976779 PMCID: PMC11417442 DOI: 10.2337/db23-1022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Accepted: 06/19/2024] [Indexed: 07/10/2024]
Abstract
The islets of Langerhans reside within the endocrine pancreas as highly vascularized microorgans that are responsible for the secretion of key hormones, such as insulin and glucagon. Islet function relies on a range of dynamic molecular processes that include Ca2+ waves, hormone pulses, and complex interactions between islet cell types. Dysfunction of these processes results in poor maintenance of blood glucose homeostasis and is a hallmark of diabetes. Recently, the development of optogenetic methods that rely on light-sensitive molecular actuators has allowed perturbation of islet function with near physiological spatiotemporal acuity. These actuators harness natural photoreceptor proteins and their engineered variants to manipulate mouse and human cells that are not normally light-responsive. Until recently, optogenetics in islet biology has primarily focused on controlling hormone production and secretion; however, studies on further aspects of islet function, including paracrine regulation between islet cell types and dynamics within intracellular signaling pathways, are emerging. Here, we discuss the applicability of optogenetics to islets cells and comprehensively review seminal as well as recent work on optogenetic actuators and their effects in islet function and diabetes mellitus. ARTICLE HIGHLIGHTS
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Affiliation(s)
- Christina G. Gangemi
- Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Bedford Park, South Australia, Australia
- Australian Regenerative Medicine Institute, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
- European Molecular Biology Laboratory Australia, Monash University, Clayton, Victoria, Australia
| | - Harald Janovjak
- Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Bedford Park, South Australia, Australia
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20
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Njei B, Al-Ajlouni Y, Lemos SY, Ugwendum D, Ameyaw P, Njei LP, Boateng S. Efficacy and Safety of GLP-1 Receptor Agonists in Patients With Metabolic Dysfunction-Associated Steatotic Liver Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Cureus 2024; 16:e71366. [PMID: 39534801 PMCID: PMC11556413 DOI: 10.7759/cureus.71366] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/11/2024] [Indexed: 11/16/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) poses a major global health challenge. glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown potential therapeutic benefits for MASLD patients, including improvements in liver function, inflammation, and fibrosis. This study aims to systematically review and meta-analyze randomized controlled trials (RCTs) to evaluate the efficacy and safety of GLP-1RAs in MASLD patients, focusing on hepatic outcomes, cardiovascular outcomes, anthropometric measurements, and mortality. Following PRISMA guidelines, a comprehensive database search was conducted to include RCTs assessing GLP-1RAs' effects on MASLD. Quality assessment was conducted using the Revised Cochrane Risk of Bias tool. Our meta-analysis used a random-effects model, calculating standardized mean differences for continuous outcomes to determine the agents' efficacy and safety. Additionally, funnel plots were generated to assess publication bias, ensuring the integrity of our meta-analytical findings. The review included 27 trials, revealing GLP-1RAs significantly improved hepatic function markers (alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, and liver fat content) and cardiovascular risk factors (fasting blood sugar, HbA1c levels, lipid profiles). Additionally, GLP-1RAs were associated with significant reductions in body weight, BMI, subcutaneous fat, and waist circumference. GLP-1RAs demonstrate a promising therapeutic role in managing MASLD, offering benefits that extend to improving liver function, mitigating cardiovascular risk, and promoting weight loss. Further research is needed to confirm these findings and optimize GLP-1RAs' usage in MASLD treatment.
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Affiliation(s)
- Basile Njei
- Department of Medicine, Yale School of Medicine, New Haven, USA
| | | | - Samira Y Lemos
- Department of Diabetes and Endocrinology, Yaoundé General Hospital, Yaoundé, CMR
| | - Derek Ugwendum
- Department of Internal Medicine, Richmond University Medical Center Affiliated with Mount Sinai Health System and Icahn School of Medicine at Mount Sinai, Staten Island, USA
| | - Prince Ameyaw
- Department of Internal Medicine, Bridgeport Hospital, Yale New Haven Health, Bridgeport, USA
| | - Lea-Pearl Njei
- Department of Biological Science, University of Maryland Baltimore County, Baltimore, USA
| | - Sarpong Boateng
- Department of Medicine, Bridgeport Hospital, Bridgeport, USA
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21
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Yale JF, Major-Pedersen A, Catarig AM, Jain R, Menzen M, Holmes P. Real-world safety profile of once-weekly semaglutide in people with type 2 diabetes: Analysis of pooled data from the SemaglUtide Real-world Evidence (SURE) programme. Diabetes Obes Metab 2024; 26:4429-4440. [PMID: 39118222 DOI: 10.1111/dom.15794] [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: 02/01/2024] [Revised: 06/28/2024] [Accepted: 06/28/2024] [Indexed: 08/10/2024]
Abstract
AIM To investigate, through post hoc analysis of nine studies from the SemaglUtide Real-world Evidence (SURE) programme, the safety of once-weekly (OW) semaglutide in adults with type 2 diabetes (T2D) and in subpopulations in routine clinical practice, complementing findings from the phase 3 randomized clinical trial (RCT) SUSTAIN programme. METHODS The SURE studies had a duration of ~30 weeks and included adults with diagnosed T2D treated with OW semaglutide. Safety information, including hypoglycaemic events, were collected and analysed for the total study population and for patient subgroups based on baseline patient characteristics, baseline co-medication and prescriber specialty. RESULTS Of the total 3505 patients, 24.3% reported adverse events (AEs), with most patients reporting non-serious (22.3%) and mild (17.1%) AEs. AEs mainly belonged to the gastrointestinal disorders system organ class (16.3% of patients). In total, 5.1% of patients reported AEs that led to treatment discontinuation, 0.5% reported serious adverse drug reactions and 0.2% had an AE with a fatal outcome, reported as unrelated to treatment. Overall, 1.1% and 0.1% of patients reported level 2 and 3 hypoglycaemic events, respectively. A higher rate of level 2 hypoglycaemia was observed in patients with baseline microvascular complications treated with insulin versus those on insulin without these complications. CONCLUSIONS Safety data reported in the real-world SURE studies were generally consistent with observations in phase 3 OW semaglutide RCTs. No new safety concerns were identified, highlighting that OW semaglutide is well tolerated by adults with T2D and in subpopulations in routine clinical practice.
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Affiliation(s)
| | | | | | - Rashmi Jain
- Novo Nordisk Service Centre India Private Ltd., Bengaluru, India
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22
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Horváth D, Stráner P, Taricska N, Fazekas Z, Menyhárd DK, Perczel A. Influence of Trp-Cage on the Function and Stability of GLP-1R Agonist Exenatide Derivatives. J Med Chem 2024; 67:16757-16772. [PMID: 39254428 PMCID: PMC11440607 DOI: 10.1021/acs.jmedchem.4c01553] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 08/22/2024] [Accepted: 08/28/2024] [Indexed: 09/11/2024]
Abstract
Exenatide (Ex4), a GLP-1 incretin mimetic polypeptide, is an effective therapeutic agent against diabetes and obesity. We highlight the indirect role of Ex4's structure-stabilizing Trp-cage (Tc) motif in governing GLP-1 receptor (GLP-1R) signal transduction. We use various Ex4 derivatives to explore how Tc compactness influences thermal stability, aggregation, enhancement of insulin secretion, and GLP-1R binding. We found that Ex4 variants decorated with fortified Tc motifs exhibit increased resistance to unfolding and aggregation but show an inverse relationship between the bioactivity and stability. Molecular dynamics simulations coupled with a rigid-body segmentation protocol to analyze dynamic interconnectedness revealed that the constrained Tc motifs remain intact within the receptor-ligand complexes but interfere with one of the major stabilizing contacts and recognition loci on the extracellular side of GLP-1R, dislodging the N-terminal activating region of the hormone mimetics, and restrict the free movement of TM6, the main signal transduction device of GLP-1R.
