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Gu JH, Samarneh M. Dose-dependent pancreatitis risk associated with GLP-1 agonists. J Diabetes Metab Disord 2025; 24:33. [PMID: 39758806 PMCID: PMC11695654 DOI: 10.1007/s40200-024-01552-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Accepted: 12/16/2024] [Indexed: 01/07/2025]
Abstract
Objectives Glucagon-like peptide 1 (GLP-1) receptor agonists have recently proven to be an effective treatment for type 2 diabetes mellitus (T2DM). However, these drugs are also known to carry a significant risk of drug-induced pancreatitis. The purpose of this study is to determine whether or not GLP-1-associated pancreatitis risk is dose-dependent. That is, we aim to determine whether the risk of developing pancreatitis increases with the administered dose of GLP-1 agonist or not. Methods We conduct a retrospective case control study using data taken from the U.S. Food and Drug Administration Adverse Events Reporting System (FAERS) database. Participants are included if they reported an adverse effect of GLP-1 agonist and reported the cumulative dose of drug administered. We measure the odds ratio of developing pancreatitis between patients who have taken a large cumulative dose of GLP-1 agonist and those with a low cumulative dose of GLP-1 agonist. The odds ratio of different GLP-1 agonists are combined via a random effects model. Results Patients with a high cumulative dose of GLP-1 agonist are associated with a higher risk of developing drug-induced pancreatitis associated with GLP-1 agonists, indicated by a statistically significant odds ratio. Furthermore, the odds ratio increases as the cumulative dose increases. Conclusions GLP-1 agonists are associated with significant pancreatitis risk which increases with larger cumulative doses.
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Affiliation(s)
- Joyce Hanyue Gu
- Lake Erie College of Osteopathic Medicine, Medical School, Seton Hill, PA USA
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2
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Watanabe H, Fujishima F, Yamazaki Y, Imamura M, Hijioka S, Hara K, Kuwahara T, Yatabe Y, Sakamoto K, Shiga H, Kawaguchi T, Suzuki H, Kanbayashi Y, Ohkoshi A, Shimada M, Niikawa H, Sato M, Fujio A, Masui T, Kasai Y, Ota H, Ozawa H, Endo H, Unno M, Sasano H, Suzuki T. GLP- 1R status using validated monoclonal antibody in 689 cases of neuroendocrine neoplasm and its correlation with somatostatin receptor scintigraphy, insulin production, and histological grades. Virchows Arch 2025:10.1007/s00428-025-04098-2. [PMID: 40281248 DOI: 10.1007/s00428-025-04098-2] [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: 01/14/2025] [Revised: 03/19/2025] [Accepted: 03/31/2025] [Indexed: 04/29/2025]
Abstract
Radiolabeled glucagon-like peptide 1 (GLP- 1) analog scintigraphy is a new, high-sensitivity imaging method for detecting small insulinomas. Somatostatin receptor scintigraphy (SRS) is an established method for detecting gastroenteropancreatic neuroendocrine tumors. However, small benign insulinomas are difficult to detect using SRS. Furthermore, GLP- 1 receptor (GLP- 1R) expression and SRS results may be inversely correlated. We identified 689 neuroendocrine neoplasms, including pancreatic neuroendocrine tumors (PanNETs) and neuroendocrine neoplasms originating from non-pancreatic sites, and performed GLP- 1R immunostaining. Among the non-insulinoma PanNETs, immunohistochemical insulin or proinsulin positive cases were categorized as Inspos, and both negative cases as Insneg. High prevalence of GLP- 1R expression was detected in PanNETs and duodenal NETs (34% and 53%, respectively). Some pulmonary NETs were GLP- 1R positive (9%). In contrast, neither GI-NEC excluding one case nor pulmonary NEC exhibited GLP- 1R expression. The percentage of GLP- 1R positive cases for Inspos, Insneg, and insulinoma was 31%, 0%, and 84%, respectively. Among PanNETs, GLP- 1R positive cases showed higher expression of insulin and proinsulin than negative cases. SRS-positive patients showed lower expression levels of insulin, proinsulin, and GLP- 1R than SRS-negative patients. The expression in PanNETs and duodenal NETs may be derived from the expression in their normal counterparts. Insulinoma and Inspos cases showed GLP- 1R expression. Furthermore, as GLP- 1R-positive patients showed significantly higher expression of insulin and proinsulin than GLP- 1R negative patients, GLP- 1R may also be associated with neoplastic insulin production and GLP- 1 analog scintigraphy may detect subclinical insulinomas. In addition, SRS-negative cases showed significantly higher GLP- 1R expression than SRS-positive cases. These results suggest the application potential of GLP- 1 analog scintigraphy in combination with SRS as a detection tool.
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Affiliation(s)
- Hirofumi Watanabe
- Department of Pathology, Tohoku University Hospital, 1 - 1 Seiryo-Machi, Aoba-Ku, Sendai, Miyagi, 980 - 8574, Japan
| | - Fumiyoshi Fujishima
- Department of Pathology, Tohoku University Hospital, 1 - 1 Seiryo-Machi, Aoba-Ku, Sendai, Miyagi, 980 - 8574, Japan.
| | - Yuto Yamazaki
- Department of Pathology, Tohoku University Hospital, 1 - 1 Seiryo-Machi, Aoba-Ku, Sendai, Miyagi, 980 - 8574, Japan
| | - Masayuki Imamura
- Department of Surgery, Kansai Electric Power Hospital, Osaka, Japan
| | - Susumu Hijioka
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center, Tokyo, Japan
| | - Kazuo Hara
- Department of Gastroenterology, Aichi Cancer Center Hospital, Aichi, Japan
| | - Takamichi Kuwahara
- Department of Gastroenterology, Aichi Cancer Center Hospital, Aichi, Japan
| | - Yasushi Yatabe
- Department of Pathology and Clinical Laboratories, National Cancer Center, Tokyo, Japan
| | | | - Hisashi Shiga
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Miyagi, Japan
| | | | - Hiroyoshi Suzuki
- Department of Diagnostic Pathology, South Miyagi Medical Center, Miyagi, Japan
| | - Yumi Kanbayashi
- Department of Dermatology, Tohoku University Graduate School of Medicine, Miyagi, Japan
| | - Akira Ohkoshi
- Department of Otorhinolaryngology, Head and Neck Surgery, Tohoku University Graduate School of Medicine, Miyagi, Japan
| | - Muneaki Shimada
- Department of Gynecology, Tohoku University Graduate School of Medicine, Miyagi, Japan
| | - Hiromichi Niikawa
- Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, Miyagi, Japan
| | - Mami Sato
- Department of Breast and Endocrine Surgery, Tohoku University Hospital, Miyagi, Japan
| | - Atsushi Fujio
- Department of Surgery, Graduate School of Medicine, Tohoku University, Miyagi, Japan
| | - Toshihiko Masui
- Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yosuke Kasai
- Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Hideki Ota
- Department of Diagnostic Radiology, Tohoku University Hospital, Miyagi, Japan
| | - Hiroshi Ozawa
- Department of Orthopaedic Surgery, Tohoku Medical and Pharmaceutical University, Miyagi, Japan
| | - Hidenori Endo
- Department of Neurosurgery, Tohoku University Graduate School of Medicine, Miyagi, Japan
| | - Michiaki Unno
- Department of Surgery, Graduate School of Medicine, Tohoku University, Miyagi, Japan
| | - Hironobu Sasano
- Department of Pathology, Tohoku University Hospital, 1 - 1 Seiryo-Machi, Aoba-Ku, Sendai, Miyagi, 980 - 8574, Japan
| | - Takashi Suzuki
- Department of Pathology, Tohoku University Hospital, 1 - 1 Seiryo-Machi, Aoba-Ku, Sendai, Miyagi, 980 - 8574, Japan
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Nassar M, Abosheaishaa H, Misra A, Dandona P, Ghanim H, Chaudhuri A. Use of glucagon-like peptide-1 receptor agonists in people with history of acute pancreatitis: TriNetX analysis. DIABETES & METABOLISM 2025; 51:101613. [PMID: 39826595 DOI: 10.1016/j.diabet.2025.101613] [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: 08/29/2024] [Revised: 01/07/2025] [Accepted: 01/11/2025] [Indexed: 01/22/2025]
Abstract
INTRODUCTION Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are used in subjects with type 2 diabetes (T2D) and obesity. However, concerns over their association with acute pancreatitis (AP) have emerged. Our aim was to evaluate the risk of recurrence of AP in subjects on GLP-1RAs with a history of AP. METHODS This retrospective study deployed the TriNetX platform. We identified adult cohorts of subjects with a history of AP and analyzed the impact of individual medications (GLP-1RAs, SGLT2i, or DPP4i) on the risk of recurrence of AP. To adjust for baseline differences, propensity score matching was done in cohorts with and without risk factors for AP. RESULTS Our analysis of 672,069 patients with a history of AP and T2D revealed significant risk reductions associated with GLP-1RAs compared to other treatments. Over one to five years, GLP-1RAs consistently showed a lower risk of AP recurrence compared to SGLT2i and DPP-4i. Specifically, over a one-year period, GLP-1RAs users had a risk reduction of -0.071 (95 % CI:0.085 to -0.057) (p < 0.001) compared to SGLT2i, and -0.064 (95 % CI:0.080 to -0.048) (p< 0.001) compared to DPP-4i. These trends persisted, with the risk differences further widening by the fifth year to -0.086 and -0.094, respectively. CONCLUSION Based on our findings, we conclude that GLP-1RAs may be safely used in subjects with a history of acute pancreatitis. While our analysis showed that there was a significantly lower risk of AP recurrence in subjects on GLP-1compared to DPP-IV inhibitors and SGLT2 inhibitors, as this is a retrospective analysis we suggest that these findings need to be confirmed in prospective studies.
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Affiliation(s)
- Mahmoud Nassar
- Endocrine fellow, Division of Endocrinology, Diabetes and Metabolism University at Buffalo, Buffalo, NY, USA
| | - Hazem Abosheaishaa
- Internal Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Anoop Misra
- Chairman, Fortis-C-DOC Centre of Excellence for Diabetes, Metabolic Diseases and Endocrinology, Chairman, National Diabetes, Obesity and Cholesterol Foundation (N-DOC), President, Diabetes Foundation (India) (DFI) India
| | - Paresh Dandona
- Professor of Medicine, Division of Endocrinology and Metabolism, Jacobs School of Medicine, University at Buffalo, Buffalo, NY, USA
| | - Husam Ghanim
- Diabetes and Endocrinology Research Lab, Research Associate Professor, Department of Medicine, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA
| | - Ajay Chaudhuri
- Professor of Medicine, Division of Endocrinology and Metabolism, Jacobs School of Medicine, University at Buffalo, Buffalo, NY, USA.
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Morehouse ZP, Ledford JD. Problematic Pharmacokinetics: A Case of Recurrent Pancreatitis Post Discontinuation of a Glucagon-Like Peptide 1 Receptor Agonists. J Pharm Pract 2025; 38:187-192. [PMID: 39109559 DOI: 10.1177/08971900241273188] [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: 12/13/2024]
Abstract
Glucagon-like peptide 1 receptor agonists (GLP-1RA) are guideline recommended agents for the treatment of type 2 diabetes mellitus (T2DM) and select agents (liraglutide and semaglutide) are FDA approved as anti-obesity pharmacotherapy options. These drugs act on the incretin hormone system within the body to revive insulin excretion, delay gastric emptying, and inhibit the production of glucagon from pancreatic alpha cells. Acute pancreatitis is a serious condition that may have a fatal outcome. It has been shown, and is now part of the prescribing information label, that GLP-1RA agents can cause changes in the pancreas that may ultimately lead to pancreatitis. We describe the case of a 53-year-old female patient with uncontrolled type II diabetes mellitus, who experienced multiple episodes of pancreatitis, from what we suspect was due to repeated exposure to the GLP-1 RA agent, semaglutide. After discontinuation of semaglutide, our patient experienced another episode of pancreatitis roughly 15-week later; which we believe may be due to the patient experiencing the effects of a smoldering pancreas brought on by repeated injury and prolonged circulation of semaglutide post-discontinuation.
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Affiliation(s)
- Zachary P Morehouse
- Department of Family Medicine, Atrium Health Carolinas Medical Center, Charlotte, NC, USA
| | - Jack D Ledford
- Division of Pharmacy, Atrium Health Carolinas Medical Center, Charlotte, NC, USA
- Department of Family and Community Medicine, Wake Forest School of Medicine, Charlotte NC, USA
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Amanatidou D, Eleftheriou P, Petrou A, Geronikaki A, Lialiaris T. Τhiazolidine-4-One Derivatives with Variable Modes of Inhibitory Action Against DPP4, a Drug Target with Multiple Activities and Established Role in Diabetes Mellitus Type II. Pharmaceuticals (Basel) 2025; 18:52. [PMID: 39861115 PMCID: PMC11768251 DOI: 10.3390/ph18010052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2024] [Revised: 12/23/2024] [Accepted: 12/29/2024] [Indexed: 01/27/2025] Open
Abstract
Background/Objectives: DPP4 is an enzyme with multiple natural substrates and probable involvement in various mechanisms. It constitutes a drug target for the treatment of diabetes II, although, also related to other disorders. While a number of drugs with competitive inhibitory action and covalent binding capacity are available, undesired side effects exist partly attributed to drug kinetics, and research for finding novel, potent, and safer compounds continues. Despite the research, a low number of uncompetitive and non-competitive inhibitors, which could be of worth for pharmaceutical and mechanism studies, was mentioned. Methods: In the present study sixteen 3-(benzo[d]thiazol-2-yl)-2-aryl thiazolidin-4-ones were selected for evaluation, based on structural characteristics and docking analysis and were tested in vitro for DPP4 inhibitory action using H-Gly-Pro-amidomethyl coumarin substrate. Their mode of inhibition was also in vitro explored. Results: Twelve compounds exhibited IC50 values at the nM range with the best showing IC50 = 12 ± 0.5 nM, better than sitagliptin. Most compounds exhibited a competitive mode of inhibition. Inhibition modes of uncompetitive, non-competitive, and mixed type were also identified. Docking analysis was in accordance with the in vitro results, with a linear correlation of logIC50 with a Probability of Binding Factor(PF) derived using docking analysis to a specific target box and to the whole enzyme. According to the docking results, two probable sites of binding for uncompetitive inhibitors were highlighted in the wider area of the active site and in the propeller loop. Conclusions: Potent inhibitors with IC50 at the nM range and competitive, non-competitive, uncompetitive, and mixed modes of action, one better than sitagliptin, were found. Docking analysis was used to estimate probable sites and ways of binding. However, crystallographic or NMR studies are needed to elucidate the exact way of binding especially for uncompetitive and non-competitive inhibitors.
