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1
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Borner T, Pataro AM, De Jonghe BC. Central mechanisms of emesis: A role for GDF15. Neurogastroenterol Motil 2025; 37:e14886. [PMID: 39108013 PMCID: PMC11866100 DOI: 10.1111/nmo.14886] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Revised: 07/08/2024] [Accepted: 07/24/2024] [Indexed: 02/06/2025]
Abstract
BACKGROUND Nausea and emesis are ubiquitously reported medical conditions and often present as treatment side effects along with polymorbidities contributing to detrimental life-threatening outcomes, such as poor nutrition, lower quality of life, and unfavorable patient prognosis. Growth differentiation factor 15 (GDF15) is a stress response cytokine secreted by a wide variety of cell types in response to a broad range of stressors. Circulating GDF15 levels are elevated in a range of medical conditions characterized by cachexia and malaise. In recent years, GDF15 has gained scientific and translational prominence with the discovery that its receptor, GDNF family receptor α-like (GFRAL), is expressed exclusively in the hindbrain. GFRAL activation may results in profound anorexia and body weight loss, effects which have attracted interest for the pharmacological treatment of obesity. PURPOSE This review highlights compelling emerging evidence indicating that GDF15 causes anorexia through the induction of nausea, emesis, and food aversions, which encourage a perspective on GDF15 system function in physiology and behavior beyond homeostatic energy regulation contexts. This highlights the potential role of GDF15 in the central mediation of nausea and emesis following a variety of physiological, and pathophysiological conditions such as chemotherapy-induced emesis, hyperemesis gravidarum, and cyclic vomiting syndrome.
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Affiliation(s)
- Tito Borner
- Department of Biobehavioral Health Sciences, School of NursingUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Department of PsychiatryUniversity of Pennsylvania, Perelman School of MedicinePhiladelphiaPennsylvaniaUSA
- Department of Biological Sciences, Human and Evolutionary Biology SectionUniversity of Southern CaliforniaLos AngelesCaliforniaUSA
| | - Allison M. Pataro
- Department of Biobehavioral Health Sciences, School of NursingUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Bart C. De Jonghe
- Department of Biobehavioral Health Sciences, School of NursingUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Department of PsychiatryUniversity of Pennsylvania, Perelman School of MedicinePhiladelphiaPennsylvaniaUSA
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2
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Vakharia M. Noninsulin Diabetes Medications in Hospitalized Children and Adolescents. Crit Care Nurs Clin North Am 2025; 37:19-33. [PMID: 39890348 DOI: 10.1016/j.cnc.2024.08.006] [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: 02/03/2025]
Abstract
The prevalence of pediatric diabetes continues to rise in the United States and worldwide. There are various forms of pediatric diabetes including type 1, type 2, and maturity onset diabetes of youth. The treatment depends on each unique type of diabetes and must be taken into consideration for patients based on presentation and clinical setting. There is limited literature supporting the use of noninsulin medications to manage pediatric diabetes in an inpatient setting. This article focuses on noninsulin medication management of children and adolescents presenting with hyperglycemia in acute care settings, both critically and noncritically ill.
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Affiliation(s)
- Mili Vakharia
- Division of Pediatric Diabetes and Endocrinology, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, 1020 MS: BCM320, 6621 Fannin Street, Houston, TX, USA.
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3
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Chen X, Song Y, Hong Y, Zhang X, Li Q, Zhou H. "NO" controversy?: A controversial role in insulin signaling of diabetic encephalopathy. Mol Cell Endocrinol 2024; 593:112346. [PMID: 39151653 DOI: 10.1016/j.mce.2024.112346] [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: 03/22/2024] [Revised: 06/14/2024] [Accepted: 08/13/2024] [Indexed: 08/19/2024]
Abstract
Insulin, a critical hormone in the human body, exerts its effects by binding to insulin receptors and regulating various cellular processes. While nitric oxide (NO) plays an important role in insulin secretion and acts as a mediator in the signal transduction pathway between upstream molecules and downstream effectors, holds a significant position in the downstream signal network of insulin. Researches have shown that the insulin-NO system exhibits a dual regulatory effect within the central nervous system, which is crucial in the regulation of diabetic encephalopathy (DE). Understanding this system holds immense practical importance in comprehending the targets of existing drugs and the development of potential therapeutic interventions. This review extensively examines the characterization of insulin, NO, Nitric oxide synthase (NOS), specific NO pathway, their interconnections, and the mechanisms underlying their regulatory effects in DE, providing a reference for new therapeutic targets of DE.
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Affiliation(s)
- Xi Chen
- Department of Pharmacology, Zhejiang University of Technology, Hangzhou, Zhejiang, 310014, China
| | - Ying Song
- Department of Pharmacology, Zhejiang University of Technology, Hangzhou, Zhejiang, 310014, China; Hangzhou King's Bio-pharmaceutical Technology Co., Ltd, Hangzhou, Zhejiang, 310007, China.
| | - Ye Hong
- Department of Pharmacology, Zhejiang University of Technology, Hangzhou, Zhejiang, 310014, China
| | - Xiaomin Zhang
- Department of Pharmacology, Zhejiang University of Technology, Hangzhou, Zhejiang, 310014, China
| | - Qisong Li
- Department of Pharmacology, Zhejiang University of Technology, Hangzhou, Zhejiang, 310014, China
| | - Hongling Zhou
- Department of Pharmacology, Zhejiang University of Technology, Hangzhou, Zhejiang, 310014, China
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4
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Lian K, Zhang K, Kan C, Hou N, Han F, Sun X, Qiu H, Guo Z. Emerging therapeutic landscape: Incretin agonists in chronic kidney disease management. Life Sci 2024; 351:122801. [PMID: 38862060 DOI: 10.1016/j.lfs.2024.122801] [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: 03/03/2024] [Revised: 05/09/2024] [Accepted: 06/04/2024] [Indexed: 06/13/2024]
Abstract
The increasing incidence of chronic kidney disease (CKD) poses a significant public health concern, prompting heightened attention to its treatment. Incretins, including glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide, are intestinal peptides released after nutrient intake, known for their hypoglycemic effects in diabetes management. Recent advancements highlight the promising outcomes of GLP-1 receptor agonists in reducing CKD risk factors and improving renal outcomes. The multifaceted functions of GLP-1, such as its anti-obesity, anti-hypertensive, anti-hyperglycemic, anti-lipid, anti-inflammatory, and endothelial function protective properties, contribute to its potential as a therapeutic agent for CKD. Although experiments suggest the potential benefits of incretin in CKD, a comprehensive understanding of its specific mechanisms is still lacking. This review aims to provide a detailed examination of current evidence and potential future directions, emphasizing the promising yet evolving landscape of incretin agonists in the context of CKD.
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Affiliation(s)
- Kexin Lian
- Department of Nephropathy, Affiliated Hospital of Shandong Second Medical University, Weifang, China; Department of Endocrinology and Metabolism, Clinical Research Center, Affiliated Hospital of Shandong Second Medical University, Weifang, China
| | - Kexin Zhang
- Department of Endocrinology and Metabolism, Clinical Research Center, Affiliated Hospital of Shandong Second Medical University, Weifang, China
| | - Chengxia Kan
- Department of Endocrinology and Metabolism, Clinical Research Center, Affiliated Hospital of Shandong Second Medical University, Weifang, China
| | - Ningning Hou
- Department of Endocrinology and Metabolism, Clinical Research Center, Affiliated Hospital of Shandong Second Medical University, Weifang, China
| | - Fang Han
- Department of Pathology, Affiliated Hospital of Shandong Second Medical University, Weifang, China
| | - Xiaodong Sun
- Department of Endocrinology and Metabolism, Clinical Research Center, Affiliated Hospital of Shandong Second Medical University, Weifang, China
| | - Hongyan Qiu
- Department of Endocrinology and Metabolism, Clinical Research Center, Affiliated Hospital of Shandong Second Medical University, Weifang, China.
| | - Zhentao Guo
- Department of Nephropathy, Affiliated Hospital of Shandong Second Medical University, Weifang, China.
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5
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Borner T, De Jonghe BC, Hayes MR. The antiemetic actions of GIP receptor agonism. Am J Physiol Endocrinol Metab 2024; 326:E528-E536. [PMID: 38477667 PMCID: PMC11194054 DOI: 10.1152/ajpendo.00330.2023] [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: 10/04/2023] [Revised: 02/08/2024] [Accepted: 03/10/2024] [Indexed: 03/14/2024]
Abstract
Nausea and vomiting are primitive aspects of mammalian physiology and behavior that ensure survival. Unfortunately, both are ubiquitously present side effects of drug treatments for many chronic diseases with negative consequences on pharmacotherapy tolerance, quality of life, and prognosis. One of the most critical clinical examples is the profound emesis and nausea that occur in patients undergoing chemotherapy, which continue to be among the most distressing side effects, even with the use of modern antiemetic medications. Similarly, antiobesity/diabetes medications that target the glucagon-like peptide-1 system, despite their remarkable metabolic success, also cause nausea and vomiting in a significant number of patients. These side effects hinder the ability to administer higher dosages for optimal glycemic and weight management and represent the major reasons for treatment discontinuation. Our inability to effectively control these side effects highlights the need to anatomically, molecularly, and functionally characterize novel neural substrates that drive and inhibit nausea and emesis. Here, we discuss clinical and preclinical evidence that highlights the glucose-dependent insulinotropic peptide receptor system as a novel therapeutic central target for the management of nausea and emesis.
