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Siddiqui HF, Waqas SA, Batool RM, Salim H, Minhas AMK, Hasni SF, Alsaid A, Sannino A, Afzal AM, Khan MS. The effect of GLP-1 receptor agonists on cardiac remodeling in heart failure patients with preserved and reduced ejection fraction: a systematic review and meta-analysis. Heart Fail Rev 2025:10.1007/s10741-025-10523-0. [PMID: 40399552 DOI: 10.1007/s10741-025-10523-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/30/2025] [Indexed: 05/23/2025]
Abstract
BACKGROUND Glucagon-like peptide-1 receptor agonists (GLP-1RA) have shown promising effects on heart failure (HF) outcomes, particularly in phenotype-specific populations. However, their impact on cardiac structure and function in HF with preserved ejection fraction (HFpEF) and reduced ejection fraction (HFrEF) remains unclear. METHODS Medline, Cochrane Library, and Scopus were queried through December 2024 for primary and secondary analyses of randomized controlled trials comparing GLP-1RA with placebo in HF patients. Outcomes included changes in left ventricular ejection fraction (LVEF), end-diastolic volume (LVEDV), end-systolic volume (LVESV), global longitudinal strain (GLS), left ventricular mass, left atrial volume (LAV), and NT-proBNP levels. Random-effects models were used to calculate weighted mean differences (WMDs) or hazard ratios (HRs). RESULTS Six trials (n = 1,195) were included, with three each evaluating HFpEF and HFrEF populations. In patients with HFpEF, GLP-1RA significantly reduced the LV mass (WMD: -8.6 g; 95% CI: -14.6, -2.6; p = 0.005) and LAV (WMD: -5.4 ml; 95% CI: -8.8, -2.0; p = 0.002) and lowered NT-proBNP concentration throughout (HR: 0.85; 95% CI: 0.8, 0.9; p < 0.001). A decrease in LAV was observed in the HFrEF population (WMD: -5.4 ml [95% CI: -8.8, -2.0]; p = 0.002). However, no significant improvements were observed in LVEF, LVEDV, LVESV, or GLS. There were significant differences between HFpEF and HFrEF for LVEDV (p = 0.01) and LVESV (p = 0.04). CONCLUSIONS GLP-1RA demonstrated phenotype-specific benefits, improving structural remodeling in HFpEF but showing limited effects in HFrEF. These findings highlight the importance of targeted therapeutic strategies based on HF phenotypes. Further research is warranted to elucidate underlying mechanisms and optimize patient selection.
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Affiliation(s)
| | - Saad Ahmed Waqas
- Department of Medicine, Dow University of Health Sciences, Karachi, Pakistan
| | | | - Hussain Salim
- Department of Medicine, Dow University of Health Sciences, Karachi, Pakistan
| | | | | | - Amro Alsaid
- Baylor Scott and White Heart Hospital, Plano, TX, USA
| | - Anna Sannino
- Baylor Scott and White Research Institute Cardiac Imaging Core Laboratory, Plano, TX, USA
| | - Aasim M Afzal
- Baylor Scott and White Heart Hospital, Plano, TX, USA
| | - Muhammad Shahzeb Khan
- Baylor Scott and White Heart Hospital, Plano, TX, USA.
- Baylor Scott and White Research Institute Cardiac Imaging Core Laboratory, Plano, TX, USA.
- Baylor College of Medicine, Temple, TX, USA.
- Baylor Scott and White Research Institute, Baylor Scott and White Health, Dallas, TX, USA.
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Karimi MA, Gholami Chahkand MS, Dadkhah PA, Sheikhzadeh F, Yaghoubi S, Esmaeilpour Moallem F, Deyhimi MS, Arab Bafrani M, Shahrokhi M, Nasrollahizadeh A. Comparative effectiveness of semaglutide versus liraglutide, dulaglutide or tirzepatide: a systematic review and meta-analysis. Front Pharmacol 2025; 16:1438318. [PMID: 40444045 PMCID: PMC12120964 DOI: 10.3389/fphar.2025.1438318] [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: 05/31/2024] [Accepted: 04/11/2025] [Indexed: 06/02/2025] Open
Abstract
Background This study seeks to compare the effectiveness of Semaglutide compared to Liraglutide, Dulaglutide, or Tirzepatide. Additionally, it aims to investigate the implications of transitioning from Dulaglutide or Liraglutide to Semaglutide. Methods We searched PubMed, Scopus, Cochrane Library, Google Scholar, and Web of Science (ClinicalTrials.gov for unpublished records) from their inception to 5 February 2025, including observational cohort studies and randomized controlled trials. Analyses were conducted using Review Manager (RevMan) version 5.4.1 and STATA 17. Results The meta-analysis comprised 16 studies and 5,997 patients. Semaglutide significantly reduced hemoglobin A1c (HbA1c) levels compared to Liraglutide (0.56; 95% CI: 0.19-0.94; p < 0.001). However, no significant differences were observed between Semaglutide and Liraglutide in terms of fasting blood sugar (FBS), body mass index (BMI), and weight change. In comparison to Dulaglutide, Semaglutide displayed superior efficacy in reducing HbA1c levels (3.72; 95% CI: 0.02-7.41; p = 0.05) and FBS (2.66; 95% CI: 0.26-5.07; p = 0.03). However, no significant differences were found in weight and BMI change. Tirzepatide exhibited a notable advantage over Semaglutide in reducing HbA1c levels (-0.45; 95% CI: -0.88 to -0.02; p = 0.04). However, no clear superiority was observed for weight and FBS change. Transitions from Liraglutide to Semaglutide did not significantly impact HbA1c levels. However, weight loss (2.48; 95% CI: 0.45-4.51; p = 0.02) and reduced FBS levels (10.76; 95% CI: 0.55-20; p = 0.04) were observed. Transitioning from Dulaglutide to Semaglutide did not significantly affect HbA1c levels and weight change. Conclusion While the precise source of heterogeneity remains elusive across most studies, analyses consistently demonstrate Semaglutide's superior efficacy compared to Liraglutide in reducing both HbA1c levels and weight. Moreover, it presents advantages over Dulaglutide, specifically in lowering FBS levels. However, Tirzepatide surpasses Semaglutide in its efficacy for reducing HbA1c levels.
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Affiliation(s)
- Mohammad Amin Karimi
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | | | | | - Shayan Yaghoubi
- Student Research Committee, Faculty of Medicine, Islamic Azad University of Ardabil, Ardabil, Iran
| | | | | | - Melika Arab Bafrani
- School of Medicine, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | | | - Amir Nasrollahizadeh
- Tehran Heart Center, Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
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Min JS, Jo SJ, Lee S, Kim DY, Kim DH, Lee CB, Bae SK. A Comprehensive Review on the Pharmacokinetics and Drug-Drug Interactions of Approved GLP-1 Receptor Agonists and a Dual GLP-1/GIP Receptor Agonist. Drug Des Devel Ther 2025; 19:3509-3537. [PMID: 40330819 PMCID: PMC12052016 DOI: 10.2147/dddt.s506957] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2024] [Accepted: 04/14/2025] [Indexed: 05/08/2025] Open
Abstract
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are peptide-derived analogs that were initially investigated to treat type 2 diabetes. Recently, a drug targeting the receptors of both GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) (tirzepatide) has been introduced to the market, and its indications have expanded to include treating obesity. Here, we review the pharmacokinetics, pharmacokinetic drug-drug interactions (DDIs), and pharmacokinetic modeling approaches of four currently available GLP-1 RAs (exenatide, liraglutide, dulaglutide, and semaglutide) and tirzepatide. To address the extremely short half-life (2 min) of native human GLP-1, structural modifications have been applied to GLP-1 RAs and a dual GLP-1/GIP RA. These include amino acid sequence substitutions, fatty acid conjugation using a linker, and fusion with albumin or the IgG fragment crystallizable (Fc) region, resulting in minimal metabolism and renal excretion. Due to their diverse structures, the pharmacokinetic profiles vary, and a prolonged half-life may be associated with an increased risk of adverse events. Clinically significant drug-metabolizing enzyme- and transporter-mediated DDIs are yet to be reported. Mechanism-of-action-mediated DDIs are currently limited to those involving delayed gastric emptying, and most studies have found them to be clinically insignificant. However, significant changes in exposure were observed for oral contraceptives and levothyroxine following the administration of tirzepatide and oral semaglutide, respectively, indicating the need for close monitoring in these instances. Thirty models have been developed to predict pharmacokinetics and physiologically based pharmacokinetic modeling can be useful for assessing mechanism-of-action-mediated DDIs. Alterations in the volume of distribution and clearance resulting from other mechanisms of action (eg, reduced fat mass, changes in cytochrome P450 activity, and glomerular filtration rate) are key factors in determining pharmacokinetics. However, the DDIs mediated by these factors remain poorly understood and require further investigation to ensure that GLP-1 RAs can be safely used with concomitant medications.
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Affiliation(s)
- Jee Sun Min
- College of Pharmacy and Integrated Research Institute of Pharmaceutical Sciences, The Catholic University of Korea, Bucheon, 14662, Republic of Korea
| | - Seong Jun Jo
- College of Pharmacy and Integrated Research Institute of Pharmaceutical Sciences, The Catholic University of Korea, Bucheon, 14662, Republic of Korea
- Department of Pharmaceutical Sciences, State University of New York, Buffalo, NY, 14214, USA
| | - Sangyoung Lee
- College of Pharmacy and Integrated Research Institute of Pharmaceutical Sciences, The Catholic University of Korea, Bucheon, 14662, Republic of Korea
| | - Duk Yeon Kim
- College of Pharmacy and Integrated Research Institute of Pharmaceutical Sciences, The Catholic University of Korea, Bucheon, 14662, Republic of Korea
| | - Da Hyun Kim
- College of Pharmacy and Integrated Research Institute of Pharmaceutical Sciences, The Catholic University of Korea, Bucheon, 14662, Republic of Korea
| | - Chae Bin Lee
- Johns Hopkins Drug Discovery, Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA
| | - Soo Kyung Bae
- College of Pharmacy and Integrated Research Institute of Pharmaceutical Sciences, The Catholic University of Korea, Bucheon, 14662, Republic of Korea
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Yu H, Davoudi M, Sadegh-Nejadi S, Miao X, Bagherieh M, Afrisham R. Impact of monotherapy and combination therapy with glucagon-like peptide-1 receptor agonists on exosomal and non-exosomal MicroRNA signatures in type 2 diabetes mellitus: a systematic review. J Transl Med 2025; 23:477. [PMID: 40281607 PMCID: PMC12032824 DOI: 10.1186/s12967-025-06461-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2025] [Accepted: 04/06/2025] [Indexed: 04/29/2025] Open
Abstract
BACKGROUND Glucagon-like peptide-1 receptor agonist (GLP-1RAs) is a potent therapy for type 2 diabetes mellitus (T2DM) and obesity, especially in patients who are resistant to long-term insulin therapy. Although microRNAs have been linked to GLP-1 signaling, their role in GLP-1RA monotherapy and combination therapy remains unclear. This review synthesizes current evidence of GLP-1RA-induced exosomal and non-exosomal miRNA changes in human and animal models of T2DM. METHODS Scopus, PubMed/Medline, Web of Science, and Google Scholar searches returned 83 studies, of which 11 met the study eligibility criteria (PROSPERO No: CRD42024586000). RESULTS Human studies showed GLP-1RA combined with metformin modulated non-exosomal miR-27b, miR-130a, and miR-210a, which were linked to cardiovascular health. In T2DM patients on metformin, higher baseline miR-378-3p or miR-126-3p correlated with greater HbA1c improvement after one year of GLP-1RA therapy. Notably, > 5% weight loss correlated with higher baseline levels of miR-15a-5p. Preclinical findings suggested GLP-1RA monotherapy increased cardiovascular action via non-exosomal miR-29b-3p, miR-34a-5p, miR-26a-5p, miR-181a-5p, and miR-93-5p. Silencing non-exosomal miR-204, miR-375, or miR-139-5p augmented exendin-4/liraglutide monotherapy-induced glucose-stimulated insulin secretion. Interestingly, GLP-1RA monotherapy reduced hepatic lipid accumulation in T2DM models with comorbid NAFLD via ABHD6 mRNA modulation by non-exosomal miR-5120. No clinical studies reported exosomal miRNAs, but a preclinical study linked GLP-1RA-induced exosomal let-7c-2-3p/miR-322-3p to bone protection in estrogen-deficient T2DM models. CONCLUSION GLP-1RAs, both as first-line and second-line therapies, are beneficial for T2DM complicated by obesity, NAFLD, cardio-metabolic disease, and postmenopausal osteoporosis. Longitudinal trials that incorporate innovative multi-omics approaches are essential for distinguishing their miRNA expression pattern from other anti-diabetics.
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Affiliation(s)
- Haifeng Yu
- Hubei Key Laboratory of Diabetes and Angiopathy, School of Pharmacy, Xianning Medical College, Hubei University of Science and Technology, Xianning, 437100, Hubei Province, China
| | - Maryam Davoudi
- Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Tehran University of Medical Sciences, Tehran, Iran
| | - Sahar Sadegh-Nejadi
- Department of Clinical Laboratory, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Xiaolei Miao
- Hubei Key Laboratory of Diabetes and Angiopathy, School of Pharmacy, Xianning Medical College, Hubei University of Science and Technology, Xianning, 437100, Hubei Province, China.
| | - Molood Bagherieh
- Ramsar Campus, Mazandaran University of Medical Sciences, Ramsar, Iran.
| | - Reza Afrisham
- Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Tehran University of Medical Sciences, Tehran, Iran.
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Al Lawati A, Alhabsi A, Rahul R, Savino ML, Alwahaibi H, Das S, Al Lawati H. Current and Emerging Parenteral and Peroral Medications for Weight Loss: A Narrative Review. Diseases 2025; 13:129. [PMID: 40422561 DOI: 10.3390/diseases13050129] [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: 02/27/2025] [Revised: 04/03/2025] [Accepted: 04/08/2025] [Indexed: 05/28/2025] Open
Abstract
Obesity is a growing global health challenge, necessitating effective treatment options beyond lifestyle interventions. This narrative review explores established and emerging pharmacotherapies for weight management, including parenteral agents like Liraglutide, Semaglutide, Setmelanotide, and Tirzepatide, as well as peroral medications such as Phentermine, Phentermine/Topiramate, Bupropion/Naltrexone, Orlistat, and Metformin. Newer treatments like Cagrilintide and Bimagrumab show promise for enhancing weight loss outcomes. Parenteral GLP-1 receptor agonists demonstrate superior efficacy compared to traditional peroral medications, with gastrointestinal side effects being the most common. Artificial intelligence presents intriguing opportunities to enhance weight loss strategies; however, its integration into clinical practice remains investigational and requires rigorous clinical validation. While current anti-obesity medications deliver significant benefits, future research must determine the efficacy, safety, and cost-effectiveness of AI-driven approaches. This includes exploring how AI can complement combination therapies and tailor personalized interventions, thereby grounding its potential benefits in robust clinical evidence. Future directions will focus on integrating AI into clinical trials to refine and personalize obesity management strategies.