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Affiliation(s)
- Dániel Horváth
- HUN-REN−ELTE
Protein Modeling Research Group, ELTE Eötvös
Loránd University, Pázmány Péter sétány 1/A, Budapest H-1117, Hungary
- Laboratory
of Structural Chemistry and Biology, ELTE
Eötvös Loránd University, Pázmány Péter sétány
1/A, Budapest H-1117, Hungary
| | - Pál Stráner
- HUN-REN−ELTE
Protein Modeling Research Group, ELTE Eötvös
Loránd University, Pázmány Péter sétány 1/A, Budapest H-1117, Hungary
- Laboratory
of Structural Chemistry and Biology, ELTE
Eötvös Loránd University, Pázmány Péter sétány
1/A, Budapest H-1117, Hungary
| | - Nóra Taricska
- HUN-REN−ELTE
Protein Modeling Research Group, ELTE Eötvös
Loránd University, Pázmány Péter sétány 1/A, Budapest H-1117, Hungary
- Laboratory
of Structural Chemistry and Biology, ELTE
Eötvös Loránd University, Pázmány Péter sétány
1/A, Budapest H-1117, Hungary
| | - Zsolt Fazekas
- Laboratory
of Structural Chemistry and Biology, ELTE
Eötvös Loránd University, Pázmány Péter sétány
1/A, Budapest H-1117, Hungary
- Hevesy
György PhD School of Chemistry, ELTE
Eötvös Loránd University, Pázmány Péter sétány
1/A, Budapest H-1117, Hungary
| | - Dóra K. Menyhárd
- Medicinal
Chemistry Research Group, HUN-REN Research
Centre for Natural Sciences, Magyar Tudósok Körútja 2, H-1117Budapest, Hungary
- HUN-REN−ELTE
Protein Modeling Research Group, ELTE Eötvös
Loránd University, Pázmány Péter sétány 1/A, Budapest H-1117, Hungary
- Laboratory
of Structural Chemistry and Biology, ELTE
Eötvös Loránd University, Pázmány Péter sétány
1/A, Budapest H-1117, Hungary
| | - András Perczel
- Medicinal
Chemistry Research Group, HUN-REN Research
Centre for Natural Sciences, Magyar Tudósok Körútja 2, H-1117Budapest, Hungary
- HUN-REN−ELTE
Protein Modeling Research Group, ELTE Eötvös
Loránd University, Pázmány Péter sétány 1/A, Budapest H-1117, Hungary
- Laboratory
of Structural Chemistry and Biology, ELTE
Eötvös Loránd University, Pázmány Péter sétány
1/A, Budapest H-1117, Hungary
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23
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Ayoub M, Aibani R, Dodd T, Ceesay M, Bhinder M, Faris C, Amin N, Daglilar E. Risk of Esophageal and Gastric Cancer in Patients with Type 2 Diabetes Receiving Glucagon-like Peptide-1 Receptor Agonists (GLP-1 RAs): A National Analysis. Cancers (Basel) 2024; 16:3224. [PMID: 39335195 PMCID: PMC11430483 DOI: 10.3390/cancers16183224] [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: 08/16/2024] [Revised: 09/17/2024] [Accepted: 09/20/2024] [Indexed: 09/30/2024] Open
Abstract
INTRODUCTION Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are becoming more popular in managing type 2 diabetes mellitus (T2DM). Concerns linger over potential links to malignancies like pancreatic and thyroid cancers, requiring more research to clarify their safety profiles. Additionally, evidence suggests GLP-1 RAs may lower colorectal and pancreatic cancer risk, especially in obese and overweight individuals, indicating a protective effect beyond weight loss. Current studies leave a gap in comprehensively understanding cancer risks associated with GLP-1 RAs, which prompts further research to enhance our understanding of their overall safety. METHODS We queried the US Collaborative Network (63 health care organizations) of the TriNetX research database. Patients with T2DM were identified and divided into two cohorts: patients on GLP-1 RAs and patients not on GLP-1 RAs. We excluded tobacco use and alcohol use disorders, obese patients with a body mass index (BMI) of >25 kg/m2, and those with a family history of gastrointestinal malignancy, infectious mononucleosis, chronic gastritis, pernicious anemia, helicobacter pylori infection, or gastroesophageal reflux disease (GERD). We used a 1:1 propensity score matching (PSM) model using patients' baseline characteristics, medications, labs, and genetics. We compared the rate of gastric cancer and esophageal cancer at the seven-year mark. RESULTS A total of 2,748,431 patients with T2DM were identified. Of those, 6% (n = 167,077) were on a GLP-1 RA and 94% (n = 2,581,354) were not on a GLP-1 RA. After PSM, both cohorts included 146,277 patients. Patients with T2DM who were on a GLP-1 RA, compared to those who were not, had a statistically significant lower risk of both gastric cancer (0.05% vs. 0.13%, p < 0.0001) and esophageal cancer (0.04% vs. 0.13%, p < 0.0001) at the seven-year mark. CONCLUSION The use of GLP-1 RAs in patients with T2DM does not significantly increase the risk of gastric or esophageal cancer. This finding supports the continued use of GLP-1 analogues as a therapeutic option in managing T2DM, considering their well-established benefits and low risk of complications. Based on the study results, these medications may even have a protective effect against these malignancies.
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Affiliation(s)
- Mark Ayoub
- Department of Internal Medicine, Charleston Area Medical Center, West Virginia University, Charleston, WV 25304, USA; (R.A.); (T.D.); (M.C.); (M.B.); (N.A.)
| | - Rafi Aibani
- Department of Internal Medicine, Charleston Area Medical Center, West Virginia University, Charleston, WV 25304, USA; (R.A.); (T.D.); (M.C.); (M.B.); (N.A.)
| | - Tiana Dodd
- Department of Internal Medicine, Charleston Area Medical Center, West Virginia University, Charleston, WV 25304, USA; (R.A.); (T.D.); (M.C.); (M.B.); (N.A.)
| | - Muhammed Ceesay
- Department of Internal Medicine, Charleston Area Medical Center, West Virginia University, Charleston, WV 25304, USA; (R.A.); (T.D.); (M.C.); (M.B.); (N.A.)
| | - Muhammad Bhinder
- Department of Internal Medicine, Charleston Area Medical Center, West Virginia University, Charleston, WV 25304, USA; (R.A.); (T.D.); (M.C.); (M.B.); (N.A.)
| | - Carol Faris
- Department of Internal Medicine, Bayonne Medical Center, Bayonne, NJ 07002, USA;
| | - Nisar Amin
- Department of Internal Medicine, Charleston Area Medical Center, West Virginia University, Charleston, WV 25304, USA; (R.A.); (T.D.); (M.C.); (M.B.); (N.A.)
| | - Ebubekir Daglilar
- Division of Gastroenterology and Hepatology, Charleston Area Medical Center, West Virginia University, Charleston, WV 25304, USA
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24
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Yu H, Ueckert S, Zhou L, Cheng J, Robertson D, Hansen L, Flor A, Parker V, Hamrén B, Khan AA. Exposure-response modeling for nausea incidence for cotadutide using a Markov modeling approach. CPT Pharmacometrics Syst Pharmacol 2024; 13:1582-1594. [PMID: 39044369 PMCID: PMC11533102 DOI: 10.1002/psp4.13194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Revised: 06/10/2024] [Accepted: 06/18/2024] [Indexed: 07/25/2024] Open
Abstract
Cotadutide is a dual glucagon-like peptide-1 (GLP-1)/glucagon receptor agonist. Gastrointestinal adverse effects are known to be associated with GLP-1 receptor agonism and can be mitigated through tolerance development via a gradual up-titration. This analysis aimed to characterize the relationship between exposure and nausea incidence and to optimize titration schemes. The model was developed with pooled data from cotadutide-administrated studies. Three different modeling approaches, proportional odds (PO), discrete-time Markov, and two-stage discrete-time Markov models, were employed to characterize the exposure-nausea relationship. The severity of nausea was modeled as different states (non-nausea, mild, and moderate/severe). The most appropriate model was selected to perform the covariate analysis, and the final covariate model was used to simulate the nausea event rates for various titration scenarios. The two Markov models demonstrated comparable performance and were better than the PO model. The covariate analysis was conducted with the standard Markov model for operational simplification and identified disease indications (NASH, obesity) and sex as covariates on Markov parameters. The simulations indicated that the biweekly titration with twofold dose escalation is superior to other titration schemes with a relatively low predicted nausea event rate at 600 μg (25%) and a shorter titration interval (8 weeks) to reach the therapeutic dose. The model can be utilized to optimize starting dose and titration schemes for other therapeutics in clinical trials to achieve an optimal risk-benefit balance and reach the therapeutic dose with minimal titration steps.
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Affiliation(s)
- Hongtao Yu
- Clinical Pharmacology and Quantitative PharmacologyClinical Pharmacology and Safety Sciences, R&D, AstraZenecaGaithersburgMarylandUSA
| | - Sebastian Ueckert
- Clinical Pharmacology and Quantitative PharmacologyClinical Pharmacology and Safety Sciences, R&D, AstraZenecaGothenburgSweden
| | - Lina Zhou
- Clinical Pharmacology and Quantitative PharmacologyClinical Pharmacology and Safety Sciences, R&D, AstraZenecaGaithersburgMarylandUSA
- Department of Pharmaceutical Sciences, College of PharmacyThe University of Tennessee Health Science CenterMemphisTennesseeUSA
| | - Jenny Cheng
- Clinical Pharmacology and Quantitative PharmacologyClinical Pharmacology and Safety Sciences, R&D, AstraZenecaGaithersburgMarylandUSA
| | - Darren Robertson
- Early Clinical Development, Cardio‐Vascular, Renal and MetabolismR&D, AstraZenecaCambridgeUK
| | - Lars Hansen
- Early Clinical Development, Cardio‐Vascular, Renal and MetabolismR&D, AstraZenecaGaithersburgUSA
| | - Armando Flor
- Early Clinical Development, Cardio‐Vascular, Renal and MetabolismR&D, AstraZenecaGaithersburgUSA
| | - Victoria Parker
- Early Clinical Development, Cardio‐Vascular, Renal and MetabolismR&D, AstraZenecaCambridgeUK
| | - Bengt Hamrén
- Clinical Pharmacology and Quantitative PharmacologyClinical Pharmacology and Safety Sciences, R&D, AstraZenecaGothenburgSweden
| | - Anis A. Khan
- Clinical Pharmacology and Quantitative PharmacologyClinical Pharmacology and Safety Sciences, R&D, AstraZenecaGaithersburgMarylandUSA
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25
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Mao T, Chen J, Su T, Xie L, Qu X, Feng R, Pan Y, Wan J, Cui X, Jia W, Gao Q, Lin Q. Causal relationships between GLP1 receptor agonists, blood lipids, and heart failure: a drug-target mendelian randomization and mediation analysis. Diabetol Metab Syndr 2024; 16:208. [PMID: 39198854 PMCID: PMC11360323 DOI: 10.1186/s13098-024-01448-z] [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: 06/26/2024] [Accepted: 08/19/2024] [Indexed: 09/01/2024] Open
Abstract
BACKGROUND Glucagon-like peptide-1 receptor (GLP1R) agonists have been shown to reduce major cardiovascular events in diabetic patients, but their role in heart failure (HF) remains controversial. Recent evidence implies their potential benefits on cardiometabolism such as lipid metabolism, which may contribute to lowering the risk of HF. Consequently, we designed a Mendelian randomization (MR) study to investigate the causal relationships of circulating lipids mediating GLP1R agonists in HF. METHODS The available cis-eQTLs for GLP1R target gene were selected as instrumental variables (IVs) of GLP1R agonism. Positive control analyses of type 2 diabetes mellitus (T2DM) and body mass index (BMI) were conducted to validate the enrolled IVs. Two-sample MR was performed to evaluate the associations between GLP1R agonism and HF as well as left ventricular ejection fraction (LVEF). Summary data for HF and LVEF were obtained from two genome-wide association studies (GWASs), which included 977,323 and 40,000 individuals of European ancestry, respectively. The primary method employed was the random-effects inverse variance weighted, with several other methods used for sensitivity analyses, including MR-Egger, MR PRESSO, and weighted median. Additionally, multivariable MR and mediation MR were applied to identify potentially causal lipid as mediator. RESULTS A total of 18 independent IVs were included. The positive control analyses showed that GLP1R agonism significantly reduced the risk of T2DM (OR = 0.79, 95% CI = 0.75-0.85, p < 0.0001) and decreased BMI (OR = 0.95, 95% CI = 0.93-0.96, p < 0.0001), ensuring the effectiveness of selected IVs. We found favorable evidence to support the protective effect of GLP1R agonism on HF (OR = 0.75, 95% CI = 0.71-0.79, p < 0.0001), but there was no obvious correlation with increased LVEF (OR = 1.01, 95% CI = 0.95-1.06, p = 0.8332). Among the six blood lipids, only low-density lipoprotein cholesterol (LDL-C) was both associated with GLP1R agonism and HF. The causal effect of GLP1R agonism on HF was partially mediated through LDL-C by 4.23% of the total effect (95% CI = 1.04-7.42%, p = 0.0093). CONCLUSIONS This study supported the causal relationships of GLP1R agonists with a reduced risk of HF. LDL-C might be the mediator in this association, highlighting the cardiometabolic benefit of GLP1R agonists on HF.