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Affiliation(s)
- Tito Borner
- Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, Pennsylvania, United States
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
- Department of Biological Sciences, Human and Evolutionary Biology Section, University of Southern California, Los Angeles, California, United States
| | - Bart C De Jonghe
- Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, Pennsylvania, United States
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
| | - Matthew R Hayes
- Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, Pennsylvania, United States
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
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6
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Eom YS, Wilson JR, Bernet VJ. Links between Thyroid Disorders and Glucose Homeostasis. Diabetes Metab J 2022; 46:239-256. [PMID: 35385635 PMCID: PMC8987680 DOI: 10.4093/dmj.2022.0013] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 02/21/2022] [Indexed: 12/13/2022] Open
Abstract
Thyroid disorders and diabetes mellitus often coexist and are closely related. Several studies have shown a higher prevalence of thyroid disorders in patients with diabetes mellitus and vice versa. Thyroid hormone affects glucose homeostasis by impacting pancreatic β-cell development and glucose metabolism through several organs such as the liver, gastrointestinal tract, pancreas, adipose tissue, skeletal muscles, and the central nervous system. The present review discusses the effect of thyroid hormone on glucose homeostasis. We also review the relationship between thyroid disease and diabetes mellitus: type 1, type 2, and gestational diabetes, as well as guidelines for screening thyroid function with each disorder. Finally, we provide an overview of the effects of antidiabetic drugs on thyroid hormone and thyroid disorders.
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Affiliation(s)
- Young Sil Eom
- Division of Endocrinology, Department of Internal Medicine, Gachon University Gil Medical Center, Gachon University College of Medicine, Incheon, Korea
| | - Jessica R. Wilson
- Division of Endocrinology, Diabetes and Metabolism, Mayo Clinic, Jacksonville, FL, USA
| | - Victor J. Bernet
- Division of Endocrinology, Diabetes and Metabolism, Mayo Clinic, Jacksonville, FL, USA
- Corresponding author: Victor J. Bernet https://orcid.org/0000-0002-2477-5631 Division of Endocrinology, Diabetes and Metabolism, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA E-mail:
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7
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AlSaadoun AR, AlSaadoun TR, Al Ghumlas AK. Liraglutide Overdose-Induced Acute Pancreatitis. Cureus 2022; 14:e21616. [PMID: 35228970 PMCID: PMC8874232 DOI: 10.7759/cureus.21616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/25/2022] [Indexed: 11/22/2022] Open
Abstract
Liraglutide, a long-acting cardioprotective glucagon-like peptide (GLP)-1 analog, is effective for medical weight loss and glycemic control in type 2 diabetes. It is generally well tolerated with mild side effects. There are few reports on complications from Liraglutide overdose. The aim of this paper is to report the case of a 25-year-old healthy female who presented with acute pancreatitis secondary to Liraglutide overdose and to review the current literature on Liraglutide used for obesity management. The current literature examining the association between acute pancreatitis and Liraglutide use, and Liraglutide overdose are inconclusive. Further research is recommended.
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8
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Borner T, Workinger JL, Tinsley IC, Fortin SM, Stein LM, Chepurny OG, Holz GG, Wierzba AJ, Gryko D, Nexø E, Shaulson ED, Bamezai A, Da Silva VAR, De Jonghe BC, Hayes MR, Doyle RP. Corrination of a GLP-1 Receptor Agonist for Glycemic Control without Emesis. Cell Rep 2021; 31:107768. [PMID: 32553160 PMCID: PMC7376604 DOI: 10.1016/j.celrep.2020.107768] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 05/10/2019] [Accepted: 05/22/2020] [Indexed: 12/21/2022] Open
Abstract
Glucagon-like peptide-1 receptor (GLP-1R) agonists used to treat type 2 diabetes mellitus often produce nausea, vomiting, and in some patients, undesired anorexia. Notably, these behavioral effects are caused by direct central GLP-1R activation. Herein, we describe the creation of a GLP-1R agonist conjugate with modified brain penetrance that enhances GLP-1R-mediated glycemic control without inducing vomiting. Covalent attachment of the GLP-1R agonist exendin-4 (Ex4) to dicyanocobinamide (Cbi), a corrin ring containing precursor of vitamin B12, produces a "corrinated" Ex4 construct (Cbi-Ex4). Data collected in the musk shrew (Suncus murinus), an emetic mammal, reveal beneficial effects of Cbi-Ex4 relative to Ex4, as evidenced by improvements in glycemic responses in glucose tolerance tests and a profound reduction of emetic events. Our findings highlight the potential for clinical use of Cbi-Ex4 for millions of patients seeking improved glycemic control without common side effects (e.g., emesis) characteristic of current GLP-1 therapeutics.
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Affiliation(s)
- Tito Borner
- Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA 19104, USA
| | | | - Ian C Tinsley
- Department of Chemistry, Syracuse University, Syracuse, NY, USA
| | - Samantha M Fortin
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Lauren M Stein
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Oleg G Chepurny
- Department of Medicine, Upstate Medical University, State University of New York, Syracuse, NY, USA
| | - George G Holz
- Department of Medicine, Upstate Medical University, State University of New York, Syracuse, NY, USA
| | | | - Dorota Gryko
- Institute of Organic Chemistry, Polish Academy of Sciences, Warsaw, Poland
| | - Ebba Nexø
- Department of Clinical Biochemistry and Clinical Medicine, University of Aarhus, Aarhus, Denmark
| | - Evan D Shaulson
- Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Ankur Bamezai
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Valentina A Rodriguez Da Silva
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Bart C De Jonghe
- Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Matthew R Hayes
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Robert P Doyle
- Department of Chemistry, Syracuse University, Syracuse, NY, USA; Department of Medicine, Upstate Medical University, State University of New York, Syracuse, NY, USA.
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9
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Tinsley IC, Borner T, Swanson ML, Chepurny OG, Doebley SA, Kamat V, Sweet IR, Holz GG, Hayes MR, De Jonghe BC, Doyle RP. Synthesis, Optimization, and Biological Evaluation of Corrinated Conjugates of the GLP-1R Agonist Exendin-4. J Med Chem 2021; 64:3479-3492. [PMID: 33677970 PMCID: PMC8279408 DOI: 10.1021/acs.jmedchem.1c00185] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
![]()
Corrination
is the conjugation of a corrin ring containing molecule,
such as vitamin B12 (B12) or B12 biosynthetic precursor
dicyanocobinamide (Cbi), to small molecules, peptides, or proteins
with the goal of modifying pharmacology. Recently, a corrinated GLP-1R
agonist (GLP-1RA) exendin-4 (Ex4) has been shown in vivo to have reduced penetration into the central nervous system relative
to Ex4 alone, producing a glucoregulatory GLP-1RA devoid of anorexia
and emesis. The study herein was designed to optimize the lead conjugate
for GLP-1R agonism and binding. Two specific conjugation sites were
introduced in Ex4, while also utilizing various linkers, so that it
was possible to identify Cbi conjugates of Ex4 that exhibit improved
binding and agonist activity at the GLP-1R. An optimized conjugate
(22), comparable with Ex4, was successfully screened
and subsequently assayed for insulin secretion in rat islets and in vivo in shrews for glucoregulatory and emetic behavior,
relative to Ex4.
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Affiliation(s)
- Ian C Tinsley
- Department of Chemistry, Syracuse University, 111 College Place, Syracuse, New York 13244, United States
| | - Tito Borner
- Department of Biobehavioral Health Sciences, University of Pennsylvania, School of Nursing, Philadelphia, Pennsylvania 19104, United States
| | - MacKenzie L Swanson
- Department of Chemistry, Syracuse University, 111 College Place, Syracuse, New York 13244, United States
| | - Oleg G Chepurny
- Department of Medicine, State University of New York, Upstate Medical University, Syracuse, New York 13210, United States
| | - Sarah A Doebley
- Department of Biobehavioral Health Sciences, University of Pennsylvania, School of Nursing, Philadelphia, Pennsylvania 19104, United States
| | - Varun Kamat
- Department of Medicine, University of Washington, Medicine Diabetes Institute, Seattle, Washington 98109, United States
| | - Ian R Sweet
- Department of Medicine, University of Washington, Medicine Diabetes Institute, Seattle, Washington 98109, United States
| | - George G Holz
- Department of Medicine, State University of New York, Upstate Medical University, Syracuse, New York 13210, United States
| | - Matthew R Hayes
- Department of Psychiatry, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania 19104, United States
| | - Bart C De Jonghe
- Department of Biobehavioral Health Sciences, University of Pennsylvania, School of Nursing, Philadelphia, Pennsylvania 19104, United States
| | - Robert P Doyle
- Department of Chemistry, Syracuse University, 111 College Place, Syracuse, New York 13244, United States.,Department of Medicine, State University of New York, Upstate Medical University, Syracuse, New York 13210, United States
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Verdecchia P, Angeli F, Cavallini C, Aita A, Turturiello D, Reboldi G. The revolution of the anti-diabetic drugs in cardiology. Eur Heart J Suppl 2020; 22:E162-E166. [PMID: 32523463 PMCID: PMC7270967 DOI: 10.1093/eurheartj/suaa084] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Beginning in December 2008, under the auspices of Food and Drug Administration, numerous controlled clinical trial were planned, and in part completed, concerning the cardiovascular (CV) effects of hypoglycaemic drug in patients with Type 2 diabetes mellitus. At least 9 studies have been concluded, 13 are still open, and 4 have been initiated and closed ahead of time. Of the nine completed studies, three concerned inhibitor of the dipeptidyl peptidase 4 (inhibitors of DPP-4), four the glucagon-like peptide 1 agonist (GLP-1 agonist), and two the inhibitor of sodium-glucose co-transporter-2 (inhibitors of SGLT-2). Only four studies demonstrated the superiority, and not the mere ‘non-inferiority’, of the anti-diabetic drugs compared to placebo, in addition to standard treatment, in terms of reduction of the primary endpoint (CV death, non-fatal myocardial infarction, and non-fatal stroke). Two of the four studies regarded GLP-1 analogues (liraglutide and semaglutide), and two inhibitors of SGLT-2 (empaglifozin and canaglifozin). As a whole, these studies provided solid data supporting major beneficial CV effects of anti-diabetic drugs. During the next 3–4 years, an equal number of studies will be completed and published, so we will soon have the ‘final word’ on this issue. In the meantime, the clinical cardiologist should become familiar with these drugs, selecting the patients able to gain the best clinical advantage from this treatment, also by establishing a close relationship with the diabetologist.