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Affiliation(s)
- Abdullah Al Lawati
- Sultan Qaboos University Hospital, Al-Khoud 123, P.O. Box 50, Muscat 123, Oman
| | - Ayman Alhabsi
- Department of Medicine, Royal College of Surgeons, 123 St Stephen's Green, D02 YN77 Dublin, Ireland
| | - Rhieya Rahul
- Department of Medicine, Royal College of Surgeons, 123 St Stephen's Green, D02 YN77 Dublin, Ireland
| | - Maria-Luisa Savino
- Department of Medicine, Royal College of Surgeons, 123 St Stephen's Green, D02 YN77 Dublin, Ireland
| | - Hamed Alwahaibi
- Department of Medicine, Royal College of Surgeons, 123 St Stephen's Green, D02 YN77 Dublin, Ireland
| | - Srijit Das
- Department of Human and Clinical Anatomy, College of Medicine and Health Sciences, Sultan Qaboos University, Al-Khoudh 123, P.O. Box 50, Muscat 123, Oman
| | - Hanan Al Lawati
- Pharmacy Program, Department of Pharmaceutics, Oman College of Health Sciences, P.O. Box 393, Muscat 113, Oman
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Li J, Mohamed B, Huang S, Peng YG. Aspiration risk and strategic approach for patients receiving GLP-1 receptor agonists undergoing elective surgery. Curr Med Res Opin 2025; 41:699-712. [PMID: 40241295 DOI: 10.1080/03007995.2025.2494646] [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: 02/18/2025] [Revised: 04/10/2025] [Accepted: 04/14/2025] [Indexed: 04/18/2025]
Abstract
Perioperative management of patients receiving a glucagon-like peptide-1 receptor agonist (GLP-1 RA) remains challenging for the anesthesiologist. Despite the approval of GLP-1 RAs 2 decades ago, the recent reports of aspiration and postoperative pulmonary complications drew attention to this group of medications and resulted in multiple societal guidelines that would provide recommendations for anesthesiologists and proceduralists on the appropriate perioperative management of GLP-1 RAs. However, despite these guidelines and proposed options, there was a lack of adequate evidence to support holding versus continuing the medication, as well as data related to the role of gastric ultrasound in that decision-making process. The release of multiple societal guidelines and studies evaluating the impact of GLP-1 RAs on perioperative outcomes resulted in more controversy and uncertainty for the clinician anesthesiologist to follow. The ultimate goal for perioperative management of these medications is to evaluate an individual patient's risk of aspiration, rather than assuming the risk is low when holding the medication appropriately or high if not holding it. Furthermore, it is unclear whether holding these types of medicines or unnecessary postponing of surgery may result in adverse outcomes. In this narrative review, we present a summary of the existing literature on the topic with a focus on the risk of aspiration and a recommendation for perioperative management to include the utilization of gastric ultrasound for surgery patients based on their risks.
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Affiliation(s)
- Juan Li
- Division of Cardiothoracic Anesthesia, Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Basma Mohamed
- Division of Neuroanesthesiology, Department of Anesthesiology, Duke University School of Medicine, Durham, NC, USA
| | - Shun Huang
- Division of Regional & Ambulatory Anesthesia, Department of Anesthesiology, Barnes Jewish Hospital, Washington University School of Medicine, St. Louis, MO, USA
| | - Yong G Peng
- Division of Cardiothoracic Anesthesia, Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, USA
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Wang M, Wang L, Sun H, Yuan H, Li Y. Mechanisms of ferroptosis and glucagon-like peptide-1 receptor agonist in post-percutaneous coronary intervention restenosis. Mol Cell Biochem 2025; 480:1465-1480. [PMID: 39283562 DOI: 10.1007/s11010-024-05118-6] [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: 08/15/2024] [Accepted: 09/06/2024] [Indexed: 02/21/2025]
Abstract
Cardiovascular disease (CVD) claims millions of lives every year, with atherosclerotic cardiovascular disease (ASCVD) being the main cause. ASCVD treatment includes drug therapy, lifestyle intervention, and Percutaneous Coronary Intervention (PCI) all of which significantly enhance cardiovascular function and reduce mortality. However, hyperplasia can lead to vascular obstruction, worsen angina symptoms, or even cause heart disease, affecting patients' long-term prognosis. Therefore, finding effective ways to combat hyperplasia is crucial for cardiovascular therapy. In recent years, ferroptosis has gained attention as a new form of cell death closely associated with several diseases, including cardiovascular diseases. It involves complex metabolic processes critical for cellular homeostasis and normal function. Abnormal proliferation and phenotypic transformation of vascular smooth muscle cells (VSMC) are crucial mechanisms underlying cardiovascular disease development. Inhibiting ferroptosis in VSMC has the potential to significantly reduce neointima proliferation. Glucagon-like peptide-1 receptor agonist (GLP-1RA) constitutes a widely employed class of hypoglycemic agents with direct implications for the cardiovascular system, mitigating adverse cardiovascular events. Research indicates that the stimulation of GLP-1 holds promise as a therapeutic strategy in mitigating cardiovascular events such as restenosis. Hence, investigating the potential of GLP-1RA as a treatment option for cardiovascular ailments carries immense clinical significance.
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Affiliation(s)
- Miao Wang
- Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Liren Wang
- Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Huanxin Sun
- Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Hong Yuan
- Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Yonghong Li
- Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China.
- Department of Cardiology, The Affiliated Cardiovascular Hospital of Qingdao University, No.59 Haier Road, Qingdao, 266071, China.
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Murphy A, Shyanti RK, Mishra M. Targeting obesity, metabolic syndrome, and prostate cancer: GLP-1 agonists as emerging therapeutic agents. Discov Oncol 2025; 16:258. [PMID: 40024963 PMCID: PMC11872791 DOI: 10.1007/s12672-025-01878-9] [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: 11/06/2024] [Accepted: 02/03/2025] [Indexed: 03/04/2025] Open
Abstract
Prostate cancer (PCa) is known as the second most common cancer and has one of the highest incidences among male cancers in the United States. In addition, obesity and metabolic syndrome are a rising and continuous issue in the United States, with 41.9% of individuals as obese. The importance of highlighting these figures is the possibility of PCa having a progressive relationship with obesity and metabolic syndromes. The drugs developed for treating obesity and diabetes pose an exciting possibility of therapeutic application for cancer in efforts to relieve the population's rising numbers. Although this connection has not been established in detail, there are some PCa key biomarkers, and their interactions with metabolic products found in obese, diabetic, and PCa patients can provide good starting points for further investigation. One of the significant links between PCa, obesity, and metabolic disease may be due to insulin metabolism. A downstream target identified that could be the link between PCa, metabolic syndromes, and obesity is the forkhead box C2 (FOXC2). FOXC2 has been known to inhibit some insulin-resistant genes and cause the proliferation of PCa. The relationships of FOXC2, insulin resistance, and GLP-1 receptor agonists as potential therapeutic applications have not been thoroughly explored. This review covers a broad relationship of PCa, obesity, metabolic syndromes, possible drugs, and therapeutic targets.
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Affiliation(s)
- Azura Murphy
- Cancer Research Center, Department of Biological Sciences, Alabama State University, Montgomery, AL, 36104, USA
| | - Ritis Kumar Shyanti
- Cancer Research Center, Department of Biological Sciences, Alabama State University, Montgomery, AL, 36104, USA
| | - Manoj Mishra
- Cancer Research Center, Department of Biological Sciences, Alabama State University, Montgomery, AL, 36104, USA.
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Miao X, Davoudi M, Alitotonchi Z, Ahmadi ES, Amraee F, Alemi A, Afrisham R. Managing cardiovascular events, hyperglycemia, and obesity in type 2 diabetes through microRNA regulation linked to glucagon-like peptide-1 receptor agonists. Diabetol Metab Syndr 2025; 17:13. [PMID: 39794819 PMCID: PMC11724456 DOI: 10.1186/s13098-025-01581-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Accepted: 01/05/2025] [Indexed: 01/13/2025] Open
Abstract
BACKGROUND AND AIMS Type 2 diabetes mellitus (T2DM) is usually complicated by cardiovascular diseases, hyperglycemia, and obesity, which worsen the outcome for the patient. Since recent evidence underlines the epigenetic role of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in the management of these comorbidities, this study compared the effects of these agents, namely liraglutide, semaglutide, dulaglutide, and exenatide, on miRNA regulation in the management of T2DM. RESULTS GLP-1RAs modify the expression of miRNAs involved in endothelial function, sugar metabolism, and adipogenesis, including but not limited to miR-27b, miR-130a, and miR-210. Baseline miR-15a-5p predict weight loss, while higher miR-378-3p and miR-126-3p levels are related to better glycemic control and lower HbA1c and FPG at one year post-treatment. miR-375-5p was also reported as a predictor of HbA1c levels. Liraglutide has a protecting effect against pancreatic β-cell apoptosis by downregulating miR-139-5p. The highly-expressed miR-375 in pancreatic islets can be considered as a biomarker for assessing the cytoprotective action of GLP-1RAs on β-cells. GLP-1RAs also enhance β-cell responsiveness by promoting GLP-1 receptor expression through the suppression of miR-204. While semaglutide, semaglutide, and dulaglutide reduce both systolic and diastolic blood pressures, lixisenatide and exenatide QW did not reveal such an effect. The long-acting exenatide-induced miR-29b-3p is required for the protection against diabetic cardiomyopathy. Liraglutide modulates critical regulators of endothelial cell function and atherosclerosis, including miR-93-5p, miR-26a-5p, and miR-181a-5p. Eventually, GLP-1RAs regulation of exosomal miRNAs, such as miR-192, implicated in the development of fibrosis and inflammation in T2DM micro-cardiovascular outcomes like DKD and DR. CONCLUSION Additional studies will be needed in the elucidation of the relations between GLP-1RA-induced miRNAs and clinical-laboratory findings concerning the diverse populations, gender, and presence of other comorbid states in treated patients with T2DM.
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Affiliation(s)
- Xiaolei Miao
- School of Pharmacy, Xianning Medical College, Hubei University of Science and Technology, Xianning, 437100, China
| | - Maryam Davoudi
- Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Tehran University of Medical Sciences, Tehran, Iran
| | - Zahra Alitotonchi
- Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Tehran University of Medical Sciences, Tehran, Iran
| | - Ensieh Sadat Ahmadi
- Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Amraee
- Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Tehran University of Medical Sciences, Tehran, Iran
| | - Ashraf Alemi
- Abadan University of Medical Sciences, Abadan, Iran.
| | - Reza Afrisham
- Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Tehran University of Medical Sciences, Tehran, Iran.
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VanderWielen BA, Brian Beam W. Perioperative Considerations for Patients on GLP1 Agonists. Adv Anesth 2024; 42:1-26. [PMID: 39443044 DOI: 10.1016/j.aan.2024.07.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2024]
Abstract
GlP-1 receptor agonists are a class of medications that are becoming increasingly popular. Large trials have shown that their use provides reliable weight loss in obese patients and improved glycemic control in diabetic patients. Its use also has broader implications for overall metabolic health and has been shown to improve cardiovascular outcomes in high-risk populations. Glucagon-like peptide 1 receptors cause multiple effects in the body through stimulation of receptors expressed in a broad range of tissues including the pancreas, liver, gastrointestinal tract, kidneys, heart, endothelium, muscle, and brain. For the anesthesia professionals the effects of these medications on gastric emptying is important.
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Joshi N, Baloch KM, Rukh S, Khan AM, Muskan F, Kumari V, Khan H, Zeeshan M, Azam G, Khalid S, Anwar IB, Ahmed IF, Nishat SM, Gandhi F. Unlocking the potential of glucagon-like peptide-1 receptor agonists in revolutionizing type 2 diabetes management: a comprehensive review. Ann Med Surg (Lond) 2024; 86:7255-7264. [PMID: 39649934 PMCID: PMC11623894 DOI: 10.1097/ms9.0000000000002712] [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: 07/06/2024] [Accepted: 10/25/2024] [Indexed: 12/11/2024] Open
Abstract
Diabetes mellitus (DM) is a long-term metabolic disorder caused by inadequate production and resistance to insulin. The prevalence of DM is rapidly increasing, with type 2 diabetes (T2D) accounting for more than 90% of cases. Despite new treatments, many patients with T2D do not meet their glycemic targets due to clinical inertia. This review provides an overview of glucagon-like peptide 1 receptor agonists (GLP-1 RAs) in the management of T2D. The review synthesizes data from clinical trials and meta-analyses on the efficacy, safety, and cost-effectiveness of GLP-1 RAs. It also discusses the mechanisms of action, classification, and barriers to adherence and persistence in therapy. GLP-1 RAs improve glycemic control by lowering A1C levels and promoting weight loss. They have cardioprotective effects and may reduce endothelial inflammation, oxidative stress, and blood pressure. Adherence to GLP-1 RAs is better with once-weekly injections, though gastrointestinal side effects and cost can affect persistence. Semaglutide and liraglutide have shown significant weight reduction, with semaglutide being particularly effective. GLP-1 RAs are cost-effective due to reduced healthcare costs associated with fewer hospitalizations and lower mortality rates. Safety concerns include gastrointestinal issues, pancreatitis, and rare cases of diabetic retinopathy and thyroid C-cell tumors. For clinical practice, GLP-1 RAs represent a valuable option not only for glycemic control but also for weight management and cardiovascular protection. Incorporating GLP-1 RAs into treatment plans can improve patient outcomes, and optimizing dosing regimens and addressing barriers such as cost and side effects are crucial to enhancing patient adherence and long-term treatment success.