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Affiliation(s)
- Tianshi Mao
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Jie Chen
- The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, China
| | - Tong Su
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, 100078, China
| | - Long Xie
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Xinyan Qu
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Ruli Feng
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Yi Pan
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Jie Wan
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, 100078, China
| | - Xiaoyun Cui
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, 100078, China
| | - Wenhao Jia
- Beijing University of Chinese Medicine Third Affiliated Hospital, Beijing, 100029, China
| | - Qun Gao
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China.
| | - Qian Lin
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China.
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26
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Goraltchouk A, Lourie J, Hollander JM, Grace Rosen H, Fujishiro AA, Luppino F, Zou K, Seregin A. Development and characterization of a first-in-class adjustable-dose gene therapy system. Gene 2024; 919:148500. [PMID: 38663689 DOI: 10.1016/j.gene.2024.148500] [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: 12/27/2023] [Revised: 04/11/2024] [Accepted: 04/22/2024] [Indexed: 05/06/2024]
Abstract
INTRODUCTION Despite significant potential, gene therapy has been relegated to the treatment of rare diseases, due in part to an inability to adjust dosage following initial administration. Other significant constraints include cost, specificity, antigenicity, and systemic toxicity of current generation technologies. To overcome these challenges, we developed a first-in-class adjustable-dose gene therapy system, with optimized biocompatibility, localization, durability, and cost. METHODS A lipid nanoparticle (LNP) delivery system was developed and characterized by dynamic light scattering for size, zeta potential, and polydispersity. Cytocompatibility and transfection efficiency were optimized in vitro using primary human adipocytes and preadipocytes. Durability, immunogenicity, and adjustment of expression were evaluated in C57BL/6 and B6 albino mice using in vivo bioluminescence imaging. Biodistribution was assessed by qPCR and immunohistochemistry; therapeutic protein expression was quantified by ELISA. RESULTS Following LNP optimization, in vitro transfection efficiency of primary human adipocytes reached 81.3 % ± 8.3 % without compromising cytocompatibility. Critical physico-chemical properties of the system (size, zeta potential, polydispersity) remained stable over a broad range of genetic cassette sizes (1,871-6,203 bp). Durable expression was observed in vivo over 6 months, localizing to subcutaneous adipose tissues at the injection site with no detectable transgene in the liver, heart, spleen, or kidney. Gene expression was adjustable using several physical and pharmacological approaches, including cryolipolysis, focused ultrasound, and pharmacologically inducible apoptosis. The ability of transfected adipocytes to express therapeutic transgenes ranging from peptides to antibodies, at potentially clinically relevant levels, was confirmed in vitro and in vivo. CONCLUSION We report the development of a novel, low-cost therapeutic platform, designed to enable the replacement of subcutaneously administered protein treatments with a single-injection, adjustable-dose gene therapy.
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Affiliation(s)
- Alex Goraltchouk
- Remedium Bio, Inc. 1116 Great Plain Ave, Suite 203, Needham, MA 02492, United States of America
| | - Jared Lourie
- Department of Exercise and Health Sciences, University of Massachusetts Boston, 100 Morrissey Blvd, Boston, MA 02125, United States of America
| | - Judith M Hollander
- Remedium Bio, Inc. 1116 Great Plain Ave, Suite 203, Needham, MA 02492, United States of America
| | - H Grace Rosen
- Department of Biology, University of Massachusetts Boston, 100 Morrissey Blvd, Boston, MA 02125, United States of America
| | - Atsutaro A Fujishiro
- Department of Exercise and Health Sciences, University of Massachusetts Boston, 100 Morrissey Blvd, Boston, MA 02125, United States of America
| | - Francesco Luppino
- Remedium Bio, Inc. 1116 Great Plain Ave, Suite 203, Needham, MA 02492, United States of America
| | - Kai Zou
- Department of Exercise and Health Sciences, University of Massachusetts Boston, 100 Morrissey Blvd, Boston, MA 02125, United States of America
| | - Alexey Seregin
- Remedium Bio, Inc. 1116 Great Plain Ave, Suite 203, Needham, MA 02492, United States of America.
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27
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Albaghlany RM, Shahsavani MB, Hoshino M, Moosavi-Movahedi AA, Ghasemi Y, Yousefi R. Optimizing expression, purification, structural and functional assessments of a novel dimeric incretin (GLP-1cpGLP-1). Biochimie 2024; 223:133-146. [PMID: 37931794 DOI: 10.1016/j.biochi.2023.10.020] [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: 09/19/2023] [Revised: 10/28/2023] [Accepted: 10/31/2023] [Indexed: 11/08/2023]
Abstract
Glucagon-like peptide-1 (GLP-1) is an incretin hormone that reduces postprandial glycemic excursions by enhancing insulin secretion. In this study, a new dimeric GLP-1 analogue (GLP-1cpGLP-1) was designed by inserting human insulin C-peptide (CP) in the middle of a dimer of [Gly8] GLP-1 (7-36). Then, the dimeric incretin (GLP-1cpGLP-1) was ligated to human αB-crystallin (αB-Cry) to create a hybrid protein, abbreviated as αB-GLP-1cpGLP-1. The constructed gene was well expressed in the bacterial host system. After specific chemical release from the hybrid protein, the dimeric incretin was purified by size exclusion chromatography (SEC). Finally, the RP-HPLC analysis indicated a purity of >99 % for the dimeric incretin. The secondary structure assessments by various spectroscopic methods, and in silico analysis suggested that the dimeric incretin has α-helical rich structure. The dynamic light scattering (DLS) analysis indicates that our dimeric incretin forms large oligomeric structures. This incretin analogue significantly reduced blood glucose levels in both healthy and diabetic mice while effectively triggering insulin release. The size exclusion HPLC also indicates the interaction of the new incretin analogue with human serum albumin, the main carrier protein in the bloodstream. Consistent with the results obtained from the biological activity assessments, this significant interaction indicates its potential as a viable therapeutic agent with a long-lasting effect. The results of our research represent a significant breakthrough in the successful design of an active incretin dimer capable of effectively controlling blood sugar levels and inducing insulin secretion in the realm of diabetes treatment.
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Affiliation(s)
- Rawayh Muslim Albaghlany
- Protein Chemistry Laboratory (PCL), Department of Biology, College of Sciences, Shiraz University, Shiraz, Iran
| | - Mohammad Bagher Shahsavani
- Protein Chemistry Laboratory (PCL), Department of Biology, College of Sciences, Shiraz University, Shiraz, Iran
| | - Masaru Hoshino
- Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, 606-8501, Japan
| | | | - Younes Ghasemi
- Department of Pharmaceutical Biotechnology and Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, 71345, Iran
| | - Reza Yousefi
- Protein Chemistry Laboratory (PCL), Department of Biology, College of Sciences, Shiraz University, Shiraz, Iran; Institute of Biochemistry and Biophysics (IBB), University of Tehran, Tehran, Iran.
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28
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Ravee A, Burroughs-Ray D, Jackson CD, Spratt SE, Sata SS. Clinical progress note: Glucagon-like peptide-1 receptor agonists and hospitalized patients. J Hosp Med 2024; 19:716-719. [PMID: 38572574 DOI: 10.1002/jhm.13357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 03/20/2024] [Accepted: 03/23/2024] [Indexed: 04/05/2024]
Affiliation(s)
- Anjali Ravee
- Division of General Internal Medicine, University of Tennessee Health Sciences Center, Memphis, Tennessee, USA
| | - Desiree Burroughs-Ray
- Division of General Internal Medicine, University of Tennessee Health Sciences Center, Memphis, Tennessee, USA
- Department of Pediatrics, University of Tennessee Health Sciences Center, Memphis, Tennessee, USA
| | - Christopher D Jackson
- Division of General Internal Medicine, University of Tennessee Health Sciences Center, Memphis, Tennessee, USA
| | - Susan E Spratt
- Division of Endocrinology, Duke University School of Medicine, Durham, North Carolina, USA
| | - Suchita Shah Sata
- Division of General Internal Medicine, Duke University School of Medicine, Durham, North Carolina, USA
- Duke University Hospital, Durham, North Carolina, USA
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Trevella P, Ekinci EI, MacIsaac RJ. Potential kidney protective effects of glucagon-like peptide-1 receptor agonists. Nephrology (Carlton) 2024; 29:457-469. [PMID: 39030739 DOI: 10.1111/nep.14336] [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: 02/25/2024] [Revised: 05/08/2024] [Accepted: 06/09/2024] [Indexed: 07/22/2024]
Abstract
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have gained increasing attention for their potential benefits in people with type 2 diabetes (T2DM) with chronic kidney disease (CKD). This class of medication has demonstrated promising results in reducing albuminuria, preserving estimated glomerular filtration rate (eGFR), and mitigating cardiovascular (CV) risk, making them potential therapeutic options for individuals with CKD. The kidney protective effects of GLP-1RAs extend beyond glycaemic control, and are thought to be attributed to their anti-inflammatory, antioxidant, and natriuretic properties. Despite these promising findings, the use of GLP-RAs has yet to be definitively shown to slow progression to chronic kidney failure, or reduce CV and kidney related death in people with T2DM and CKD. The Research Study to See How Semaglutide (a once weekly subcutaneous administered GLP-1RA) Works Compared to Placebo in People with Type 2 Diabetes and Chronic Kidney Disease (FLOW trial) was recently stopped because of efficacy. The primary end point for the FLOW trial consists of a composite endpoint of (i) onset of chronic kidney failure; (ii) death from kidney failure; (iii) cardiovascular death; and (iv) onset of a persistent ≥50% reduction in eGFR from baseline. It has also been reported by the sponsors of the trial that the primary end point of the trial was reduced by 24% with both CKD and CV outcomes contributing to risk reduction. In anticipation of the results of the FLOW trial being published, we review the current evidence surrounding kidney outcomes and proposed kidney protective pathways associated with GLP-1RA use.