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Affiliation(s)
- Paolo Verdecchia
- Fondazione Umbra Cuore e Ipertensione-ONLUS, Struttura Complessa di Cardiologia, Ospedale S. Maria della Misericordia, Perugia, Italy
| | - Fabio Angeli
- Struttura Complessa di Cardiologia e Fisiopatologia Cardiovascolare, Ospedale S. Maria della Misericordia, Perugia, Italy
| | - Claudio Cavallini
- Fondazione Umbra Cuore e Ipertensione-ONLUS, Struttura Complessa di Cardiologia, Ospedale S. Maria della Misericordia, Perugia, Italy
| | - Adolfo Aita
- Fondazione Umbra Cuore e Ipertensione-ONLUS, Struttura Complessa di Cardiologia, Ospedale S. Maria della Misericordia, Perugia, Italy
| | - Dario Turturiello
- Struttura Complessa di Cardiologia e Fisiopatologia Cardiovascolare, Ospedale S. Maria della Misericordia, Perugia, Italy
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11
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Knerr PJ, Mowery SA, Finan B, Perez-Tilve D, Tschöp MH, DiMarchi RD. Selection and progression of unimolecular agonists at the GIP, GLP-1, and glucagon receptors as drug candidates. Peptides 2020; 125:170225. [PMID: 31786282 DOI: 10.1016/j.peptides.2019.170225] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Revised: 11/26/2019] [Accepted: 11/27/2019] [Indexed: 02/07/2023]
Abstract
The continued global growth in the prevalence of obesity coupled with the limited number of efficacious and safe treatment options elevates the importance of innovative pharmaceutical approaches. Combinatorial strategies that harness the metabolic benefits of multiple hormonal mechanisms have emerged at the preclinical and more recently clinical stages of drug development. A priority has been anti-obesity unimolecular peptides that function as balanced, high potency poly-agonists at two or all the cellular receptors for the endocrine hormones glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon. This report reviews recent progress in this area, with emphasis on what the initial clinical results demonstrate and what remains to be addressed.
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Affiliation(s)
- Patrick J Knerr
- Novo Nordisk Research Center Indianapolis, Indianapolis, IN, USA
| | | | - Brian Finan
- Novo Nordisk Research Center Indianapolis, Indianapolis, IN, USA
| | - Diego Perez-Tilve
- Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Matthias H Tschöp
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Garching, Germany
| | - Richard D DiMarchi
- Novo Nordisk Research Center Indianapolis, Indianapolis, IN, USA; Department of Chemistry, Indiana University, Bloomington, IN, USA.
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12
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Nafisah SB, Almatrafi D, Al-Mulhim K. Liraglutide overdose: A case report and an updated review. Turk J Emerg Med 2020; 20:46-49. [PMID: 32355902 PMCID: PMC7189825 DOI: 10.4103/2452-2473.276386] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Accepted: 11/03/2019] [Indexed: 01/28/2023] Open
Abstract
Little is known about liraglutide overdose and in particular its association with hypoglycemia. The aim of this study was to report on an accidental case of liraglutide overdose and to review similar cases in the literature. Here, we report a case of a young female presented with an accidental injection of 18 mg of liraglutide subcutaneously. She presented with relative hypoglycemia with gastrointestinal symptoms that resembled pancreatitis. We concluded with several implications and policies targeting accidental injections from the use of such medication and similar subcutaneous medications in clinical practice.
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Affiliation(s)
| | - Daliah Almatrafi
- Department of Emergency, King Fahd Medical City, Riyadh, Saudi Arabia
| | - Khalid Al-Mulhim
- Department of Emergency, King Fahd Medical City, Riyadh, Saudi Arabia
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13
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Ahmed HM, Khraishah H, Cho L. Cardioprotective anti-hyperglycaemic medications: a review of clinical trials. Eur Heart J 2019; 39:2368-2375. [PMID: 29236983 DOI: 10.1093/eurheartj/ehx668] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Accepted: 11/20/2017] [Indexed: 02/06/2023] Open
Abstract
Despite extensive clinical efforts to achieve stricter glycaemic control over the past few decades, cardiovascular (CV) disease remains the leading cause of death among diabetic patients. Recently, sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 receptor (GLP-1-R) agonists have gained attention due to their apparent effects in reducing CV mortality. Four CV randomized controlled trials: EMPA-REG, CANVAS, LEADER, and SUSTAIN-6, found a decrease in CV events among patients with type 2 diabetes on empagliflozin, canagliflozin, liraglutide, and semaglutide, respectively. In light of this data, the US Food and Drug Administration has recently approved empagliflozin for CV mortality reduction in type 2 diabetic patients, making it the first diabetes medication approved for such an indication. The purpose of this review is to summarize the results of novel anti-hyperglycaemic medication trials, and shed light on their mode of action and cardioprotective pathways.
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Affiliation(s)
- Haitham M Ahmed
- Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, 9500 Euclid Ave, Desk JB1 Cleveland, OH, USA
| | - Haitham Khraishah
- Beth Israel Deaconess Medical Center, 330 Brookline Ave Boston, MA, USA
| | - Leslie Cho
- Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, 9500 Euclid Ave, Desk JB1 Cleveland, OH, USA
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14
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Gouni-Berthold I, Berthold HK. Current Options for the Pharmacotherapy of Obesity. Curr Pharm Des 2019; 25:2019-2032. [PMID: 31298150 DOI: 10.2174/1381612825666190708192630] [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: 04/30/2019] [Accepted: 06/24/2019] [Indexed: 11/22/2022]
Abstract
650 millions of adults are obese worldwide - in the US alone, forty percent of the adults are obese. Although the obesity pandemic is constantly expanding at very high costs for health care systems, the currently available options of pharmacotherapy for obesity are rather limited. Despite intensive research efforts, the vast majority of the anti-obesity drugs developed up to now have a rather limited efficacy and/or safety profile. In the last fifty years, various drugs reached advanced states of clinical development but were either never marketed or were initially approved but withdrawn later due to safety issues. However, the understanding of the pathophysiology of obesity has been steadily improving and new, promising drugs targeting various selective obesityassociated and energy-homeostasis-related pathways are now available. When lifestyle changes alone fail to combat, then additional pharmacotherapy with an acceptable efficacy and safety profile could provide a useful therapeutic option.
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Affiliation(s)
- Ioanna Gouni-Berthold
- Polyclinic for Endocrinology, Diabetes and Preventive Medicine, University Hospital of Cologne, Cologne, Germany.,Polyclinic for Endocrinology, Diabetes and Preventive Medicine, University of Cologne, Cologne, Germany
| | - Heiner K Berthold
- Department of Internal Medicine and Geriatrics, Bethel Clinic (EvKB), Bielefeld, Germany
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15
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Biondi B, Kahaly GJ, Robertson RP. Thyroid Dysfunction and Diabetes Mellitus: Two Closely Associated Disorders. Endocr Rev 2019; 40:789-824. [PMID: 30649221 PMCID: PMC6507635 DOI: 10.1210/er.2018-00163] [Citation(s) in RCA: 286] [Impact Index Per Article: 47.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2018] [Accepted: 10/15/2018] [Indexed: 12/13/2022]
Abstract
Thyroid dysfunction and diabetes mellitus are closely linked. Several studies have documented the increased prevalence of thyroid disorders in patients with diabetes mellitus and vice versa. This review critically discusses the different underlying mechanisms linking type 1 and 2 diabetes and thyroid dysfunction to demonstrate that the association of these two common disorders is unlikely a simple coincidence. We assess the current state of knowledge on the central and peripheral control of thyroid hormone on food intake and glucose and lipid metabolism in target tissues (such as liver, white and brown adipose tissue, pancreatic β cells, and skeletal muscle) to explain the mechanism linking overt and subclinical hypothyroidism to type 2 diabetes and metabolic syndrome. We also elucidate the common susceptibility genes and the pathogenetic mechanisms contributing to the autoimmune mechanism involved in the onset of type 1 diabetes mellitus and autoimmune thyroid disorders. An untreated thyroid dysfunction can impair the metabolic control of diabetic patients, and this association can have important repercussions on the outcome of both of these disorders. Therefore, we offer recommendations for the diagnosis, management, and screening of thyroid disorders in patients with diabetes mellitus, including the treatment of diabetic patients planning a pregnancy. We also discuss the major causes of failure to achieve an optimal management of thyroid dysfunction in diabetic patients and provide recommendations for assessing and treating these disorders during therapy with antidiabetic drugs. An algorithm for a correct approach of these disorders when linked is also provided.