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Affiliation(s)
- Nandan Joshi
- Department of Internal Medicine, Surat Municipal Institute of Medical Education and Research, Surat, India
| | - Kanwal Mir Baloch
- Department of Internal Medicine, Liaquat University of Medical and Health Sciences, Jamshoro, Pakistan
| | - Shah Rukh
- Department of Internal Medicine, Jinnah Sindh Medical University, Karachi, Pakistan
| | - Abdul Moiz Khan
- Department of Internal Medicine, Sahiwal Medical College, Sahiwal, Pakistan
| | - Fnu Muskan
- Department of Internal Medicine, Khairpur Medical College, Khairpur, Pakistan
| | - Verkha Kumari
- Department of Internal Medicine, Liaquat National Hospital and Medical College, Karachi, Pakistan
| | - Hasher Khan
- Department of Internal Medicine, Dow Medical College, Karachi, Pakistan
| | - Mohd Zeeshan
- Department of Internal Medicine, Career Institute of Medical Sciences and Hospital, Lucknow, India
| | - Ghufran Azam
- Department of Internal Medicine, Liaquat University of Medical and Health Sciences, Jamshoro, Pakistan
| | - Saif Khalid
- Department of Internal Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Insa Binte Anwar
- Department of Internal Medicine, Liaquat National Hospital and Medical College, Karachi, Pakistan
| | - Iqra Furqan Ahmed
- Department of Internal Medicine, Liaquat National Hospital and Medical College, Karachi, Pakistan
| | - Syeed Mahmud Nishat
- Department of Internal Medicine, Shaheed Suhrawardy Medical College, Dhaka, Bangladesh
| | - Fenil Gandhi
- Department of Family Medicine, PGY2, Lower Bucks Hospital, Bristol, PA, USA
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Alghamdi FA, Alshegifi HA, Alhuthayli RS, Helal T, Huwait TA, Alharbi T, Akbar AF, Alshehri W, AlSheikh SM. Bridging the Gap Between Diabetes and Cardiovascular Disease: A Comparative Review of Different Glucagon-Like Peptide-1 (GLP-1) Agonists: Efficacy, Safety, and Patient Outcomes. Cureus 2024; 16:e74345. [PMID: 39720384 PMCID: PMC11668125 DOI: 10.7759/cureus.74345] [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: 11/24/2024] [Indexed: 12/26/2024] Open
Abstract
Diabetes mellitus, particularly Type 2 diabetes (T2DM) remains a significant concern globally with an increase in prevalence reported in recent years. If diabetes is not managed properly, it can lead to several complications including an increased risk of cardiovascular disease (CVD). Cardiovascular complications such as coronary heart disease, peripheral artery disease, and stroke are common among individuals with diabetes. Therefore, the timely management of diabetes becomes very important. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have emerged as a promising class of medications that offer benefits beyond glycemic control. Among various benefits, GLP-1 RAs can promote pancreatic β-cell proliferation and reduce their apoptosis. They also exert central effects on appetite and energy balance. Furthermore, the weight-lowering potential of GLP-1 RAs has also been documented in literature which can provide indirect benefit to CVD prevention. Long-term GLP-1 RAs generally have superior efficacy over short-term GLP-1 RAs in terms of controlling overnight and fasting plasma glucose levels. However, short-acting GLP-1 RAs, such as exenatide and lixisenatide, maintain their influence on gastric emptying during prolonged use. Adverse events, particularly, gastrointestinal adverse events, remain a concern with GLP-1 RA use. These symptoms usually appear at the start of treatment but fade as the body adjusts to the medication. GLP-1 RAs have shown beneficial effects on cardiovascular health, including a reduction in the incidence of major adverse cardiovascular events. In conclusion, GLP-1 RAs provide multifaceted benefits in T2DM as they not only maintain glycemic control but also decrease cardiovascular risk.
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Affiliation(s)
- Feras A Alghamdi
- Family Medicine, King Fahad Military Medical Complex, Jeddah, SAU
| | | | | | - Turki Helal
- Family Medicine, King Abdulaziz Medical City Jeddah, Jeddah, SAU
| | - Turki A Huwait
- Family Medicine, King Abdulaziz Medical City Jeddah, Jeddah, SAU
| | - Turki Alharbi
- Family Medicine, King Abdulaziz Medical City Jeddah, Jeddah, SAU
| | | | - Wejdan Alshehri
- Medicine, King Abdulaziz University Faculty of Medicine, Jeddah, SAU
- Family Medicine, King Abdulaziz Medical City Jeddah, Jeddah, SAU
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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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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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Rahman SS, Klamrak A, Nopkuesuk N, Nabnueangsap J, Janpan P, Choowongkomon K, Daduang J, Daduang S. Impacts of Plu kaow ( Houttuynia cordata Thunb.) Ethanolic Extract on Diabetes and Dyslipidemia in STZ Induced Diabetic Rats: Phytochemical Profiling, Cheminformatics Analyses, and Molecular Docking Studies. Antioxidants (Basel) 2024; 13:1064. [PMID: 39334723 PMCID: PMC11428413 DOI: 10.3390/antiox13091064] [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: 07/29/2024] [Revised: 08/24/2024] [Accepted: 08/27/2024] [Indexed: 09/30/2024] Open
Abstract
The increasing prevalence of diabetes and dyslipidemia poses significant health challenges, impacting millions of people globally and leading to high rates of illness and death. This study aimed to explore the potential antidiabetic and hypolipidemic effects of Plu kaow (Houttuynia cordata Thunb.) ethanolic extract (PK) in streptozotocin (STZ) induced diabetic rats, focusing on its molecular mechanisms. Diabetes was induced in fasting Long Evans rats using streptozotocin (65 mg/kg b. w.), with glibenclamide (5 mg/kg/day) used as the standard experimental drug. The treated groups received oral supplementation of PK (500 mg/kg/day) for 28 days. The study evaluated blood glucose levels, lipid status, body weight, liver, kidney, and heart function biomarkers, antioxidant activity, and histological examination of various organs. Additionally, untargeted metabolomics, cheminformatics, and molecular docking were employed to elucidate the probable mechanisms of action of PK. Based on metabolomic profiling data, the PK was found to contain various putative antidiabetic agents such as kaempferol 7-neohesperidoside, isochlorogenic acid C, rutin, datiscin, and diosmin and they have been proposed to significantly (p < 0.001) reduce blood glucose levels and modulated hyperlipidemia. PK also improved the tested liver, kidney, and heart function biomarkers and reversed damage to normal pancreatic, liver, kidney, and heart cells in histological analysis. In conclusion, PK shows promise as a potential treatment or management option for diabetes and hyperlipidemia, as well as their associated complications in diabetic rats.
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Affiliation(s)
- Shaikh Shahinur Rahman
- Division of Pharmacognosy and Toxicology, Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand
- Department of Applied Nutrition and Food Technology, Faculty of Biological Sciences, Islamic University, Kushtia 7003, Bangladesh
| | - Anuwatchakij Klamrak
- Division of Pharmacognosy and Toxicology, Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Napapuch Nopkuesuk
- Division of Pharmacognosy and Toxicology, Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Jaran Nabnueangsap
- Salaya Central Instrument Facility RSPG, Research Management and Development Division, Office of the President, Mahidol University, Nakhon Pathom 73170, Thailand
| | - Piyapon Janpan
- Division of Pharmacognosy and Toxicology, Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Kiattawee Choowongkomon
- Department of Biochemistry, Faculty of Science, Kasetsart University, Bangkok 10900, Thailand
| | - Jureerut Daduang
- Department of Clinical Chemistry, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Sakda Daduang
- Division of Pharmacognosy and Toxicology, Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand
- Protein and Proteomics Research Center for Commercial and Industrial Purposes (ProCCI), Khon Kaen University, Khon Kaen 40002, Thailand
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Ghazanfar H, Javed N, Qasim A, Sosa F, Altaf F, Khan S, Mahasamudram J, Jyala A, Kandhi SD, Shin D, Mantri N, Sun H, Hanumanthu S, Patel H, Makker J, Balar B, Dev A, Chilimuri S. Is it necessary to stop glucagon-like peptide-1 receptor agonists prior to endoscopic procedure? A retrospective study. World J Gastroenterol 2024; 30:3221-3228. [PMID: 39086638 PMCID: PMC11287410 DOI: 10.3748/wjg.v30.i26.3221] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Revised: 05/14/2024] [Accepted: 06/24/2024] [Indexed: 07/09/2024] Open
Abstract
BACKGROUND Glucagon-like peptide-1 receptor agonists (GLP-1 RA) are effective in diabetes and obesity, reducing hyperglycemia by increasing insulin release and delaying gastric emptying. However, they can cause gastroparesis, raising concerns about aspiration during procedures. Recent guidelines advise discontinuing GLP-1 RA before surgery to reduce the risk of pulmonary aspiration. AIM To evaluate the effect of GLP-1 RAs on gastric residual contents during endoscopic procedures. METHODS A retrospective chart review at BronxCare Health System, New York, from January 2019 to October 2023, assessed gastric residue and aspiration in GLP-1 RA patients undergoing endoscopic procedures. Two groups were compared based on dietary status before the procedure. Data included demographics, symptoms of gastroparesis, opiate use, hemoglobin A1c, GLP-1 agonist indication, endoscopic details, and aspiration occurrence. IBM SPSS was used for analysis, calculating means, standard deviations, and applying Pearson's chi-square and t-tests for associations, with P < 0.05 as being significant. RESULTS During the study, 306 patients were included, with 41.2% on a clear liquid/low residue diet and 58.8% on a regular diet before endoscopy. Most patients (63.1%) were male, with a mean age of 60 ± 12 years. The majority (85.6%) were on GLP-1 RAs for diabetes, and 10.1% reported digestive symptoms before endoscopy. Among those on a clear liquid diet, 1.5% had residual food at endoscopy compared to 10% on a regular diet, which was statistically significant (P = 0.03). Out of 31 patients with digestive symptoms, 13% had residual food, all from the regular diet group (P = 0.130). No complications were reported during or after the procedures. CONCLUSION The study reflects a significant rise in GLP-1 RA use for diabetes and obesity. A 24-hour liquid diet seems safe for endoscopic procedures without aspiration. Patients with upper gastrointestinal symptoms might have a higher residual food risk, though not statistically significant. Further research is needed to assess risks based on diabetes duration, gastroparesis, and GLP-1 RA dosing, aiming to minimize interruptions in therapy during procedures.
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Affiliation(s)
- Haider Ghazanfar
- Division of Gastroenterology, Department of Internal Medicine, BronxCare Health System, Icahn School of Medicine at Mount Sinai, Bronx, NY 10457, United States
| | - Nismat Javed
- Department of Internal Medicine, BronxCare Health System, Icahn School of Medicine at Mount Sinai, Bronx, NY 10457, United States
| | - Abeer Qasim
- Department of Internal Medicine, BronxCare Health System, Icahn School of Medicine at Mount Sinai, Bronx, NY 10457, United States
| | - Franklin Sosa
- Department of Internal Medicine, BronxCare Health System, Icahn School of Medicine at Mount Sinai, Bronx, NY 10457, United States
| | - Faryal Altaf
- Department of Internal Medicine, BronxCare Health System, Icahn School of Medicine at Mount Sinai, Bronx, NY 10457, United States
| | - Shazia Khan
- Department of Internal Medicine, BronxCare Health System, Icahn School of Medicine at Mount Sinai, Bronx, NY 10457, United States
| | - Jaydeep Mahasamudram
- Department of Internal Medicine, BronxCare Health System, Icahn School of Medicine at Mount Sinai, Bronx, NY 10457, United States
| | - Abhilasha Jyala
- Division of Gastroenterology, Department of Internal Medicine, BronxCare Health System, Icahn School of Medicine at Mount Sinai, Bronx, NY 10457, United States
| | - Sameer Datta Kandhi
- Division of Gastroenterology, Department of Internal Medicine, BronxCare Health System, Icahn School of Medicine at Mount Sinai, Bronx, NY 10457, United States
| | - Dongmin Shin
- Division of Gastroenterology, Department of Internal Medicine, BronxCare Health System, Icahn School of Medicine at Mount Sinai, Bronx, NY 10457, United States
| | - Nikhitha Mantri
- Division of Gastroenterology, Department of Internal Medicine, BronxCare Health System, Icahn School of Medicine at Mount Sinai, Bronx, NY 10457, United States
| | - Haozhe Sun
- Division of Gastroenterology, Department of Internal Medicine, BronxCare Health System, Icahn School of Medicine at Mount Sinai, Bronx, NY 10457, United States
| | - Siddarth Hanumanthu
- Department of Internal Medicine, BronxCare Health System, Icahn School of Medicine at Mount Sinai, Bronx, NY 10457, United States
| | - Harish Patel
- Division of Gastroenterology, Department of Internal Medicine, BronxCare Health System, Icahn School of Medicine at Mount Sinai, Bronx, NY 10457, United States
| | - Jasbir Makker
- Division of Gastroenterology, Department of Internal Medicine, BronxCare Health System, Icahn School of Medicine at Mount Sinai, Bronx, NY 10457, United States
| | - Bhavna Balar
- Division of Gastroenterology, Department of Internal Medicine, BronxCare Health System, Icahn School of Medicine at Mount Sinai, Bronx, NY 10457, United States
| | - Anil Dev
- Division of Gastroenterology, Department of Internal Medicine, BronxCare Health System, Icahn School of Medicine at Mount Sinai, Bronx, NY 10457, United States
| | - Sridhar Chilimuri
- Division of Gastroenterology, Department of Internal Medicine, BronxCare Health System, Icahn School of Medicine at Mount Sinai, Bronx, NY 10457, United States
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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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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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Alajous S, Budhiraja P. New-Onset Diabetes Mellitus after Kidney Transplantation. J Clin Med 2024; 13:1928. [PMID: 38610694 PMCID: PMC11012473 DOI: 10.3390/jcm13071928] [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: 02/01/2024] [Revised: 03/19/2024] [Accepted: 03/24/2024] [Indexed: 04/14/2024] Open
Abstract
New-Onset Diabetes Mellitus after Transplantation (NODAT) emerges as a prevalent complication post-kidney transplantation, with its incidence influenced by variations in NODAT definitions and follow-up periods. The condition's pathophysiology is marked by impaired insulin sensitivity and β-cell dysfunction. Significant risk factors encompass age, gender, obesity, and genetics, among others, with the use of post-transplant immunosuppressants intensifying the condition. NODAT's significant impact on patient survival and graft durability underscores the need for its prevention, early detection, and treatment. This review addresses the complexities of managing NODAT, including the challenges posed by various immunosuppressive regimens crucial for transplant success yet harmful to glucose metabolism. It discusses management strategies involving adjustments in immunosuppressive protocols, lifestyle modifications, and pharmacological interventions to minimize diabetes risk while maintaining transplant longevity. The importance of early detection and proactive, personalized intervention strategies to modify NODAT's trajectory is also emphasized, advocating for a shift towards more anticipatory post-transplant care.