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Affiliation(s)
- Philippa Trevella
- Department of Endocrinology & Diabetes, St Vincent's Hospital Melbourne, Fitzroy, Victoria, Australia
| | - Elif I Ekinci
- Department of Endocrinology, Austin Health, Melbourne, Vitoria, Australia
- Department of Medicine, Austin Health, Melbourne Medical School, Parkville, Victoria, Australia
- Australian Centre for Accelerating Diabetes Innovations, School of Medicine, University of Melbourne, Parkville, Victoria, Australia
| | - Richard J MacIsaac
- Department of Endocrinology & Diabetes, St Vincent's Hospital Melbourne, Fitzroy, Victoria, Australia
- Australian Centre for Accelerating Diabetes Innovations, School of Medicine, University of Melbourne, Parkville, Victoria, Australia
- Department of Medicine St Vincent's Hospital Melbourne, University of Melbourne, Fitzroy, Vitoria, Australia
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Freet CS, Evans B, Brick TR, Deneke E, Wasserman EJ, Ballard SM, Stankoski DM, Kong L, Raja-Khan N, Nyland JE, Arnold AC, Krishnamurthy VB, Fernandez-Mendoza J, Cleveland HH, Scioli AD, Molchanow A, Messner AE, Ayaz H, Grigson PS, Bunce SC. Ecological momentary assessment and cue-elicited drug craving as primary endpoints: study protocol for a randomized, double-blind, placebo-controlled clinical trial testing the efficacy of a GLP-1 receptor agonist in opioid use disorder. Addict Sci Clin Pract 2024; 19:56. [PMID: 39061093 PMCID: PMC11282646 DOI: 10.1186/s13722-024-00481-7] [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: 11/28/2023] [Accepted: 06/07/2024] [Indexed: 07/28/2024] Open
Abstract
BACKGROUND Despite continuing advancements in treatments for opioid use disorder (OUD), continued high rates of relapse indicate the need for more effective approaches, including novel pharmacological interventions. Glucagon-like peptide 1 receptor agonists (GLP-1RA) provide a promising avenue as a non-opioid medication for the treatment of OUD. Whereas GLP-1RAs have shown promise as a treatment for alcohol and nicotine use disorders, to date, no controlled clinical trials have been conducted to determine if a GLP-1RA can reduce craving in individuals with OUD. The purpose of the current protocol was to evaluate the potential for a GLP-1RA, liraglutide, to safely and effectively reduce craving in an OUD population in residential treatment. METHOD This preliminary study was a randomized, double-blinded, placebo-controlled clinical trial designed to test the safety and efficacy of the GLP-1RA, liraglutide, in 40 participants in residential treatment for OUD. Along with taking a range of safety measures, efficacy for cue-induced craving was evaluated prior to (Day 1) and following (Day 19) treatment using a Visual Analogue Scale (VAS) in response to a cue reactivity task during functional near-infrared spectroscopy (fNIRS) and for craving. Efficacy of treatment for ambient craving was assessed using Ecological Momentary Assessment (EMA) prior to (Study Day 1), across (Study Days 2-19), and following (Study Days 20-21) residential treatment. DISCUSSION This manuscript describes a protocol to collect clinical data on the safety and efficacy of a GLP-1RA, liraglutide, during residential treatment of persons with OUD, laying the groundwork for further evaluation in a larger, outpatient OUD population. Improved understanding of innovative, non-opioid based treatments for OUD will have the potential to inform community-based interventions and health policy, assist physicians and health care professionals in the treatment of persons with OUD, and to support individuals with OUD in their effort to live a healthy life. TRIAL REGISTRATION ClinicalTrials.gov: NCT04199728. Registered 16 December 2019, https://clinicaltrials.gov/study/NCT04199728?term=NCT04199728 . PROTOCOL VERSION 10 May 2023.
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Affiliation(s)
- Christopher S Freet
- Department of Psychiatry and Behavioral Health, The Pennsylvania State University College of Medicine, Hershey, PA, USA
| | - Brianna Evans
- Department of Neural and Behavioral Sciences, The Pennsylvania State University College of Medicine, Hershey, PA, USA
| | - Timothy R Brick
- Department of Human Development and Family Studies, The Pennsylvania State University, University Park, PA, USA
- Institute for Computational and Data Sciences, The Pennsylvania State University, University Park, PA, USA
| | - Erin Deneke
- Fran and Doug Tieman Center for Research, Caron Treatment Centers, Wernersville, PA, USA
| | - Emily J Wasserman
- Department of Public Health Sciences, The Pennsylvania State University College of Medicine, Hershey, PA, USA
| | - Sarah M Ballard
- Department of Neural and Behavioral Sciences, The Pennsylvania State University College of Medicine, Hershey, PA, USA
| | - Dean M Stankoski
- Fran and Doug Tieman Center for Research, Caron Treatment Centers, Wernersville, PA, USA
| | - Lan Kong
- Department of Public Health Sciences, The Pennsylvania State University College of Medicine, Hershey, PA, USA
| | - Nazia Raja-Khan
- Department of Psychiatry and Behavioral Health, The Pennsylvania State University College of Medicine, Hershey, PA, USA
- Department of Medicine, The Pennsylvania State University College of Medicine, Hershey, PA, USA
- Department of Obstetrics & Gynecology, The Pennsylvania State University College of Medicine, Hershey, PA, USA
| | - Jennifer E Nyland
- Department of Neural and Behavioral Sciences, The Pennsylvania State University College of Medicine, Hershey, PA, USA
| | - Amy C Arnold
- Department of Neural and Behavioral Sciences, The Pennsylvania State University College of Medicine, Hershey, PA, USA
| | - Venkatesh Basappa Krishnamurthy
- Department of Medicine and Psychiatry, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Julio Fernandez-Mendoza
- Department of Psychiatry and Behavioral Health, The Pennsylvania State University College of Medicine, Hershey, PA, USA
| | - H Harrington Cleveland
- Department of Human Development and Family Studies, The Pennsylvania State University, University Park, PA, USA
| | - Adam D Scioli
- Fran and Doug Tieman Center for Research, Caron Treatment Centers, Wernersville, PA, USA
| | | | | | - Hasan Ayaz
- School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA, USA
| | - Patricia S Grigson
- Department of Neural and Behavioral Sciences, The Pennsylvania State University College of Medicine, Hershey, PA, USA
| | - Scott C Bunce
- Department of Psychiatry and Behavioral Health, The Pennsylvania State University College of Medicine, Hershey, PA, USA.
- Penn State University College of Medicine, Milton S. Hershey Medical Center, H073, 500 University Drive, Hershey, PA, 17033-0850, USA.
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Xie X, Valiente PA, Kim J, Kim PM. HelixDiff, a Score-Based Diffusion Model for Generating All-Atom α-Helical Structures. ACS CENTRAL SCIENCE 2024; 10:1001-1011. [PMID: 38799672 PMCID: PMC11117309 DOI: 10.1021/acscentsci.3c01488] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Revised: 03/20/2024] [Accepted: 03/22/2024] [Indexed: 05/29/2024]
Abstract
Here, we present HelixDiff, a score-based diffusion model for generating all-atom helical structures. We developed a hot spot-specific generation algorithm for the conditional design of α-helices targeting critical hotspot residues in bioactive peptides. HelixDiff generates α-helices with near-native geometries for most test scenarios with root-mean-square deviations (RMSDs) less than 1 Å. Significantly, HelixDiff outperformed our prior GAN-based model with regard to sequence recovery and Rosetta scores for unconditional and conditional generations. As a proof of principle, we employed HelixDiff to design an acetylated GLP-1 D-peptide agonist that activated the glucagon-like peptide-1 receptor (GLP-1R) cAMP accumulation without stimulating the glucagon-like peptide-2 receptor (GLP-2R). We predicted that this D-peptide agonist has a similar orientation to GLP-1 and is substantially more stable in MD simulations than our earlier D-GLP-1 retro-inverse design. This D-peptide analogue is highly resistant to protease degradation and induces similar levels of AKT phosphorylation in HEK293 cells expressing GLP-1R compared to the native GLP-1. We then discovered that matching crucial hotspots for the GLP-1 function is more important than the sequence orientation of the generated D-peptides when constructing D-GLP-1 agonists.