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Affiliation(s)
- Bernadette Biondi
- Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - George J Kahaly
- Department of Medicine I, Johannes Gutenberg University Medical Center, Mainz, Germany
| | - R Paul Robertson
- Department of Medicine, Division of Endocrinology and Metabolism, University of Washington School of Medicine, Seattle, Washington.,Department of Pharmacology, University of Washington, Seattle, Washington
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16
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Ho HJ, Shirakawa H, Hirahara K, Sone H, Kamiyama S, Komai M. Menaquinone-4 Amplified Glucose-Stimulated Insulin Secretion in Isolated Mouse Pancreatic Islets and INS-1 Rat Insulinoma Cells. Int J Mol Sci 2019; 20:ijms20081995. [PMID: 31018587 PMCID: PMC6515216 DOI: 10.3390/ijms20081995] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2019] [Revised: 04/15/2019] [Accepted: 04/22/2019] [Indexed: 12/21/2022] Open
Abstract
Vitamin K2 is indispensable for blood coagulation and bone metabolism. Menaquinone-4 (MK-4) is the predominant homolog of vitamin K2, which is present in large amounts in the pancreas, although its function is unclear. Meanwhile, β-cell dysfunction following insulin secretion has been found to decrease in patients with type 2 diabetes mellitus. To elucidate the physiological function of MK-4 in pancreatic β-cells, we studied the effects of MK-4 treatment on isolated mouse pancreatic islets and rat INS-1 cells. Glucose-stimulated insulin secretion significantly increased in isolated islets and INS-1 cells treated with MK-4. It was further clarified that MK-4 enhanced cAMP levels, accompanied by the regulation of the exchange protein directly activated by the cAMP 2 (Epac2)-dependent pathway but not the protein kinase A (PKA)-dependent pathway. A novel function of MK-4 on glucose-stimulated insulin secretion was found, suggesting that MK-4 might act as a potent amplifier of the incretin effect. This study therefore presents a novel potential therapeutic approach for impaired insulinotropic effects.
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Affiliation(s)
- Hsin-Jung Ho
- Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, Sendai 980-8572, Japan.
| | - Hitoshi Shirakawa
- Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, Sendai 980-8572, Japan.
- International Education and Research Center for Food Agricultural Immunology, Graduate School of Agricultural Science, Tohoku University, Sendai 980-8572, Japan.
| | - Keisukei Hirahara
- Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, Sendai 980-8572, Japan.
| | - Hideyuki Sone
- Department of Health and Nutrition, Faculty of Human Life Studies, University of Niigata Prefecture, Niigata 950-8680, Japan.
| | - Shin Kamiyama
- Department of Health and Nutrition, Faculty of Human Life Studies, University of Niigata Prefecture, Niigata 950-8680, Japan.
| | - Michio Komai
- Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, Sendai 980-8572, Japan.
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17
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Grancini V, Resi V, Palmieri E, Pugliese G, Orsi E. Management of diabetes mellitus in patients undergoing liver transplantation. Pharmacol Res 2019; 141:556-573. [PMID: 30690071 DOI: 10.1016/j.phrs.2019.01.042] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Revised: 01/24/2019] [Accepted: 01/24/2019] [Indexed: 02/07/2023]
Abstract
Diabetes is a common feature in cirrhotic individuals both before and after liver transplantation and negatively affects prognosis. Certain aetiological agents of chronic liver disease and loss of liver function per se favour the occurrence of pre-transplant diabetes in susceptible individuals, whereas immunosuppressant treatment, changes in lifestyle habits, and donor- and procedure-related factors contribute to diabetes development/persistence after transplantation. Challenges in the management of pre-transplant diabetes include the profound nutritional alterations characterizing cirrhotic individuals and the limitations to the use of drugs with liver metabolism. Special issues in the management of post-transplant diabetes include the diabetogenic potential of immunosuppressant drugs and the increased cardiovascular risk characterizing solid organ transplant survivors. Overall, the pharmacological management of cirrhotic patients undergoing liver transplantation is complicated by the lack of specific guidelines reflecting the paucity of data on the impact of glycaemic control and the safety and efficacy of anti-hyperglycaemic agents in these individuals.
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Affiliation(s)
- Valeria Grancini
- Diabetes Service, Endocrinology and Metabolic Diseases Unit, IRCCS "Cà Granda - Ospedale Maggiore Policlinico" Foundation, and Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Veronica Resi
- Diabetes Service, Endocrinology and Metabolic Diseases Unit, IRCCS "Cà Granda - Ospedale Maggiore Policlinico" Foundation, and Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Eva Palmieri
- Diabetes Service, Endocrinology and Metabolic Diseases Unit, IRCCS "Cà Granda - Ospedale Maggiore Policlinico" Foundation, and Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Giuseppe Pugliese
- Department of Clinical and Molecular Medicine, "La Sapienza" University, and Diabetes Unit, Sant'Andrea University Hospital, Rome, Italy
| | - Emanuela Orsi
- Diabetes Service, Endocrinology and Metabolic Diseases Unit, IRCCS "Cà Granda - Ospedale Maggiore Policlinico" Foundation, and Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.
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18
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Sfairopoulos D, Liatis S, Tigas S, Liberopoulos E. Clinical pharmacology of glucagon-like peptide-1 receptor agonists. Hormones (Athens) 2018; 17:333-350. [PMID: 29949126 DOI: 10.1007/s42000-018-0038-0] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Accepted: 05/14/2018] [Indexed: 02/06/2023]
Abstract
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are an important asset in the armamentarium for the treatment of type 2 diabetes mellitus (type 2 DM). Incretin failure is a critical etiopathogenetic feature of type 2 DM, which, if reversed, results in improved glycaemic control. GLP-1 RAs are injectable peptides that resemble the structure and function of endogenous incretin GLP-1, but as they are not deactivated by the dipeptidyl peptidase-4 (DPP-4), their half-life is prolonged compared with native GLP-1. Based on their ability to activate GLP-1 receptor, GLP-1 RAs are classified as short-acting (exenatide twice-daily and lixisenatide once-daily), and long-acting (liraglutide once-daily and the once-weekly formulations of exenatide extended-release, dulaglutide, and albiglutide). Semaglutide, another long-acting, once-weekly GLP-1 RA, was recently approved by the FDA and EMA. Although all of these agents potently reduce haemoglobin A1C (HbA1c), there are unique features and fundamental differences among them related to fasting and postprandial hyperglycaemia reduction, weight loss potency, cardiovascular protection efficacy, and adverse events profile. It is imperative that current evidence be integrated and applied in the context of an individualised patient-centred approach. This should include not only glucose management but also targeting as many as possible of the pathophysiologic mechanisms responsible for type 2 DM development and progression.
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Affiliation(s)
- Dimitrios Sfairopoulos
- Department of Internal Medicine, School of Medicine, University of Ioannina, Stavrou Niarchou Str, 45110, Ioannina, Greece
| | - Stavros Liatis
- First Department of Propaedeutic and Internal Medicine, Medical School, Laiko General Hospital, National and Kapodistrian University of Athens, 10559, Athens, Greece
| | - Stelios Tigas
- Department of Endocrinology, School of Medicine, University of Ioannina, 45110, Ioannina, Greece
| | - Evangelos Liberopoulos
- Department of Internal Medicine, School of Medicine, University of Ioannina, Stavrou Niarchou Str, 45110, Ioannina, Greece.
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19
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Van Name MA, Guandalini C, Steffen A, Patel A, Tamborlane W. The present and future treatment of pediatric type 2 diabetes. Expert Rev Endocrinol Metab 2018; 13:207-212. [PMID: 30063424 DOI: 10.1080/17446651.2018.1499467] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
INTRODUCTION Treatment of type 2 diabetes (T2D) in children and adolescents is particularly challenging. Metformin monotherapy is the standard initial treatment for youth with T2D, once metabolic control is restored with insulin in patients who present with ketosis and/or marked hyperglycemia. Insulin, the only other drug approved for use in youth with T2D, is also used as add-on therapy when patients fail metformin mono-therapy. AREAS COVERED In this paper, we will summarize the current use of both metformin and insulin in the treatment of pediatric type 2 diabetes, as well as comment on their limitations. Given the rapid progression of T2D in youth, there is also considerable interest in treating youth with new oral and injectable agents that have been approved for use in adults with T2D. The potential for improving clinical outcomes of each of the main classes of new drugs for the treatment of pediatric T2D will be summerized. EXPERT COMMENTARY We will conclude by reviewing why phase 3 randomized clinical trials examining the safety and efficacy of these medications in the pediatric population have been difficult to complete and discuss a potential pathway to overcome these obstacles to regulatory approval for these drugs for adolescents with T2D.