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Affiliation(s)
- Dionysia Amanatidou
- Department of Biomedical Sciences, School of Health, International Hellenic University, 57400 Thessaloniki, Greece;
| | - Phaedra Eleftheriou
- Department of Biomedical Sciences, School of Health, International Hellenic University, 57400 Thessaloniki, Greece;
| | - Anthi Petrou
- Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (A.P.); (A.G.)
| | - Athina Geronikaki
- Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (A.P.); (A.G.)
| | - Theodoros Lialiaris
- School of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece;
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Fu D, Shu X, Zhou G, Ji M, Liao G, Zou L. Connection between oral health and chronic diseases. MedComm (Beijing) 2025; 6:e70052. [PMID: 39811802 PMCID: PMC11731113 DOI: 10.1002/mco2.70052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 12/07/2024] [Accepted: 12/10/2024] [Indexed: 01/16/2025] Open
Abstract
Chronic diseases have emerged as a paramount global health burden, accounting for 74% of global mortality and causing substantial economic losses. The oral cavity serves as a critical indicator of overall health and is inextricably linked to chronic disorders. Neglecting oral health can exacerbate localized pathologies and accelerate the progression of chronic conditions, whereas effective management has the potential to reduce their incidence and mortality. Nevertheless, limited resources and lack of awareness often impede timely dental intervention, delaying optimal therapeutic measures. This review provides a comprehensive analysis of the impact of prevalent chronic diseases-such as diabetes mellitus, rheumatoid arthritis, cardiovascular disorders, and chronic respiratory diseases-on oral health, along with an exploration of how changes in oral health affect these chronic conditions through both deterioration and intervention mechanisms. Additionally, novel insights into the underlying pathophysiological mechanisms governing these relationships are presented. By synthesizing these advancements, this review aims to illuminate the complex interrelationship between oral health and chronic diseases while emphasizing the urgent need for greater collaboration between dental practitioners and general healthcare providers to improve overall health outcomes.
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Affiliation(s)
- Di Fu
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral DiseasesSichuan UniversityChengduSichuanChina
| | - Xingyue Shu
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral DiseasesSichuan UniversityChengduSichuanChina
| | - Ge Zhou
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral DiseasesSichuan UniversityChengduSichuanChina
| | - Mengzhen Ji
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral DiseasesSichuan UniversityChengduSichuanChina
| | - Ga Liao
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral DiseasesSichuan UniversityChengduSichuanChina
- Department of Information Management, Department of Stomatology Informatics, West China Hospital of StomatologySichuan UniversityChengduSichuanChina
| | - Ling Zou
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Department of Conservative Dentistry and Endodontics, West China Hospital of StomatologySichuan UniversityChengduSichuanChina
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Forouzanmehr B, Hemmati MA, Atkin SL, Jamialahmadi T, Yaribeygi H, Sahebkar A. GLP-1 mimetics and diabetic ketoacidosis: possible interactions and clinical consequences. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025; 398:351-362. [PMID: 39172148 DOI: 10.1007/s00210-024-03384-1] [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: 04/02/2024] [Accepted: 08/14/2024] [Indexed: 08/23/2024]
Abstract
Diabetic ketoacidosis is a serious diabetes-related consequence that occurs in type 1 diabetes and less commonly in type 2 diabetes and is a major cause of death. It results from the metabolic consequences due to a lack of insulin secretion or impaired insulin activity in diabetes leading to dysregulated pathophysiologic pathways resulting in excessive ketone body formation. While ketone bodies are physiologic molecules, their high levels reduce the physiological pH of the blood and induce ketoacidosis, leading to increasing metabolic dysfunction. Glucagon-like peptide-1 (GLP-1) mimetics are a class of recently developed diabetes therapy that do not lead to hypoglycemic, but some reports have suggested a relationship between GLP-1 mimetics and ketogenesis. To clarify the possible interactions between GLP-1 mimetics and ketogenesis in diabetes, this review was undertaken to collate and interpret the literature.
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Affiliation(s)
- Behina Forouzanmehr
- Student Research Committee, Semnan University of Medical Sciences, Semnan, Iran
| | | | - Stephen L Atkin
- Research Department, Royal College of Surgeons in Ireland Bahrain, Adliya, Bahrain
| | - Tannaz Jamialahmadi
- Medical Toxicology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Habib Yaribeygi
- Research Center of Physiology, Semnan University of Medical Sciences, Semnan, Iran.
| | - Amirhossein Sahebkar
- Center for Global Health Research, Saveetha Medical College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India.
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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Wiese J, Dakkak B, Ugonabo O, El-Dallal M, Frandah W. A Case Report of Acute Pancreatitis in Food-Induced Anaphylaxis. Cureus 2024; 16:e71017. [PMID: 39525265 PMCID: PMC11548797 DOI: 10.7759/cureus.71017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/05/2024] [Indexed: 11/16/2024] Open
Abstract
Food allergy-induced pancreatitis is a rare condition that presents unique diagnostic challenges. While acute pancreatitis (AP) is typically linked to factors such as gallstones, alcohol consumption, metabolic issues, medications, and autoimmune conditions, food allergies are seldom considered a potential cause. Diagnosing food allergy-induced pancreatitis often requires a high index of suspicion and the exclusion of more common causes of pancreatitis. Here we report a 54-year-old female patient who presented at the emergency department (ED) experiencing an anaphylactic reaction to food. After receiving treatment for anaphylaxis, she developed acute abdominal pain 12 hours later. A CT scan of the abdomen indicated AP. The patient was managed with supportive care, including analgesics and intravenous fluids, and did not experience any further complications. Other potential causes and risk factors for AP were ruled out or deemed unlikely. This case highlights the significance of diagnosing AP, particularly food allergy-induced pancreatitis in patients with anaphylaxis. Early detection and early initiation of therapy can subsequently reduce morbidity and mortality.
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Affiliation(s)
- Jennifer Wiese
- Internal Medicine, Marshall University Joan C. Edwards School of Medicine, Huntington, USA
| | - Bassel Dakkak
- Internal Medicine, Marshall University Joan C. Edwards School of Medicine, Huntington, USA
| | - Onyinye Ugonabo
- Internal Medicine, School of Medicine, Marshall University Hospital, Huntington, USA
| | - Mohammed El-Dallal
- Gastroenterology, Marshall University Joan C. Edwards School of Medicine, Huntington, USA
| | - Wesam Frandah
- Internal Medicine/Gastroenterology, Marshall University Joan C. Edwards School of Medicine, Huntington, USA
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9
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Cheng Z, Wang S, Li F, Jin C, Mo C, Zheng J, Li X, Liang F, Yang J, Gu D. The potential adverse effects of hypodermic glucagon-like peptide -1 receptor agonist on patients with type 2 diabetes: A population-based study. J Diabetes 2024; 16:e70013. [PMID: 39435881 PMCID: PMC11494487 DOI: 10.1111/1753-0407.70013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Revised: 08/22/2024] [Accepted: 09/07/2024] [Indexed: 10/23/2024] Open
Abstract
BACKGROUND Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), a class of injectable antidiabetic drugs, have shown significant efficacies in improving glycemic and weight control in patients with type 2 diabetes (T2D). However, the long-term safety of GLP-1 RAs remains insufficiently studied. This study aimed to provide real-world evidence on potential adverse outcomes associated with GLP-1 RAs use in T2D patients without major chronic diseases including impaired cardiac or renal function. METHODS We conducted a retrospective cohort study involving 7746 T2D patients on GLP-1 RAs in Shenzhen, China. They were compared with 124 371 metformin-only users and 36 146 insulin-only users, forming two therapy control groups. GLP-1 RAs users were also further 1:2 paired with the control groups. Competing risk survival analyses were conducted to assess the incidence risks, presenting subdistributional hazard ratios (sHRs) with 95% confidence intervals (CIs) for various adverse outcomes associated with GLP-1 RAs use. RESULTS Compared with metformin-only users, GLP-1 RAs use was associated with increased risks of various adverse outcomes (sHRs with 95% CIs), including pancreatitis (2.01, 1.24-3.24), acute nephritis (3.20, 2.17-4.70), kidney failure (3.73, 2.74-5.08), thyroid cancer (2.25, 1.23-4.10), and thyroid dysfunction (1.27, 1.00-1.63), respectively; Similar results were also found when compared with insulin-only users. Importantly, long-term (≥12 months) GLP-1 RAs use may further elevate the incidence risks of pancreatitis, acute nephritis, thyroid cancer, and thyroid dysfunction. CONCLUSION Compared with traditional T2D treatments, GLP-1 RAs use may be associated with increased risks of various adverse outcomes in a Chinese population. Cautions were strongly warranted in the use of GLP-1 RAs. Further validation is crucial across diverse populations.
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Affiliation(s)
- Zhiyuan Cheng
- School of Public Health and Emergency ManagementSouthern University of Science and TechnologyShenzhenChina
- Shenzhen Key Laboratory of Cardiovascular Health and Precision MedicineSouthern University of Science and TechnologyShenzhenChina
| | - Shuang Wang
- Shenzhen Health Development Research and Data Management CenterShenzhenChina
| | - Fu‐rong Li
- School of Public Health and Emergency ManagementSouthern University of Science and TechnologyShenzhenChina
- Shenzhen Key Laboratory of Cardiovascular Health and Precision MedicineSouthern University of Science and TechnologyShenzhenChina
| | - Cheng Jin
- School of Public Health and Emergency ManagementSouthern University of Science and TechnologyShenzhenChina
- Shenzhen Key Laboratory of Cardiovascular Health and Precision MedicineSouthern University of Science and TechnologyShenzhenChina
| | - Chunbao Mo
- School of Public Health and Emergency ManagementSouthern University of Science and TechnologyShenzhenChina
- Shenzhen Key Laboratory of Cardiovascular Health and Precision MedicineSouthern University of Science and TechnologyShenzhenChina
| | - Jing Zheng
- Shenzhen Health Development Research and Data Management CenterShenzhenChina
| | - Xia Li
- School of Public Health and Emergency ManagementSouthern University of Science and TechnologyShenzhenChina
- Shenzhen Key Laboratory of Cardiovascular Health and Precision MedicineSouthern University of Science and TechnologyShenzhenChina
- School of MedicineSouthern University of Science and TechnologyShenzhenChina
| | - Fengchao Liang
- School of Public Health and Emergency ManagementSouthern University of Science and TechnologyShenzhenChina
- Shenzhen Key Laboratory of Cardiovascular Health and Precision MedicineSouthern University of Science and TechnologyShenzhenChina
- School of MedicineSouthern University of Science and TechnologyShenzhenChina
| | - Jinkui Yang
- Department of Endocrinology, Beijing Tongren HospitalCapital Medical UniversityBeijingChina
| | - Dongfeng Gu
- School of Public Health and Emergency ManagementSouthern University of Science and TechnologyShenzhenChina
- Shenzhen Key Laboratory of Cardiovascular Health and Precision MedicineSouthern University of Science and TechnologyShenzhenChina
- School of MedicineSouthern University of Science and TechnologyShenzhenChina
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10
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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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Lee HY, Ko SH, Park S, Kim K, Kim SY, Cho IJ, Cho EJ, Kim HC, Park JH, Ryu SK, Moon MK, Ihm SH. The role of glucagon-like peptide-1 receptor agonists (GLP1-RAs) in the management of the hypertensive patient with metabolic syndrome: a position paper from the Korean society of hypertension. Clin Hypertens 2024; 30:24. [PMID: 39217384 PMCID: PMC11366170 DOI: 10.1186/s40885-024-00279-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Accepted: 06/16/2024] [Indexed: 09/04/2024] Open
Abstract
Obesity is the one of the most important components of metabolic syndrome. Because obesity related hypertension accounts for two thirds of essential hypertension, managing obesity and metabolic syndrome is a crucial task in the management of hypertension. However, the current non-pharmacological therapies have limitations for achieving or maintaining ideal body weight. Recently, glucagon-like peptide-1 receptor agonists (GLP1-RAs) have demonstrated excellent weight control effects, accompanied by corresponding reductions in blood pressure. GLP1-RAs have shown cardiovascular and renal protective effects in cardiovascular outcome trials both in primary and secondary prevention. In this document, the Korean Society of Hypertension intends to remark the current clinical results of GLP1-RAs and recommend the government and health-policy makers to define obesity as a disease and to establish forward-looking policies for GLP1-RA treatment for obesity treatment, including active reimbursement policies.
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Affiliation(s)
- Hae Young Lee
- Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Seung-Hyun Ko
- Department of Internal Medicine, Division of Endocrinology and Metabolism, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Sungjoon Park
- Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Kyuho Kim
- Department of Internal Medicine, Division of Endocrinology and Metabolism, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Song-Yi Kim
- Department of Internal Medicine, Division of Cardiology, Jeju National University Hospital, Jeju, Republic of Korea
| | - In-Jeong Cho
- Department of Internal Medicine, Division of Cardiology, Ewha Womans University Seoul Hospital, Ewha Womans University College of Medicine, Seoul, Republic of Korea
| | - Eun Joo Cho
- Department of Internal Medicine, Division of Cardiology, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Hyeon Chang Kim
- Department of Preventive Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jae-Hyeong Park
- Department of Cardiology in Internal Medicine, Chungnam National University, Chungnam National University Hospital, Daejeon, Republic of Korea
| | - Sung Kee Ryu
- Wellness Healthcare Center, Ewha Womans University Seoul Hospital, Seoul, Republic of Korea
| | - Min Kyong Moon
- Department of Internal Medicine, Division of Endocrinology & Metabolism, Seoul National University Boramae Medical Center, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Sang-Hyun Ihm
- Department of Internal Medicine, Division of Cardiology, Bucheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
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12
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Pratley R, Saeed ZI, Casu A. Incretin mimetics and acute pancreatitis: enemy or innocent bystander? Curr Opin Gastroenterol 2024; 40:404-412. [PMID: 38967917 DOI: 10.1097/mog.0000000000001057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/06/2024]
Abstract
PURPOSE OF REVIEW The incretin enhancers and mimetics, including dipeptidyl peptidase-4 (DPP-4) inhibitors, GLP-1 receptor agonists (GLP-1RA) and GLP-1/GIP co-agonists, have become mainstays in the treatment of type 2 diabetes (T2D). Recently, the approval of certain GLP-1RA and GLP-1/GIP co-agonists for the treatment of obesity has broadened their popularity and use. In this review, we summarize the evidence for an association of these drugs with acute pancreatitis and other adverse events of special interest to gastroenterologists. RECENT FINDINGS In addition to pancreatic islets, GLP-1 receptors are expressed in the exocrine cells of the pancreas. There is inconsistent evidence for an association of DPP-4 inhibitors, GLP-1RA and co-agonists with risk for acute pancreatitis in individual trials. Meta-analyses of long-term randomized controlled trials indicate a small risk of acute pancreatitis associated with DPP-4 inhibitors but not GLP-1RA or co-agonists. Cholecystitis and cholelithiasis may be more common among those treated with GLP-1RA and GLP-1/GIP co-agonists. There is no evidence that any of these drugs are associated with an increased risk of pancreatic cancer. SUMMARY While drugs that leverage the incretin system are increasingly being used for patients with T2D and obesity, caution in warranted in those with a history of pancreatitis and gallbladder disease.