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Affiliation(s)
- Xuezhi Xie
- Donnelly
Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario M5S 3E1, Canada
- Department
of Computer Science, University of Toronto, Toronto, Ontario M5S 3E1, Canada
| | - Pedro A Valiente
- Donnelly
Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario M5S 3E1, Canada
| | - Jisun Kim
- Donnelly
Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario M5S 3E1, Canada
| | - Philip M Kim
- Donnelly
Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario M5S 3E1, Canada
- Department
of Computer Science, University of Toronto, Toronto, Ontario M5S 3E1, Canada
- Department
of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 3E1, Canada
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Mansour NM, El-Masry AA, El-Sherbiny DT, Moustafa MA. White analytical insight for sensitive fluorescent determination of semaglutide and tirzepatide in pharmaceuticals and biological matrices. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2024; 313:124159. [PMID: 38508074 DOI: 10.1016/j.saa.2024.124159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Revised: 02/05/2024] [Accepted: 03/13/2024] [Indexed: 03/22/2024]
Abstract
The present study is focused on the sensitive determination of newly FDA-approved glucagon-like-peptide agonists semaglutide (SEM) and tirzepatide (TIR). Direct, selective and label-free spectrofluorometric method was proposed and validated (according to ICH guidelines) for determination SEM and TIR in their pure form, newly approved pharmaceuticals and spiked human plasma. The developed method was based on measuring the native fluorescence of SEM and TIR in ethanol at 294.8 and 303 nm after being excited at 216 and 225 nm for SEM and TIR in order. The method sensibility allowed the quantification of both drugs in nano-scale up to 10 ng/mL. Several experimental variables including solvent type, surfactant, and pH were optimized after several attempts to get the best sensitivity for both drugs. The mean recovery percentage of SEM was compared and found in agreement with the reported method using student's t-test and the variance ratio F-test. Additionally, the greenness and whiteness profiles for this approach were evaluated using the GAPI, AGREE, and RGB algorithm; the positive results supported its use as great candidates for successful implementation in quality control labs and the pharmaceutical analysis companies.
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Affiliation(s)
- Noura M Mansour
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa 35712, Egypt; Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
| | - Amal A El-Masry
- Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
| | - Dina T El-Sherbiny
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa 35712, Egypt; Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
| | - Mohamed A Moustafa
- Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
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Jafar A, Pasqua MR. Postprandial glucose-management strategies in type 1 diabetes: Current approaches and prospects with precision medicine and artificial intelligence. Diabetes Obes Metab 2024; 26:1555-1566. [PMID: 38263540 DOI: 10.1111/dom.15463] [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: 11/28/2023] [Revised: 01/01/2024] [Accepted: 01/05/2024] [Indexed: 01/25/2024]
Abstract
Postprandial glucose control can be challenging for individuals with type 1 diabetes, and this can be attributed to many factors, including suboptimal therapy parameters (carbohydrate ratios, correction factors, basal doses) because of physiological changes, meal macronutrients and engagement in postprandial physical activity. This narrative review aims to examine the current postprandial glucose-management strategies tested in clinical trials, including adjusting therapy settings, bolusing for meal macronutrients, adjusting pre-exercise and postexercise meal boluses for postprandial physical activity, and other therapeutic options, for individuals on open-loop and closed-loop therapies. Then we discuss their challenges and future avenues. Despite advancements in insulin delivery devices such as closed-loop systems and decision-support systems, many individuals with type 1 diabetes still struggle to manage their glucose levels. The main challenge is the lack of personalized recommendations, causing suboptimal postprandial glucose control. We suggest that postprandial glucose control can be improved by (i) providing personalized recommendations for meal macronutrients and postprandial activity; (ii) including behavioural recommendations; (iii) using other personalized therapeutic approaches (e.g. glucagon-like peptide-1 receptor agonists, sodium-glucose co-transporter inhibitors, amylin analogues, inhaled insulin) in addition to insulin therapy; and (iv) integrating an interpretability report to explain to individuals about changes in treatment therapy and behavioural recommendations. In addition, we suggest a future avenue to implement precision recommendations for individuals with type 1 diabetes utilizing the potential of deep reinforcement learning and foundation models (such as GPT and BERT), employing different modalities of data including diabetes-related and external background factors (i.e. behavioural, environmental, biological and abnormal events).
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Affiliation(s)
- Adnan Jafar
- Department of Biomedical Engineering, McGill University, Montreal, Quebec, Canada
| | - Melissa-Rosina Pasqua
- Division of Endocrinology, Department of Medicine, McGill University, Montreal, Quebec, Canada
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Abstract
ABSTRACT Type 2 diabetes mellitus (T2DM) is a chronic medical condition affecting millions of individuals worldwide. The burden of disease is significant, as demonstrated by high morbidity and mortality and billions of healthcare dollars spent. The pathophysiology of T2DM is complex, with eight primary deficits. In recent years, an increased focus has been placed on incretin hormones, such as glucagon-like peptide-1 (GLP-1) for its glucose-lowering benefits. Several FDA-approved short-acting and long-acting GLP-1 receptor agonists (GLP-1 RAs) are available in the United States for the treatment of T2DM. These are liraglutide, exenatide, dulaglutide, and semaglutide, all administered via subcutaneous injection. Semaglutide is also available in an oral formulation. A newer dual glucose-dependent insulinotropic peptide (GIP) and GLP-1 RA, tirzepatide, is available as a subcutaneous injectable. In addition to improving glycemic control, GLP-1 RAs have been shown to lower total body weight, BP, and cholesterol as well as to improve renal function and beta-cell proliferation. These agents should be considered in every patient with T2DM due to their substantial clinical benefits and potential to help reduce disease burden.
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Affiliation(s)
- LaDonna Clark
- LaDonna Clark is director of clinical education in the Physician Assistant Studies Program at Gardner-Webb University in Boiling Springs, N.C. The author has disclosed no potential conflicts of interest, financial or otherwise
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35
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Casella S, Galli K. Appendicitis: A Hidden Danger of GLP-1 Receptor Agonists? J Pharm Technol 2024; 40:108-111. [PMID: 38525095 PMCID: PMC10959081 DOI: 10.1177/87551225231216638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/26/2024] Open
Abstract
Introduction: While glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have become increasingly prescribed, use is often inhibited by the gastrointestinal adverse effects that patients must endure. Nausea, vomiting, and cholelithiasis are most commonly associated with use, with little to no data or labeling reflecting risk of appendicitis or associated symptoms. Appendicitis etiology is theorized to develop secondary to obstruction of the vermiform via infection or fecalith causing an increase in intraluminal pressure. It is hypothesized that given the aforementioned gastrointestinal effects associated with GLP-1 RAs, patients taking such agents may be more at risk for developing this acute condition. Patient Case: We describe a case of a 48-year-old woman who presented to the emergency department several months after being initiated on Ozempic (semaglutide). This report aims to analyze the potential secondary adverse effects that may result from GLP-1 RA use. Her examination was positive for focal abdominal tenderness and leukocytosis along with imaging suggestive of appendicitis. Her acute condition ultimately required an appendectomy. Discussion: While minimal data are available to suggest significant causation between GLP-1 RAs and appendicitis, a literature and database search revealed that instances may be more common than previously thought. Conclusion: Trial results and adverse event reporting systems report an infrequent incidence in patients using these medications, but this report aims to contribute to the literature describing this potential adverse event.
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Affiliation(s)
- Sarah Casella
- School of Pharmacy, University of Connecticut, Storrs, CT, USA
| | - Katelyn Galli
- School of Pharmacy, University of Connecticut, Storrs, CT, USA
- Department of Pharmacy, Hartford Healthcare, Norwich, CT, USA
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36
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Long B, Pelletier J, Koyfman A, Bridwell RE. GLP-1 agonists: A review for emergency clinicians. Am J Emerg Med 2024; 78:89-94. [PMID: 38241775 DOI: 10.1016/j.ajem.2024.01.010] [Citation(s) in RCA: 18] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 01/07/2024] [Accepted: 01/08/2024] [Indexed: 01/21/2024] Open
Abstract
INTRODUCTION Glucagon-like peptide 1 (GLP-1) based therapies, including GLP-1 agonists, are currently in use for treatment of diabetes and obesity. However, several complications may occur with their use. OBJECTIVE This narrative review provides a focused evaluation of GLP-1 agonist therapy and associated complications for emergency clinicians. DISCUSSION GLP-1 agonists potentiate insulin release and reduce gastric emptying and food intake. These agents have demonstrated significant improvements in glucose control in diabetics and weight loss in obese patients. The two most common agents include subcutaneous semaglutide (Ozempic, approved for type 2 diabetes, and Wegovy, approved for weight loss) and liraglutide (Saxenda, approved for weight loss, and Victoza, approved for type 2 diabetes), though an oral formulation of semaglutide is available (Rybelsus). While these drugs are associated with improved long-term outcomes, there are a variety of associated adverse events. The most common include gastrointestinal (GI) adverse events such as nausea, vomiting, diarrhea, and abdominal pain. Pancreatitis and biliary disease may also occur. Hypersensitivity including injection site reactions have been associated with use, with reports of anaphylaxis and other rashes. Renal adverse events are most commonly associated with severe GI losses. Hypoglycemia may occur when these agents are used with sulfonylureas or insulin. There is also an increased risk of diabetic retinopathy. Due to the current shortage and expense of these medications, many patients have attempted to obtain these medications from non-licensed and unregulated agents, which may be associated with increased risk of serious complications. CONCLUSIONS An understanding of the indications for GLP-1 agonist use and associated adverse events can assist emergency clinicians.
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Affiliation(s)
- Brit Long
- Department of Emergency Medicine, Brooke Army Medical Center, Fort Sam Houston, TX, USA.
| | - Jessica Pelletier
- Department of Emergency Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Alex Koyfman
- Department of Emergency Medicine, UT Southwestern, Dallas, TX, USA
| | - Rachel E Bridwell
- Department of Emergency Medicine, Madigan Army Medical Center, Tacoma, WA, USA
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Schlünder K, Cipriano M, Zbinden A, Fuchs S, Mayr T, Schenke-Layland K, Loskill P. Microphysiological pancreas-on-chip platform with integrated sensors to model endocrine function and metabolism. LAB ON A CHIP 2024; 24:2080-2093. [PMID: 38441218 DOI: 10.1039/d3lc00838j] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/27/2024]
Abstract
Pancreatic in vitro research is of major importance to advance mechanistic understanding and development of treatment options for diseases such as diabetes mellitus. We present a thermoplastic-based microphysiological system aiming to model the complex microphysiological structure and function of the endocrine pancreas with concurrent real-time read-out capabilities. The specifically tailored platform enables self-guided trapping of single islets at defined locations: β-cells are assembled to pseudo-islets and injected into the tissue chamber using hydrostatic pressure-driven flow. The pseudo-islets can further be embedded in an ECM-like hydrogel mimicking the native microenvironment of pancreatic islets in vivo. Non-invasive real-time monitoring of the oxygen levels on-chip is realized by the integration of luminescence-based optical sensors to the platform. To monitor insulin secretion kinetics in response to glucose stimulation in a time-resolved manner, an automated cycling of different glucose conditions is implemented. The model's response to glucose stimulation can be monitored via offline analysis of insulin secretion and via specific changes in oxygen consumption due to higher metabolic activity of pseudo-islets at high glucose levels. To demonstrate applicability for drug testing, the effects of antidiabetic medications are assessed and changes in dynamic insulin secretion are observed in line with the respective mechanism of action. Finally, by integrating human pancreatic islet microtissues, we highlight the flexibility of the platform and demonstrate the preservation of long-term functionality of human endocrine pancreatic tissue.