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Affiliation(s)
- Michelle Anne Van Name
- a Department of Pediatrics , Yale School of Medicine, Yale-New Haven Children's Hospital , New Haven , Connecticut , USA
| | - Cindy Guandalini
- a Department of Pediatrics , Yale School of Medicine, Yale-New Haven Children's Hospital , New Haven , Connecticut , USA
| | - Amy Steffen
- a Department of Pediatrics , Yale School of Medicine, Yale-New Haven Children's Hospital , New Haven , Connecticut , USA
| | - Anisha Patel
- a Department of Pediatrics , Yale School of Medicine, Yale-New Haven Children's Hospital , New Haven , Connecticut , USA
| | - William Tamborlane
- a Department of Pediatrics , Yale School of Medicine, Yale-New Haven Children's Hospital , New Haven , Connecticut , USA
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20
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Optimization of peptide-based polyagonists for treatment of diabetes and obesity. Bioorg Med Chem 2018; 26:2873-2881. [DOI: 10.1016/j.bmc.2017.10.047] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2017] [Accepted: 10/31/2017] [Indexed: 12/28/2022]
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21
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Nargis T, Kumar K, Ghosh AR, Sharma A, Rudra D, Sen D, Chakrabarti S, Mukhopadhyay S, Ganguly D, Chakrabarti P. KLK5 induces shedding of DPP4 from circulatory Th17 cells in type 2 diabetes. Mol Metab 2017; 6:1529-1539. [PMID: 29107298 PMCID: PMC5681279 DOI: 10.1016/j.molmet.2017.09.004] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2017] [Revised: 09/07/2017] [Accepted: 09/15/2017] [Indexed: 12/21/2022] Open
Abstract
OBJECTIVE Increasing plasma levels and activity of dipeptidyl peptidase-4 (DPP4 or CD26) are associated with rapid progression of metabolic syndrome to overt type 2 diabetes mellitus (T2DM). While DPP4 inhibitors are increasingly used as anti-hyperglycemic agents, the reason for the increase in plasma DPP4 activity in T2DM patients remains elusive. METHODS We looked into the source of plasma DPP4 activity in a cohort of 135 treatment naive nonobese (BMI < 30) T2DM patients. A wide array of ex vivo, in vitro, and in silico methods were employed to study enzyme activity, gene expression, subcellular localization, protease identification, surface expression, and protein-protein interactions. RESULTS We show that circulating immune cells, particularly CD4+ T cells, served as an important source for the increase in plasma DPP4 activity in T2DM. Moreover, we found kallikrein-related peptidase 5 (KLK5) as the enzyme responsible for cleaving DPP4 from the cell surface by directly interacting with the extracellular loop. Expression and secretion of KLK5 is induced in CD4+ T cells of T2DM patients. In addition, KLK5 shed DPP4 from circulating CD4+ T helper (Th)17 cells and shed it into the plasma of T2DM patients. Similar cleavage and shedding activities were not seen in controls. CONCLUSIONS Our study provides mechanistic insights into the molecular interaction between KLK5 and DPP4 as well as CD4+ T cell derived KLK5 mediated enzymatic cleavage of DPP4 from cell surface. Thus, our study uncovers a hitherto unknown cellular source and mechanism behind enhanced plasma DPP4 activity in T2DM.
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Affiliation(s)
- Titli Nargis
- Division of Cell Biology and Physiology, CSIR-Indian Institute of Chemical Biology, Kolkata, India
| | - Krishna Kumar
- Division of Structural Biology and Bioinformatics, CSIR-Indian Institute of Chemical Biology, Kolkata, India
| | - Amrit Raj Ghosh
- Division of Cancer Biology and Inflammatory Disorder, CSIR-Indian Institute of Chemical Biology, Kolkata, India
| | - Amit Sharma
- Academy of Immunology and Microbiology, Institute for Basic Science (IBS), Pohang 37673, Republic of Korea
| | - Dipayan Rudra
- Academy of Immunology and Microbiology, Institute for Basic Science (IBS), Pohang 37673, Republic of Korea
| | - Debrup Sen
- Zoology Department, Vidyasagar College, Kolkata, India
| | - Saikat Chakrabarti
- Division of Structural Biology and Bioinformatics, CSIR-Indian Institute of Chemical Biology, Kolkata, India
| | - Satinath Mukhopadhyay
- Department of Endocrinology & Metabolism, Institute of Postgraduate Medical Education and Research, Kolkata, India
| | - Dipyaman Ganguly
- Division of Cancer Biology and Inflammatory Disorder, CSIR-Indian Institute of Chemical Biology, Kolkata, India.
| | - Partha Chakrabarti
- Division of Cell Biology and Physiology, CSIR-Indian Institute of Chemical Biology, Kolkata, India.
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22
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Boettcher BR. Gastric bypass surgery mimetic approaches. Drug Discov Today 2017; 22:1242-1249. [PMID: 28576430 DOI: 10.1016/j.drudis.2017.04.009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2017] [Revised: 04/11/2017] [Accepted: 04/18/2017] [Indexed: 01/10/2023]
Abstract
Gastric bypass surgery is effectively a polypharmacological approach for treatment of obesity, type 2 diabetes and nonalcoholic steatohepatitis (NASH). The gastric bypass mimetic approaches reviewed are fixed-dose combinatorial pharmacological approaches. There are two key concepts incorporated into these gastric bypass surgery mimetic approaches. The first key concept is that the combination of glucagon-like peptide 1 (GLP-1) and fibroblast growth factor 21 (FGF21) is essential for success of any gastric bypass surgery mimetic approach. This combination affords the potential for durable weight loss, glycemic control and reduction in liver lipids. The second key concept is that a fixed-dose combination approach is preferred over post-approval combination of the individual components because the individual components alone often lack sufficient efficacy for development.
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23
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Layden BT, Wicksteed B, Mauvais-Jarvis F. Incretin-Based Therapies: Revisiting Their Mode of Action. Endocrinology 2017; 158:1560-1563. [PMID: 28575434 PMCID: PMC5460946 DOI: 10.1210/en.2017-00252] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2017] [Accepted: 03/15/2017] [Indexed: 01/15/2023]
Affiliation(s)
- Brian T Layden
- Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Illinois at Chicago, Chicago, Illinois 60612
- Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois 60612
| | - Barton Wicksteed
- Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Illinois at Chicago, Chicago, Illinois 60612
| | - Franck Mauvais-Jarvis
- Diabetes Research and Gender Medicine Laboratory, Section of Endocrinology and Metabolism, Department of Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana 70112
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24
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Wan Y, Bao X, Huang J, Zhang X, Liu W, Cui Q, Jiang D, Wang Z, Liu R, Wang Q. Novel GLP-1 Analog Supaglutide Reduces HFD-Induced Obesity Associated with Increased Ucp-1 in White Adipose Tissue in Mice. Front Physiol 2017; 8:294. [PMID: 28555111 PMCID: PMC5430033 DOI: 10.3389/fphys.2017.00294] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Accepted: 04/24/2017] [Indexed: 12/14/2022] Open
Abstract
GLP-1, an important incretin hormone plays an important role in the regulation of glucose homeostasis. However, the therapeutic use of native GLP-1 is limited due to its short half-life. We recently developed a novel GLP-1 mimetics (supaglutide) by genetically engineering recombinant fusion protein production techniques. We demonstrated that this formulation possessed long-lasting GLP-1 actions and was effective in glycemic control in both type 1 and type 2 diabetes rodent models. Here, we investigated the effects of supaglutide in regulating energy homeostasis in obese mice. Mice were fed with high-fat diet (HFD) for 6 months to induce obesity and then subjected to supaglutide treatment (300 μg/kg, bi-weekly for 4 weeks), and placebo as control. Metabolic conditions were monitored and energy expenditure was assessed by indirect calorimetry (CLAMS). Cold tolerance test was performed to evaluate brown-adipose tissue (BAT) activities in response to cold challenge. Glucose tolerance and insulin resistance were evaluated by intraperitoneal glucose tolerance test and insulin tolerance tests. Liver and adipose tissues were collected for histology analysis. Expression of uncoupling protein 1(Ucp1) in adipose tissues was evaluated by Western blotting. We found that supaglutide treatment reduced body weight, which was associated with reduced food intake. Compared to the placebo control, supaglutide treatment improved lipid profile, i.e., significantly decreased circulating total cholesterol levels, declined serum triglyceride, and free fatty acid levels. Importantly, the intervention significantly reduced fatty liver, decreased liver triglyceride content, and concomitantly ameliorated liver injury exemplified by declined hepatic alanine aminotransferase (ALT) and aspartic transaminase (AST) content. Remarkably, supaglutide reduced hepatic lipid accumulation and altered morphometry in favor of small adipocytes in fat. This is consistent with the observation that supaglutide increased tolerance of the mice to cold environment associated with up-regulation of Ucp1 in the inguinal fat. Furthermore, supaglutide improved glucose tolerance, and insulin sensitivity in the obese mice suggesting improved glucose and energy homeostasis. Our findings suggest that supaglutide exerts beneficial effect on established obesity through reducing energy intake and is associated with brown remodeling of white adipose tissue.