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Affiliation(s)
- Richard Pratley
- AdventHealth Translational Research Institute, Orlando, Florida
| | - Zeb I Saeed
- Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Anna Casu
- AdventHealth Translational Research Institute, Orlando, Florida
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13
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Tuersun A, Hou G, Cheng G. Pancreatitis and Pancreatic Cancer Risk Among Patients With Type 2 Diabetes Receiving Dipeptidyl Peptidase 4 Inhibitors: An Updated Meta-Analysis of Randomized Controlled Trials. Clin Ther 2024; 46:650-656. [PMID: 39084911 DOI: 10.1016/j.clinthera.2024.06.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Revised: 06/11/2024] [Accepted: 06/21/2024] [Indexed: 08/02/2024]
Abstract
PURPOSE This meta-analysis sought to assess the relationship between dipeptidyl peptidase-4 inhibitors (DPP-4) and the risk of pancreatitis and pancreatic cancer by synthesizing data from randomized, controlled trials, in light of the conflicting findings from observational studies and previous meta-analyses. METHODS Cochrane, Embase, ClinicalTrials.gov, and PubMed databases that compared the use of DPP-4 inhibitors and that reported pancreatitis and pancreatic cancer events in patients with diabetes mellitus Type 2 (T2DM) were searched using specific terms. Studies were included if they satisfied the following inclusion criteria: They were randomized trials comparing DPP-4 inhibitors use in patients with T2DM; The study's duration was longer than 24 weeks; And they reported pancreatitis and pancreatic cancer events. Stata 15 MP was used to analyze the data, and odds ratios (OR) with 95% confidence intervals (CI) were used to represent the results. FINDINGS A total of 81,737 participants with T2DM were included in the analysis. The results showed that during a mean follow-up period of 24 to 520 weeks, The use of DPP-4 inhibitors was not associated with an increased risk of pancreatitis (Peto-OR 0.97; 95% CI: 0.74, 1.27) or pancreatic cancer (Peto-OR = 0.88; 95% CI: 0.59, 1.30). IMPLICATIONS Current evidence fails to validate a significant correlation between DPP-4 therapy and pancreatitis or pancreatic cancer. However, subgroup analyses showed that sitagliptin was associated with a significant reduction in pancreatitis risk compared to the control group; furthermore, when comparing different types of control medications, a significant decrease in pancreatic cancer risk was observed among DPP-4 users compared to GLP-1 users.
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Affiliation(s)
- Adili Tuersun
- School of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, Liaoning, China
| | - Guanxin Hou
- Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang, Liaoning, China
| | - Gang Cheng
- Department of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning, China.
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14
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Anazco D, Acosta A, Cathcart-Rake EJ, D'Andre SD, Hurtado MD. Weight-centric prevention of cancer. OBESITY PILLARS 2024; 10:100106. [PMID: 38495815 PMCID: PMC10943063 DOI: 10.1016/j.obpill.2024.100106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/16/2024] [Revised: 02/29/2024] [Accepted: 02/29/2024] [Indexed: 03/19/2024]
Abstract
Background The link between excess adiposity and carcinogenesis has been well established for multiple malignancies, and cancer is one of the main contributors to obesity-related mortality. The potential role of different weight-loss interventions on cancer risk modification has been assessed, however, its clinical implications remain to be determined. In this clinical review, we present the data assessing the effect of weight loss interventions on cancer risk. Methods In this clinical review, we conducted a comprehensive search of relevant literature using MEDLINE, Embase, Web of Science, and Google Scholar databases for relevant studies from inception to January 20, 2024. In this clinical review, we present systematic reviews and meta-analysis, randomized clinical trials, and prospective and retrospective observational studies that address the effect of different treatment modalities for obesity in cancer risk. In addition, we incorporate the opinions from experts in the field of obesity medicine and oncology regarding the potential of weight loss as a preventative intervention for cancer. Results Intentional weight loss achieved through different modalities has been associated with a reduced cancer incidence. To date, the effect of weight loss on the postmenopausal women population has been more widely studied, with multiple reports indicating a protective effect of weight loss on hormone-dependent malignancies. The effect of bariatric interventions as a protective intervention for cancer has been studied extensively, showing a significant reduction in cancer incidence and mortality, however, data for the effect of bariatric surgery on certain specific types of cancer is conflicting or limited. Conclusion Medical nutrition therapy, exercise, antiobesity medication, and bariatric interventions, might lead to a reduction in cancer risk through weight loss-dependent and independent factors. Further evidence is needed to better determine which population might benefit the most, and the amount of weight loss required to provide a clinically significant preventative effect.
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Affiliation(s)
- Diego Anazco
- Precision Medicine for Obesity Program, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN, USA
| | - Andres Acosta
- Precision Medicine for Obesity Program, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN, USA
| | | | | | - Maria D. Hurtado
- Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Department of Medicine, Mayo Clinic, Jacksonville, FL, USA
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15
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Wayne CD, Benbetka C, Besner GE, Narayanan S. Challenges of Managing Type 3c Diabetes in the Context of Pancreatic Resection, Cancer and Trauma. J Clin Med 2024; 13:2993. [PMID: 38792534 PMCID: PMC11122338 DOI: 10.3390/jcm13102993] [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: 04/10/2024] [Revised: 05/04/2024] [Accepted: 05/10/2024] [Indexed: 05/26/2024] Open
Abstract
Type 3c diabetes mellitus (T3cDM), also known as pancreatogenic or pancreoprivic diabetes, is a specific type of DM that often develops as a result of diseases affecting the exocrine pancreas, exhibiting an array of hormonal and metabolic characteristics. Several pancreatic exocrine diseases and surgical procedures may cause T3cDM. Diagnosing T3cDM remains difficult as the disease characteristics frequently overlap with clinical presentations of type 1 DM (T1DM) or type 2 DM (T2DM). Managing T3cDM is likewise challenging due to numerous confounding metabolic dysfunctions, including pancreatic endocrine and exocrine insufficiencies and poor nutritional status. Treatment of pancreatic exocrine insufficiency is of paramount importance when managing patients with T3cDM. This review aims to consolidate the latest information on surgical etiologies of T3cDM, focusing on partial pancreatic resections, total pancreatectomy, pancreatic cancer and trauma.
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Affiliation(s)
- Colton D. Wayne
- Department of Pediatric Surgery, Nationwide Children’s Hospital, 700 Children’s Drive, Columbus, OH 43205, USA; (C.D.W.); (G.E.B.)
- Center for Perinatal Research, Nationwide Children’s Hospital, Columbus, OH 43205, USA
- Department of Surgery, Baylor University Medical Center, 3600 Gaston Ave, Dallas, TX 75246, USA
| | | | - Gail E. Besner
- Department of Pediatric Surgery, Nationwide Children’s Hospital, 700 Children’s Drive, Columbus, OH 43205, USA; (C.D.W.); (G.E.B.)
- Center for Perinatal Research, Nationwide Children’s Hospital, Columbus, OH 43205, USA
| | - Siddharth Narayanan
- Department of Pediatric Surgery, Nationwide Children’s Hospital, 700 Children’s Drive, Columbus, OH 43205, USA; (C.D.W.); (G.E.B.)
- Center for Perinatal Research, Nationwide Children’s Hospital, Columbus, OH 43205, USA
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16
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Butuca A, Dobrea CM, Arseniu AM, Frum A, Chis AA, Rus LL, Ghibu S, Juncan AM, Muntean AC, Lazăr AE, Gligor FG, Morgovan C, Vonica-Tincu AL. An Assessment of Semaglutide Safety Based on Real World Data: From Popularity to Spontaneous Reporting in EudraVigilance Database. Biomedicines 2024; 12:1124. [PMID: 38791086 PMCID: PMC11117978 DOI: 10.3390/biomedicines12051124] [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: 04/26/2024] [Revised: 05/13/2024] [Accepted: 05/16/2024] [Indexed: 05/26/2024] Open
Abstract
Some glucagon-like peptide-1 receptor agonists (GLP-1 RAs), first used in the treatment of type 2 diabetes mellitus (T2DM), have been approved for the treatment of obesity in patients with or without T2DM (liraglutide-LIR, semaglutide-SEM, and tirzepatide-TIR). Social media had an important influence on the off-label use of GLP-1 RAs for obesity, especially for SEM. We analyzed the Google queries related to SEM to assess people's interest in this drug. We also investigated the occurrence of adverse drug reactions (ADRs) by searching the EudraVigilance database (EV) for Individual Case Safety Reports (ICSRs) that reported SEM as the suspected drug and performed a descriptive and a disproportionality analysis. The data obtained for SEM were compared to other GLP-1 RAs. SEM had the highest proportions of searches on Google associated with the term "weight loss" and presented the lowest number of severe ADRs, but it also had the highest number of ICSRs reported in EV. Even though no unexpected safety issues have been reported for it until now, SEM has a hi3gh tendency for overdose reports. The most frequent off-label use was reported for SEM and TIR. In order to lower the risks of ADRs, the off-label use should be reduced and carefully monitored.
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Affiliation(s)
- Anca Butuca
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 2A Lucian Blaga St., 550169 Sibiu, Romania; (A.B.); (C.M.D.); (A.M.A.); (A.F.); (A.A.C.); (L.L.R.); (A.M.J.); (A.C.M.); (F.G.G.); (C.M.); (A.L.V.-T.)
| | - Carmen Maximiliana Dobrea
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 2A Lucian Blaga St., 550169 Sibiu, Romania; (A.B.); (C.M.D.); (A.M.A.); (A.F.); (A.A.C.); (L.L.R.); (A.M.J.); (A.C.M.); (F.G.G.); (C.M.); (A.L.V.-T.)
| | - Anca Maria Arseniu
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 2A Lucian Blaga St., 550169 Sibiu, Romania; (A.B.); (C.M.D.); (A.M.A.); (A.F.); (A.A.C.); (L.L.R.); (A.M.J.); (A.C.M.); (F.G.G.); (C.M.); (A.L.V.-T.)
| | - Adina Frum
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 2A Lucian Blaga St., 550169 Sibiu, Romania; (A.B.); (C.M.D.); (A.M.A.); (A.F.); (A.A.C.); (L.L.R.); (A.M.J.); (A.C.M.); (F.G.G.); (C.M.); (A.L.V.-T.)
| | - Adriana Aurelia Chis
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 2A Lucian Blaga St., 550169 Sibiu, Romania; (A.B.); (C.M.D.); (A.M.A.); (A.F.); (A.A.C.); (L.L.R.); (A.M.J.); (A.C.M.); (F.G.G.); (C.M.); (A.L.V.-T.)
| | - Luca Liviu Rus
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 2A Lucian Blaga St., 550169 Sibiu, Romania; (A.B.); (C.M.D.); (A.M.A.); (A.F.); (A.A.C.); (L.L.R.); (A.M.J.); (A.C.M.); (F.G.G.); (C.M.); (A.L.V.-T.)
| | - Steliana Ghibu
- Department of Pharmacology, Physiology and Pathophysiology, Faculty of Pharmacy, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
| | - Anca Maria Juncan
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 2A Lucian Blaga St., 550169 Sibiu, Romania; (A.B.); (C.M.D.); (A.M.A.); (A.F.); (A.A.C.); (L.L.R.); (A.M.J.); (A.C.M.); (F.G.G.); (C.M.); (A.L.V.-T.)
| | - Andrei Catalin Muntean
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 2A Lucian Blaga St., 550169 Sibiu, Romania; (A.B.); (C.M.D.); (A.M.A.); (A.F.); (A.A.C.); (L.L.R.); (A.M.J.); (A.C.M.); (F.G.G.); (C.M.); (A.L.V.-T.)
| | - Antonina Evelina Lazăr
- National Institute of Research and Development for Electrochemistry and Condensed Matter, 144 Dr. A. P. Podeanu, 300569 Timisoara, Romania;
| | - Felicia Gabriela Gligor
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 2A Lucian Blaga St., 550169 Sibiu, Romania; (A.B.); (C.M.D.); (A.M.A.); (A.F.); (A.A.C.); (L.L.R.); (A.M.J.); (A.C.M.); (F.G.G.); (C.M.); (A.L.V.-T.)
| | - Claudiu Morgovan
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 2A Lucian Blaga St., 550169 Sibiu, Romania; (A.B.); (C.M.D.); (A.M.A.); (A.F.); (A.A.C.); (L.L.R.); (A.M.J.); (A.C.M.); (F.G.G.); (C.M.); (A.L.V.-T.)
| | - Andreea Loredana Vonica-Tincu
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 2A Lucian Blaga St., 550169 Sibiu, Romania; (A.B.); (C.M.D.); (A.M.A.); (A.F.); (A.A.C.); (L.L.R.); (A.M.J.); (A.C.M.); (F.G.G.); (C.M.); (A.L.V.-T.)
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Lin Y, Xu G, Li L, Xiang J, Zhai L. Incretin-based drugs decrease the incidence of prostate cancer in type 2 diabetics: A pooling-up analysis. Medicine (Baltimore) 2024; 103:e38018. [PMID: 38758855 PMCID: PMC11098233 DOI: 10.1097/md.0000000000038018] [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: 03/20/2024] [Accepted: 04/05/2024] [Indexed: 05/19/2024] Open
Abstract
Incretin-based drugs, a class of Antidiabetic medications (ADMs) used in the treatment of type 2 diabetes, may affect the incidence of prostate cancer (PCa). But real-world evidence for this possible effect is lacking. Therefore, the aim of this study is to assess the effect of incretin-based drugs on the incidence of PCa, including glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors. We searched PubMed, Embase, and Cochrane Library databases for eligible studies through September 2023. Two independent reviewers performed screening and data extraction. We used the Cochrane Handbook for Systematic Reviews and the Newcastle-Ottawa Scale (NOS) to assess the quality of included randomized controlled trials (RCTs) and cohort studies. We did a meta-analysis of available trial data to calculate overall risk ratios (RRs) for PCa. A total of 1238 articles were identified in our search. After screening for eligibility, 7 high-quality studies met the criteria for meta-analysis, including 2 RCTs and 5 cohort studies, with a total of 1165,738 patients. Compared with the control group, we found that incretin-based drugs reduced the relative risk of PCa by 35% (95% confidence interval (CI), 0.17-0.49; P = .0006). In subgroup analysis, the RR values for GLP-1 receptor agonists and DPP-4 inhibitors were 62% (95% CI, 0.45-0.85; P = .003) and 72% (95% CI, 0.46-1.12; P = .14), respectively. Incretin-based drugs are associated with lower incidence of prostate cancer and may have a preventive effect on prostate cancer in patients with type 2 diabetes.
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Affiliation(s)
- Yuxiang Lin
- Department of Urology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Guangyong Xu
- Department of Urology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Liangyu Li
- Department of Urology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jingyi Xiang
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Lingyun Zhai
- Department of Urology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Natale F, Luisi E, Franzese R, Mollo N, Solimene A, Caso VM, Corvino A, Golino P, Cimmino G. Semaglutide in Cardiometabolic Diseases: SELECTing the Target Population. J Cardiovasc Dev Dis 2024; 11:145. [PMID: 38786967 PMCID: PMC11122593 DOI: 10.3390/jcdd11050145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 05/01/2024] [Accepted: 05/04/2024] [Indexed: 05/25/2024] Open
Abstract
Cardiovascular diseases remain the main cause of death and disability worldwide. Despite the tremendous improvement in pharmacological, minimally invasive and rehabilitative strategies, global deaths due to cardiovascular diseases are still increasing. Additional risk factors have been recently proposed, and thanks to scientific progress, novel drugs for the control of the main risk factors focusing on the cardiometabolic pathways have been identified. Glucagon-like peptide-1 (GLP-1) receptor agonists represent an innovative step in the management of patients affected by type 2 diabetes mellitus. In addition to their significant efficacy on glycemic homeostasis, some members of this class of drugs have indications in the treatment of obesity. Furthermore, accumulated evidence in the literature has finally suggested a protective role in cardiovascular health. The possible role of GLP-1R agonist drugs (GLP-1RAs) on the mechanisms underlying chronic inflammation and the almost ubiquitous distribution of GLP-1 receptors could explain the enormous versatility of these drugs. Semaglutide is a GLP-1RA recently proven to be effective in cardiovascular outcomes. In the present article, we will review the available data on semaglutide in light of the most recent publications to better characterize the target population achieving cardiovascular benefits.