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Affiliation(s)
- Katharina Schlünder
- Department for Microphysiological Systems, Institute of Biomedical Engineering, Eberhard Karls University Tübingen, Tübingen, Germany.
- NMI Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Germany
| | - Madalena Cipriano
- Department for Microphysiological Systems, Institute of Biomedical Engineering, Eberhard Karls University Tübingen, Tübingen, Germany.
| | - Aline Zbinden
- Department for Medical Technologies and Regenerative Medicine, Institute of Biomedical Engineering, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Stefanie Fuchs
- Institute for Analytical Chemistry and Food Chemistry, Graz University of Technology, Graz, Austria
| | - Torsten Mayr
- Institute for Analytical Chemistry and Food Chemistry, Graz University of Technology, Graz, Austria
| | - Katja Schenke-Layland
- NMI Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Germany
- Department for Medical Technologies and Regenerative Medicine, Institute of Biomedical Engineering, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Peter Loskill
- Department for Microphysiological Systems, Institute of Biomedical Engineering, Eberhard Karls University Tübingen, Tübingen, Germany.
- NMI Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Germany
- 3R-Center for In vitro Models and Alternatives to Animal Testing, Eberhard Karls University Tübingen, Tübingen, Germany
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38
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Gao C, Krashes MJ. Neuroscience of eating: Pace and portion control. Curr Biol 2024; 34:R155-R157. [PMID: 38412828 DOI: 10.1016/j.cub.2024.01.033] [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: 02/29/2024]
Abstract
Satiety-promoting neurons of the hindbrain have long been known for their role in meal termination. An innovative new study now reveals how different hindbrain cell types mediate appetite on distinct timescales.
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Affiliation(s)
- Claire Gao
- Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Michael J Krashes
- Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA; National Institute on Drug Abuse (NIDA), National Institutes of Health, Baltimore, MD 21224, USA.
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39
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Véniant MM, Lu SC, Atangan L, Komorowski R, Stanislaus S, Cheng Y, Wu B, Falsey JR, Hager T, Thomas VA, Ambhaikar M, Sharpsten L, Zhu Y, Kurra V, Jeswani R, Oberoi RK, Parnes JR, Honarpour N, Neutel J, Strande JL. A GIPR antagonist conjugated to GLP-1 analogues promotes weight loss with improved metabolic parameters in preclinical and phase 1 settings. Nat Metab 2024; 6:290-303. [PMID: 38316982 PMCID: PMC10896721 DOI: 10.1038/s42255-023-00966-w] [Citation(s) in RCA: 68] [Impact Index Per Article: 68.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Accepted: 12/12/2023] [Indexed: 02/07/2024]
Abstract
Obesity is a major public health crisis. Multi-specific peptides have emerged as promising therapeutic strategies for clinical weight loss. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are endogenous incretins that regulate weight through their receptors (R). AMG 133 (maridebart cafraglutide) is a bispecific molecule engineered by conjugating a fully human monoclonal anti-human GIPR antagonist antibody to two GLP-1 analogue agonist peptides using amino acid linkers. Here, we confirm the GIPR antagonist and GLP-1R agonist activities in cell-based systems and report the ability of AMG 133 to reduce body weight and improve metabolic markers in male obese mice and cynomolgus monkeys. In a phase 1, randomized, double-blind, placebo-controlled clinical study in participants with obesity ( NCT04478708 ), AMG 133 had an acceptable safety and tolerability profile along with pronounced dose-dependent weight loss. In the multiple ascending dose cohorts, weight loss was maintained for up to 150 days after the last dose. These findings support continued clinical evaluation of AMG 133.
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Affiliation(s)
- Murielle M Véniant
- Amgen Research, Department of Cardiometabolic Disorders, Thousand Oaks, CA, USA.
| | - Shu-Chen Lu
- Amgen Research, Department of Cardiometabolic Disorders, Thousand Oaks, CA, USA
| | - Larissa Atangan
- Amgen Research, Department of Cardiometabolic Disorders, Thousand Oaks, CA, USA
| | - Renee Komorowski
- Amgen Research, Department of Cardiometabolic Disorders, Thousand Oaks, CA, USA
| | - Shanaka Stanislaus
- Amgen Research, Department of Cardiometabolic Disorders, Thousand Oaks, CA, USA
| | - Yuan Cheng
- Amgen Research, Department of Therapeutic Discovery, Thousand Oaks, CA, USA
| | - Bin Wu
- Amgen Research, Department of Therapeutic Discovery, Thousand Oaks, CA, USA
| | - James R Falsey
- Amgen Research, Department of Therapeutic Discovery, Thousand Oaks, CA, USA
| | - Todd Hager
- Amgen Research, Department of Translational Safety & Bioanalytical Sciences, Thousand Oaks, CA, USA
| | - Veena A Thomas
- Amgen Research, Department of Pharmacokinetics and Drug Metabolism, South San Francisco, CA, USA
| | - Malhar Ambhaikar
- Pre-pivotal Drug Substance Technologies, Amgen, Thousand Oaks, CA, USA
| | | | - Yineng Zhu
- Amgen Early Development, Amgen, Thousand Oaks, CA, USA
| | - Vamsi Kurra
- Amgen Research, Department of Translational Safety & Bioanalytical Sciences, Thousand Oaks, CA, USA
| | - Rohini Jeswani
- Amgen Research, Department of Translational Safety & Bioanalytical Sciences, Thousand Oaks, CA, USA
| | | | - Jane R Parnes
- Amgen Early Development, Amgen, Thousand Oaks, CA, USA
| | | | - Joel Neutel
- Orange County Research Center, Tustin, CA, USA
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Mullins GR, Hodsdon ME, Li YG, Anglin G, Urva S, Schneck K, Bardos JN, Martins RF, Brown K, Calderon B. Tirzepatide Immunogenicity on Pharmacokinetics, Efficacy, and Safety: Analysis of Data From Phase 3 Studies. J Clin Endocrinol Metab 2024; 109:361-369. [PMID: 37700637 PMCID: PMC10795913 DOI: 10.1210/clinem/dgad532] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 08/25/2023] [Accepted: 09/05/2023] [Indexed: 09/14/2023]
Abstract
CONTEXT Antidrug antibodies (ADA) can potentially affect drug pharmacokinetics, safety, and efficacy. OBJECTIVE This work aimed to evaluate treatment-emergent (TE) ADA in tirzepatide (TZP)-treated participants across 7 phase 3 trials and their potential effect on pharmacokinetics, efficacy, and safety. METHODS ADA were assessed at baseline and throughout the study until end point, defined as week 40 (SURPASS-1, -2, and -5) or week 52 (SURPASS-3, -4, Japan-Mono, and Japan-Combo). Samples for ADA characterization were collected at SURPASS trial sites. Participants included ADA-evaluable TZP-treated patients with type 2 diabetes (N = 5025). Interventions included TZP 5, 10, or 15 mg. ADA were detected and characterized for their ability to cross-react with native glucose-dependent insulinotropic polypeptide (nGIP) and glucagon-like peptide-1 (nGLP-1), neutralize tirzepatide activity on GIP and GLP-1 receptors, and neutralize nGIP and nGLP-1. RESULTS TE ADA developed in 51.1% of tirzepatide-treated patients. Proportions were similar across dose groups. Maximum ADA titers ranged from 1:20 to 1: 81 920 among TE ADA+ patients. Neutralizing antibodies (NAb) against TZP activity on GIP and GLP-1 receptors were observed in 1.9% and 2.1% of patients, respectively. Less than 1.0% of patients had cross-reactive NAb against nGIP or nGLP-1. TE ADA status, ADA titer, and NAb status had no effect on the pharmacokinetics or efficacy of TZP. More TE ADA+ patients experienced hypersensitivity reactions or injection site reactions than TE ADA- patients. The majority of hypersensitivity and injection site reactions were nonserious and nonsevere, and most events occurred and/or resolved irrespective of TE ADA status or titer. CONCLUSION Immunogenicity did not affect TZP pharmacokinetics or efficacy. The majority of hypersensitivity or injection site reactions experienced by TE ADA+ patients were mild to moderate in severity.
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Affiliation(s)
- Garrett R Mullins
- Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA
| | - Michael E Hodsdon
- Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA
| | - Ying Grace Li
- Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA
| | - Greg Anglin
- Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA
| | - Shweta Urva
- Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA
| | - Karen Schneck
- Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA
| | - Jennifer N Bardos
- Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA
| | | | - Katelyn Brown
- Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA
| | - Boris Calderon
- Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA
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Mac Curtain BM, O'Brien L, El Sherif O, Mc Cormack A, Carolan E, Ryan JD, O'Shea D, Gallagher TK. Biguanides and glucagon like peptide 1 receptor agonists in the amelioration of post liver transplant weight gain; a scoping review of the mechanism of action, safety and efficacy. GASTROENTEROLOGY AND HEPATOLOGY FROM BED TO BENCH 2024; 17:17-27. [PMID: 38737926 PMCID: PMC11080689 DOI: 10.22037/ghfbb.v17i1.2899] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Accepted: 12/02/2023] [Indexed: 05/14/2024]
Abstract
Weight gain post-liver transplant can lead to adverse patient outcomes in the post-transplant period. Pharmacotherapy and other measures can be utilised to reduce the burden and occurrence of weight gain in this population. We explored the mechanism of action, safety, and efficacy of these medications, specifically GLP-1 receptor agonists and metformin, focusing on liver transplant patients. This scoping review was conducted in line with the scoping review structure as outlined by the PRISMA guidelines. Metformin and GLP-1 receptor agonists have been observed to be safe and effective in liver transplant patients. Experimental models have found liver-centric weight loss mechanisms in this drug cohort. There is a paucity of evidence about the use of antihyperglycemics in a post-transplant population for weight loss purposes. However, some small studies have shown strong safety and efficacy data. The evidence in relation to using these medications in patients with metabolic syndrome for weight loss warrants further study in a transplant population.