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Affiliation(s)
- Yun Wan
- Department of Endocrinology and Metabolism, Huashan Hospital, Fudan UniversityShanghai, China
| | - Xi Bao
- Yinnuo Pharmaceutical Technology Co. Ltd.Shanghai, China
| | - Jiabao Huang
- Yinnuo Pharmaceutical Technology Co. Ltd.Shanghai, China
| | - Xiangyu Zhang
- Yinnuo Pharmaceutical Technology Co. Ltd.Shanghai, China
| | - Wenjuan Liu
- Department of Endocrinology and Metabolism, Huashan Hospital, Fudan UniversityShanghai, China.,Division of Endocrinology and Metabolism, Keenan Research Centre for Biomedical Science, St. Michael's HospitalToronto, ON, Canada
| | - Qiaoli Cui
- Department of Endocrinology and Metabolism, Huashan Hospital, Fudan UniversityShanghai, China
| | - Dongdong Jiang
- Department of Endocrinology and Metabolism, Huashan Hospital, Fudan UniversityShanghai, China
| | - Zhihong Wang
- Department of Endocrinology and Metabolism, Huashan Hospital, Fudan UniversityShanghai, China
| | - Rui Liu
- Department of Endocrinology and Metabolism, Huashan Hospital, Fudan UniversityShanghai, China
| | - Qinghua Wang
- Department of Endocrinology and Metabolism, Huashan Hospital, Fudan UniversityShanghai, China.,Yinnuo Pharmaceutical Technology Co. Ltd.Shanghai, China.,Division of Endocrinology and Metabolism, Keenan Research Centre for Biomedical Science, St. Michael's HospitalToronto, ON, Canada.,Departments of Physiology and Medicine, Faculty of Medicine, University of TorontoON, Canada
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25
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Mietlicki-Baase EG, Koch-Laskowski K, McGrath LE, Krawczyk J, Pham T, Lhamo R, Reiner DJ, Hayes MR. Daily supplementation of dietary protein improves the metabolic effects of GLP-1-based pharmacotherapy in lean and obese rats. Physiol Behav 2017; 177:122-128. [PMID: 28433470 DOI: 10.1016/j.physbeh.2017.04.017] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2017] [Revised: 04/01/2017] [Accepted: 04/18/2017] [Indexed: 12/30/2022]
Abstract
Glucagon-like peptide-1 (GLP-1) is an incretin hormone released from intestinal L-cells in response to food entering into the gastrointestinal tract. GLP-1-based pharmaceuticals improve blood glucose regulation and reduce feeding. Specific macronutrients, when ingested, may trigger GLP-1 secretion and enhance the effects of systemic sitagliptin, a pharmacological inhibitor of DPP-IV (an enzyme that rapidly degrades GLP-1). In particular, macronutrient constituents found in dairy foods may act as potent secretagogues for GLP-1, and acute preclinical trials show that ingestion of dairy protein may represent a promising adjunct behavioral therapy in combination with sitagliptin. To test this hypothesis further, chow-maintained or high-fat diet (HFD)-induced obese rats received daily IP injections of sitagliptin (6mg/kg) or saline in combination with a twice-daily 8ml oral gavage of milk protein concentrate (MPC; 80/20% casein/whey; 0.5kcal/ml), soy protein (non-dairy control; 0.5kcal/ml) or 0.9% NaCl for two months. Food intake and body weight were recorded every 24-48h; blood glucose regulation was examined at baseline and at 3 and 6.5weeks via a 2h oral glucose tolerance test (OGTT; 25% glucose; 2g/kg). MPC and soy protein significantly suppressed cumulative caloric intake in HFD but not chow-maintained rats. AUC analyses for OGTT show suppression in glycemia by sitagliptin with MPC or soy in chow- and HFD-maintained rats, suggesting that chronic ingestion of dairy or soy proteins may augment endogenous GLP-1 signaling and the glycemic- and food intake-suppressive effects of DPP-IV inhibition.
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Affiliation(s)
- Elizabeth G Mietlicki-Baase
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States
| | - Kieran Koch-Laskowski
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States
| | - Lauren E McGrath
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States
| | - Joanna Krawczyk
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States
| | - Tram Pham
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States
| | - Rinzin Lhamo
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States
| | - David J Reiner
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States
| | - Matthew R Hayes
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States.
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26
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Bugáňová M, Pelantová H, Holubová M, Šedivá B, Maletínská L, Železná B, Kuneš J, Kačer P, Kuzma M, Haluzík M. The effects of liraglutide in mice with diet-induced obesity studied by metabolomics. J Endocrinol 2017; 233:93-104. [PMID: 28138003 DOI: 10.1530/joe-16-0478] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2017] [Accepted: 01/30/2017] [Indexed: 01/09/2023]
Abstract
Liraglutide is the glucagon-like peptide-1 receptor agonist widely used for the treatment of type 2 diabetes mellitus. Recently, it has been demonstrated to decrease cardiovascular morbidity and mortality in patients with type 2 diabetes and high cardiovascular risk. Although the major modes of liraglutide action are well-known, its detailed action at the metabolic level has not been studied. To this end, we explored the effect of 2-week liraglutide treatment in C57BL/6 male mice with obesity and diabetes induced by 13 weeks of high-fat diet using NMR spectroscopy to capture the changes in urine metabolic profile induced by the therapy. The liraglutide treatment decreased body and fat pads weight along with blood glucose and triglyceride levels. NMR spectroscopy identified 11 metabolites significantly affected by liraglutide treatment as compared to high-fat diet-fed control group. These metabolites included ones involved in nicotinamide adenine dinucleotide metabolism, β-oxidation of fatty acids and microbiome changes. Although majority of the metabolites changed after liraglutide treatment were similar as the ones previously identified after vildagliptin administration in a similar mouse model, the changes in creatinine, taurine and trigonelline were specific for liraglutide administration. The significance of these changes and its possible use in the personalization of antidiabetic therapy in humans requires further research.
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Affiliation(s)
- Martina Bugáňová
- Institute of MicrobiologyAcademy of Sciences of the Czech Republic, Prague, Czech Republic
- Faculty of Chemical TechnologyUniversity of Chemistry and Technology Prague, Prague, Czech Republic
| | - Helena Pelantová
- Institute of MicrobiologyAcademy of Sciences of the Czech Republic, Prague, Czech Republic
| | - Martina Holubová
- Institute of Organic Chemistry and BiochemistryAcademy of Sciences of the Czech Republic, Prague, Czech Republic
| | - Blanka Šedivá
- Faculty of Applied SciencesUniversity of West Bohemia, Plzeň, Czech Republic
| | - Lenka Maletínská
- Institute of Organic Chemistry and BiochemistryAcademy of Sciences of the Czech Republic, Prague, Czech Republic
| | - Blanka Železná
- Institute of Organic Chemistry and BiochemistryAcademy of Sciences of the Czech Republic, Prague, Czech Republic
| | - Jaroslav Kuneš
- Institute of Organic Chemistry and BiochemistryAcademy of Sciences of the Czech Republic, Prague, Czech Republic
- Institute of PhysiologyAcademy of Sciences of the Czech Republic, Prague, Czech Republic
| | - Petr Kačer
- Institute of MicrobiologyAcademy of Sciences of the Czech Republic, Prague, Czech Republic
- Faculty of Chemical TechnologyUniversity of Chemistry and Technology Prague, Prague, Czech Republic
| | - Marek Kuzma
- Institute of MicrobiologyAcademy of Sciences of the Czech Republic, Prague, Czech Republic
| | - Martin Haluzík
- Centre for Experimental Medicine and Diabetes CentreInstitute for Clinical and Experimental Medicine, Prague, Czech Republic
- Institute of Medical Biochemistry and Laboratory Diagnostics1st Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
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27
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Leporini C, Piro R, Ursini F, Maida F, Palleria C, Arturi F, Pavia M, De Sarro G, Russo E. Monitoring safety and use of old and new treatment options for type 2 diabetic patients: a two-year (2013-2016) analysis. Expert Opin Drug Saf 2017; 15:17-34. [PMID: 27718744 DOI: 10.1080/14740338.2016.1246531] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
OBJECTIVE To compare patients' and physicians' perceptions regarding effectiveness and tolerability of non-insulin hypoglycemic drugs in a cohort of type 2 diabetic patients; to verify whether a possible tridimensional link between effectiveness, tolerability, and adherence affects long-term therapeutic outcomes. METHODS A two-year observational study was performed in 1389 Type 2 diabetic patients by involving general practitioner clinics and Diabetes Centers. A decimal scale and the Morisky questionnaire were used, respectively, to assess effectiveness and tolerability perceptions, and medication adherence. RESULTS Physicians perceived therapy as more efficacious compared to their patients: perceived effectiveness was steady for physicians during the study whereas patients' perception not significantly decreased (mean score from >8 to 7.84 ± 1.69). Physicians assigned higher tolerability scores compared to patients but only at the beginning of the study; interestingly, physicians' tolerability perception was poorer than patients' perception at last follow-up (mean score = 7.57 ± 1.40 vs. 7.88 ± 1.84). Favorable (score >7) patients' perceptions about treatment effectiveness and tolerability were associated with higher adherence. Patients showed medium adherence across the study. CONCLUSIONS A mutual relationship between clinical effectiveness, adverse drug reactions, and adherence has been established, significantly impacting the clinical management of diabetic patients. A careful monitoring of this link by clinicians appears therefore necessary.