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Affiliation(s)
- Francesco Natale
- Vanvitelli Cardiology Unit, Monaldi Hospital, 80131 Naples, Italy; (F.N.); (P.G.)
| | - Ettore Luisi
- Vanvitelli Cardiology Unit, Monaldi Hospital, 80131 Naples, Italy; (F.N.); (P.G.)
- Department of Translational Medical Sciences, Section of Cardiology, University of Campania Luigi Vanvitelli, 80131 Naples, Italy
| | - Rosa Franzese
- Vanvitelli Cardiology Unit, Monaldi Hospital, 80131 Naples, Italy; (F.N.); (P.G.)
- Department of Translational Medical Sciences, Section of Cardiology, University of Campania Luigi Vanvitelli, 80131 Naples, Italy
| | - Noemi Mollo
- Vanvitelli Cardiology Unit, Monaldi Hospital, 80131 Naples, Italy; (F.N.); (P.G.)
- Department of Translational Medical Sciences, Section of Cardiology, University of Campania Luigi Vanvitelli, 80131 Naples, Italy
| | - Achille Solimene
- Vanvitelli Cardiology Unit, Monaldi Hospital, 80131 Naples, Italy; (F.N.); (P.G.)
- Department of Translational Medical Sciences, Section of Cardiology, University of Campania Luigi Vanvitelli, 80131 Naples, Italy
| | - Valentina Maria Caso
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80131 Naples, Italy
- Pharmacy Unit, Monaldi Hospital, 80131 Naples, Italy
| | | | - Paolo Golino
- Vanvitelli Cardiology Unit, Monaldi Hospital, 80131 Naples, Italy; (F.N.); (P.G.)
- Department of Translational Medical Sciences, Section of Cardiology, University of Campania Luigi Vanvitelli, 80131 Naples, Italy
| | - Giovanni Cimmino
- Department of Translational Medical Sciences, Section of Cardiology, University of Campania Luigi Vanvitelli, 80131 Naples, Italy
- Cardiology Unit, AOU Luigi Vanvitelli, 80138 Naples, Italy
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19
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Kawakita E, Kanasaki K. Cancer biology in diabetes update: Focusing on antidiabetic drugs. J Diabetes Investig 2024; 15:525-540. [PMID: 38456597 PMCID: PMC11060166 DOI: 10.1111/jdi.14152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 12/25/2023] [Accepted: 01/08/2024] [Indexed: 03/09/2024] Open
Abstract
The association of type 2 diabetes with certain cancer risk has been of great interest for years. However, the effect of diabetic medications on cancer development is not fully understood. Prospective clinical trials have not elucidated the long-term influence of hypoglycemic drugs on cancer incidence and the safety for cancer-bearing patients with diabetes, whereas numerous preclinical studies have shown that antidiabetic drugs could have an impact on carcinogenesis processes beyond the glycemic control effect. Because there is no evidence of the safety profile of antidiabetic agents on cancer biology, careful consideration would be required when prescribing any medicines to patients with diabetes and existing tumor. In this review, we discuss the potential influence of each diabetes therapy in cancer 'initiation', 'promotion' and 'progression'.
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Affiliation(s)
- Emi Kawakita
- Department of Internal Medicine 1, Faculty of MedicineShimane UniversityIzumoJapan
| | - Keizo Kanasaki
- Department of Internal Medicine 1, Faculty of MedicineShimane UniversityIzumoJapan
- The Center for Integrated Kidney Research and Advance, Faculty of MedicineShimane UniversityIzumoJapan
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20
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Laeeq T, Ahmed M, Sattar H, Zeeshan MH, Ali MB. Role of SGLT2 Inhibitors, DPP-4 Inhibitors, and Metformin in Pancreatic Cancer Prevention. Cancers (Basel) 2024; 16:1325. [PMID: 38611003 PMCID: PMC11011099 DOI: 10.3390/cancers16071325] [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: 01/29/2024] [Revised: 03/08/2024] [Accepted: 03/27/2024] [Indexed: 04/14/2024] Open
Abstract
Pancreatic carcinoma is a highly aggressive tumor that usually presents when it has already metastasized. Therapeutic options for cure remain scarce and rely on combination chemotherapy with limited sustainability. Diabetes is considered an important risk factor for the development of pancreatic cancer due to the production of proinflammatory cytokines, which result in increased cell proliferation. More than half of patients diagnosed with pancreatic cancer eventually develop diabetes due to the destruction of insulin-producing cells. The interlinkage of both diseases might identify a possible preventative strategy for reducing the incidence of pancreatic carcinoma. This study reviewed the recent literature on the association between pancreatic cancer risk and SGLT2 inhibitors, GLP-1 RA, DPP-4 inhibitors, and biguanides. There are mixed data regarding the relationship between GLP-1 RA and DPP-4 inhibitors and pancreatic cancer, with some trials suggesting that they might increase the risk. In contrast, studies have mostly revealed that SGLT2 inhibitors have an antiproliferative effect on various tumors, such as liver, pancreatic, prostate, bowel, lung, and breast carcinoma, which might be due to their mechanism of blockage of reabsorption of glucose by cells, lowering the amount of available glucose for the growth of tumor cells. Metformin, the first-line agent for diabetes, has also been shown to be associated with decreasing pancreatic cancer risk and improving prognosis in those who already have the disease. Dedicated trials are needed to further delineate the association of antidiabetic drugs with the risk of pancreatic cancer in the general population, as previous studies have mostly focused on diabetic patients.
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Affiliation(s)
- Tooba Laeeq
- Internal Medicine, University of Nevada, 4505 S Maryland Pkwy, Las Vegas, NV 89154, USA
| | - Maheen Ahmed
- Internal Medicine, Dow University of Health Sciences, Mission Rd., New Labour Colony, Karachi 74200, Pakistan; (M.A.); (M.H.Z.)
| | - Hina Sattar
- Internal Medicine, Dow University of Health Sciences, Mission Rd., New Labour Colony, Karachi 74200, Pakistan; (M.A.); (M.H.Z.)
| | - Muhammad Hamayl Zeeshan
- Internal Medicine, Dow University of Health Sciences, Mission Rd., New Labour Colony, Karachi 74200, Pakistan; (M.A.); (M.H.Z.)
| | - Meher Binte Ali
- Internal Medicine, University of Maryland Medical Center, 827 Linden Ave., Baltimore, MD 21201, USA
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21
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de Andrade Mesquita L, Wayerbacher LF, Schwartsmann G, Gerchman F. Obesity, diabetes, and cancer: epidemiology, pathophysiology, and potential interventions. ARCHIVES OF ENDOCRINOLOGY AND METABOLISM 2023; 67:e000647. [PMID: 37364149 PMCID: PMC10660996 DOI: 10.20945/2359-3997000000647] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Accepted: 02/22/2023] [Indexed: 06/28/2023]
Abstract
The proportion of deaths attributable to cancer is rising, and malignant neoplasms have become the leading cause of death in high-income countries. Obesity and diabetes are now recognized as risk factors for several types of malignancies, especially endometrial, colorectal, and postmenopausal breast cancers. Mechanisms implicated include disturbances in lipid-derived hormone secretion, sex steroids biosynthesis, hyperinsulinemia, and chronic inflammation. Intentional weight loss is associated with a mitigation of risk for obesity-related cancers, a phenomenon observed specially with bariatric surgery. The impact of pharmacological interventions for obesity and diabetes is not uniform: while metformin seems to protect against cancer, other agents such as lorcaserin may increase the risk of malignancies. However, these interpretations must be carefully considered, since most data stem from bias-prone observational studies, and high-quality randomized controlled trials with appropriate sample size and duration are needed to achieve definite conclusions. In this review, we outline epidemiological and pathophysiological aspects of the relationship between obesity, diabetes, and malignancies. We also highlight pieces of evidence regarding treatment effects on cancer incidence in these populations.
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Affiliation(s)
- Leonardo de Andrade Mesquita
- Programa de Pós-graduação em Ciências Médicas: Endocrinologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil
- Hospital de Clínicas de Porto Alegre, Porto Alegre, Brasil, Porto Alegre, RS, Brasil
| | - Laura Fink Wayerbacher
- Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil
| | - Gilberto Schwartsmann
- Hospital de Clínicas de Porto Alegre, Porto Alegre, Brasil, Porto Alegre, RS, Brasil
- Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil
| | - Fernando Gerchman
- Programa de Pós-graduação em Ciências Médicas: Endocrinologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil
- Hospital de Clínicas de Porto Alegre, Porto Alegre, Brasil, Porto Alegre, RS, Brasil,
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22
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Del Rio T, Ubhi M, Irizarry Nieves LE, Fermin B, Sury K. Necrotizing Pancreatitis Secondary to Hydrochlorothiazide and Alogliptin: A Case Report. Cureus 2023; 15:e37754. [PMID: 37214053 PMCID: PMC10193513 DOI: 10.7759/cureus.37754] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/18/2023] [Indexed: 05/23/2023] Open
Abstract
Drug-induced pancreatitis occurs rarely but should be considered when more common causes have been ruled out. While simple to treat, mortality increases should it progress to a necrotizing process. Here, we present the case of a patient simultaneously using two drugs associated with pancreatitis, which we considered acted synergistically and consequently worsened the patient's outcome.
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Affiliation(s)
- Teresa Del Rio
- Internal Medicine, Wyckoff Heights Medical Center, Brooklyn, USA
| | - Manveer Ubhi
- Internal Medicine, Wyckoff Heights Medical Center, Brooklyn, USA
| | | | - Basilides Fermin
- Internal Medicine, Wyckoff Heights Medical Center, Brooklyn, USA
| | - Kala Sury
- Pulmonary Critical Care, Internal Medicine, Wyckoff Heights Medical Center, Brooklyn, USA
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23
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Gidda H, Singh I, Mohamed A, Nashed B. Mild Pancreatitis Induced by Linagliptin Revealed by a Medication Review. Cureus 2023; 15:e36455. [PMID: 37090411 PMCID: PMC10116583 DOI: 10.7759/cureus.36455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/20/2023] [Indexed: 04/25/2023] Open
Abstract
As dipeptidyl peptidase-4 inhibitors are becoming more utilized in the treatment of diabetes, it is important to recognize their side effects and become more familiar with them. As these side effects arise, physicians are more prepared to recognize and discontinue these medications. This case report describes a 34-year-old male who initially presented with a hemoglobin A1c greater than 16%. After titration of his diabetic medications, he presented with pancreatitis diagnosed by symptoms and imaging. Common causes of pancreatitis were ruled out, including biliary pathology, alcohol use, tobacco use, elevated calcium levels, and hypertriglyceridemia. The patient followed up in the clinic with persistent symptoms. A review of his medication list revealed pancreatitis as a side effect of linagliptin. After holding this medication, his symptoms improved over the course of a month.
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Affiliation(s)
- Harish Gidda
- Internal Medicine, Ascension St. John Hospital, Detroit, USA
| | - Inderpal Singh
- Internal Medicine, Ascension St. John Hospital, Detroit, USA
| | - Ayman Mohamed
- Internal Medicine, Ascension St. John Hospital, Detroit, USA
| | - Bola Nashed
- Internal Medicine, Ascension St. John Hospital, Detroit, USA
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Hidayat K, Zhou YY, Du HZ, Qin LQ, Shi BM, Li ZN. A systematic review and meta-analysis of observational studies of the association between the use of incretin-based therapies and the risk of pancreatic cancer. Pharmacoepidemiol Drug Saf 2023; 32:107-125. [PMID: 36224724 DOI: 10.1002/pds.5550] [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: 10/15/2021] [Revised: 09/25/2022] [Accepted: 10/04/2022] [Indexed: 01/26/2023]
Abstract
BACKGROUND Some early reports in the medical literature have raised concern about a possible increased risk of pancreatic cancer associated with the use of two broad classes of incretin-based therapies, dipeptidyl peptidase-4 inhibitors, and glucagon-like peptide-1 receptor agonists. This possibility has been somewhat mitigated by the null findings meta-analyses of randomized controlled trials, but the usefulness of their findings was hampered by serious shortcomings of lack of power and representativeness. These shortcomings can typically be addressed by observational studies, but observational studies on the topic have yielded conflicting findings. A systematic review and meta-analysis of observational studies was performed to qualitatively and quantitatively appraise the totality of evidence on the association between the use of incretin-based therapies and the risk of pancreatic cancer in routine clinical practice. METHODS The PubMed, Web of Science, Embase, and Google Scholar databases were searched. The study quality was appraised using the ROBINS-I tool and based on the presence of pharmacoepidemiology biases. A random-effects model was used to estimate the summary relative risks with corresponding CIs. RESULTS A total of 14 studies were included. The qualitative assessment revealed that all studies had inadequate follow-up (≤5 years), 12 studies were suspected to suffer from time-lag bias (due to inappropriate choice of comparator group) to varying extent, five studies included prevalent users, five studies did not implement exposure lag period, five studies had a serious risk of bias due to confounding, and one study had a time-window bias. The quantitative assessment showed no indication of an increased risk when all studies were pooled together (RR 1.04, 95% CI 0.87, 1.24) and when the analysis was restricted to the studies with the least bias (RR 0.77, 95% CI 0.51, 1.17). However, the pooled RRs were more frequently higher in the studies with less rigorous design and analysis. Specifically, a tendency toward an increased risk was observed in the studies with (RR 1.34, 95% CI 1.04, 1.72) or possibly with (RR 1.10, 95% CI 0.89, 1.36) time-lag bias, in the studies that did not apply (RR 1.23, 95% CI 0.93, 1.63) or with potentially inadequate exposure lag period of 6 months (RR 1.13, 95% CI 0.66, 1.94), in the studies that inappropriate comparator group of a combination of unspecified (RR 1.49, 95% CI 1.25, 1.78) or non-insulin (RR 1.15, 95% CI 0.93, 1.42) antidiabetic drugs, and in the studies with serious risk of bias due to confounding (RR 1.18, 95% CI 0.56, 2.49). CONCLUSIONS In summary, the totality of evidence from observational studies does not support the claim that the use of incretin-based therapies is associated with an increased risk of pancreatic cancer in routine clinical practice. The increased risk of pancreatic cancer observed in observational studies reflects bias resulting from suboptimal methodological approaches, which need to be avoided by future studies.