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Affiliation(s)
| | - Pooja Budhiraja
- Division of Medicine, Mayo Clinic Arizona, Phoenix, AZ 85054, USA;
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20
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Xie X, Wu C, Hao Y, Wang T, Yang Y, Cai P, Zhang Y, Huang J, Deng K, Yan D, Lin H. Benefits and risks of drug combination therapy for diabetes mellitus and its complications: a comprehensive review. Front Endocrinol (Lausanne) 2023; 14:1301093. [PMID: 38179301 PMCID: PMC10766371 DOI: 10.3389/fendo.2023.1301093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Accepted: 11/27/2023] [Indexed: 01/06/2024] Open
Abstract
Diabetes is a chronic metabolic disease, and its therapeutic goals focus on the effective management of blood glucose and various complications. Drug combination therapy has emerged as a comprehensive treatment approach for diabetes. An increasing number of studies have shown that, compared with monotherapy, combination therapy can bring significant clinical benefits while controlling blood glucose, weight, and blood pressure, as well as mitigating damage from certain complications and delaying their progression in diabetes, including both type 1 diabetes (T1D), type 2 diabetes (T2D) and related complications. This evidence provides strong support for the recommendation of combination therapy for diabetes and highlights the importance of combined treatment. In this review, we first provided a brief overview of the phenotype and pathogenesis of diabetes and discussed several conventional anti-diabetic medications currently used for the treatment of diabetes. We then reviewed several clinical trials and pre-clinical animal experiments on T1D, T2D, and their common complications to evaluate the efficacy and safety of different classes of drug combinations. In general, combination therapy plays a pivotal role in the management of diabetes. Integrating the effectiveness of multiple drugs enables more comprehensive and effective control of blood glucose without increasing the risk of hypoglycemia or other serious adverse events. However, specific treatment regimens should be tailored to individual patients and implemented under the guidance of healthcare professionals.
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Affiliation(s)
- Xueqin Xie
- Center for Informational Biology, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
| | - Changchun Wu
- Center for Informational Biology, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
| | - Yuduo Hao
- Center for Informational Biology, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
| | - Tianyu Wang
- Center for Informational Biology, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
| | - Yuhe Yang
- Center for Informational Biology, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
| | - Peiling Cai
- School of Basic Medical Sciences, Chengdu University, Chengdu, China
| | - Yang Zhang
- Innovative Institute of Chinese Medicine and Pharmacy, Academy for Interdiscipline, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jian Huang
- Center for Informational Biology, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
| | - Kejun Deng
- Center for Informational Biology, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
| | - Dan Yan
- Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Hao Lin
- Center for Informational Biology, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
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Ferhatbegović L, Mršić D, Macić-Džanković A. The benefits of GLP1 receptors in cardiovascular diseases. FRONTIERS IN CLINICAL DIABETES AND HEALTHCARE 2023; 4:1293926. [PMID: 38143794 PMCID: PMC10739421 DOI: 10.3389/fcdhc.2023.1293926] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Accepted: 11/16/2023] [Indexed: 12/26/2023]
Abstract
Glucagon like peptide-1 (GLP-1) receptor agonists are well established drugs for the treatment of type 2 diabetes (T2D). In addition to glycemic control, GLP-1 receptor agonists have beneficial other effects. They act by binding to GLP-1 receptors, which are widely distributed in the body, including cardiomyocytes and blood vessels. The aim of this article is to provide a comprehensive review of GLP-1 receptor agonists impact on cardiovascular outcomes and risk reduction. In the last decade, several cardiovascular outcomes trials (CVOT) have been conducted in order to explore cardiovascular benefit of GLP-1 receptor agonists. CVOTs primarily proved cardiovascular safety and tolerability of different GLP-1 receptor agonists, but also showed cardiovascular benefit of specific drugs. CVOTs have shown that GLP-1 receptor agonists reduce MACE in patients with T2D compared to placebo. In addition, they have positive impact on several cardiovascular risk factors such as obesity by promoting weight loss, blood pressure and blood lipid levels. Also, they stimulate the endothelium to produce nitric oxide, reduce oxidative stress, and have antiatherogenic and antiinflammatory effects. Studies have shown their positive impact on kidney outcomes in patients with T2D compared to placebo. The results of previous trials are encouraging in terms of multiple positive effects of GLP-1 receptor agonists. However, further research is needed to understand their full potential and all details of their mechanism of action, which will enable to expand the therapeutic indications and to determine their optimal use in clinical practice.
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Affiliation(s)
- Lamija Ferhatbegović
- Department of Internal Medicine, Cantonal Hospital Zenica, Zenica, Bosnia and Herzegovina
| | - Denis Mršić
- Clinic for Internal Diseases, University Clinical Center Tuzla, Tuzla, Bosnia and Herzegovina
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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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Wojtara M, Mazumder A, Syeda Y, Mozgała N. Glucagon-Like Peptide-1 Receptor Agonists for Chronic Weight Management. Adv Med 2023; 2023:9946924. [PMID: 37771634 PMCID: PMC10533252 DOI: 10.1155/2023/9946924] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 08/08/2023] [Accepted: 09/08/2023] [Indexed: 09/30/2023] Open
Abstract
Rates of obesity have risen over the past few decades. Subsequently, the popularity of the pharmaceutical weight-loss drug market has grown over the past few years to meet growing demand. Among the most commonly prescribed drugs for weight management, many are glucagon-like peptide-1 receptor agonists (GLP-1 agonists) which are also utilized for the management of type 2 diabetes. There is a substantial and growing body of research comparing the efficacy of different clinical trials and examining long-term safety. This literature review examines the rise of off-label prescribing practices in the management of weight, with a focus on GLP-1 agonists. Physicians and patients should be aware of the unique aspects of existing treatment options, the impacts of off-label prescribing, and the effects of these medications. This review emphasizes the importance of informed decision-making, as well as the need for further research to guide future clinical practice.
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Affiliation(s)
- Magda Wojtara
- Department of Human Genetics, University of Michigan Medical School, Ann Arbor, USA
| | - Ashmita Mazumder
- Department of Psychology, University of Toronto, Toronto, Canada
| | - Yusra Syeda
- Daphne Cockwell School of Nursing, Toronto Metropolitan University, Toronto, Canada
| | - Nikodem Mozgała
- Collegium Medicum, Jan Kochanowski University, Kielce, Poland
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Martín-Vázquez E, Cobo-Vuilleumier N, López-Noriega L, Lorenzo PI, Gauthier BR. The PTGS2/COX2-PGE 2 signaling cascade in inflammation: Pro or anti? A case study with type 1 diabetes mellitus. Int J Biol Sci 2023; 19:4157-4165. [PMID: 37705740 PMCID: PMC10496497 DOI: 10.7150/ijbs.86492] [Citation(s) in RCA: 43] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 07/24/2023] [Indexed: 09/15/2023] Open
Abstract
Prostaglandins are lipid mediators involved in physiological processes, such as constriction or dilation of blood vessels, but also pathophysiological processes, which include inflammation, pain and fever. They are produced by almost all cell types in the organism by activation of Prostaglandin endoperoxide synthases/Cyclooxygenases. The inducible Prostaglandin Endoperoxide Synthase 2/Cyclooxygenase 2 (PTGS2/COX2) plays an important role in pathologies associated with inflammatory signaling. The main product derived from PTGS2/COX2 expression and activation is Prostaglandin E2 (PGE2), which promotes a wide variety of tissue-specific effects, pending environmental inputs. One of the major sources of PGE2 are infiltrating inflammatory cells - the production of this molecule increases drastically in damaged tissues. Immune infiltration is a hallmark of type 1 diabetes mellitus, a multifactorial disease that leads to autoimmune-mediated pancreatic beta cell destruction. Controversial effects for the PTGS2/COX2-PGE2 signaling cascade in pancreatic islet cells subjected to diabetogenic conditions have been reported, allocating PGE2 as both, cause and consequence of inflammation. Herein, we review the main effects of this molecular pathway in a tissue-specific manner, with a special emphasis on beta cell mass protection/destruction and its potential role in the prevention or development of T1DM. We also discuss strategies to target this pathway for future therapies.
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Affiliation(s)
- Eugenia Martín-Vázquez
- Andalusian Center of Molecular Biology and Regenerative Medicine CABIMER, Junta de Andalucia-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
| | - Nadia Cobo-Vuilleumier
- Andalusian Center of Molecular Biology and Regenerative Medicine CABIMER, Junta de Andalucia-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
| | - Livia López-Noriega
- Andalusian Center of Molecular Biology and Regenerative Medicine CABIMER, Junta de Andalucia-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
| | - Petra I. Lorenzo
- Andalusian Center of Molecular Biology and Regenerative Medicine CABIMER, Junta de Andalucia-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
| | - Benoit R. Gauthier
- Andalusian Center of Molecular Biology and Regenerative Medicine CABIMER, Junta de Andalucia-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
- Centro de Investigacion Biomedica en Red de Diabetes y Enfermedades Metabolicas Asociadas (CIBERDEM), Madrid, Spain
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Anala AD, Saifudeen ISH, Ibrahim M, Nanda M, Naaz N, Atkin SL. The Potential Utility of Tirzepatide for the Management of Polycystic Ovary Syndrome. J Clin Med 2023; 12:4575. [PMID: 37510690 PMCID: PMC10380206 DOI: 10.3390/jcm12144575] [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: 06/06/2023] [Revised: 06/27/2023] [Accepted: 07/02/2023] [Indexed: 07/30/2023] Open
Abstract
Polycystic ovary syndrome (PCOS) is the most prevalent endocrinopathy in women of reproductive age. The metabolic dysfunction associated with PCOS increases the probability of developing type 2 diabetes (T2D), endometrial cancer, and cardiovascular disease. Research has shown that the metabolic features of PCOS may be improved by weight loss following treatment with glucagon-like peptide-1 receptor (GLP-1R) agonists. Tirzepatide is a dual GLP-GIP (gastric inhibitory polypeptide) receptor agonist that shares a very similar mechanism of action with GLP-1R agonists, and it is hypothesized that it may be a potential contender in the treatment of PCOS. The success of GLP-1R agonists is usually hindered by their adverse gastrointestinal effects, leading to reduced compliance. The mechanism of action of Tirzepatide partly addresses this issue, as its dual receptor affinity may reduce the intensity of gastrointestinal symptoms. Tirzepatide has been licensed for the treatment of type 2 diabetes and given the metabolic issues and obesity that accompanies PCOS, it may be of value in its management for those PCOS patients who are obese with metabolic syndrome, although it may not benefit those who are of normal weight. This study reviews the current therapies for the treatment of PCOS and evaluates the potential use of Tirzepatide to address the symptoms of PCOS, including reproductive dysfunction, obesity, and insulin resistance.
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Affiliation(s)
- Alekya Devi Anala
- School of Medicine, Royal College of Surgeons in Ireland Bahrain, Adliya 15503, Bahrain
| | | | - Maryam Ibrahim
- School of Medicine, Royal College of Surgeons in Ireland Bahrain, Adliya 15503, Bahrain
| | - Moksha Nanda
- School of Medicine, Royal College of Surgeons in Ireland Bahrain, Adliya 15503, Bahrain
| | - Nida Naaz
- School of Medicine, Royal College of Surgeons in Ireland Bahrain, Adliya 15503, Bahrain
| | - Stephen L Atkin
- School of Medicine, Royal College of Surgeons in Ireland Bahrain, Adliya 15503, Bahrain
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Ajabnoor GMA, Hashim KT, Alzahrani MM, Alsuheili AZ, Alharbi AF, Alhozali AM, Enani S, Eldakhakhny B, Elsamanoudy A. The Possible Effect of the Long-Term Use of Glucagon-like Peptide-1 Receptor Agonists (GLP-1RA) on Hba1c and Lipid Profile in Type 2 Diabetes Mellitus: A Retrospective Study in KAUH, Jeddah, Saudi Arabia. Diseases 2023; 11:diseases11010050. [PMID: 36975599 PMCID: PMC10046996 DOI: 10.3390/diseases11010050] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2023] [Revised: 03/01/2023] [Accepted: 03/03/2023] [Indexed: 03/17/2023] Open
Abstract
(1) Background: Type 2 diabetes (T2DM) is a chronic metabolic disease with serious health complications. T2DM is associated with many chronic illnesses, including kidney failure, cardiovascular diseases (CVD), vision loss, and other related diseases. Obesity is one of the major factors associated with insulin resistance and dyslipidemia. Recently, the development of GLP-1 Receptor agonist (GLP-1RA) showed great therapeutic potential for T2DM. Aim: To retrospectively investigate the association of the long-term use of GLP-1RA therapy in T2DM patients with HbA1c levels and dyslipidemia. (2) Methods: Retrospective data collection and analysis of demographic, clinical records, and biochemical parameters were carried out for 72 T2DM taking GLP-1RA treatments for six months. (3) Results: A total of 72 T2DM patients with a mean age = 55 (28 male and 44 female) were divided into two groups. Group 1 received statins (n = 63), and group 2 did not receive statins (n = 9). The GLP-1RA effect on BMI was significantly decreased in group 1 (p < 0.01). A significant effect was observed for HbA1c in both groups for six months of treatment duration (p < 0.05). The AST levels significantly decreased in group 2 from 25.2 to 19.4 U\L (p = 0.011). (4) Conclusions: GLP-1RA treatments were associated with weight reduction and improved glycemic control for T2DM patients. Moreover, it is suggested that it has anti-inflammatory and hepatoprotective effects. However, no direct association was found with the lipid profile in all groups of T2DM.