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Affiliation(s)
- Christian Leporini
- a School of Medicine and Surgery, Department of Health Sciences, Clinical Pharmacology and Pharmacovigilance Unit , 'Magna Graecia' University of Catanzaro , Catanzaro , Italy
| | - Rosanna Piro
- b 'S Francesco di Paola' Hospital , Diabetology and Metabolic Diseases Unit , Paola , Italy
| | - Francesco Ursini
- a School of Medicine and Surgery, Department of Health Sciences, Clinical Pharmacology and Pharmacovigilance Unit , 'Magna Graecia' University of Catanzaro , Catanzaro , Italy
| | - Francesca Maida
- a School of Medicine and Surgery, Department of Health Sciences, Clinical Pharmacology and Pharmacovigilance Unit , 'Magna Graecia' University of Catanzaro , Catanzaro , Italy
| | - Caterina Palleria
- a School of Medicine and Surgery, Department of Health Sciences, Clinical Pharmacology and Pharmacovigilance Unit , 'Magna Graecia' University of Catanzaro , Catanzaro , Italy
| | - Franco Arturi
- c Department of Medical and Surgical Sciences, Internal Medicine Unit of 'Mater Domini' University Hospital , 'Magna Graecia' University of Catanzaro , Catanzaro , Italy
| | - Maria Pavia
- d Department of Health Sciences, Medical School , University of Catanzaro 'Magna Græcia', Campus of Germaneto , Catanzaro , Italy
| | - Giovambattista De Sarro
- a School of Medicine and Surgery, Department of Health Sciences, Clinical Pharmacology and Pharmacovigilance Unit , 'Magna Graecia' University of Catanzaro , Catanzaro , Italy
| | - Emilio Russo
- a School of Medicine and Surgery, Department of Health Sciences, Clinical Pharmacology and Pharmacovigilance Unit , 'Magna Graecia' University of Catanzaro , Catanzaro , Italy
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28
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Abstract
Incretin-based therapies are important addition to our armamentarium for the treatment of type 2 diabetes (T2DM). There are six Glucagon-like peptide-1 receptor agonists (GLP-1RAs) which have received regulatory approval for clinical use. The short-acting GLP-1RAs include exenatide twice daily, liraglutide once daily, and lixisenatide once daily. The approved long-acting GLP-1RAs are administered weekly and are exenatide, albiglutide, and dulaglutide. Although all of these therapies lower hemoglobin A1C (HbA1C), there also are unique features of GLP-1RAs that have been made manifest from clinical trial data with regard to weight-loss efficacy, fasting and post-prandial glucose control, cardiovascular safety and protection, and gastrointestinal and injection adverse effects. It is imperative to consider these features when tailoring the choice of a GLP-1RA to patient specific characteristics.
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Affiliation(s)
- Susan L Samson
- Department of Medicine, Baylor College of Medicine, One Baylor Plaza, ABBR R615, Houston, TX, 77030, USA.
| | - Alan J Garber
- Departments of Medicine, Molecular and Cellular Biology, Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, BCM 620, Houston, TX, 77030, USA
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29
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Bacha F, Klinepeter Bartz S. Insulin resistance, role of metformin and other non-insulin therapies in pediatric type 1 diabetes. Pediatr Diabetes 2016; 17:545-558. [PMID: 26592507 DOI: 10.1111/pedi.12337] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2015] [Revised: 09/17/2015] [Accepted: 10/12/2015] [Indexed: 12/28/2022] Open
Abstract
Type 1 diabetes mellitus (T1DM) in youth is a challenging chronic medical condition. Its management should address not only the glycemic control but also insulin resistance and cardiovascular disease risk factors which are increasingly recognized to be present in youth with TID. Current knowledge on the mechanisms of insulin resistance in T1DM is reviewed. The use of adjunctive therapies that are beneficial to achieve adequate glycemic control while mitigating the effects of insulin resistance are discussed with a focus on metformin therapy and an overview of other new pharmacologic agents.
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Affiliation(s)
- Fida Bacha
- Children's Nutrition Research Center, Texas Children's Hospital, Baylor College of Medicine Houston, Houston, TX, USA. .,Division of Pediatric Endocrinology and Diabetes, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.
| | - Sara Klinepeter Bartz
- Children's Nutrition Research Center, Texas Children's Hospital, Baylor College of Medicine Houston, Houston, TX, USA.,Division of Pediatric Endocrinology and Diabetes, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA
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30
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Tseng CM, Liao WC, Chang CY, Lee CT, Tseng CH, Hsu YC, Lin JT. Incretin-based pharmacotherapy and risk of adverse pancreatic events in the ethnic Chinese with diabetes mellitus: A population-based study in Taiwan. Pancreatology 2016; 17:76-82. [PMID: 27743712 DOI: 10.1016/j.pan.2016.10.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2016] [Revised: 10/03/2016] [Accepted: 10/06/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND Pancreatic safety remains a concern for diabetic patients using incretin-based medications. We aimed to determine if there was an association between incretin-based therapy and an increased risk for acute pancreatitis and pancreatic cancer in patients with type 2 diabetes mellitus (DM). METHODS This retrospective population-based cohort study analyzed data from the Taiwan National Health Insurance Research Database. A total of 13 171 eligible type 2 DM patients who had received incretin-based treatment for a minimum of two months were matched 1:1 for age, gender, diabetes complications severity index, and inception date with DM patients who never used this pharmacotherapy. The cohorts were compared for occurrence of acute pancreatitis and pancreatic cancer. The association between incretin-based therapy and acute pancreatitis was assessed using a Cox proportional hazard model and stratified analyses. RESULTS Acute pancreatitis occurred in 71 (0.54%) incretin users and 66 (0.50%) non-users, respectively (P = 0.67). The association remained insignificant (adjusted hazard ratio [HR], 1.06; 95% confidence interval [CI] = 0.72-1.55) after adjustment for cholelithiasis (adjusted HR, 2.76; 95% CI = 1.32-5.75) and alcohol-related disease (adjusted HR 9.14, 95% CI = 2.08-40.14) in the Cox model. Stratified analyses affirmed no association between incretin-based therapy and pancreatitis in any subgroup. Pancreatic cancer occurred in 6 (0.05%) and 10 (0.08%) patients in the user and non-user cohort, respectively (P = 0.32). CONCLUSION Incretin-based therapy is not associated with acute pancreatitis and short-term pancreatic cancer risk among ethnic Chinese patients with diabetes. This study supports the pancreatic safety of incretin-based pharmacotherapy.
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Affiliation(s)
- Chao-Ming Tseng
- Division of Gastroenterology and Hepatology, E-Da Hospital/I-Shou University, Kaohsiung, Taiwan; Division of Gastroenterology and Hepatology, E-Da Cancer Hospital/I-Shou University, Kaohsiung, Taiwan
| | - Wei-Chih Liao
- Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan; Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Chi-Yang Chang
- Division of Gastroenterology and Hepatology, E-Da Hospital/I-Shou University, Kaohsiung, Taiwan
| | - Ching-Tai Lee
- Division of Gastroenterology and Hepatology, E-Da Hospital/I-Shou University, Kaohsiung, Taiwan
| | - Cheng-Hao Tseng
- Division of Gastroenterology and Hepatology, E-Da Hospital/I-Shou University, Kaohsiung, Taiwan; Division of Gastroenterology and Hepatology, E-Da Cancer Hospital/I-Shou University, Kaohsiung, Taiwan
| | - Yao-Chun Hsu
- Division of Gastroenterology and Hepatology, E-Da Hospital/I-Shou University, Kaohsiung, Taiwan; Center for Database Research, E-Da Hospital/I-Shou University, Kaohsiung, Taiwan; Graduate Institute of Clinical Medicine, China Medical University, Taichung, Taiwan; School of Public Health, Fu Jen Catholic University, New Taipei City, Taiwan.
| | - Jaw-Town Lin
- Division of Gastroenterology and Hepatology, E-Da Hospital/I-Shou University, Kaohsiung, Taiwan; School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan
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31
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Affiliation(s)
- Peter C Butler
- Larry L. Hillblom Islet Research Center, David Geffen School of Medicine, University of California-Los Angeles
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32
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Abstract
Glucagon-like peptide-1, produced predominantly in enteroendocrine cells, controls glucose metabolism and energy homeostasis through regulation of islet hormone secretion, gastrointestinal motility, and food intake, enabling development of GLP-1 receptor (GLP-1R) agonists for the treatment of diabetes and obesity. GLP-1 also acts on the immune system to suppress inflammation, and GLP-1R signaling in multiple tissues impacts cardiovascular function in health and disease. Here we review how GLP-1 and clinically approved GLP-1R agonists engage mechanisms that influence the risk of developing cardiovascular disease. We discuss how GLP-1R agonists modify inflammation, cardiovascular physiology, and pathophysiology in normal and diabetic animals through direct and indirect mechanisms and review human studies illustrating mechanisms linking GLP-1R signaling to modification of the cardiovascular complications of diabetes. The risks and benefits of GLP-1R agonists are updated in light of recent data suggesting that GLP-1R agonists favorably modify outcomes in diabetic subjects at high risk for cardiovascular events.
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Affiliation(s)
- Daniel J Drucker
- Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Toronto, ON M5G 1X5, Canada.