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Affiliation(s)
- Khemayanto Hidayat
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Soochow University, Suzhou, China.,Department of Nutrition and Food Hygiene, School of Public Health, Soochow University, Suzhou, China
| | - Ying-Yi Zhou
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Hong-Zhen Du
- Department of Nutrition, The First Hospital of Hebei Medical University, Hebei Province Key Laboratory of Nutrition, Shijiazhuang, China
| | - Li-Qiang Qin
- Department of Nutrition and Food Hygiene, School of Public Health, Soochow University, Suzhou, China
| | - Bi-Min Shi
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Zeng-Ning Li
- Department of Nutrition, The First Hospital of Hebei Medical University, Hebei Province Key Laboratory of Nutrition, Shijiazhuang, China
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25
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Krishnan A, Hadi Y, Hutson WR, Thakkar S, Singh S. Glucagon-Like Peptide 1-Based Therapies and Risk of Pancreatic Cancer in Patients With Diabetes and Obesity. Pancreas 2022; 51:1398-1403. [PMID: 37099785 DOI: 10.1097/mpa.0000000000002197] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/28/2023]
Abstract
OBJECTIVES There have been conflicting reports concerning an increased risk of pancreatic cancer (PC) in new users of glucagon-like peptide-1 agonists (GLP-1As). We aimed to explore whether the use of GLP-1A is associated with an increased risk of PC. METHODS A multicenter, retrospective cohort study was conducted using TriNetX. Adult patients with diabetes and/or overweight and obesity who were newly treated with GLP-1A or metformin for the first time between 2006 and 2021 were matched 1:1 using propensity score matching. The risk of PC was estimated using a Cox proportional hazards model. RESULTS A total of 492,760 patients were identified in the GLP-1A and 918,711 patients in the metformin group. After propensity score matching, both cohorts (370,490 each) were well matched. During follow-up, 351 patients in the GLP-1A and 956 on metformin developed PC after an exposure lag of 1 year. Glucagon-like peptide-1 agonists was associated with a significantly lower risk of PC (hazard ratio, 0.47; 95% confidence interval, 0.42-0.52). CONCLUSIONS The use of GLP-1A in patients with obesity/diabetes is associated with a lower risk of PC compared with a similar cohort of patients using metformin. Our study findings reassure clinicians and patients with apprehensions about any possible association between GLP-1A and PC.
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Affiliation(s)
- Arunkumar Krishnan
- From the Department of Medicine, Section of Gastroenterology and Hepatology, West Virginia University School of Medicine, Morgantown, WV
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26
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Yang Z, Lv Y, Yu M, Mei M, Xiang L, Zhao S, Li R. GLP-1 receptor agonist-associated tumor adverse events: A real-world study from 2004 to 2021 based on FAERS. Front Pharmacol 2022; 13:925377. [PMID: 36386208 PMCID: PMC9640975 DOI: 10.3389/fphar.2022.925377] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Accepted: 09/26/2022] [Indexed: 09/10/2023] Open
Abstract
Background: GLP-1 receptor agonists (GLP-1RA) have demonstrated cardiovascular benefits, but the relationship between GLP-1RA and tumors is controversial. Recently, clinical trials reported higher rates of malignancy with semaglutide than control group. As real-world evidence of GLP-1RA-associated tumor risk is very limited, we explored the association of GLP-1RA and all types of neoplasms by mining the FDA Adverse Event Reporting System (FAERS) database. Methods: The FAERS data from the first quarter (Q1) of 2004 to the second quarter (Q2) of 2020 in the AERSMine were extracted to conduct disproportionality analysis, which was used by the proportional reporting ratio (PRR) to assess the relationship between GLP-1RA and all types of neoplasms. Then, the details of disproportionate GLP-1RA-associated tumor cases from Q1 2004 to Q2 2021 in the FAERS Public Dashboard were collected to analyze demographic characteristics. Results: A total of 8718 GLP-1RA-associated tumors were reported. Excluding cases with pre-existing tumors, other glucose-lowering drugs, and other GLP-1RA-related adverse events, diabetes cases with GLP-1RA as the main suspected drug were selected. GLP-1RA did not cause a disproportionate increase in all tumor cases (PRR 0.83) at the SOC level, and there was also no increase in most types of tumors associated with GLP-1RA at the HLGT/HLT levels. Significant signals were detected between GLP-1RA and certain tumors, including thyroid cancers [medullary thyroid cancer (PRR 27.43) and papillary thyroid cancer (PRR 8.68)], pancreatic neoplasms malignant (PRR 9.86), and islet cell neoplasms and APUDoma NEC (PRR 2.86). The combination of GLP-1RA with dipeptidyl-peptidase IV inhibitors (DPP4i) perhaps caused the increased reporting rate in some tumors. Conclusion: Our study provided new real-world evidence for oncology safety information of GLP-1RA. Given the wide use of GLP-1RA, clinicians should be well informed about important potential adverse events. Our pharmacovigilance analysis also prompted clinicians to raise concerns about potential tumor-related adverse effects when combining GLP-1RA with DPP4i.
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Affiliation(s)
| | | | | | | | | | | | - Rong Li
- Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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27
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Kulkarni S, Posgai AL, Kusmartseva I, Wasserfall CH, Atkinson MA, Butler AE. Exocrine and Endocrine Inflammation Increases Cellular Replication in the Pancreatic Duct Compartment in Type 1 Diabetes. J Endocr Soc 2022; 6:bvac136. [PMID: 36249412 PMCID: PMC9557836 DOI: 10.1210/jendso/bvac136] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Indexed: 01/21/2023] Open
Abstract
Context We recently demonstrated increased cellular proliferation in the pancreatic ductal gland (PDG) compartment of organ donors with type 1 diabetes, suggesting that PDGs may harbor progenitor cells capable of pancreatic regeneration. Objective We evaluated the impact of diabetes and pancreatic inflammation on PDG and interlobular duct (ILD) cellular proliferation and profiles. Methods Endocrine hormone expression (insulin, glucagon, somatostatin, pancreatic polypeptide) and proliferating Ki67+ cells were localized within the PDG and ILD compartments by multicolor immunohistochemistry in cross-sections from the head, body, and tail regions of pancreata from those with (n = 31) or without type 1 diabetes (n = 43). Whole-slide scanned images were analyzed using digital pathology. Results Type 1 diabetes donors with insulitis or histologically identified pancreatitis had increased cellular replication in the ILD and PDG compartments. Interestingly, while cellular proliferation within the pancreatic ductal tree was significantly increased in type 1 diabetes (PDG mean = 3.36%, SEM = 1.06; ILD mean = 2.78%, SEM = 0.97) vs nondiabetes(ND) subjects without pancreatic inflammation (PDG mean = 1.18%, SEM = 0.42; ILD mean = 0.74%, SEM = 0.15, P < 0.05), robust replication was also observed in ND donors with pancreatitis (PDG mean = 3.52%, SEM = 1.33; ILD mean = 2.18%, SEM = 0.54, P < 0.05). Few polyhormonal cells were present in the ILD (type 1 diabetes = 0.04 ± 0.02%; ND = 0.08 ± 0.03%, P = 0.40) or PDG compartment (type 1 diabetes = 0.02 ± 0.01%; ND = 0.08 ± 0.13%, P = 0.63). Conclusion These data suggest that increased pancreatic ductal cell replication is associated with sustained pancreatic inflammation; however, as replicating cells were hormone-negative, PDGs do not appear to represent a compelling endogenous source of hormone-positive endocrine cells.
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Affiliation(s)
- Shweta Kulkarni
- Department of Pathology, Immunology, and Laboratory Medicine, Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL 32611, USA
| | - Amanda L Posgai
- Department of Pathology, Immunology, and Laboratory Medicine, Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL 32611, USA
| | - Irina Kusmartseva
- Department of Pathology, Immunology, and Laboratory Medicine, Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL 32611, USA
| | - Clive H Wasserfall
- Department of Pathology, Immunology, and Laboratory Medicine, Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL 32611, USA
| | - Mark A Atkinson
- Department of Pathology, Immunology, and Laboratory Medicine, Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL 32611, USA
- Department of Pediatrics, Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL 32611, USA
| | - Alexandra E Butler
- Department of Research, Royal College of Surgeons in Ireland-Bahrain, 15503 Adliya, Bahrain
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Zhu B, Qu S. The Relationship Between Diabetes Mellitus and Cancers and Its Underlying Mechanisms. Front Endocrinol (Lausanne) 2022; 13:800995. [PMID: 35222270 PMCID: PMC8873103 DOI: 10.3389/fendo.2022.800995] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2021] [Accepted: 01/12/2022] [Indexed: 12/27/2022] Open
Abstract
Epidemiological studies suggest associations between diabetes mellitus and some cancers. The risk of a number of cancers appears to be increased in diabetes mellitus. On the other hand, some cancer and cancer therapies could lead to diabetes mellitus. Genetic factors, obesity, inflammation, oxidative stress, hyperglycemia, hyperinsulinemia, cancer therapies, insulin and some oral hypoglycemic drugs appear to play a role in the crosstalk between diabetes mellitus and cancers. This review summarized the associations between various types of diabetes and cancers and updated available evidence of underlying mechanisms between diabetes and cancers.
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Affiliation(s)
| | - Shen Qu
- Department of Endocrinology and Metabolism, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, China
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29
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Duan X, Wang W, Pan Q, Guo L. Type 2 Diabetes Mellitus Intersects With Pancreatic Cancer Diagnosis and Development. Front Oncol 2021; 11:730038. [PMID: 34485159 PMCID: PMC8415500 DOI: 10.3389/fonc.2021.730038] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Accepted: 07/30/2021] [Indexed: 12/12/2022] Open
Abstract
The relationship between type 2 diabetes mellitus (T2DM) and pancreatic cancer (PC) is complex. Diabetes is a known risk factor for PC, and new-onset diabetes (NOD) could be an early manifestation of PC that may be facilitate the early diagnosis of PC. Metformin offers a clear benefit of inhibiting PC, whereas insulin therapy may increase the risk of PC development. No evidence has shown that novel hypoglycemic drugs help or prevent PC. In this review, the effects of T2DM on PC development are summarized, and novel strategies for the prevention and treatment of T2DM and PC are discussed.
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Affiliation(s)
- Xiaoye Duan
- Department of Endocrinology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
- Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Weihao Wang
- Department of Endocrinology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Qi Pan
- Department of Endocrinology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Lixin Guo
- Department of Endocrinology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
- Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
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30
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Inzucchi SE, Peixoto AJ, Testani JM. Glucose-Lowering Drugs to Reduce Cardiovascular Risk in Type 2 Diabetes. N Engl J Med 2021; 385:671-672. [PMID: 34379938 DOI: 10.1056/nejmc2107340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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31
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Abstract
The glucagon-like peptide-1 receptor agonist (GLP-1RA) semaglutide is the most recently approved agent of this drug class, and the only GLP-1RA currently available as both subcutaneous and oral formulation. While GLP-1RAs effectively improve glycemic control and cause weight loss, potential safety concerns have arisen over the years. For semaglutide, such concerns have been addressed in the extensive phase 3 registration trials including cardiovascular outcome trials for both subcutaneous (SUSTAIN: Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes) and oral (PIONEER: Peptide InnOvatioN for the Early diabEtes tReatment) semaglutide and are being studied in further trials and registries, including real world data studies. In the current review we discuss the occurrence of adverse events associated with semaglutide focusing on hypoglycemia, gastrointestinal side effects, pancreatic safety (pancreatitis and pancreatic cancer), thyroid cancer, gallbladder events, cardiovascular aspects, acute kidney injury, diabetic retinopathy (DRP) complications and injection-site and allergic reactions and where available, we highlight potential underlying mechanisms. Furthermore, we discuss whether effects are specific for semaglutide or a class effect. We conclude that semaglutide induces mostly mild-to-moderate and transient gastrointestinal disturbances and increases the risk of biliary disease (cholelithiasis). No unexpected safety issues have arisen to date, and the established safety profile for semaglutide is similar to that of other GLP-1RAs where definitive conclusions for pancreatic and thyroid cancer cannot be drawn at this point due to low incidence of these conditions. Due to its potent glucose-lowering effect, patients at risk for deterioration of existing DRP should be carefully monitored if treated with semaglutide, particularly if also treated with insulin. Given the beneficial metabolic and cardiovascular actions of semaglutide, and the low risk for severe adverse events, semaglutide has an overall favorable risk/benefit profile for patient with type 2 diabetes.
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Affiliation(s)
| | - Daniël H. Van Raalte
- Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Center, Amsterdam, Netherlands
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Manell E, Puuvuori E, Svensson A, Velikyan I, Hulsart-Billström G, Hedenqvist P, Holst JJ, Jensen Waern M, Eriksson O. Exploring the GLP-1-GLP-1R axis in porcine pancreas and gastrointestinal tract in vivo by ex vivo autoradiography. BMJ Open Diabetes Res Care 2021; 9:9/1/e002083. [PMID: 33903116 PMCID: PMC8076945 DOI: 10.1136/bmjdrc-2020-002083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 02/18/2021] [Accepted: 04/10/2021] [Indexed: 12/03/2022] Open
Abstract
INTRODUCTION Glucagon-like peptide-1 (GLP-1) increases insulin secretion from pancreatic beta-cells and GLP-1 receptor (GLP-1R) agonists are widely used as treatment for type 2 diabetes mellitus. Studying occupancy of the GLP-1R in various tissues is challenging due to lack of quantitative, repeatable assessments of GLP-1R density. The present study aimed to describe the quantitative distribution of GLP-1Rs and occupancy by endogenous GLP-1 during oral glucose tolerance test (OGTT) in pigs, a species that is used in biomedical research to model humans. RESEARCH DESIGN AND METHODS GLP-1R distribution and occupancy were measured in pancreas and gastrointestinal tract by ex vivo autoradiography using the GLP-1R-specific radioligand 177Lu-exendin-4 in two groups of pigs, control or bottle-fed an oral glucose load. Positron emission tomography (PET) data from pigs injected with 68Ga-exendin-4 in a previous study were used to retrieve data on biodistribution of GLP-1R in the gastrointestinal tract. RESULTS High homogenous uptake of 177Lu-exendin-4 was found in pancreas, and even higher uptake in areas of duodenum. Low uptake of 177Lu-exendin-4 was found in stomach, jejunum, ileum and colon. During OGTT, there was no increase in plasma GLP-1 concentrations and occupancy of GLP-1Rs was low. The ex vivo autoradiography results were highly consistent with to the biodistribution of 68Ga-exendin-4 in pigs scanned by PET. CONCLUSION We identified areas with similarities as well as important differences regarding GLP-1R distribution and occupancy in pigs compared with humans. First, there was strong ligand binding in the exocrine pancreas in islets. Second, GLP-1 secretion during OGTT is minimal and GLP-1 might not be an important incretin in pigs under physiological conditions. These findings offer new insights on the relevance of porcine diabetes models.