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Affiliation(s)
- Ghada M. A. Ajabnoor
- Department of Clinical Biochemistry, Faculty of Medicine, King Abdulaziz University, Jeddah 22252, Saudi Arabia
- King Abdulaziz University Hospital, Faculty of Medicine, King Abdulaziz University, Jeddah 22252, Saudi Arabia
| | - Kamal Talat Hashim
- Faculty of Medicine, King Abdulaziz University, Jeddah 22252, Saudi Arabia
| | | | | | | | - Amani Matook Alhozali
- King Abdulaziz University Hospital, Faculty of Medicine, King Abdulaziz University, Jeddah 22252, Saudi Arabia
- Department of Medicine, College of Medicine, King Abdulaziz University, Jeddah 22252, Saudi Arabia
| | - Sumia Enani
- Department of Food and Nutrition, Faculty of Human Sciences and Design, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Basmah Eldakhakhny
- Department of Clinical Biochemistry, Faculty of Medicine, King Abdulaziz University, Jeddah 22252, Saudi Arabia
| | - Ayman Elsamanoudy
- Department of Clinical Biochemistry, Faculty of Medicine, King Abdulaziz University, Jeddah 22252, Saudi Arabia
- Medical Biochemistry and Molecular Biology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
- Correspondence:
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Liu JS, Su SC, Kuo FC, Li PF, Huang CL, Ho LJ, Chen KC, Liu YC, Lin CP, Cheng AC, Lee CH, Lin FH, Hung YJ, Liu HY, Lu CH, Hsieh CH. The efficacy and safety of combined GLP-1RA and basal insulin therapy among inadequately controlled T2D with premixed insulin therapy. Medicine (Baltimore) 2023; 102:e33167. [PMID: 36897731 PMCID: PMC9997828 DOI: 10.1097/md.0000000000033167] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Accepted: 02/13/2023] [Indexed: 03/11/2023] Open
Abstract
This study investigated the effect of a combination of glucagon-like peptide-1 receptor agonist (GLP-1 RA) and basal insulin (BI) in poorly controlled type 2 diabetes mellitus previously treated with premixed insulin. The possible therapeutic benefit of the subject is mainly hoped to provide a direction for optimizing treatment options to reduce the risk of hypoglycemia and weight gain. A single-arm, open-label study was conducted. The antidiabetic regimen was switched to GLP-1 RA plus BI to replace previous treatment with premixed insulin in type 2 diabetes mellitus subjects. After 3 months of treatment modification, GLP-1 RA plus BI was compared for superior outcomes by continuous glucose monitoring system. There were 34 subjects at the beginning, 4 withdrew due to gastrointestinal discomfort, and finally 30 subjects completed the trial, of which 43% were male; the average age was 58 ± 9 years old, and the average duration of diabetes was 12 ± 6 years, the baseline glycated hemoglobin level was 8.6 ± 0.9 %. The initial insulin dose of premixed insulin was 61 ± 18 units, and the final insulin dose of GLP-1 RA + BI was 32 ± 12 units (P < .001). Time out of range (from 59%-42%), time-in-range (from 39%-56%) as well as glucose variability index including standard deviation also improved, mean magnitude of glycemic excursions, mean daily difference and continuous population in continuous glucose monitoring system, continuous overall net glycemic action (CONGA). Also noted was a decrease in body weight (from 70.9 kg-68.6 kg) and body mass index (all P values < .05). It provided important information for physicians to decide to modify therapeutic strategy as individualized needs.
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Affiliation(s)
- Jhih-Syuan Liu
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Sheng-Chiang Su
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Feng-Chih Kuo
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Peng-Fei Li
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Chia-Luen Huang
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Li-Ju Ho
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Kuan-Chan Chen
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Yi-Chen Liu
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Chih-Ping Lin
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC
| | - An-Che Cheng
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Chien-Hsing Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Fu-Huang Lin
- School of Public Health, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Yi-Jen Hung
- Institute of Preventive Medicine, National Defense Medical Center, Taipei, Taiwan, ROC
| | | | - Chieh-Hua Lu
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Chang-Hsun Hsieh
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC
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Han W, Wang L, Ohbayashi K, Takeuchi M, O'Farrell L, Coskun T, Rakhat Y, Yabe D, Iwasaki Y, Seino Y, Yada T. Glucose-dependent insulinotropic polypeptide counteracts diet-induced obesity along with reduced feeding, elevated plasma leptin and activation of leptin-responsive and proopiomelanocortin neurons in the arcuate nucleus. Diabetes Obes Metab 2023; 25:1534-1546. [PMID: 36852745 DOI: 10.1111/dom.15001] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 01/16/2023] [Accepted: 01/30/2023] [Indexed: 03/01/2023]
Abstract
AIM To clarify the effects of glucose-dependent insulinotropic polypeptide (GIP) receptor agonists (GIPRAs) on feeding and body weight. MATERIALS AND METHODS Acute and subchronic effects of subcutaneous GIPFA-085, a long-acting GIPRA, on blood glucose, food intake, body weight, respiratory exchange ratio and plasma leptin levels were measured in diet-induced obese (DIO) mice and/or functional leptin-deficient ob/ob mice. The effects of GIPFA-085 on the hypothalamic arcuate nucleus (ARC) neurons from lean and DIO mice were studied by measuring cytosolic Ca2+ concentration ([Ca2+ ]i ). RESULTS Single bolus GIPFA-085 (30, 300 nmol/kg) dose-dependently reduced blood glucose in glucose tolerance tests, elevated plasma leptin levels at 0.5-6 hours and inhibited food intake at 2-24 hours after injection in DIO mice. Daily GIPFA-085 (300 nmol/kg) inhibited food intake and increased fat utilization on day 1, and reduced body weight gain on days 3-12 of treatment in DIO, but not ob/ob, mice. GIPFA-085 increased [Ca2+ ]i in the ARC leptin-responsive and proopiomelanocortin (POMC) neurons. GIPFA-085 and leptin cooperated to increase [Ca2+ ]i in ARC neurons and inhibit food intake. CONCLUSIONS GIPFA-085 acutely inhibits feeding and increases lipid utilization, and sustainedly lowers body weight in DIO mice via mechanisms involving rises in leptin and activation of ARC leptin-responsive and POMC neurons. This study highlights the therapeutic potential of GIPRAs for treating obesity and diabetes.
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Affiliation(s)
- Wanxin Han
- Center for Integrative Physiology, Kansai Electric Power Medical Research Institute, Kyoto, Japan
- Department of Diabetes, Endocrinology and Metabolism/Rheumatology and Clinical Immunology, Gifu University Graduate School of Medicine, Gifu, Japan
- Division of Diabetes, Metabolism and Endocrinology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Lei Wang
- Center for Integrative Physiology, Kansai Electric Power Medical Research Institute, Kyoto, Japan
- Department of Diabetes, Endocrinology and Metabolism/Rheumatology and Clinical Immunology, Gifu University Graduate School of Medicine, Gifu, Japan
- Division of Diabetes, Metabolism and Endocrinology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Kento Ohbayashi
- Laboratory of Animal Science, Graduate School of Life and Environmental Sciences, Kyoto Prefectural University, Kyoto, Japan
| | | | | | | | - Yermek Rakhat
- Center for Integrative Physiology, Kansai Electric Power Medical Research Institute, Kyoto, Japan
- Department of Diabetes, Endocrinology and Metabolism/Rheumatology and Clinical Immunology, Gifu University Graduate School of Medicine, Gifu, Japan
- Division of Diabetes, Metabolism and Endocrinology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Daisuke Yabe
- Department of Diabetes, Endocrinology and Metabolism/Rheumatology and Clinical Immunology, Gifu University Graduate School of Medicine, Gifu, Japan
- Yutaka Seino Distinguished Center for Diabetes Research, Kansai Electric Power Hospital, Osaka, Japan
- Center for One Medicine Innovative Translational Research, Gifu University Institute for Advanced Study, Gifu, Japan
| | - Yusaku Iwasaki
- Laboratory of Animal Science, Graduate School of Life and Environmental Sciences, Kyoto Prefectural University, Kyoto, Japan
| | - Yutaka Seino
- Yutaka Seino Distinguished Center for Diabetes Research, Kansai Electric Power Hospital, Osaka, Japan
| | - Toshihiko Yada
- Center for Integrative Physiology, Kansai Electric Power Medical Research Institute, Kyoto, Japan
- Department of Diabetes, Endocrinology and Metabolism/Rheumatology and Clinical Immunology, Gifu University Graduate School of Medicine, Gifu, Japan
- Division of Diabetes, Metabolism and Endocrinology, Kobe University Graduate School of Medicine, Kobe, Japan
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Diabetic Kidney Disease in Post-Transplant Diabetes Mellitus: Causes, Treatment and Outcomes. Biomedicines 2023; 11:biomedicines11020470. [PMID: 36831005 PMCID: PMC9953284 DOI: 10.3390/biomedicines11020470] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 01/12/2023] [Accepted: 01/27/2023] [Indexed: 02/08/2023] Open
Abstract
Kidney transplant recipients are a unique subgroup of chronic kidney disease patients due to their single functioning kidney, immunosuppressive agent usage, and long-term complications related to transplantation. Post-transplant diabetes mellitus (PTDM) has a significant adverse effect on renal outcomes in particular. As transplantations enable people to live longer, cardiovascular morbidity and mortality become more prevalent, and PTDM is a key risk factor for these complications. Although PTDM results from similar risk factors to those of type 2 diabetes, the conditions differ in their pathophysiology and clinical features. Transplantation itself is a risk factor for diabetes due to chronic exposure to immunosuppressive agents. Considering current evidence, this article describes the risk factors, pathogenesis, diagnostic criteria, prevention strategies, and management of PTDM. The therapeutic options are discussed regarding their safety and potential drug-drug interactions with immunosuppressive agents.
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Evaluating the Efficacy and Safety of Long-Acting GLP-1 Receptor Agonists in T1DM Patients. ENDOCRINES 2023. [DOI: 10.3390/endocrines4010008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/09/2023] Open
Abstract
(1) Background: Glucagon-like peptide 1 receptor agonists (GLP-1 RA) are a class of therapeutic agents that mimic the endogenous incretin hormone GLP-1. While this class of agents is not approved for Type 1 Diabetes (T1DM) due to concern of increased diabetic ketoacidosis (DKA) risk, long-acting GLP-1 medications are being commonly prescribed off label for T1DM in clinical practice. Several studies addressed the efficacy and safety of short-acting GLP-1 agonists therapy in patients with T1DM, but the data on long-acting agents are lacking. In our study, we aim to fill in this gap and help healthcare providers in their clinical decision making on the use of these agents for T1DM patients. (2) Methods: We conducted a retrospective chart review of T1DM patients on a long-acting GLP-1 for at least six months. Our retrospective chart review included information starting two years prior to starting GLP-1, and six or more months after starting GLP-1. Parameters collected included HbA1c, 14-day Continuous Glucose Monitor (CGM) and blood glucose (BG) data, and metabolic data (weight, systolic and diastolic blood pressure, and cholesterol levels). Statistical analysis was conducted using paired t-tests on R and Excel with α of 0.05. (3) Results: Our cohort consisted of 54 participants with T1DM on a long-acting GLP-1 (semaglutide, dulaglutide, exenatide extended-release [ER], albiglutide). Mean GLP-1 treatment duration was 23.85 ± 15.46 months. HbA1c values decreased significantly by an average of 0.71% percentage points (%-points, p = 0.002) comparing pre-therapy vs. on GLP-1 treatment. Similarly, for pre-therapy vs. on GLP-1 treatment values, CGM results were significant for increased time in range by 12.15%-points (p = 0.0009) showing a decreased average time in hyperglycemia (BG > 180 mg/dL) by a mean difference of 11.97%-points (p = 0.006), decreased 14-day mean BG by 19 mg/dl (p = 0.01), decreased 14-day BG standard deviation by 8.45 mg/dl (p = 0.01), decreased incidence of DKA hospitalization, and a decrease in weight by 3.16 kg (p = 0.007). (4) Conclusions: As more data emerges on cardiovascular and renal benefits of long acting GLP-1 in type 2 diabetes, there have been no reported outcomes in T1DM. Our study is the first to demonstrate glycemic and metabolic benefits of this class of medication as an adjunct therapy to insulin in T1DM, and safety of its use over an average of 1.5–2 years’ time. This study represents real life experience and the data warrants confirmation by additional prospective studies.
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Akter S, Afrin S, Kim J, Kang J, Razzak MA, Berggren PO, Hwang I. Production of active Exendin-4 in Nicotiana benthamiana and its application in treatment of type-2 diabetics. FRONTIERS IN PLANT SCIENCE 2022; 13:1062658. [PMID: 36618620 PMCID: PMC9812950 DOI: 10.3389/fpls.2022.1062658] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Accepted: 12/05/2022] [Indexed: 06/17/2023]
Abstract
GLP-1 (Glucagon-like peptide-1) is a peptide that stimulates insulin secretion from the β-cell for glycemic control of the plasma blood glucose level. Its mimetic exenatide (synthetic Exendin-4) with a longer half-life of approximately 3.3-4 h is widely used in clinical application to treat diabetes. Currently, exenatide is chemically synthesized. In this study, we report that the GLP-1 analogue recombinant Exendin-4 (Exdn-4) can be produced at a high level in Nicotiana benthamiana, with an estimated yield of 50.0 µg/g fresh biomass. For high-level expression, we generated a recombinant gene, B:GB1:ddCBD1m:8xHis : Exendin-4 (BGC : Exdn-4), for the production of Exendin-4 using various domains such as the BiP signal peptide, the GB1 domain (B1 domain of streptococcal G protein), a double cellulose binding domain 1 (CBD1), and 8 His residues (8xHis) to the N-terminus of Exendin-4. GB1 was used to increase the expression, whereas double CBD1 and 8xHis were included as affinity tags for easy purification using MCC beads and Ni2+-NTA resin, respectively. BGC : Exdn-4 was purified by single-step purification to near homogeneity using both Ni2+-NTA resin and microcrystalline cellulose (MCC) beads. Moreover, Exdn-4 without any extra residues was produced from BGC : Exdn-4 bound onto MCC beads by treating with enterokinase. Plant-produced Exdn-4 (Exendin-4) was as effective as chemically synthesized Exendin-4 in glucose-induced insulin secretion (GIIS) from mouse MIN6m9 cells a pancreatic beta cell line.
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Affiliation(s)
- Shammi Akter
- Department of Life Sciences, Pohang University of Science and Technology, Pohang, South Korea
| | - Shajia Afrin
- Department of Research and Development, BioN Inc., Pohang, South Korea
| | - Jaeyoon Kim
- Department of Research and Development, BioN Inc., Pohang, South Korea
| | - Joohyun Kang
- Department of Life Sciences, Pohang University of Science and Technology, Pohang, South Korea
| | - Md Abdur Razzak
- Department of Life Sciences, Pohang University of Science and Technology, Pohang, South Korea
| | - Per-Olof Berggren
- The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden
| | - Inhwan Hwang
- Department of Life Sciences, Pohang University of Science and Technology, Pohang, South Korea
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Mirzaei F, Khodadadi I, Majdoub N, Vafaei SA, Tayebinia H, Abbasi E. Role of Glucagon-like Peptide-1 (GLP-1) Agonists in the Management of Diabetic Patients with or without COVID-19. THE OPEN MEDICINAL CHEMISTRY JOURNAL 2022. [DOI: 10.2174/18741045-v16-e2212130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Glucagon-like peptide 1 (GLP-1) is a gut-derived hormone released after a meal, which alleviates hyperglycemia, increases β-cell survival, reduces body weight, and reduces inflammation. These thrilling effects motivated clinical studies to discover the potential use of GLP-1 receptor agonists (GLP-1 RAs) in the management of T2D. GLP-1 RAs are potential anti-diabetic agents that can reduce blood pressure, glucose levels, HbA1c and, weight loss without hypoglycemia risk. This manuscript reviews the importance of GLP-1 RAs and their role in the management of T2D with or without COVID-19 infection. Hence, this manuscript can help physicians and researchers to choose the most appropriate drugs for the individualized treatment of subjects.