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Affiliation(s)
| | - Luke O'Brien
- Hepatopancreatobiliary Group, St Vincent's University Hospital, Dublin 4, Ireland
| | - Omar El Sherif
- National Liver Transplant Unit, St Vincent's University Hospital, Dublin 4, Ireland
| | - Aidan Mc Cormack
- National Liver Transplant Unit, St Vincent's University Hospital, Dublin 4, Ireland
| | - Emer Carolan
- Department of Hepatology, Beaumont Hospital, Dublin 9, Ireland
| | - John D Ryan
- Department of Hepatology, Beaumont Hospital, Dublin 9, Ireland
| | - Donal O'Shea
- Department of Endocrinology, St Vincent's University Hospital, Dublin 4, Ireland
| | - Tom K Gallagher
- Hepatopancreatobiliary Group, St Vincent's University Hospital, Dublin 4, Ireland
- National Liver Transplant Unit, St Vincent's University Hospital, Dublin 4, Ireland
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Allam S, Sartaj S, Moquim H, Husnain MA, Bustos D, Lakkimsetti M, Randhawa AK, Gupta I. Role of Liraglutide Use in Patients With Heart Failure. Cureus 2023; 15:e50065. [PMID: 38186489 PMCID: PMC10769535 DOI: 10.7759/cureus.50065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/06/2023] [Indexed: 01/09/2024] Open
Abstract
Heart failure is a clinical condition in which the heart is unable to maintain adequate cardiac output. Liraglutide is a glucagon-like peptide 1 (GLP-1) analogue that is used for the treatment of type 2 diabetes mellitus, but recent evidence suggests that it might have a beneficial role in treating heart failure. We conducted a review of existing literature and found five relevant studies. Data from these studies were extracted and then extrapolated into results following analysis. Four of the five studies found an increase in heart rate in heart failure patients. All five studies reported an increased rate of hospitalization. The five studies also showed an increased risk of adverse effects such as arrhythmia, ventricular tachycardia, atrial fibrillation, and worsening of heart failure. Given the scarcity of evidence in the available literature on liraglutide in heart failure, more research on this population is required.
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Affiliation(s)
- Sanjana Allam
- Internal Medicine, Gandhi Medical College, Secunderabad, IND
| | - Sahil Sartaj
- Internal Medicine, Melmaruvathur Adiparasakthi Institute of Medical Sciences and Research, Melmaruvathur, IND
| | - Hiba Moquim
- Internal Medicine, Shadan Institute of Medical Sciences, Hyderabad, IND
| | - Muhammad Ammar Husnain
- Internal Medicine, Combined Military Hospital Lahore Medical College and Institute of Dentistry, Lahore, PAK
| | - Daniel Bustos
- Internal Medicine, Pontifical Catholic University of Ecuador, Quito, ECU
| | | | - Avneet K Randhawa
- Internal Medicine, Maharishi Markandeshwar Institute of Medical Sciences and Research, Ambala, IND
| | - Ishita Gupta
- Internal Medicine, Dr. Rajendra Prasad Government Medical College, Tanda, Kangra, IND
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Povar-Echeverría M, Méndez-Bailón M, Martín-Sánchez FJ, Montero-Pérez-Barquero M, Trullàs JC, Miró Ò. Prognostic impact of metformin in patients with type 2 diabetes mellitus and acute heart failure: Combined analysis of the EAHFE and RICA registries. Rev Clin Esp 2023; 223:542-551. [PMID: 37717921 DOI: 10.1016/j.rceng.2023.09.007] [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: 06/02/2023] [Accepted: 07/29/2023] [Indexed: 09/19/2023]
Abstract
INTRODUCTION Patients with diabetes mellitus (DM) and heart failure (HF) have a worse prognosis despite therapeutic advances in both diseases. Sodium-glucose co-transporter type 2 and GLP-1 receptor agonists have shown cardiovascular benefits and they have been positioned as the first step in the treatment of DM in patients with HF or high cardiovascular risk. However, in the pivotal trials the majority of patients receive concomitant treatment with metformin. Randomized clinical trials have not yet been developed to assess the prognostic impact of metformin at the cardiovascular level. Our objective has been centered in analyzing whether patients with DM and acute HF who receive treatment with metformin at the time of discharge may have a better prognosis at one year of follow-up. METHODS Prospective cohort trial using the combined analysis of the two main Spanish HF registries, the EAHFE Registry (Epidemiology of Acute Heart Failure in Emergency Departments) and the RICA (National Registry of Patients with Heart Failure). RESULTS 33% (1453) of a total of 4403 patients with DM type 2 received treatment with metformin. This group presents significantly lower mortality after one year of treatment (22 versus 32%; Log Rank test P < 0.001). In the adjusted analysis of mortality, patients receiving treatment with metformin have lower mortality at one year of follow-up regardless of the rest of the variables (RR 0,814; 95%IC 0,712-0,930; P < 0.01). CONCLUSIONS Patients with DM type 2 and acute HF who receive metformin have a better prognosis after one year of follow-up, so we believe that this drug should continue to be a fundamental pillar in the treatment of these patients.
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Affiliation(s)
- M Povar-Echeverría
- Internal Medicine Service, Hospital Comarcal de Barbastro, Barbastro, Huesca, Spain.
| | - M Méndez-Bailón
- Internal Medicine Service, Hospital Universitario Clínico San Carlos, Facultad de Medicina, Universidad Complutense, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IDISS), Madrid, Spain
| | - F J Martín-Sánchez
- Internal Medicine Service, Hospital Universitario Clínico San Carlos, Facultad de Medicina, Universidad Complutense, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IDISS), Madrid, Spain
| | - M Montero-Pérez-Barquero
- Internal Medicine Service, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía, Córdoba, Spain
| | - J C Trullàs
- Internal Medicine Service, Hospital d'Olot i Comarcal de la Garrotxa, Olot, Girona, Spain; Grupo de Investigación en Reparación y Regeneración Q2 Tisular (TR2Lab), Institut de Recerca i Innovació en Ciències de la Vida i de la Salut a la Catalunya Central, Barcelona, Spain
| | - Ò Miró
- Emergencies Service, Hospital Clínic de Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain
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Annaji M, Mita N, Heard J, Kang X, Poudel I, Fasina O, Baskaran P, Boddu SHS, Tiwari AK, Chen P, Lyman CC, Babu RJ. 3D-Printed Capsaicin-Loaded Injectable Implants for Targeted Delivery in Obese Patients. AAPS PharmSciTech 2023; 24:200. [PMID: 37783858 DOI: 10.1208/s12249-023-02647-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Accepted: 08/29/2023] [Indexed: 10/04/2023] Open
Abstract
Diet-induced obesity and hyperlipidemia are a growing public health concern leading to various metabolic disorders. Capsaicin, a major bioactive compound obtained from natural chili peppers, has demonstrated its numerous beneficial roles in treating obesity and weight loss. Current treatment involves either administration of antiobesity drugs or surgical procedures such as Roux-en-Y-gastric bypass or sleeve gastrectomy, both of which are associated with serious side effects and poor patient acceptance. Capsaicin, a pungent molecule, has low oral bioavailability. Therefore, there is a need for the development of site-specific drug delivery system for capsaicin. The present study is aimed at preparing and characterizing 3D-printed capsaicin-loaded rod-shaped implants by thermoplastic extrusion-based 3D printing technology. The implants were printed with capsaicin-loaded into a biodegradable polymer, polycaprolactone, at different drug loadings and infill densities. The surface morphology revealed a smooth and uniform external surface without any capsaicin crystals. DSC thermograms showed no significant changes/exothermic events among the blends suggesting no drug polymer interactions. The in vitro release studies showed a biphasic release profile for capsaicin, and the release was sustained for more than three months (~ 85% released) irrespective of drug loading and infill densities. The HPLC method was stability-indicating and showed good resolution for its analogs, dihydrocapsaicin and nordihydrocapsaicin. The implants were stable for three months at accelerated conditions (40°C) without any significant decrease in the assay of capsaicin. Therefore, capsaicin-loaded implants can serve as a long-acting injectable formulation for targeting the adipose tissue region in obese patients.
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Affiliation(s)
- Manjusha Annaji
- Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, Alabama, 36849, USA
| | - Nur Mita
- Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, Alabama, 36849, USA
- Faculty of Pharmacy, Mulawarman University, Samarinda, Kalimantan Timur, Indonesia
| | - Jessica Heard
- Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, Alabama, 36849, USA
| | - Xuejia Kang
- Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, Alabama, 36849, USA
- Materials Research and Education Center, Materials Engineering, Department of Mechanical Engineering, Auburn University, Auburn, Alabama, 36849, USA
| | - Ishwor Poudel
- Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, Alabama, 36849, USA
| | - Oladiran Fasina
- Department of Biosystems Engineering, Samuel Ginn College of Engineering, Auburn University, Auburn, Alabama, 36849, USA
| | - Padmamalini Baskaran
- College of Pharmacy, Howard University, Washington, District of Columbia, 20059, USA
| | - Sai H S Boddu
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Ajman University, Ajman, United Arab Emirates
- Center of Medical and Bio-Allied Health Sciences Research, Ajman University, P.O. Box 346, Ajman, United Arab Emirates
| | - Amit K Tiwari
- Department of Pharmacology and Experimental Therapeutics, University of Toledo, Toledo, Ohio, 43614, USA
| | - Pengyu Chen
- Materials Research and Education Center, Materials Engineering, Department of Mechanical Engineering, Auburn University, Auburn, Alabama, 36849, USA
| | - Candace C Lyman
- Department of Clinical Sciences, College of Veterinary Medicine, Auburn University, Auburn, Alabama, 36849, USA
| | - R Jayachandra Babu
- Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, Alabama, 36849, USA.