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Affiliation(s)
- Elin Manell
- Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden
| | - Emmi Puuvuori
- Science for Life Laboratory, Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden
| | - Anna Svensson
- Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden
| | - Irina Velikyan
- Science for Life Laboratory, Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden
| | - Gry Hulsart-Billström
- Science for Life Laboratory, Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden
| | - Patricia Hedenqvist
- Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden
| | - Jens Juul Holst
- NNF Centre for Basic Metabolic Research and Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Marianne Jensen Waern
- Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden
| | - Olof Eriksson
- Science for Life Laboratory, Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden
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Sharko A, Samuel S, Jain N. Acute Pancreatitis Induced by Linagliptin: A Rare but Dangerous Side Effect. Cureus 2021; 13:e14104. [PMID: 33927920 PMCID: PMC8075763 DOI: 10.7759/cureus.14104] [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] [Indexed: 11/30/2022] Open
Abstract
Diabetes mellitus type 2 (DMT2) is a highly prevalent disease both in the United States and worldwide. Multiple treatment options are currently available, and several new groups of medications have been introduced over the last couple of decades. One of these groups is dipeptidyl peptidase-4 (DPP-4) inhibitors. These medications have side effects, some of which are severe and potentially life-threatening; however, some of their side effects have been underreported since they are relatively new. When prescribing these medications, it is essential to be cautious, especially with patients at an increased risk of developing an adverse effect. We present the case of a 57-year-old male who developed DPP-4 inhibitor-induced acute pancreatitis after the initiation of linagliptin. The patient did not have any apparent risk factors for pancreatitis as he did not drink alcohol or smoke cigarettes, his lipid panel was within normal limits, and he had a cholecystectomy five years prior. His linagliptin was held in the hospital and discontinued post-discharge, which led to the resolution of his symptoms.
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Affiliation(s)
- Artem Sharko
- Internal Medicine, Northwestern Medicine McHenry Hospital, McHenry, USA
| | - Shirly Samuel
- Internal Medicine, Northwestern Medicine McHenry Hospital, McHenry, USA
| | - Nikita Jain
- Internal Medicine, Northwestern Medicine McHenry Hospital, McHenry, USA
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赵 磊, 张 晓, 冯 聚, 肖 忠, 刘 泳, 龙 泓, 陈 向, 唐 卫. [Exenatide promotes cholesterol efflux in pancreatic tissue of obese diabetic rats]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2021; 41:370-375. [PMID: 33849827 PMCID: PMC8075781 DOI: 10.12122/j.issn.1673-4254.2021.03.08] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Indexed: 11/24/2022]
Abstract
OBJECTIVE To study the effect of exenatide on the expression of ABCA1 and cholesterol metabolism in the pancreas of obese diabetic rats. OBJECTIVE Twenty-four normal male SD rats and 18 obese diabetic rats (induced by high-fat feeding and STZ injection) were both divided equally into 2 groups for injections of saline or exenatide. After treatment for a week, the expression of ABCA1, cholesterol metabolism, and islet function of the rats were examined using real-time PCR, Western blotting, oil red O staining, cholesterol content determination, and HE staining. OBJECTIVE The expressions of ABCA1 at both mRNA and protein levels in pancreatic tissue were significantly lower in obese diabetic rats than in normal SD rats. The obese diabetic rats showed obvious lipid deposition and increased cholesterol content in the pancreatic tissue with significantly reduced islet volume and structural changes (P < 0.05); exenatide treatment of the diabetic rats significantly up-regulated ABCA1 expression, reduced lipid deposition and cholesterol content in pancreatic tissue, and increased number and volume of the islets, which presented with more orderly alignment (P < 0.05). OBJECTIVE Obese diabetic rats have lowered ABCA1 expression, cholesterol efflux block, and cholesterol accumulation in the pancreatic tissue. Exenatide can up-regulate ABCA1 expression and promote cholesterol efflux to reduce cholesterol content in the pancreatic tissue and improve islet function in obese diabetic rats.
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Affiliation(s)
- 磊 赵
- 南华大学附属第一医院 胃肠外科，湖南 衡阳 421001Department of Gastrointestinal Surgery, First Affiliated Hospital, University of South China, Hengyang 421001, China
| | - 晓宁 张
- 南华大学附属第一医院 胃肠外科，湖南 衡阳 421001Department of Gastrointestinal Surgery, First Affiliated Hospital, University of South China, Hengyang 421001, China
| | - 聚玲 冯
- 南华大学衡阳医学院转化医学研究室，湖南 衡阳 421001Research Lab of Translational Medicine, Hengyang Medical School, University of South China, Hengyang 421001, China
| | - 忠盛 肖
- 南华大学附属第一医院 胃肠外科，湖南 衡阳 421001Department of Gastrointestinal Surgery, First Affiliated Hospital, University of South China, Hengyang 421001, China
| | - 泳 刘
- 南华大学附属第一医院 胃肠外科，湖南 衡阳 421001Department of Gastrointestinal Surgery, First Affiliated Hospital, University of South China, Hengyang 421001, China
| | - 泓 龙
- 南华大学附属第一医院 胃肠外科，湖南 衡阳 421001Department of Gastrointestinal Surgery, First Affiliated Hospital, University of South China, Hengyang 421001, China
| | - 向恒 陈
- 南华大学附属第一医院 胃肠外科，湖南 衡阳 421001Department of Gastrointestinal Surgery, First Affiliated Hospital, University of South China, Hengyang 421001, China
| | - 卫平 唐
- 南华大学附属第一医院 肝胆外科，湖南 衡阳 421001Department of Hepatobiliary Surgery, First Affiliated Hospital, University of South China, Hengyang 421001, China
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Gurgel Penaforte-Saboia J, Couri CEB, Vasconcelos Albuquerque N, Lauanna Lima Silva V, Bitar da Cunha Olegario N, Oliveira Fernandes V, Montenegro Junior RM. Emerging Roles of Dipeptidyl Peptidase-4 Inhibitors in Delaying the Progression of Type 1 Diabetes Mellitus. Diabetes Metab Syndr Obes 2021; 14:565-573. [PMID: 33603422 PMCID: PMC7882449 DOI: 10.2147/dmso.s294742] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 01/26/2021] [Indexed: 12/17/2022] Open
Abstract
Type 1 diabetes mellitus (T1DM) results from the immune cell-mediated destruction of functional pancreatic β-cells. In the presymptomatic period, T1DM is characterized by the presence of two or more autoantibodies against the islet cells in patients without glycemic decompensation. Therapeutic strategies that can modify the autoimmune process could slow the progression of T1DM. Dipeptidyl peptidase-4 (DPP-4) or CD26, a multifunctional serine protease with a dual function (regulatory protease and binding protein), can modulate inflammation and immune cell-mediated β-cell destruction. CD26 is involved in T-cell co-stimulation, migration, memory development, thymic maturation, and emigration patterns. DPP-4 degrades the peptide hormones GLP-1 and GIP. In addition to regulating glucose metabolism, DPP-4 exerts anti-apoptotic, regenerative, and proliferative effects to promote β-cell mass expansion. GLP-1 receptor signaling may regulate murine lymphocyte proliferation and maintenance of peripheral regulatory T-cells. In patients with T1DM, the serum DPP-4 activity is upregulated. Several studies have suggested that the upregulated DPP-4 activity is correlated with T1DM pathophysiology. DPP-4, which is preferentially expressed on the Th1 surface, can promote the polarization of Th1 immunity, a prerequisite for T1DM development. CD26 inhibition can suppress T-cell proliferation and Th1 cytokine production and stimulate tumor growth factor beta-1 (TGF-β1) secretion, which plays an important role in the regulation of autoimmunity in T1DM. Studies on humans or animal models of T1DM have suggested that DPP-4 inhibitors can improve β-cell function and attenuate autoimmunity in addition to decreasing insulin dependence. This review summarizes the emerging roles of DPP-4 inhibitors in potentially delaying the progression of T1DM.
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Affiliation(s)
- Jaquellyne Gurgel Penaforte-Saboia
- Clinical Research Unit, Walter Cantidio University Hospital, Federal University of Ceará, Fortaleza, Brazil
- Department of Clinical Medicine, Federal University of Ceará, Fortaleza, Brazil
| | - Carlos Eduardo Barra Couri
- Center for Cell-Based Therapy, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil
| | - Natasha Vasconcelos Albuquerque
- Clinical Research Unit, Walter Cantidio University Hospital, Federal University of Ceará, Fortaleza, Brazil
- Department of Community Health, Federal University of Ceará, Fortaleza, Brazil
| | | | - Natália Bitar da Cunha Olegario
- Clinical Research Unit, Walter Cantidio University Hospital, Federal University of Ceará, Fortaleza, Brazil
- Department of Clinical Medicine, Federal University of Ceará, Fortaleza, Brazil
| | - Virgínia Oliveira Fernandes
- Clinical Research Unit, Walter Cantidio University Hospital, Federal University of Ceará, Fortaleza, Brazil
- Department of Clinical Medicine, Federal University of Ceará, Fortaleza, Brazil
- Department of Community Health, Federal University of Ceará, Fortaleza, Brazil
| | - Renan Magalhães Montenegro Junior
- Clinical Research Unit, Walter Cantidio University Hospital, Federal University of Ceará, Fortaleza, Brazil
- Department of Clinical Medicine, Federal University of Ceará, Fortaleza, Brazil
- Department of Community Health, Federal University of Ceará, Fortaleza, Brazil
- Correspondence: Renan Magalhães Montenegro Junior Federal University of Ceará, Rua Coronel Nunes de Melo s/n, Fortaleza, 60430-270, Ceará, BrazilTel +55 8533668600Fax +55 85 3366-8619 Email
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Caltabiano R, Condorelli D, Panza S, Boitani C, Musso N, Ježek D, Memeo L, Colarossi L, Rago V, Mularoni V, Spadola S, Castiglione R, Santoro M, Aquila S, D'Agata R. Glucagon-like peptide-1 receptor is expressed in human and rodent testis. Andrology 2020; 8:1935-1945. [PMID: 33460247 DOI: 10.1111/andr.12871] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Revised: 07/13/2020] [Accepted: 07/15/2020] [Indexed: 01/25/2023]
Abstract
BACKGROUND The incretin hormone glucagon-like peptide-l (GLP-1) is an important regulator of post-prandial insulin secretion, acting through a G protein-coupled cell surface receptor (GLP-1R). In addition to its expression in pancreatic β-cells, several studies suggested that GLP-1R is located in extra-pancreatic tissues. OBJECTIVES In this study, we examined for the first time the testicular distribution of the GLP-1R, both in normal human and neoplastic testicular tissues as well as in rodent testis and rodent testicular cell lines. METHODS AND METHODS The GLP-1R distribution in testicular section has been evaluated by immunohistochemistry, the specificity of IHC was validated by demonstrating a positive staining for GLP-1RmRNA by RISH technology. While GLP-1R expression in terms of protein was detected by western blot analysis, Moreover, mRNA levels were determined in human testis, in rodent Leydig, and Sertoli cell lines. RESULTS Using immunohistochemistrya specific staining for GLP-1R was detected in Leydig cells. The specificity of IHC was validated by demonstrating a positive staining for GLP-1RmRNA only in these cell types. Species differences in the GLP-1R expression between humans and rodents were observed. Interestingly, a decreased expression of the receptor in rodent tumor Leydig cell line and an absence in human Leydig tumor samples was detected. DISCUSSION It may be hypothesized that GLP-1R acts like an oncosuppressor in Leydig tumors. A role in regulation of hormone secretion by GLP-1 has been shown in other endocrine cells, therefore we hypothesized that GLP-1R is able to modulate somehow the Leydig cell function. CONCLUSION In our findings, a careful evaluation of human testicular tissues and rodent testis revealed Leydig cells as a potential target for GLP-1. Collectively, an effect of GLP-1R in Leydig cell function may be presumed although future studies are needed to ascertain the GLP-1R's role both in normal and tumor Leydig cells.
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Affiliation(s)
- Rosario Caltabiano
- Department "G.F. Ingrassia"- Section of Anatomical Pathology, University of Catania, Catania, Italy
| | - Daniele Condorelli
- Department of Biomedical and Biotechnological Sciences, Section of medical Biochemistry, University of Catania, Catania, Italy
| | - Salvatore Panza
- Centro Sanitario, University of Calabria, Arcavacata di Rende, Cosenza, Italy.,Department of Pharmacy and Sciences of Health and Nutrition, University of Calabria, Cosenza, Italy
| | - Carla Boitani
- Department of Anatomy, Histology, Forensic Medicine, Orthopedics, University of Rome "La Sapienza", Rome, Italy
| | - Nicolò Musso
- Department of Biomedical and Biotechnological Sciences, Section of medical Biochemistry, University of Catania, Catania, Italy
| | - Davor Ježek
- Department of Histology and Embryology, Centre of Excellence for Reproductive and Regenerative Medicine, Zagreb, Croatia
| | - Lorenzo Memeo
- Division of Pathology, Mediterranean Institute of Oncology, Catania, Italy
| | - Lorenzo Colarossi
- Division of Pathology, Mediterranean Institute of Oncology, Catania, Italy
| | - Vittoria Rago
- Department of Pharmacy and Sciences of Health and Nutrition, University of Calabria, Cosenza, Italy
| | - Valentina Mularoni
- Department of Anatomy, Histology, Forensic Medicine, Orthopedics, University of Rome "La Sapienza", Rome, Italy
| | - Saveria Spadola
- Department "G.F. Ingrassia"- Section of Anatomical Pathology, University of Catania, Catania, Italy
| | - Roberto Castiglione
- Department of Experimental and Clinical Medicine, University of Catania, Catania, Italy
| | - Marta Santoro
- Centro Sanitario, University of Calabria, Arcavacata di Rende, Cosenza, Italy.,Department of Pharmacy and Sciences of Health and Nutrition, University of Calabria, Cosenza, Italy
| | - Saveria Aquila
- Centro Sanitario, University of Calabria, Arcavacata di Rende, Cosenza, Italy.,Department of Pharmacy and Sciences of Health and Nutrition, University of Calabria, Cosenza, Italy
| | - Rosario D'Agata
- Department of Experimental and Clinical Medicine, University of Catania, Catania, Italy
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Roy A, Sahoo J, Kamalanathan S, Naik D, Mohan P, Pottakkat B. Islet cell dysfunction in patients with chronic pancreatitis. World J Diabetes 2020; 11:280-292. [PMID: 32843931 PMCID: PMC7415230 DOI: 10.4239/wjd.v11.i7.280] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 05/02/2020] [Accepted: 05/22/2020] [Indexed: 02/06/2023] Open
Abstract
Chronic pancreatitis (CP) is characterized by progressive inflammation and fibrosis of the pancreas that eventually leads to pancreatic exocrine and endocrine insufficiency. Diabetes in the background of CP is very difficult to manage due to high glycemic variability and concomitant malabsorption. Progressive beta cell loss leading to insulin deficiency is the cardinal mechanism underlying diabetes development in CP. Alpha cell dysfunction leading to deranged glucagon secretion has been described in different studies using a variety of stimuli in CP. However, the emerging evidence is varied probably because of dependence on the study procedure, the study population as well as on the stage of the disease. The mechanism behind islet cell dysfunction in CP is multifactorial. The intra-islet alpha and beta cell regulation of each other is often lost. Moreover, secretion of the incretin hormones such as glucagon like peptide-1 and glucose-dependent insulinotropic polypeptide is dysregulated. This significantly contributes to islet cell disturbances. Persistent and progressive inflammation with changes in the function of other cells such as islet delta cells and pancreatic polypeptide cells are also implicated in CP. In addition, the different surgical procedures performed in patients with CP and antihyperglycemic drugs used to treat diabetes associated with CP also affect islet cell function. Hence, different factors such as chronic inflammation, dysregulated incretin axis, surgical interventions and anti-diabetic drugs all affect islet cell function in patients with CP. Newer therapies targeting alpha cell function and beta cell regeneration would be useful in the management of pancreatic diabetes in the near future.