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Blonde L, Umpierrez GE, Reddy SS, McGill JB, Berga SL, Bush M, Chandrasekaran S, DeFronzo RA, Einhorn D, Galindo RJ, Gardner TW, Garg R, Garvey WT, Hirsch IB, Hurley DL, Izuora K, Kosiborod M, Olson D, Patel SB, Pop-Busui R, Sadhu AR, Samson SL, Stec C, Tamborlane WV, Tuttle KR, Twining C, Vella A, Vellanki P, Weber SL. American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. Endocr Pract 2022; 28:923-1049. [PMID: 35963508 PMCID: PMC10200071 DOI: 10.1016/j.eprac.2022.08.002] [Citation(s) in RCA: 234] [Impact Index Per Article: 78.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 08/01/2022] [Accepted: 08/02/2022] [Indexed: 02/06/2023]
Abstract
OBJECTIVE The objective of this clinical practice guideline is to provide updated and new evidence-based recommendations for the comprehensive care of persons with diabetes mellitus to clinicians, diabetes-care teams, other health care professionals and stakeholders, and individuals with diabetes and their caregivers. METHODS The American Association of Clinical Endocrinology selected a task force of medical experts and staff who updated and assessed clinical questions and recommendations from the prior 2015 version of this guideline and conducted literature searches for relevant scientific papers published from January 1, 2015, through May 15, 2022. Selected studies from results of literature searches composed the evidence base to update 2015 recommendations as well as to develop new recommendations based on review of clinical evidence, current practice, expertise, and consensus, according to established American Association of Clinical Endocrinology protocol for guideline development. RESULTS This guideline includes 170 updated and new evidence-based clinical practice recommendations for the comprehensive care of persons with diabetes. Recommendations are divided into four sections: (1) screening, diagnosis, glycemic targets, and glycemic monitoring; (2) comorbidities and complications, including obesity and management with lifestyle, nutrition, and bariatric surgery, hypertension, dyslipidemia, retinopathy, neuropathy, diabetic kidney disease, and cardiovascular disease; (3) management of prediabetes, type 2 diabetes with antihyperglycemic pharmacotherapy and glycemic targets, type 1 diabetes with insulin therapy, hypoglycemia, hospitalized persons, and women with diabetes in pregnancy; (4) education and new topics regarding diabetes and infertility, nutritional supplements, secondary diabetes, social determinants of health, and virtual care, as well as updated recommendations on cancer risk, nonpharmacologic components of pediatric care plans, depression, education and team approach, occupational risk, role of sleep medicine, and vaccinations in persons with diabetes. CONCLUSIONS This updated clinical practice guideline provides evidence-based recommendations to assist with person-centered, team-based clinical decision-making to improve the care of persons with diabetes mellitus.
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Affiliation(s)
| | | | - S Sethu Reddy
- Central Michigan University, Mount Pleasant, Michigan
| | | | | | | | | | | | - Daniel Einhorn
- Scripps Whittier Diabetes Institute, La Jolla, California
| | | | | | - Rajesh Garg
- Lundquist Institute/Harbor-UCLA Medical Center, Torrance, California
| | | | | | | | | | | | - Darin Olson
- Colorado Mountain Medical, LLC, Avon, Colorado
| | | | | | - Archana R Sadhu
- Houston Methodist; Weill Cornell Medicine; Texas A&M College of Medicine; Houston, Texas
| | | | - Carla Stec
- American Association of Clinical Endocrinology, Jacksonville, Florida
| | | | - Katherine R Tuttle
- University of Washington and Providence Health Care, Seattle and Spokane, Washington
| | | | | | | | - Sandra L Weber
- University of South Carolina School of Medicine-Greenville, Prisma Health System, Greenville, South Carolina
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Cardiovascular Risk after Kidney Transplantation: Causes and Current Approaches to a Relevant Burden. J Pers Med 2022; 12:jpm12081200. [PMID: 35893294 PMCID: PMC9329988 DOI: 10.3390/jpm12081200] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 07/11/2022] [Accepted: 07/20/2022] [Indexed: 11/17/2022] Open
Abstract
Background. Cardiovascular disease is a frequent complication after kidney transplantation and represents the leading cause of mortality in this population. Material and Methods. We searched for the relevant articles in the National Institutes of Health library of medicine, transplant, cardiologic and nephrological journals. Results. The pathogenesis of cardiovascular disease in kidney transplant is multifactorial. Apart from non-modifiable risk factors, such as age, gender, genetic predisposition and ethnicity, several traditional and non-traditional modifiable risk factors contribute to its development. Traditional factors, such as diabetes, hypertension and dyslipidemia, may be present before and may worsen after transplantation. Immunosuppressants and impaired graft function may strongly influence the exacerbation of these comorbidities. However, in the last years, several studies showed that many other cardiovascular risk factors may be involved in kidney transplantation, including hyperuricemia, inflammation, low klotho and elevated Fibroblast Growth Factor 23 levels, deficient levels of vitamin D, vascular calcifications, anemia and poor physical activity and quality of life. Conclusions. The timely and effective treatment of time-honored and recently discovered modifiable risk factors represent the basis of the prevention of cardiovascular complications in kidney transplantation. Reduction of cardiovascular risk can improve the life expectancy, the quality of life and the allograft function and survival.
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Tanycytes control hypothalamic liraglutide uptake and its anti-obesity actions. Cell Metab 2022; 34:1054-1063.e7. [PMID: 35716660 PMCID: PMC7613793 DOI: 10.1016/j.cmet.2022.06.002] [Citation(s) in RCA: 60] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 08/08/2021] [Accepted: 06/01/2022] [Indexed: 11/24/2022]
Abstract
Liraglutide, an anti-diabetic drug and agonist of the glucagon-like peptide one receptor (GLP1R), has recently been approved to treat obesity in individuals with or without type 2 diabetes. Despite its extensive metabolic benefits, the mechanism and site of action of liraglutide remain unclear. Here, we demonstrate that liraglutide is shuttled to target cells in the mouse hypothalamus by specialized ependymoglial cells called tanycytes, bypassing the blood-brain barrier. Selectively silencing GLP1R in tanycytes or inhibiting tanycytic transcytosis by botulinum neurotoxin expression not only hampers liraglutide transport into the brain and its activation of target hypothalamic neurons, but also blocks its anti-obesity effects on food intake, body weight and fat mass, and fatty acid oxidation. Collectively, these striking data indicate that the liraglutide-induced activation of hypothalamic neurons and its downstream metabolic effects are mediated by its tanycytic transport into the mediobasal hypothalamus, strengthening the notion of tanycytes as key regulators of metabolic homeostasis.
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36
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Wang L, Cheng CK, Yi M, Lui KO, Huang Y. Targeting endothelial dysfunction and inflammation. J Mol Cell Cardiol 2022; 168:58-67. [PMID: 35460762 DOI: 10.1016/j.yjmcc.2022.04.011] [Citation(s) in RCA: 77] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 04/05/2022] [Accepted: 04/14/2022] [Indexed: 12/15/2022]
Abstract
Vascular endothelium maintains vascular homeostasis through liberating a spectrum of vasoactive molecules, both protective and harmful regulators of vascular tone, structural remodeling, inflammation and atherogenesis. An intricate balance between endothelium-derived relaxing factors (nitric oxide, prostacyclin and endothelium-derived hyperpolarizing factor) and endothelium-derived contracting factors (superoxide anion, endothelin-1 and constrictive prostaglandins) tightly regulates vascular function. Disruption of such balance signifies endothelial dysfunction, a critical contributor in aging and chronic cardiometabolic disorders, such as obesity, diabetes, hypertension, dyslipidemia and atherosclerotic vascular diseases. Among many proposed cellular and molecular mechanisms causing endothelial dysfunction, oxidative stress and inflammation are often the pivotal players and they are naturally considered as useful targets for intervention in patients with cardiovascular and metabolic diseases. In this article, we provide a recent update on the therapeutic values of pharmacological agents, such as cyclooxygenase-2 inhibitors, renin-angiotensin-system inhibitors, bone morphogenic protein 4 inhibitors, peroxisome proliferator-activated receptor δ agonists, and glucagon-like peptide 1-elevating drugs, and the physiological factors, particularly hemodynamic forces, that improve endothelial function by targeting endothelial oxidative stress and inflammation.
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Affiliation(s)
- Li Wang
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China
| | - Chak Kwong Cheng
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China
| | - Min Yi
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China
| | - Kathy O Lui
- Department of Chemical Pathology and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong, China
| | - Yu Huang
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China.
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Butt S, Gagnon J, Saleh M. A Protective Role for Glucagon-like Peptide-2 in Heat-stable Enterotoxin b (STb)-Induced L-Cell Toxicity. Endocrinology 2022; 163:6546206. [PMID: 35266539 DOI: 10.1210/endocr/bqac029] [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: 11/19/2021] [Indexed: 11/19/2022]
Abstract
Enterotoxigenic Escherichia coli (ETEC)-derived purified heat-stable enterotoxin b (STb) is responsible for secretory diarrhea in livestock and humans. STb disrupts intestinal fluid homeostasis, epithelial barrier function, and promotes cell death. Glucagon-like peptide-2 (GLP-2) is a potent intestinotrophic hormone secreted by enteroendocrine L cells. GLP-2 enhances crypt cell proliferation, epithelial barrier function, and inhibits enterocyte apoptosis. Whether STb can affect GLP-2 producing L cells remains to be elucidated. First, secreted-His-labeled STb from transformed E coli was collected and purified. When incubated with L-cell models (GLUTag, NCI-H716, and secretin tumor cell line [STC-1]), fluorescent immunocytochemistry revealed STb was internalized and was differentially localized in the cytoplasm and nucleus. Cell viability experiments with neutral red and resazurin revealed that STb was toxic in all but the GLUTag cells. STb stimulated 2-hour GLP-2 secretion in all cell models. Interestingly, GLUTag cells produced the highest amount of GLP-2 when treated with STb, demonstrating an inverse relationship in GLP-2 secretion and cell toxicity. To demonstrate a protective role for GLP-2, GLUTag-conditioned media (rich in GLP-2) blocked STb toxicity in STC-1 cells. Confirming a protective role of GLP-2, teduglutide was able to improve cell viability in cells treated with H2O2. In conclusion, STb interacts with the L cell, stimulates secretion, and may induce toxicity if GLP-2 is not produced at high levels. GLP-2 or receptor agonists have the ability to improve cell viability in response to toxins. These results suggest that GLP-2 secretion can play a protective role during STb intoxication. This work supports future investigation into the use of GLP-2 therapies in enterotoxigenic-related diseases.
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Affiliation(s)
- Shahnawaz Butt
- Laurentian University, School of Natural Sciences, Sudbury, Ontario P3E 2C6, Canada
| | - Jeffrey Gagnon
- Laurentian University, School of Natural Sciences, Sudbury, Ontario P3E 2C6, Canada
| | - Mazen Saleh
- Laurentian University, School of Natural Sciences, Sudbury, Ontario P3E 2C6, Canada
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Chen YH, Chen QQ, Wang CL. Treatment and five-year follow-up of type A insulin resistance syndrome: A case report. World J Clin Cases 2022; 10:2522-2528. [PMID: 35434067 PMCID: PMC8968608 DOI: 10.12998/wjcc.v10.i8.2522] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 11/02/2021] [Accepted: 02/10/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Type A insulin resistance syndrome (TAIRS) is a rare disorder characterized by severe insulin resistance due to defects in insulin receptor signaling. No specific drugs are available for the treatment of TAIRS. We report a case of TAIRS successfully treated with pioglitazone and flutamide for 5 years.
CASE SUMMARY We present the rare case of a female patient aged 11 years and 9 mo with type A insulin resistance and an INSR heterozygous mutation (c.3614C>T), who was treated with a combination of pioglitazone and flutamide. This treatment regimen reduced hemoglobin A1c, fasting insulin and androgen levels.
CONCLUSION Pioglitazone attenuated insulin resistance in this patient with TAIRS, and flutamide ameliorated masculinization.
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Affiliation(s)
- Yong-Hua Chen
- Department of Pediatrics, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Qing-Qing Chen
- Department of Pediatrics, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Chun-Lin Wang
- Department of Pediatrics, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
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Rentzeperi E, Pegiou S, Koufakis T, Grammatiki M, Kotsa K. Sex Differences in Response to Treatment with Glucagon-like Peptide 1 Receptor Agonists: Opportunities for a Tailored Approach to Diabetes and Obesity Care. J Pers Med 2022; 12:jpm12030454. [PMID: 35330453 PMCID: PMC8950819 DOI: 10.3390/jpm12030454] [Citation(s) in RCA: 61] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 03/02/2022] [Accepted: 03/10/2022] [Indexed: 02/04/2023] Open
Abstract
The available data suggest differences in the course of type 2 diabetes mellitus (T2DM) between men and women, influenced by the distinguishing features of the sex. Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are a relatively new class of antidiabetic drugs that act by mimicking the function of endogenous glucagon-like peptide 1. They constitute valuable agents for the management of T2DM as, in addition to exerting a strong hypoglycemic action, they present cardiorenal protective properties, promote weight loss, and have a good safety profile, particularly with respect to the risk of hypoglycemia. Due to the precedent of studies having identified sexual dimorphic elements regarding the action of other antidiabetic agents, ongoing research has attempted to examine whether this is also the case for GLP-1 RAs. Until now, sex differences have been observed in the impact of GLP1-RAs on glycemic control, weight reduction, and frequency of adverse events. On the contrary, the question of whether these drugs differentially affect the two sexes with respect to cardiovascular risk and incidence of major adverse cardiovascular events remains under investigation. Knowledge of the potential sex-specific effects of these medications is extremely useful for the implementation of individualized therapeutic plans in the treatment of T2DM. This narrative review aims to present the available data regarding the sex-specific action of GLP-1 RAs as well as to discuss the potential pathophysiologic mechanisms explaining these dissimilarities.