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Zaongo SD, Chen Y. Metformin may be a viable adjunctive therapeutic option to potentially enhance immune reconstitution in HIV-positive immunological non-responders. Chin Med J (Engl) 2023; 136:2147-2155. [PMID: 37247620 PMCID: PMC10508460 DOI: 10.1097/cm9.0000000000002493] [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: 12/08/2022] [Indexed: 05/31/2023] Open
Abstract
ABSTRACT Incomplete immune reconstitution remains a global challenge for human immunodeficiency virus (HIV) treatment in the present era of potent antiretroviral therapy (ART), especially for those individuals referred to as immunological non-responders (INRs), who exhibit dramatically low CD4 + T-cell counts despite the use of effective antiretroviral therapy, with long-term inhibition of viral replication. In this review, we provide a critical overview of the concept of ART-treated HIV-positive immunological non-response, and also explain the known mechanisms which could potentially account for the emergence of immunological non-response in some HIV-infected individuals treated with appropriate and effective ART. We found that immune cell exhaustion, combined with chronic inflammation and the HIV-associated dysbiosis syndrome, may represent strategic aspects of the immune response that may be fundamental to incomplete immune recovery. Interestingly, we noted from the literature that metformin exhibits properties and characteristics that may potentially be useful to specifically target immune cell exhaustion, chronic inflammation, and HIV-associated gut dysbiosis syndrome, mechanisms which are now recognized for their critically important complicity in HIV disease-related incomplete immune recovery. In light of evidence discussed in this review, it can be seen that metformin may be of particularly favorable use if utilized as adjunctive treatment in INRs to potentially enhance immune reconstitution. The approach described herein may represent a promising area of therapeutic intervention, aiding in significantly reducing the risk of HIV disease progression and mortality in a particularly vulnerable subgroup of HIV-positive individuals.
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Affiliation(s)
| | - Yaokai Chen
- Division of Infectious diseases, Chongqing Public Health Medical Center, Chongqing 400036, China
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Selvarajan R, Subramanian R. A Peptide in a Pill - Oral Semaglutide in the Management of Type 2 Diabetes. Diabetes Metab Syndr Obes 2023; 16:1709-1720. [PMID: 37312901 PMCID: PMC10259523 DOI: 10.2147/dmso.s385196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Accepted: 11/01/2022] [Indexed: 06/15/2023] Open
Abstract
T2DM (type 2 diabetes mellitus) is a chronic and progressive illness with high morbidity and death rates. Oral semaglutide (Rybelsus®) is a combination of semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA), and sodium N- (8- [2-hydroxybenzoyl] amino) caprylate (SNAC), an absorption enhancer that facilitates semaglutide absorption across the gastric epithelium in a concentration-dependent manner. This family of drugs apart from glucose lowering effects causes significant weight loss with lower risk of hypoglycemia, and some of them have been linked to a significant reduced major adverse cardiovascular events. GLP-1 RAs may assist persons with T2DM and chronic kidney disease (CKD), a major microvascular consequence of T2DM, in ways other than lowering blood sugar. Several large clinical studies, the bulk of which are cardiovascular outcome trials, show that GLP-1 RA treatment is safe and tolerated for persons with T2DM and impaired renal function and that it may potentially have renoprotective characteristics. This article focuses on the advances of oral GLP1-RA and describes the key milestones and predicted advantages.
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Affiliation(s)
- Raja Selvarajan
- Department of Diabetes and Research Kaveri Healthcare, Bangalore, Karnataka, India
| | - Rashmi Subramanian
- Department of Research and Development, Kaveri Healthcare, Bangalore, Karnataka, India
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Selvarajan R, Subramanian R. A Peptide in a Pill – Oral Semaglutide in the Management of Type 2 Diabetes. Diabetes Metab Syndr Obes 2023; Volume 16:1709-1720. [DOI: https:/doi.org/10.2147/dmso.s385196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 06/24/2023] Open
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Hu H, Luo J, Liu Y, Li H, Jin R, Li S, Wei J, Wei H, Chen T. Improvement effect of a next-generation probiotic L. plantarum-pMG36e-GLP-1 on type 2 diabetes mellitus via the gut-pancreas-liver axis. Food Funct 2023; 14:3179-3195. [PMID: 36912589 DOI: 10.1039/d3fo00044c] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/06/2023]
Abstract
Next-generation probiotics (NGPs) are currently being investigated as therapeutic agents that impact the gut microbiota and disease development. Glucagon-like peptide-1 (GLP-1) shows an excellent therapeutic effect on diabetes, but has an extremely short half-life in vivo. Here, we constructed a novel and diabetes-specific NGP, the genetically engineered strain Lactobacillus plantarum (L. plantarum)-pMG36e-GLP-1, and evaluated its ameliorative effect on type 2 diabetes mellitus (T2DM) in artificially induced mice and transgenic mice. In vitro, L. plantarum-pMG36e-GLP-1 showed good genetic stability and probiotic characteristics. In the high-fat diet combined with streptozotocin (HFD/STZ)-induced T2DM mice, L. plantarum-pMG36e-GLP-1 relieved the diabetic symptoms, regulated the intestinal microbiota, and reduced the inflammatory reaction in the pancreatic tissue. Meanwhile, the apoptosis of pancreatic islet cells was inhibited, while islet tissue morphology repairs, islet β-cell proliferation, and insulin secretion were all promoted by L. plantarum-pMG36e-GLP-1. Furthermore, a similar effect of the engineered strain on diabetic symptoms and the pancreas was observed in db/db mice, and the metabolism of lipids in the liver was regulated. Together, the findings of this study confirmed the anti-hyperglycemic effect of the engineered strain L. plantarum-pMG36e-GLP-1, providing a promising approach for T2DM treatment.
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Affiliation(s)
- Hong Hu
- National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang 330031, P. R. China.
| | - Jie Luo
- School of Public Health and Key Laboratory of Preventive Medicine, Nanchang University, Nanchang 330031, P. R. China
| | - Ying Liu
- Life Science Institute, Nanchang University, Nanchang 330031, P. R. China
| | - Hongyu Li
- School of Queen Mary, Nanchang University, Nanchang, 330031, P. R. China
| | - Rui Jin
- School of Queen Mary, Nanchang University, Nanchang, 330031, P. R. China
| | - Shengjie Li
- National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang 330031, P. R. China.
| | - Jing Wei
- National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang 330031, P. R. China.
| | - Hong Wei
- Precision Medicine Institute, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, P. R. China.
| | - Tingtao Chen
- National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang 330031, P. R. China.
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Menzen M, Berentzen TL, Catarig AM, Pieperhoff S, Simon J, Jacob S. Real-World Use of Once-Weekly Semaglutide in Type 2 Diabetes: Results from SemaglUtide Real-world Evidence (SURE) Germany. Exp Clin Endocrinol Diabetes 2023; 131:205-215. [PMID: 36599459 PMCID: PMC10101737 DOI: 10.1055/a-2007-2061] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
CONTEXT Efficacy and safety of once-weekly semaglutide in type 2 diabetes were established in the phase 3 SUSTAIN trials, which included patients across the continuum of type 2 diabetes care. It is useful to complement these findings with real-world evidence. OBJECTIVE SURE Germany evaluated once-weekly semaglutide in a real-world type 2 diabetes patient population. DESIGN/SETTING The prospective observational study was conducted at 93 clinical practices in adults with+≥ 1 documented glycated haemoglobin value ≤12 weeks before initiation of semaglutide. INTERVENTION Once-weekly semaglutide was prescribed at the physicians' discretion. MAIN OUTCOMES The primary endpoint was change in glycated haemoglobin from baseline to end-of-study (~30 weeks). Secondary endpoints included changes in body weight and patient-reported outcomes. All adverse events were systematically collected and reported, including patient-reported documented and/or severe hypoglycaemia. RESULTS Of 779 patients in the full analysis set, 669 (85.9%) completed the study on treatment with semaglutide, comprising the effectiveness analysis set. In this data set, estimated mean changes in glycated haemoglobin and body weight from baseline to end-of-study were -1.0%point (-10.9 mmol/mol; P<0.0001) and -4.5 kg (-4.2%; P<0.0001). Sensitivity analyses supported the primary analysis. Improvements were observed in other secondary endpoints, including patient-reported outcomes. No new safety concerns were identified. CONCLUSIONS In a real-world population in Germany, patients with type 2 diabetes treated with once-weekly semaglutide experienced clinically significant improvements in glycaemic control and body weight. These results support the use of once-weekly semaglutide in routine clinical practice in adult patients with type 2 diabetes in Germany.
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Affiliation(s)
- Markus Menzen
- Gemeinschaftskrankenhaus Bonn, Innere Medizin - Diabetologie und Endokrinologie, Bonn, Germany
| | | | | | | | - Jörg Simon
- MVZ im Altstadt-Carree Fulda GmbH, Fulda, Germany
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50
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Grigson PS, Hobkirk AL, Grigson PS, Hobkirk AL. Addiction III: From mouse to man. Brain Res Bull 2023; 193:22-26. [PMID: 36464128 DOI: 10.1016/j.brainresbull.2022.12.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022]
Affiliation(s)
- Patricia Sue Grigson
- Department of Neural and Behavioral Sciences, Penn State College of Medicine, USA.
| | - Andrea L Hobkirk
- Department of Psychiatry and Behavioral Health, Penn State College of Medicine, USA.
| | - Patricia Sue Grigson
- Department of Neural and Behavioral Sciences, Penn State College of Medicine, USA
| | - Andrea L Hobkirk
- Department of Psychiatry and Behavioral Health, Penn State College of Medicine, USA
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