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Affiliation(s)
- Ayan Roy
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Jayaprakash Sahoo
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Sadishkumar Kamalanathan
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Dukhabandhu Naik
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Pazhanivel Mohan
- Department of Medical Gastroenterology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Biju Pottakkat
- Department of Surgical Gastroenterology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
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Cao C, Yang S, Zhou Z. GLP-1 receptor agonists and pancreatic safety concerns in type 2 diabetic patients: data from cardiovascular outcome trials. Endocrine 2020; 68:518-525. [PMID: 32103407 DOI: 10.1007/s12020-020-02223-6] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 02/09/2020] [Indexed: 12/15/2022]
Abstract
PURPOSE Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been suggested to be associated with an increased risk of pancreatitis and pancreatic cancer. The aim of this meta-analysis was to collect data from large-scale cardiovascular outcome trials (CVOTs) to assess the effect of GLP-1RAs on the incidence of acute pancreatitis and pancreatic cancer. METHODS Database of Medline, Embase, and the Cochrane Central Register of Controlled Trials were extensively searched up to October 10, 2019. Randomized controlled trials were eligible if they compared GLP-RA with placebo as add-on therapy to standard care in T2DM patients, and reported outcomes required for cardiovascular safety studies and events of acute pancreatitis and/or pancreatic cancer. Peto odds ratio (OR) with 95% confidence interval (CI) was calculated for acute pancreatitis and pancreatic cancer. RESULTS Seven CVOTs enrolling 56,004 patients with T2DM were identified, with a median follow-up time ranging from 1.3 to 5.4 years. A total of 180 cases of acute pancreatitis and 108 cases of pancreatic cancer were reported. The risk of either acute pancreatitis or pancreatic cancer with GLP-1-RA treatment was not significantly different from that observed in placebo arm (Peto OR [95% CI] 1.05 [0.78-1.40], P = 0.76, and 1.12 [0.77-1.63], P = 0.56, respectively), and the results remained robust to sensitivity analyses. CONCLUSION Pooled analysis of CVOTs did not suggest any increased risk of either acute pancreatitis or pancreatic cancer with GLP-1RA treatment in T2DM patients.
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Affiliation(s)
- Chuqing Cao
- Department of Metabolism & Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
- Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China
| | - Shuting Yang
- Department of Metabolism & Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
- Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China
| | - Zhiguang Zhou
- Department of Metabolism & Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China.
- Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China.
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Graham GV, Conlon JM, Abdel-Wahab YH, Flatt PR. Glucagon from the phylogenetically ancient paddlefish provides a template for the design of a long-acting peptide with effective anti-diabetic and anti-obesity activities. Eur J Pharmacol 2020; 878:173101. [PMID: 32320703 DOI: 10.1016/j.ejphar.2020.173101] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Revised: 03/26/2020] [Accepted: 04/06/2020] [Indexed: 12/13/2022]
Abstract
This study has examined the in vitro and in vivo anti-diabetic properties of the peptidase-resistant analogues [D-Ser2]palmitoyl-paddlefish glucagon and [D-Ser2]palmitoyl-lamprey glucagon. The peptides stimulated insulin release from BRIN-BD11 clonal β-cells and isolated mouse pancreatic islets and also enhanced cAMP production in cells transfected with the human GLP-1 receptor and with the human glucagon receptor. The insulinotropic actions of the peptides were attenuated in INS-1 cells lacking GLP-1 and glucagon receptors. [D-Ser2]palmitoyl-paddlefish glucagon stimulated proliferation of BRIN-BD11 cells and protected against cytokine-mediated apoptosis as effectively as GLP-1. The analogue was more effective than the native peptide or the lamprey glucagon analogue in acutely lowering blood glucose and elevating plasma insulin in lean mice even when administered up to 4 h before a glucose load. Twice daily administration of [D-Ser2]palmitoyl-paddlefish glucagon to high-fat fed mice over 21 days reduced food intake, body weight, non-fasting blood glucose and plasma insulin concentrations, as well as significantly improving glucose tolerance and insulin resistance and decreasing α-cell area and pancreatic insulin content. Islet expression of the Gcgr, Glp1r, Gipr and Slc2a2 (GLUT-2) genes significantly increased. These data demonstrate that long-acting peptide [D-Ser2]palmitoyl-paddlefish glucagon exerts beneficial metabolic properties in diabetic mice via Ggcr- and Glp1r-activated pathways and so shows potential as a template for further development into an agent for treatment of patients with obesity-related Type 2 diabetes.
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Affiliation(s)
- Galyna V Graham
- Diabetes Research Group, School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine, BT52 1SA, Northern Ireland, UK
| | - J Michael Conlon
- Diabetes Research Group, School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine, BT52 1SA, Northern Ireland, UK.
| | - Yasser H Abdel-Wahab
- Diabetes Research Group, School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine, BT52 1SA, Northern Ireland, UK
| | - Peter R Flatt
- Diabetes Research Group, School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine, BT52 1SA, Northern Ireland, UK
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Singh AK, Gangopadhyay KK, Singh R. Risk of acute pancreatitis with incretin-based therapy: a systematic review and updated meta-analysis of cardiovascular outcomes trials. Expert Rev Clin Pharmacol 2020; 13:461-468. [PMID: 32129106 DOI: 10.1080/17512433.2020.1736041] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Accepted: 02/25/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND The link of acute pancreatitis (AP) with Incretin based therapies (IBTs) in type 2 diabetes has existed since United States Food and Drug Administration alert in 2010. This issue still remains unresolved due to conflicting results among studies. RESEARCH DESIGN AND METHODS We performed a systematic search of the PubMed, Embase, and Cochrane Library databases until 31 July 2019, and retrieved all cardiovascular outcome trials (CVOTs) of IBTs conducted for ≥12 months that reported the pre-specified and or pre-adjudicated pancreatitis outcomes. Subsequently, we conducted a meta-analysis to study the risk of AP observed with IBT in CVOTs. RESULTS A meta-analysis of seven CVOTs of GLP-1 receptor agonists (GLP-1RAs) compared with placebo (N = 55,932) found no significant increase in AP (odds ratio [OR], 1.05; 95% confidence interval [CI], 0.77-1.42; p = 0.77). In contrast, meta-analysis of five CVOTs comparing DPP-4 inhibitors with placebo (N = 47,714) and six CVOTs comparing DPP-4 inhibitors with placebo or active comparator (N = 53,747), found a significant increase (OR, 1.81; 95% CI, 1.21-2.70; p = 0.04 and OR, 1.54; 95% CI, 1.08-2.18; p = 0.02, respectively) in AP without any significant heterogeneity. CONCLUSIONS This meta-analysis revealed a significant association between pancreatitis and DPP-4 inhibitors; however, no such association was observed for GLP-1RAs.
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Affiliation(s)
| | | | - Ritu Singh
- Department of Gynecology & Obstetrics, G. D Hospital & Diabetes Institute , Kolkata, India
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SAYİNER ZA, İNAN DEMİROĞLU G, AKARSU E, ARAZ M. The Relationship Between Dipeptidyl Peptidase-4 Inhibitor Usage and Asymptomatic Amylase Lipase Increment in Type 2 Diabetes Mellitus Patients. Turk J Pharm Sci 2020; 17:68-73. [PMID: 32454763 PMCID: PMC7227863 DOI: 10.4274/tjps.galenos.2018.83788] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Accepted: 10/25/2018] [Indexed: 12/01/2022]
Abstract
OBJECTIVES In different studies, it has been shown that the use of dipeptidyl peptidase-4 (DPP-4) inhibitors (DPP-4 inh) does not increase the risk of pancreatitis or pancreatic cancer. Although the number of studies involving clinical pancreatitis clinics is sufficient, the number of studies involving clinical non-pancreatitis hyperamylasemia is rare. The aim of the study was to investigate the relationship between DPP-4 inh usage and amylase and lipase increment without clinical pancreatitis symptoms. MATERIALS AND METHODS Eighty-seven patients who met the inclusion criteria were enrolled. The patients were divided into 3 groups according to their use of saxagliptin, sitagliptin, or vildagliptin. All patients included in the study were receiving metformin at a dose of 2 g/day. Fasting blood glucose, postprandial blood glucose, HbA1C, serum creatinine, ALT, amylase, and lipase results were recorded at the beginning of treatment and at the end of 3 months. RESULTS There was an increase in all groups in terms of amylase and lipase values but there was no significant difference between the groups in terms of increase (p>0.05) There was no statistically significant increase in the saxagliptin and vildagliptin groups (p>0.05) when the baseline and 3-month values of lipase and amylase increase were examined. However, there was a statistically significant increase in amylase and lipase in the sitagliptin group (p<0.05). CONCLUSION The use of DPP-4 inh can increase amylase and lipase levels without clinical findings of acute pancreatitis in the patient. DPP-4 inh should be used with caution in patients at risk for pancreatitis and pancreatic cancer. Patients using DPP-4 inh, especially sitagliptin, should be evaluated carefully for pancreatitis risk factors.
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Affiliation(s)
- Zeynel Abidin SAYİNER
- Gaziantep University, School of Medicine, Department of Endocrinology and Metabolism, Gaziantep, Turkey
| | - Gamze İNAN DEMİROĞLU
- Gaziantep University, School of Medicine, Department of Internal Medicine, Gaziantep, Turkey
| | - Ersin AKARSU
- Gaziantep University, School of Medicine, Department of Endocrinology and Metabolism, Gaziantep, Turkey
| | - Mustafa ARAZ
- Gaziantep University, School of Medicine, Department of Endocrinology and Metabolism, Gaziantep, Turkey
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Dicembrini I, Montereggi C, Nreu B, Mannucci E, Monami M. Pancreatitis and pancreatic cancer in patientes treated with Dipeptidyl Peptidase-4 inhibitors: An extensive and updated meta-analysis of randomized controlled trials. Diabetes Res Clin Pract 2020; 159:107981. [PMID: 31870827 DOI: 10.1016/j.diabres.2019.107981] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Revised: 11/22/2019] [Accepted: 12/12/2019] [Indexed: 02/07/2023]
Abstract
AIM Observational studies and metanalyses of randomized trials on Dipeptidyl Peptidase-4 inhibitors (DPP4i) reported discordant results on the risk of pancreatitis and pancreatic cancer with this class of drugs. Aim of the present meta-analysis is the assessment of the effect of DPP4i treatment on the incidence of pancreatitis and pancreatic cancer, collecting all available evidence from randomized controlled trials. Methods Data Sources: an extensive Medline, Embase and Cochrane Database search for sitagliptin or vildagliptin or omarigliptin or saxagliptin or alogliptin or trelagliptin or anagliptin or linagliptin or gemigliptin or evogliptin or teneligliptin was performed up to up to September 30th, 2019. All trials performed on type 2 diabetes, with duration ≥24 weeks, and comparing of DPP4i with placebo or active drugs were collected. The study has been registered on PROSPERO (#153344). Mantel-Haenszel odds ratio (MH-OR) with 95% Confidence Interval (95% CI) was calculated for all outcomes defined above. Results A total of 165 eligible trials were identified. DPP-4 inhibitors were not associated with an increased risk of pancreatitis (MH-OR 1.13 [0.86, 1.47]) or pancreatic cancer (MH-OR 0.86 [0.60, 1.24]) with no significant differences across individual molecules of the class. CONCLUSIONS available data do not support the hypothesis of an association of DPP4i treatment with pancreatitis. Present data do not suggest any association of DPP4i with pancreatic cancer, although they are insufficient to draw definitive conclusions.
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Affiliation(s)
| | | | - Besmir Nreu
- Diabetology, Careggi Hospital and University of Florence, Italy
| | | | - Matteo Monami
- Diabetology, Careggi Hospital and University of Florence, Italy.
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Deng H, Yang F, Ma X, Wang Y, Chen Q, Yuan L. Long-Term Liraglutide Administration Induces Pancreas Neogenesis in Adult T2DM Mice. Cell Transplant 2020; 29:963689720927392. [PMID: 32584149 PMCID: PMC7563804 DOI: 10.1177/0963689720927392] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2020] [Revised: 04/22/2020] [Accepted: 04/23/2020] [Indexed: 12/23/2022] Open
Abstract
In vivo beta-cell neogenesis may be one way to treat diabetes. We aimed to investigate the effect of glucagon-like peptide-1 (GLP-1) on beta-cell neogenesis in type 2 diabetes mellitus (T2DM). Male C57BL/6J mice, 6 wk old, were randomly divided into three groups: Control, T2DM, and T2DM + Lira. T2DM was induced using high-fat diet and intraperitoneal injection of streptozotocin (40 mg/kg/d for 3 d). At 8 wk after streptozotocin injection, T2DM + Lira group was injected intraperitoneally with GLP-1 analog liraglutide (0.8 mg/kg/d) for 4 wk. Apparently for the first time, we report the appearance of a primitive bud connected to pancreas in all adult mice from each group. The primitive bud was characterized by scattered single monohormonal cells expressing insulin, GLP-1, somatostatin, or pancreatic polypeptide, and four-hormonal cells, but no acinar cells and ductal epithelial cells. Monohormonal cells in it were small, newborn, immature cells that rapidly proliferated and expressed cell markers indicative of immaturity. In parallel, Ngn3+ endocrine progenitors and Nestin+ cells existed in the primitive bud. Liraglutide facilitated neogenesis and rapid growth of acinar cells, pancreatic ducts, and blood vessels in the primitive bud. Meanwhile, scattered hormonal cells aggregated into cell clusters and grew into larger islets; polyhormonal cells differentiated into monohormonal cells. Extensive growth of exocrine and endocrine glands resulted in the neogenesis of immature pancreatic lobes in adult mice of T2DM + Lira group. Contrary to predominant acinar cells in mature pancreatic lobes, there were still a substantial number of mesenchymal cells around acinar cells in immature pancreatic lobes, which resulted in the loose appearance. Our results suggest that adult mice preserve the capacity of pancreatic neogenesis from the primitive bud, which liraglutide facilitates in adult T2DM mice. To our knowledge, this is the first time such a phenomenon has been reported.