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40
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Montero N, Oliveras L, Soler MJ, Cruzado JM. Management of post-transplant diabetes mellitus: an opportunity for novel therapeutics. Clin Kidney J 2022; 15:5-13. [PMID: 35265335 PMCID: PMC8901587 DOI: 10.1093/ckj/sfab131] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Indexed: 12/16/2022] Open
Abstract
Post-transplant diabetes mellitus (PTDM) is a common problem after kidney transplantation (KT), occurring in 50% of high-risk recipients. The clinical importance of PTDM lies in its impact as a significant risk factor for cardiovascular and chronic kidney disease (CKD) after solid organ transplantation. Kidney Disease: Improving Global Outcomes (KDIGO) has recently updated the treatment guidelines for diabetes management in CKD with emphasis on the newer antidiabetic agents such as dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter 2 inhibitors as add-on therapy to metformin. Given all these new diabetes treatments and the updated KDIGO guidelines, it is necessary to evaluate and give guidance on their use for DM management in KT recipients. This review summarizes the scarce published literature about the use of these new agents in the KT field. In summary, it is absolutely necessary to generate evidence in order to be able to safely use these new treatments in the KT population to improve blood glucose control, but specially to evaluate their potential cardiovascular and renal benefits that would seem to be independent of blood glucose control in PTDM patients.
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Affiliation(s)
- Nuria Montero
- Department of Nephrology, L'Hospitalet de Llobregat, Hospital Universitari de Bellvitge, Barcelona, Spain
| | - Laia Oliveras
- Department of Nephrology, L'Hospitalet de Llobregat, Hospital Universitari de Bellvitge, Barcelona, Spain
| | - Maria José Soler
- Department of Nephrology, Hospital Vall d'Hebron, Barcelona, Spain
| | - Josep Maria Cruzado
- Department of Nephrology, L'Hospitalet de Llobregat, Hospital Universitari de Bellvitge, Barcelona, Spain
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Vo Van L, Pham EC, Nguyen CV, Duong NTN, Vi Le Thi T, Truong TN. In vitro and in vivo antidiabetic activity, isolation of flavonoids, and in silico molecular docking of stem extract of Merremia tridentata (L.). Biomed Pharmacother 2022; 146:112611. [PMID: 35062075 DOI: 10.1016/j.biopha.2021.112611] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 12/25/2021] [Accepted: 12/26/2021] [Indexed: 12/11/2022] Open
Abstract
The antidiabetic activity of stem-ethanol extract (SE) and the flavonoid-rich fraction (FF) of Merremia tridentata (L.) were investigated on alloxan-induced diabetic mice. Apigenin, cosmosiin, and quercitrin are flavonoids isolated for the first time from stem extracts. In addition, cynaroside was found to be at the highest level in SE and FF with a percentage of 4.375% and 58.430%, respectively. The administration of SE (100 mg/kg) and FF (50, 75 mg/kg) daily for 20 days resulted in a better hypoglycemic effect than the reference drugs, glibenclamide (5 mg/kg), and metformin (10 mg/kg). Furthermore, SE and FF were shown to significantly improve the plasma lipid profiles at the end of the study. Docking's study suggests that cynaroside, cosmosiin, and quercitrin are the most desirable compounds for hypoglycemic effects in many antidiabetic targets. Especially, SE and FF showed strongly α-amylase and α-glucosidase inhibitory activities (IC50 = 1.61-1.72 mg/mL on α-amylase and IC50 = 0.24-0.44 mg/mL on α-glucosidase). Therefore, SE and FF of Merremia tridentata is a potential drug with antidiabetic and hypoglycemic action as indicated by in vivo, in silico, and in vitro studies.
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Affiliation(s)
- Lenh Vo Van
- Faculty of Pharmacy, Lac Hong University, 810000 Dong Nai Province, Viet Nam
| | - Em Canh Pham
- Department of Medicinal Chemistry, Faculty of Pharmacy, Hong Bang International University, 700000 Ho Chi Minh City, Viet Nam.
| | - Cuong Viet Nguyen
- Faculty of Pharmacy, Lac Hong University, 810000 Dong Nai Province, Viet Nam
| | | | - Tuong Vi Le Thi
- Department of Pharmacology - Clinical Pharmacy, Faculty of Pharmacy, City Children's Hospital, 700000 Ho Chi Minh City, Viet Nam
| | - Tuyen Ngoc Truong
- Department of Organic Chemistry, Faculty of Pharmacy, University of Medicine and Pharmacy, 700000 Ho Chi Minh City, Viet Nam
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Pirro V, Roth KD, Lin Y, Willency JA, Milligan PL, Wilson JM, Ruotolo G, Haupt A, Newgard CB, Duffin KL. Effects of Tirzepatide, a Dual GIP and GLP-1 RA, on Lipid and Metabolite Profiles in Subjects With Type 2 Diabetes. J Clin Endocrinol Metab 2022; 107:363-378. [PMID: 34608929 DOI: 10.1210/clinem/dgab722] [Citation(s) in RCA: 66] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Indexed: 01/06/2023]
Abstract
CONTEXT Tirzepatide substantially reduced hemoglobin A1c (HbA1c) and body weight in subjects with type 2 diabetes (T2D) compared with the glucagon-like peptide 1 receptor agonist dulaglutide. Improved glycemic control was associated with lower circulating triglycerides and lipoprotein markers and improved markers of beta-cell function and insulin resistance (IR), effects only partially attributable to weight loss. OBJECTIVE Assess plasma metabolome changes mediated by tirzepatide. DESIGN Phase 2b trial participants were randomly assigned to receive weekly subcutaneous tirzepatide, dulaglutide, or placebo for 26 weeks. Post hoc exploratory metabolomics and lipidomics analyses were performed. SETTING Post hoc analysis. PARTICIPANTS 259 subjects with T2D. INTERVENTION(S) Tirzepatide (1, 5, 10, 15 mg), dulaglutide (1.5 mg), or placebo. MAIN OUTCOME MEASURE(S) Changes in metabolite levels in response to tirzepatide were assessed against baseline levels, dulaglutide, and placebo using multiplicity correction. RESULTS At 26 weeks, a higher dose tirzepatide modulated a cluster of metabolites and lipids associated with IR, obesity, and future T2D risk. Branched-chain amino acids, direct catabolic products glutamate, 3-hydroxyisobutyrate, branched-chain ketoacids, and indirect byproducts such as 2-hydroxybutyrate decreased compared to baseline and placebo. Changes were significantly larger with tirzepatide compared with dulaglutide and directly proportional to reductions of HbA1c, homeostatic model assessment 2-IR indices, and proinsulin levels. Proportional to metabolite changes, triglycerides and diglycerides were lowered significantly compared to baseline, dulaglutide, and placebo, with a bias toward shorter and highly saturated species. CONCLUSIONS Tirzepatide reduces body weight and improves glycemic control and uniquely modulates metabolites associated with T2D risk and metabolic dysregulation in a direction consistent with improved metabolic health.
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Affiliation(s)
| | | | - Yanzhu Lin
- Eli Lilly and Company, Indianapolis, IN, USA
| | | | | | | | | | - Axel Haupt
- Eli Lilly and Company, Indianapolis, IN, USA
| | - Christopher B Newgard
- Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Department of Pharmacology and Cancer Biology and Department of Medicine, Endocrinology Division, Duke University Medical Center, Durham, NC, USA
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Amaro A, Sugimoto D, Wharton S. Efficacy and safety of semaglutide for weight management: evidence from the STEP program. Postgrad Med 2022; 134:5-17. [PMID: 36691309 DOI: 10.1080/00325481.2022.2147326] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Obesity is a global health challenge. It is a multifactorial, complex, and progressive disease associated with various health complications and increased mortality. Lifestyle modifications are central to weight management but may be insufficient to maintain clinically meaningful weight loss. Pharmacotherapies are recommended as an adjunct to lifestyle interventions to induce and sustain clinically meaningful weight loss and reduce the risk of comorbidities in appropriate patients. Glucagon-like peptide-1 is an incretin metabolic hormone responsible for a range of physiological effects, including glucose and appetite regulation. Several glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been approved for the treatment of type 2 diabetes since 2005 including exenatide (short- and extended-release), lixisenatide, liraglutide, dulaglutide, albiglutide, and semaglutide. Of these, semaglutide (subcutaneous) and liraglutide are currently US Food and Drug Administration (FDA)-approved for chronic weight management in patients with or without diabetes. The phase 3 Semaglutide Treatment Effect in People with obesity (STEP) program was designed to investigate the effect of semaglutide versus placebo on weight loss, safety, and tolerability in adults with overweight or obesity. Following the submission of the results of the STEP 1-4 trials, the FDA approved once-weekly subcutaneous semaglutide 2.4 mg for chronic weight management in people with overweight or obesity in April 2021. Data from the program demonstrated that semaglutide (2.4 mg once weekly) achieved significant and sustained weight loss, together with improvements in cardiometabolic risk factors compared with placebo, and was generally well tolerated, with a safety profile consistent with other GLP-1RAs. The most common adverse events reported in STEP 1-5 were gastrointestinal events, which were transient, mild-to-moderate in severity, and typically resolved without permanent treatment discontinuation. This article reviews the data from STEP 1-5 and highlights clinically relevant findings for primary care providers.
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Affiliation(s)
- Anastassia Amaro
- Penn Metabolic Medicine, Division of Endocrinology, University of Pennsylvania, Philadelphia, PA, USA
| | | | - Sean Wharton
- York University, McMaster University and Wharton Weight Management Clinic, Toronto, Ontario, Canada
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Bosma KJ, Andrei SR, Katz LS, Smith AA, Dunn JC, Ricciardi VF, Ramirez MA, Baumel-Alterzon S, Pace WA, Carroll DT, Overway EM, Wolf EM, Kimple ME, Sheng Q, Scott DK, Breyer RM, Gannon M. Pharmacological blockade of the EP3 prostaglandin E 2 receptor in the setting of type 2 diabetes enhances β-cell proliferation and identity and relieves oxidative damage. Mol Metab 2021; 54:101347. [PMID: 34626853 PMCID: PMC8529552 DOI: 10.1016/j.molmet.2021.101347] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 09/02/2021] [Accepted: 09/23/2021] [Indexed: 12/27/2022] Open
Abstract
OBJECTIVE Type 2 diabetes is characterized by hyperglycemia and inflammation. Prostaglandin E2, which signals through four G protein-coupled receptors (EP1-4), is a mediator of inflammation and is upregulated in diabetes. We have shown previously that EP3 receptor blockade promotes β-cell proliferation and survival in isolated mouse and human islets ex vivo. Here, we analyzed whether systemic EP3 blockade could enhance β-cell mass and identity in the setting of type 2 diabetes using mice with a spontaneous mutation in the leptin receptor (Leprdb). METHODS Four- or six-week-old, db/+, and db/db male mice were treated with an EP3 antagonist daily for two weeks. Pancreata were analyzed for α-cell and β-cell proliferation and β-cell mass. Islets were isolated for transcriptomic analysis. Selected gene expression changes were validated by immunolabeling of the pancreatic tissue sections. RESULTS EP3 blockade increased β-cell mass in db/db mice through enhanced β-cell proliferation. Importantly, there were no effects on α-cell proliferation. EP3 blockade reversed the changes in islet gene expression associated with the db/db phenotype and restored the islet architecture. Expression of the GLP-1 receptor was slightly increased by EP3 antagonist treatment in db/db mice. In addition, the transcription factor nuclear factor E2-related factor 2 (Nrf2) and downstream targets were increased in islets from db/db mice in response to treatment with an EP3 antagonist. The markers of oxidative stress were decreased. CONCLUSIONS The current study suggests that EP3 blockade promotes β-cell mass expansion in db/db mice. The beneficial effects of EP3 blockade may be mediated through Nrf2, which has recently emerged as a key mediator in the protection against cellular oxidative damage.
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Affiliation(s)
- Karin J Bosma
- Dept. of Veterans Affairs Tennessee Valley Authority, Nashville, TN, USA; Dept. of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Spencer R Andrei
- Dept. of Veterans Affairs Tennessee Valley Authority, Nashville, TN, USA; Dept. of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Liora S Katz
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Ashley A Smith
- Dept. of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
| | - Jennifer C Dunn
- Dept. of Veterans Affairs Tennessee Valley Authority, Nashville, TN, USA; Dept. of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | | | - Marisol A Ramirez
- Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN, USA; Dept. of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Sharon Baumel-Alterzon
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - William A Pace
- Dept. of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA
| | - Darian T Carroll
- Dept. of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
| | - Emily M Overway
- Dept. of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
| | - Elysa M Wolf
- Program in Cancer Biology, Vanderbilt University, Nashville, TN, USA
| | - Michelle E Kimple
- Dept. of Medicine, University of Wisconsin, Madison, WI, USA; William S. Middleton Memorial Veterans Hospital, Madison, WI, USA
| | - Quanhu Sheng
- Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN, USA; Dept. of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Donald K Scott
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Richard M Breyer
- Dept. of Veterans Affairs Tennessee Valley Authority, Nashville, TN, USA; Dept. of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Maureen Gannon
- Dept. of Veterans Affairs Tennessee Valley Authority, Nashville, TN, USA; Dept. of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; Dept. of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA.
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Peng Y, Lin H, Tian S, Liu S, Li J, Lv X, Chen S, Zhao L, Pu F, Chen X, Shu H, Qing X, Shao Z. Glucagon-like peptide-1 receptor activation maintains extracellular matrix integrity by inhibiting the activity of mitogen-activated protein kinases and activator protein-1. Free Radic Biol Med 2021; 177:247-259. [PMID: 34737144 DOI: 10.1016/j.freeradbiomed.2021.10.034] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 09/04/2021] [Accepted: 10/27/2021] [Indexed: 12/25/2022]
Abstract
Disruption of the intervertebral disc extracellular matrix (ECM) is a hallmark of intervertebral disc degeneration (IDD), which is largely attributed to excessive oxidative stress. However, there is a lack of clinically feasible approaches to promote the reconstruction of the disc ECM. Glucagon-like peptide-1 (GLP-1), a safe polypeptide hormone adopted to treat type 2 diabetes mellitus, has shown great potential for relieving oxidative stress-related damage. To our knowledge, this is the first study to reveal that exenatide, a GLP-1 receptor (GLP-1R) agonist, can upregulate disc ECM synthesis and attenuate oxidative stress-induced ECM degradation and IDD. Mechanistically, we found that exenatide inhibited the activation of mitogen-activated protein kinases (MAPK) signaling pathway and the formation of BATF/JUNs heterodimers (an index of activator protein-1 (AP-1) activity). The restoration of MAPK signaling activation reversed the protective effects of exenatide and enhanced downstream BATF/JUNs binding. BATF overexpression was also found to aggravate disc ECM damage, even in the presence of exenatide. In summary, exenatide is an effective agent that regulates ECM anabolic balance and restores disc degeneration by inhibiting MAPK activation and its downstream AP-1 activity. The present study provides a therapeutic rationale for activating the GLP-1 receptor against IDD and establishes the important role of AP-1 activity in the pathogenesis of IDD.