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Affiliation(s)
- Hongjun Deng
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China
| | - Fengying Yang
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China
| | - Xiaoyi Ma
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China
| | - Ying Wang
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China
| | - Qi Chen
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China
| | - Li Yuan
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China
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Shawky LM, Morsi AA, El Bana E, Hanafy SM. The Biological Impacts of Sitagliptin on the Pancreas of a Rat Model of Type 2 Diabetes Mellitus: Drug Interactions with Metformin. BIOLOGY 2019; 9:E6. [PMID: 31881657 PMCID: PMC7167819 DOI: 10.3390/biology9010006] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 12/22/2019] [Accepted: 12/23/2019] [Indexed: 12/25/2022]
Abstract
Sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, is a beneficial class of antidiabetic drugs. However, a major debate about the risk of developing pancreatitis is still existing. The aim of the work was to study the histological and immunohistochemical effects of sitagliptin on both endocrine and exocrine pancreases in a rat model of type 2 diabetes mellitus and to correlate these effects with the biochemical findings. Moreover, a possible synergistic effect of sitagliptin, in combination with metformin, was also evaluated. Fifty adult male rats were used and assigned into five equal groups. Group 1 served as control. Group 2 comprised of untreated diabetic rats. Group 3 diabetic rats received sitagliptin. Group 4 diabetic rats received metformin. Group 5 diabetic rats received both combined. Treatments were given for 4 weeks after the induction of diabetes. Blood samples were collected for biochemical assay before the sacrification of rats. Pancreases were removed, weighed, and were processed for histological and immunohistochemical examination. In the untreated diabetic group, the islets appeared shrunken with disturbed architecture and abnormal immunohistochemical reactions for insulin, caspase-3, and inducible nitric oxide synthase (iNOS). The biochemical findings were also disturbed. Morphometrically, there was a significant decrease in the islet size and islet number. Treatment with sitagliptin, metformin, and their combination showed an improvement, with the best response in the combined approach. No evidence of pancreatic injury was identified in the sitagliptin-treated groups. In conclusion, sitagliptin had a cytoprotective effect on beta-cell damage. Furthermore, the data didn't indicate any detrimental effects of sitagliptin on the exocrine pancreas.
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Affiliation(s)
- Lamiaa M. Shawky
- Department of Histology and Cell Biology, Benha Faculty of Medicine, Benha University, Benha 13511, Egypt;
| | - Ahmed A. Morsi
- Department of Histology and Cell Biology, Faculty of Medicine, Fayoum University, Fayoum 63511, Egypt
| | - Eman El Bana
- Department of Anatomy, Benha Faculty of Medicine, Benha University, Benha 13511, Egypt;
| | - Safaa Masoud Hanafy
- Department of Anatomy, Faculty of Medicine for Girls, Al-Azhar University, Cairo 11865, Egypt;
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45
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Knudsen LB. Inventing Liraglutide, a Glucagon-Like Peptide-1 Analogue, for the Treatment of Diabetes and Obesity. ACS Pharmacol Transl Sci 2019; 2:468-484. [PMID: 32259078 DOI: 10.1021/acsptsci.9b00048] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Indexed: 01/08/2023]
Abstract
Glucagon-like peptide-1 (GLP-1) has been in focus since the early 1980s as a long looked for incretin hormone, released from the gastrointestinal tract and with an important effect on glucose-dependent insulin secretion, providing efficient glucose lowering, with little risk for hypoglycemia. The enzyme dipeptidyl peptidase-4 (DPP-4) degrades GLP-1 very fast, and the remaining metabolite is cleared rapidly by the kidneys. Liraglutide is a fatty acid acylated analogue of GLP-1 that provides efficacy for 24 h/day. The mechanism of action for liraglutide is reviewed in detail with focus on pancreatic efficacy and safety, thyroid safety, and weight loss mechanism. Evolving science hypothesizes that GLP-1 has important effects on atherosclerosis, relevant for the cardiovascular benefit seen in the treatment of diabetes and obesity. Also, GLP-1 may be relevant in neurodegenerative diseases.
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Affiliation(s)
- Lotte Bjerre Knudsen
- Global Drug Discovery, Novo Nordisk, Novo Nordisk Park, DK-2760 Maaloev, Denmark
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Vetter ML, Johnsson K, Hardy E, Wang H, Iqbal N. Pancreatitis Incidence in the Exenatide BID, Exenatide QW, and Exenatide QW Suspension Development Programs: Pooled Analysis of 35 Clinical Trials. Diabetes Ther 2019; 10:1249-1270. [PMID: 31077072 PMCID: PMC6612359 DOI: 10.1007/s13300-019-0627-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Indexed: 12/25/2022] Open
Abstract
INTRODUCTION Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used for treatment of type 2 diabetes mellitus; however, there have been concerns that GLP-1RA treatment may be associated with an increased incidence of pancreatitis. This study aimed to evaluate the incidence of pancreatitis in a pooled population of type 2 diabetes trials from the clinical development program of the GLP-1RA exenatide as well as to describe patient-level data for all reported cases. METHODS The primary analysis examined pooled data among patients with type 2 diabetes from the controlled arms of 35 trials (ranging from 4 to 234 weeks' duration) in the integrated clinical databases for exenatide twice daily, once weekly, and once-weekly suspension, excluding comparator arms with other incretin-based therapies. The exposure-adjusted incidence rate (EAIR) of pancreatitis was calculated for exenatide and non-exenatide (non-incretin-based therapy or placebo) treatment groups. Patient-level data were described for all pancreatitis incidences. RESULTS The primary analysis included 5596 patients who received exenatide and 4462 in the non-exenatide group. The mean duration of study medication exposure for the exenatide and non-exenatide treatment groups was 57.0 and 47.9 weeks, respectively. Pancreatitis was diagnosed in 14 patients (exenatide, n = 8; non-exenatide, n = 6), of whom 13 recovered with or without sequelae. The pancreatitis EAIR was 0.1195 events per 100 patient-years [95% confidence interval (CI), 0.0516-0.2154] in the exenatide group versus 0.1276 events per 100 patient-years (95% CI 0.0468-0.2482) in the non-exenatide treatment group. The EAIR ratio for the exenatide versus non-exenatide treatment group was 0.761 (95% CI 0.231-2.510). CONCLUSION In this pooled analysis of 10,058 patients among studies comparing exenatide with other glucose-lowering medications or placebo, pancreatitis was rare. The EAIRs of pancreatitis were low and similar between exenatide and non-exenatide treatment groups. No evidence of an association between exenatide and pancreatitis was observed. FUNDING Bristol-Myers Squibb and AstraZeneca. Plain language summary available for this article.
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Affiliation(s)
- Marion L Vetter
- Bristol-Myers Squibb, Lawrenceville, NJ, USA
- Janssen Pharmaceutical Companies of Johnson & Johnson, Philadelphia, PA, USA
| | | | | | - Hui Wang
- AstraZeneca, Gaithersburg, MD, USA
- Fisher Clinical Research Institute, San Jose, CA, USA
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Yu CG, Fu Y, Fang Y, Zhang N, Sun RX, Zhao D, Feng YM, Zhang BY. Fighting Type-2 Diabetes: Present and Future Perspectives. Curr Med Chem 2019; 26:1891-1907. [PMID: 28990512 DOI: 10.2174/0929867324666171009115356] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2017] [Revised: 05/01/2017] [Accepted: 09/28/2017] [Indexed: 02/06/2023]
Abstract
BACKGROUND Type-2 diabetes mellitus accounts for 80-90% of diabetic patients. So far, the treatment of diabetes mainly aims at elevating insulin level and lowering glucose level in the peripheral blood and mitigating insulin resistance. Physiologically, insulin secretion from pancreatic β cells is delicately regulated. Thus, how insulin-related therapies could titrate blood glucose appropriately and avoid the occurrence of hypoglycemia remains an important issue for decades. Similar question is addressed on how to attenuate vascular complication in diabetic subjects. METHODS We overviewed the evolution of each class of anti-diabetic drugs that have been used in clinical practice, focusing on their mechanisms, clinical results and cautions. RESULTS Glucagon-like peptide-1 receptor agonists stimulate β cells for insulin secretion in response to diet but not in fasting stage, which make them superior than conventional insulinsecretion stimulators. DPP-4 inhibitors suppress glucagon-like peptide-1 degradation. Sodium/ glucose co-transporter 2 inhibitors enhance glucose clearance through urine excretion. The appearance of these new drugs provides new information about glycemic control. We update the clinical findings of Glucagon-like peptide-1 receptor agonists, DPP-4 inhibitors and Sodium/glucose cotransporter 2 inhibitors in glycemic control and the risk or progression of cardiovascular disease in diabetic patients. Stem cell therapy might be an alternative tool for diabetic patients to improve β cell regeneration and peripheral ischemia. We summarize the clinical results of mesenchymal stem cells transplanted into patients with diabetic limb and foot. CONCLUSION A stepwise intensification of dual and triple therapy for individual diabetic patient is required to achieve therapeutic target.
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Affiliation(s)
- Cai-Guo Yu
- Beijing Key Laboratory of Diabetic Prevention and Research, Department of Endocrinology, Lu He hospital, Capital Medical University, Beijing 100149, China
| | - Ying Fu
- Beijing Key Laboratory of Diabetic Prevention and Research, Department of Endocrinology, Lu He hospital, Capital Medical University, Beijing 100149, China
| | - Yuan Fang
- Beijing Key Laboratory of Diabetic Prevention and Research, Department of Endocrinology, Lu He hospital, Capital Medical University, Beijing 100149, China
| | - Ning Zhang
- Beijing Key Laboratory of Diabetic Prevention and Research, Department of Endocrinology, Lu He hospital, Capital Medical University, Beijing 100149, China
| | - Rong-Xin Sun
- Beijing Key Laboratory of Diabetic Prevention and Research, Department of Endocrinology, Lu He hospital, Capital Medical University, Beijing 100149, China
| | - Dong Zhao
- Beijing Key Laboratory of Diabetic Prevention and Research, Department of Endocrinology, Lu He hospital, Capital Medical University, Beijing 100149, China
| | - Ying-Mei Feng
- Beijing Key Laboratory of Diabetic Prevention and Research, Department of Endocrinology, Lu He hospital, Capital Medical University, Beijing 100149, China
| | - Bao-Yu Zhang
- Beijing Key Laboratory of Diabetic Prevention and Research, Department of Endocrinology, Lu He hospital, Capital Medical University, Beijing 100149, China
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Abstract
Recent articles have highlighted the lack of reproducibility of data from scientific publications. Here we would argue that a better way to describe and also tackle this matter is to use the term "lack of robustness," since it points toward potential solutions. Presenting several case reports, we highlight examples with common underlying issues from Novo Nordisk's experience: animal model variability, reagent quality, and inter-lab variability. We discuss means to prevent these issues and argue for increased collaborative work and transparent manuscript revision procedures. Collectively, we believe these measures will help promote a more rapid and efficient self-corrective process in diabetes drug target research.
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Karp I, Sivaswamy A, Booth C. Does the use of incretin-based medications increase the risk of cancer in patients with type-2 diabetes mellitus? Pharmacoepidemiol Drug Saf 2019; 28:489-499. [PMID: 30779266 DOI: 10.1002/pds.4746] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Revised: 12/01/2018] [Accepted: 01/07/2019] [Indexed: 01/19/2023]
Abstract
PURPOSE Incretin-based medications are a novel class of agents for the treatment of type-2 diabetes mellitus (DM2). The safety profile of these medications is not firmly established, and concerns have been raised about their potential carcinogenicity. The objective of our study was to produce new evidence on the effect of incretin-based medications on cancer risk in patients with DM2. METHODS We conducted a "retrospective cohort" study with data from the Clinical Practice Research Datalink and the Hospital Episodes Statistics in the UK. New users of either an incretin-based medication (n = 18 885) or a sulfonylurea medication (n = 36 929) between 2007 and 2013 were identified and followed for up to 8 years. Cox proportional-hazards models were used to estimate the quasi-intention-to-treat and quasi-per-protocol hazard-ratios for the association between incretin-based medications with cancer while adjusting for potential confounders. RESULTS The adjusted hazard ratio (95% confidence interval) for use of incretin-based medications versus use of sulfonylurea medications for the overall-cancer outcome was 0.97 (0.90, 1.05) in the quasi-intention-to-treat analysis and 0.90 (0.81, 1.00) in the quasi-per-protocol analysis. In both analyses, the hazard-ratio functions over the 8-year follow-up seemed fairly constant, and the 8-year cumulative-risk functions in the two subcohorts were similar. CONCLUSIONS Our study suggests that the use of incretin-based medications in patients with DM2 does not increase the risk of cancer relative to the use of sulfonylurea medications, at least in the first several years of the use. Further research is needed to assess long-term effects of the use of incretin-based medications on cancer risk.
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Affiliation(s)
- Igor Karp
- Department of Epidemiology and Biostatistics, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.,Département de médecine sociale et préventive, Université de Montréal, Montréal, Québec, Canada
| | - Atul Sivaswamy
- Department of Epidemiology and Biostatistics, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada
| | - Christopher Booth
- Department of Oncology, Queen's University, Kingston, Ontario, Canada.,Department of Public Health Sciences, Queen's University, Kingston, Ontario, Canada
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Liu Y, Zhang X, Chai S, Zhao X, Ji L. Risk of Malignant Neoplasia with Glucagon-Like Peptide-1 Receptor Agonist Treatment in Patients with Type 2 Diabetes: A Meta-Analysis. J Diabetes Res 2019; 2019:1534365. [PMID: 31396537 PMCID: PMC6664552 DOI: 10.1155/2019/1534365] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Accepted: 07/02/2019] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Glucagon-like peptide-1 (GLP-1) receptor agonists are effective glucose-lowering drugs, but there is concern that they may increase the risk of malignant neoplasia. The present meta-analysis examined the safety of GLP-1 receptor agonists with regard to malignant neoplasia. METHODS We analyzed data from randomized controlled trials with a minimum duration of 24 weeks that assessed the incidence of neoplasms in type 2 diabetes patients receiving GLP-1 receptor agonists compared with placebo or other hypoglycemic drugs. We searched the MEDLINE, Embase, and Cochrane databases with a language restriction of English through October 1, 2018, and carried out a meta-analysis of the available trial data using a fixed effects model to calculate odds ratios (ORs) for neoplasia. RESULTS Thirty-four relevant articles, providing data for 50452 patients, were included in the meta-analysis. Compared with the incidence of malignant neoplasia with placebo or other interventions, no increase in malignant neoplasm formation was observed with the use of GLP-1 receptor agonists (OR 1.04, 95% confidence interval (CI) 0.94-1.15; p = 0.46), liraglutide (OR 1.08, 95% CI 0.91-1.27; p = 0.38), exenatide (OR 1.00, 95% CI 0.86-1.16; p = 1.00), semaglutide (OR 0.89, 95% CI 0.35-2.22; p = 0.80), or albiglutide (OR 1.07, 95% CI 0.23-4.88; p = 0.93). A subanalysis of trials lasting longer than 3 years also showed no increase in the neoplasia risk with GLP-1 receptor agonist use (OR 1.03, 95% CI 0.92-1.15; p = 0.60). Between-trial statistical heterogeneity was low for all comparisons. CONCLUSION GLP-1 receptor agonists can be used without safety concerns related to malignant neoplasia in patients with type 2 diabetes.
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Affiliation(s)
- Yufang Liu
- Department of Endocrinology, Peking University International Hospital, Beijing 102206, China
| | - Xiaomei Zhang
- Department of Endocrinology, Peking University International Hospital, Beijing 102206, China
| | - Sanbao Chai
- Department of Endocrinology, Peking University International Hospital, Beijing 102206, China
| | - Xin Zhao
- Department of Endocrinology, Peking University International Hospital, Beijing 102206, China
| | - Linong Ji
- Department of Endocrinology, Peking University People's Hospital, Beijing 100044, China
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