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Affiliation(s)
- Yizhong Peng
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Hui Lin
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Shuo Tian
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Sheng Liu
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Jinye Li
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Xiao Lv
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Songfeng Chen
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou City, 450052, China
| | - Lei Zhao
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Feifei Pu
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Xi Chen
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Hongyang Shu
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, China; Hubei Key Laboratory of Genetics and Molecular Mechanism of Cardiologic Disorders, Huazhong University of Science and Technology, Wuhan, 430000, China
| | - Xiangcheng Qing
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
| | - Zengwu Shao
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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Bonilha I, Hajduch E, Luchiari B, Nadruz W, Le Goff W, Sposito AC. The Reciprocal Relationship between LDL Metabolism and Type 2 Diabetes Mellitus. Metabolites 2021; 11:metabo11120807. [PMID: 34940565 PMCID: PMC8708656 DOI: 10.3390/metabo11120807] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 11/25/2021] [Accepted: 11/25/2021] [Indexed: 12/14/2022] Open
Abstract
Type 2 diabetes mellitus and insulin resistance feature substantial modifications of the lipoprotein profile, including a higher proportion of smaller and denser low-density lipoprotein (LDL) particles. In addition, qualitative changes occur in the composition and structure of LDL, including changes in electrophoretic mobility, enrichment of LDL with triglycerides and ceramides, prolonged retention of modified LDL in plasma, increased uptake by macrophages, and the formation of foam cells. These modifications affect LDL functions and favor an increased risk of cardiovascular disease in diabetic individuals. In this review, we discuss the main findings regarding the structural and functional changes in LDL particles in diabetes pathophysiology and therapeutic strategies targeting LDL in patients with diabetes.
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Affiliation(s)
- Isabella Bonilha
- Cardiology Division, Atherosclerosis and Vascular Biology Laboratory (AtheroLab), State University of Campinas (Unicamp), Campinas 13083-887, Brazil; (I.B.); (B.L.)
| | - Eric Hajduch
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, F-75006 Paris, France;
| | - Beatriz Luchiari
- Cardiology Division, Atherosclerosis and Vascular Biology Laboratory (AtheroLab), State University of Campinas (Unicamp), Campinas 13083-887, Brazil; (I.B.); (B.L.)
| | - Wilson Nadruz
- Cardiology Division, Cardiovascular Pathophysiology Laboratory, State University of Campinas (Unicamp), Campinas 13083-887, Brazil;
| | - Wilfried Le Goff
- Unité de Recherche sur les Maladies Cardiovasculaires, le Métabolisme et la Nutrition, ICAN, Inserm, Sorbonne Université, F-75013 Paris, France;
| | - Andrei C. Sposito
- Cardiology Division, Atherosclerosis and Vascular Biology Laboratory (AtheroLab), State University of Campinas (Unicamp), Campinas 13083-887, Brazil; (I.B.); (B.L.)
- Correspondence: ; Tel.: +55-19-3521-7098; Fax: +55-19-3289-410
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Hopton OM, Waterbury NV, Egge JA, Lund BC. Clinical Impact of GLP-1 receptor agonists in veterans receiving basal-bolus insulin. Pharmacotherapy 2021; 42:45-52. [PMID: 34807465 DOI: 10.1002/phar.2648] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 10/19/2021] [Accepted: 10/19/2021] [Indexed: 01/01/2023]
Abstract
BACKGROUND In 2017, an estimated 7.4 million Americans used insulin to treat diabetes. Insulin is proven to lower A1c but can result in hypoglycemia and weight gain. Combining insulin with a glucagon-like peptide-1 receptor agonist (GLP-1-RA) may provide additional blood glucose control while limiting undesirable effects including weight gain. OBJECTIVE To characterize the clinical impact of adding a GLP-1-RA to a basal-bolus insulin regimen in patients with type 2 diabetes. METHODS This retrospective observational study used national Veteran's Health Administration data to identify patients with an existing basal-bolus insulin regimen who initiated a GLP-1-RA between January 1, 2005 and December 31, 2017. A1c, insulin total daily dose (TDD), and weight were collected at GLP-1-RA initiation (baseline), 3-, 6-, and 12-month time points and then analyzed using an intent-to-treat approach with the last observation carried forward. Decreases in A1c ≥ 0.5% and weight ≥2 kg were deemed clinically significant. RESULTS Among 7651 patients initiating GLP-1-RA therapy, mean A1c had a clinically significant decline at 3, 6, and 12 months by -0.5%, -0.7%, and -0.7%, respectively, from a mean baseline of 9%. Patients with lower baseline A1c levels did not have clinically significant changes in A1c, whereas patients with baseline A1c ≥9% had more clinically significant declines. Insulin TDD decreased by -32, -38, and -42 units/day at 3, 6, and 12 months, respectively, where the mean decrease in insulin TDD at 12 months was 79 units/day among patients who discontinued bolus insulin (52.3%) compared with a mean decrease of 2 units/day among those who continued bolus insulin. Mean weight reductions at 3, 6, and 12 months were -1.2, -2.3, and -2.9 kg, respectively, from a mean baseline of 120.6 kg. CONCLUSION Combining a GLP-1-RA with basal-bolus insulin had a clinically significant improvement on blood glucose control, lowered insulin TDD, and reduced weight. These outcomes were achieved within 3 to 6 months following GLP-1-RA initiation and were maintained through 1 year.
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Affiliation(s)
- Olivia M Hopton
- Department of Pharmacy, Iowa City Veterans Affairs Health Care System, Iowa City, Iowa, USA
| | - Nancee V Waterbury
- Department of Pharmacy, Iowa City Veterans Affairs Health Care System, Iowa City, Iowa, USA
| | - Jason A Egge
- Department of Pharmacy, Iowa City Veterans Affairs Health Care System, Iowa City, Iowa, USA
| | - Brian C Lund
- Center for Access & Delivery Research and Evaluation and Department of Pharmacy, Iowa City Veterans Affairs Health Care System, Iowa City, Iowa, USA
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Pechenov S, Revell J, Will S, Naylor J, Tyagi P, Patel C, Liang L, Tseng L, Huang Y, Rosenbaum AI, Balic K, Konkar A, Grimsby J, Subramony JA. Development of an orally delivered GLP-1 receptor agonist through peptide engineering and drug delivery to treat chronic disease. Sci Rep 2021; 11:22521. [PMID: 34795324 PMCID: PMC8602401 DOI: 10.1038/s41598-021-01750-0] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Accepted: 11/01/2021] [Indexed: 01/13/2023] Open
Abstract
Peptide therapeutics are increasingly used in the treatment of disease, but their administration by injection reduces patient compliance and convenience, especially for chronic diseases. Thus, oral administration of a peptide therapeutic represents a significant advance in medicine, but is challenged by gastrointestinal instability and ineffective uptake into the circulation. Here, we have used glucagon-like peptide-1 (GLP-1) as a model peptide therapeutic for treating obesity-linked type 2 diabetes, a common chronic disease. We describe a comprehensive multidisciplinary approach leading to the development of MEDI7219, a GLP-1 receptor agonist (GLP-1RA) specifically engineered for oral delivery. Sites of protease/peptidase vulnerabilities in GLP-1 were removed by amino acid substitution and the peptide backbone was bis-lipidated to promote MEDI7219 reversible plasma protein binding without affecting potency. A combination of sodium chenodeoxycholate and propyl gallate was used to enhance bioavailability of MEDI7219 at the site of maximal gastrointestinal absorption, targeted by enteric-coated tablets. This synergistic approach resulted in MEDI7219 bioavailability of ~ 6% in dogs receiving oral tablets. In a dog model of obesity and insulin resistance, MEDI7219 oral tablets significantly decreased food intake, body weight and glucose excursions, validating the approach. This novel approach to the development of MEDI7219 provides a template for the development of other oral peptide therapeutics.
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Affiliation(s)
- Sergei Pechenov
- Drug Delivery, Dosage Form Design and Development, AstraZeneca, Gaithersburg, MD, USA
| | | | - Sarah Will
- Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), Biopharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA
| | - Jacqueline Naylor
- Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Puneet Tyagi
- Drug Delivery, Dosage Form Design and Development, AstraZeneca, Gaithersburg, MD, USA
| | - Chandresh Patel
- Drug Delivery, Dosage Form Design and Development, AstraZeneca, Gaithersburg, MD, USA
| | - Lihuan Liang
- Bioscience Renal, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - Leo Tseng
- Bioscience Renal, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, South San Francisco, CA, USA
| | - Yue Huang
- Bioscience Renal, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, South San Francisco, CA, USA
| | - Anton I Rosenbaum
- Integrated Bioanalysis, Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, South San Francisco, CA, USA
| | - Kemal Balic
- Integrated Bioanalysis, Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, South San Francisco, CA, USA
| | - Anish Konkar
- Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), Biopharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA
| | - Joseph Grimsby
- Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), Biopharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA
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Chatzis DG, Kolokathis K, Magounaki K, Chatzidakis S, Avramidis K, Leopoulou M, Angelopoulos TP, Doupis J. Changing the Concept: From the Traditional Glucose-centric to the New Cardiorenal-metabolic Approach for the Treatment of Type 2 Diabetes. TOUCHREVIEWS IN ENDOCRINOLOGY 2021; 17:92-101. [PMID: 35118454 PMCID: PMC8676106 DOI: 10.17925/ee.2021.17.2.92] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Accepted: 06/29/2021] [Indexed: 11/24/2022]
Abstract
Type 2 diabetes mellitus (T2DM) is a chronic disease with a constantly increasing prevalence worldwide. It is well established that T2DM affects both the macro- and microvasculature, and its presence is associated with a high risk of acute and chronic cardiovascular events. Traditionally, the management of T2DM has been mainly focused on the optimization of blood glucose levels with the use of antidiabetic medications. During recent years, however, an impressive accumulation of evidence has arisen from studies designed to explore the plausible effects of new antidiabetic drugs on cardiovascular outcomes in patients with diabetes. This review article aims to emphasize the findings of these studies and to highlight the substantial role of the newer classes of antidiabetic drugs in treating T2DM in a holistic, cardiorenal-metabolic approach, thus shifting the paradigm from the traditional, simplistic, glucose-lowering approach.
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Affiliation(s)
| | - Konstantinos Kolokathis
- Department of Internal Medicine and Diabetes, Salamis Naval and Veterans Hospital, Salamis Naval Base, Salamis, Attiki, Greece
| | | | | | - Konstantinos Avramidis
- Department of Internal Medicine and Diabetes, Salamis Naval and Veterans Hospital, Salamis Naval Base, Salamis, Attiki, Greece
| | | | | | - John Doupis
- Department of Internal Medicine and Diabetes, Salamis Naval and Veterans Hospital, Salamis Naval Base, Salamis, Attiki, Greece
- Iatriko Paleou Falirou Medical Center, Athens, Greece
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Cheng CK, Luo JY, Lau CW, Cho WCS, Ng CF, Ma RCW, Tian XY, Huang Y. A GLP-1 analog lowers ER stress and enhances protein folding to ameliorate homocysteine-induced endothelial dysfunction. Acta Pharmacol Sin 2021; 42:1598-1609. [PMID: 33495519 PMCID: PMC8463564 DOI: 10.1038/s41401-020-00589-x] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 10/15/2020] [Indexed: 02/02/2023]
Abstract
Hyperhomocysteinemia (HHcy) is an independent risk factor for cardiovascular diseases and increases mortality in type 2 diabetic patients. HHcy induces endoplasmic reticulum (ER) stress and oxidative stress to impair endothelial function. The glucagon-like peptide 1 (GLP-1) analog exendin-4 attenuates endothelial ER stress, but the detailed vasoprotective mechanism remains elusive. The present study investigated the beneficial effects of exendin-4 against HHcy-induced endothelial dysfunction. Exendin-4 pretreatment reversed homocysteine-induced impairment of endothelium-dependent relaxations in C57BL/6 mouse aortae ex vivo. Four weeks subcutaneous injection of exendin-4 restored the impaired endothelial function in both aortae and mesenteric arteries isolated from mice with diet-induced HHcy. Exendin-4 treatment lowered superoxide anion accumulation in the mouse aortae both ex vivo and in vivo. Exendin-4 decreased the expression of ER stress markers (e.g., ATF4, spliced XBP1, and phosphorylated eIF2α) in human umbilical vein endothelial cells (HUVECs), and this change was reversed by cotreatment with compound C (CC) (AMPK inhibitor). Exendin-4 induced phosphorylation of AMPK and endothelial nitric oxide synthase in HUVECs and arteries. Exendin-4 increased the expression of endoplasmic reticulum oxidoreductase (ERO1α), an important ER chaperone in endothelial cells, and this effect was mediated by AMPK activation. Experiments using siRNA-mediated knockdown or adenoviral overexpression revealed that ERO1α mediated the inhibitory effects of exendin-4 on ER stress and superoxide anion production, thus ameliorating HHcy-induced endothelial dysfunction. The present results demonstrate that exendin-4 reduces HHcy-induced ER stress and improves endothelial function through AMPK-dependent ERO1α upregulation in endothelial cells and arteries. AMPK activation promotes the protein folding machinery in endothelial cells to suppress ER stress.
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Affiliation(s)
- Chak Kwong Cheng
- School of Biomedical Sciences and Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong SAR, China
- Heart and Vascular Institute and Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Jiang-Yun Luo
- School of Biomedical Sciences and Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong SAR, China
- Heart and Vascular Institute and Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Chi Wai Lau
- School of Biomedical Sciences and Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong SAR, China
- Heart and Vascular Institute and Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - William Chi-Shing Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Kowloon, Hong Kong SAR, China
| | - Chi Fai Ng
- Department of Surgery, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Ronald Ching Wan Ma
- Department of Medicine and Therapeutics, Hong Kong Institute of Diabetes and Obesity, and The Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Xiao Yu Tian
- School of Biomedical Sciences and Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong SAR, China.
- Heart and Vascular Institute and Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China.
| | - Yu Huang
- School of Biomedical Sciences and Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong SAR, China.
- Heart and Vascular Institute and Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China.
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