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33
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Early pancreatic carcinogenesis - risk factors, early symptoms, and the impact of antidiabetic drugs. Eur J Gastroenterol Hepatol 2016; 28:e19-25. [PMID: 27120389 DOI: 10.1097/meg.0000000000000646] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Risk factors (long-term diabetes, obesity) and early symptoms (new-onset diabetes, loss of weight, or persistent low body mass) are the initial symptoms of pancreatic carcinogenesis. They may be influenced by antidiabetic drugs and their correct evaluation is a prerequisite for early diagnosis of pancreatic cancer (PC). We review the risk factors, early symptoms, and the impact of antidiabetic drugs on early pancreatic carcinogenesis. The main source of data was the database Medline/PubMed and abstracts of international congresses (DDW, UEGW). The risk factors and early symptoms are integral components of the familial PC surveillance and sporadic PC screening. Preventive programs should always be include multistep and multidisciplinary procedures. The correct evaluation of antidiabetic drugs and their interactions with other components of pancreatic carcinogenesis may influence the early diagnosis of PC.
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34
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Klemann C, Wagner L, Stephan M, von Hörsten S. Cut to the chase: a review of CD26/dipeptidyl peptidase-4's (DPP4) entanglement in the immune system. Clin Exp Immunol 2016; 185:1-21. [PMID: 26919392 DOI: 10.1111/cei.12781] [Citation(s) in RCA: 317] [Impact Index Per Article: 35.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2015] [Revised: 02/14/2016] [Accepted: 02/21/2016] [Indexed: 12/11/2022] Open
Abstract
CD26/DPP4 (dipeptidyl peptidase 4/DP4/DPPIV) is a surface T cell activation antigen and has been shown to have DPP4 enzymatic activity, cleaving-off amino-terminal dipeptides with either L-proline or L-alanine at the penultimate position. It plays a major role in glucose metabolism by N-terminal truncation and inactivation of the incretins glucagon-like peptide-1 (GLP) and gastric inhibitory protein (GIP). In 2006, DPP4 inhibitors have been introduced to clinics and have been demonstrated to efficiently enhance the endogenous insulin secretion via prolongation of the half-life of GLP-1 and GIP in patients. However, a large number of studies demonstrate clearly that CD26/DPP4 also plays an integral role in the immune system, particularly in T cell activation. Therefore, inhibition of DPP4 might represent a double-edged sword. Apart from the metabolic benefit, the associated immunological effects of long term DPP4 inhibition on regulatory processes such as T cell homeostasis, maturation and activation are not understood fully at this stage. The current data point to an important role for CD26/DPP4 in maintaining lymphocyte composition and function, T cell activation and co-stimulation, memory T cell generation and thymic emigration patterns during immune-senescence. In rodents, critical immune changes occur at baseline levels as well as after in-vitro and in-vivo challenge. In patients receiving DPP4 inhibitors, evidence of immunological side effects also became apparent. The scope of this review is to recapitulate the role of CD26/DPP4 in the immune system regarding its pharmacological inhibition and T cell-dependent immune regulation.
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Affiliation(s)
- C Klemann
- Center of Pediatric Surgery, Hannover Medical School, Hannover.,Center of Chronic Immunodeficiency, University Medical Center Freiburg, University Medical Center Freiburg
| | - L Wagner
- Deutschsprachige Selbsthilfegruppe für Alkaptonurie (DSAKU) e.V.,Department for Experimental Therapy, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - M Stephan
- Clinic for Psychosomatics and Psychotherapy, Hannover Medical School, Hannover
| | - S von Hörsten
- Department for Experimental Therapy, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
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35
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Drab SR. Glucagon-Like Peptide-1 Receptor Agonists for Type 2 Diabetes: A Clinical Update of Safety and Efficacy. Curr Diabetes Rev 2016; 12:403-413. [PMID: 26694823 PMCID: PMC5101635 DOI: 10.2174/1573399812666151223093841] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2015] [Revised: 12/21/2015] [Accepted: 12/21/2015] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly being used for the treatment of type 2 diabetes mellitus, but consideration of benefits and potential adverse events is required. This review examines the state of glycemic control, weight loss, blood pressure, and tolerability, as well as the current debate about the safety of GLP-1 RAs, including risk of pancreatitis, pancreatic cancer, and thyroid cancer. METHODS A MEDLINE search (2010-2015) identified publications that discussed longer-acting GLP-1 RAs. Search terms included GLP-1 receptor agonists, liraglutide, exenatide, lixisenatide, semaglutide, dulaglutide, albiglutide, efficacy, safety, pancreatitis, pancreatic cancer, and thyroid cancer. Abstracts from the American Diabetes Association, European Association for the Study of Diabetes, and American Association of Clinical Endocrinologists from 2010 to 2015 were also searched. Efficacy and safety studies, pooled analyses, and meta-analyses were prioritized. RESULTS Research has confirmed that GLP-1 RAs provide robust glycemic control, weight loss, and blood pressure re-duction. Current studies do not prove increased risk of pancreatitis, pancreatic cancer, or thyroid cancer but more trials are needed since publications that indicate safety or suggest increased risk have methodological flaws that prevent firm conclusions to be drawn about these rare, long-term events. CONCLUSION GLP-1 RA therapy in the context of individualized, patient-centered care continues to be supported by current literature. GLP-1 RA therapy provides robust glycemic control, blood pressure reduction, and weight loss, but studies are still needed to address concerns about tolerability and safety, including pancreatitis and cancer.
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Affiliation(s)
- Scott R Drab
- University of Pittsburgh School of Pharmacy, 719 Salk Hall, Pittsburgh, PA 15261, USA.
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36
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Abstract
Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are the known incretin hormones in humans, released predominantly from the enteroendocrine K and L cells within the gut. Their secretion is regulated by a complex of integrated mechanisms involving direct contact for the activation of different chemo-sensors on the brush boarder of K and L cells and several indirect neuro-immuno-hormonal loops. The biological actions of GIP and GLP-1 are fundamental determinants of islet function and blood glucose homeostasis in health and type 2 diabetes. Moreover, there is increasing recognition that GIP and GLP-1 also exert pleiotropic extra-glycaemic actions, which may represent therapeutic targets for human diseases. In this review, we summarise current knowledge of the biology of incretin hormones in health and metabolic disorders and highlight the therapeutic potential of incretin hormones in metabolic regulation.
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Affiliation(s)
- Tongzhi Wu
- Discipline of Medicine, The University of Adelaide, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia, 5000, Australia
| | - Christopher K Rayner
- Discipline of Medicine, The University of Adelaide, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia, 5000, Australia.
- Centre of Research Excellence in Translating Nutritional Science into Good Health, The University of Adelaide, Adelaide, Australia.
| | - Michael Horowitz
- Discipline of Medicine, The University of Adelaide, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia, 5000, Australia
- Centre of Research Excellence in Translating Nutritional Science into Good Health, The University of Adelaide, Adelaide, Australia
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37
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Jaiswal M, Martin CL, Brown MB, Callaghan B, Albers JW, Feldman EL, Pop-Busui R. Effects of exenatide on measures of diabetic neuropathy in subjects with type 2 diabetes: results from an 18-month proof-of-concept open-label randomized study. J Diabetes Complications 2015; 29:1287-94. [PMID: 26264399 PMCID: PMC4656068 DOI: 10.1016/j.jdiacomp.2015.07.013] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2015] [Revised: 07/10/2015] [Accepted: 07/11/2015] [Indexed: 02/06/2023]
Abstract
OBJECTIVE Experimental studies have reported potential benefit of glucagon-like peptide-1(GLP-1) receptor agonists in preventing diabetic peripheral neuropathy (DPN). We therefore performed a proof-of-concept pilot study to evaluate the effect of exenatide, a GLP-1 agonist, on measures of DPN and cardiovascular autonomic neuropathy (CAN) in patients with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS Forty-six T2D subjects (age 54±10years, diabetes duration 8±5years, HbA1c 8.2±1.3%) with mild to moderate DPN at baseline were randomized to receive either twice daily exenatide (n=22) or daily insulin glargine (n=24). The subjects, with similar HbA1c levels, were followed for 18months. The primary end point was the prevalence of confirmed clinical neuropathy (CCN). Changes in measures of CAN, other measures of small fiber neuropathy such as intra-epidermal nerve fiber density (IENFD), and quality of life were also analyzed. RESULTS Glucose control was similar in both groups during the study. There were no statistically significant treatment group differences in the prevalence of CCN, IENFD, measures of CAN, nerve conductions studies, or quality of life indices. CONCLUSIONS In this pilot study of patients with T2D and mild to moderate DPN, 18months of exenatide treatment had no significant effect on measures of neuropathy compared with glargine treatment.
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Affiliation(s)
- Mamta Jaiswal
- Department of Neurology, University of Michigan, Ann Arbor, MI
| | - Catherine L Martin
- Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, MI
| | - Morton B Brown
- Department of Biostatistics, University of Michigan, Ann Arbor, MI
| | - Brian Callaghan
- Department of Neurology, University of Michigan, Ann Arbor, MI
| | - James W Albers
- Department of Neurology, University of Michigan, Ann Arbor, MI
| | - Eva L Feldman
- Department of Neurology, University of Michigan, Ann Arbor, MI
| | - Rodica Pop-Busui
- Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, MI.
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38
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Haluzík M, Mráz M, Svačina Š. Balancing benefits and risks in patients receiving incretin-based therapies: focus on cardiovascular and pancreatic side effects. Drug Saf 2015; 37:1003-10. [PMID: 25391858 DOI: 10.1007/s40264-014-0238-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Incretin-based therapies either increase endogenous levels of glucagon-like peptide-1 by prolonging its half-life (DPP-4 inhibitors) or directly stimulate its receptor (glucagon-like peptide-1 analogues; GLP-1 RA). They are currently widely used for the treatment of patients with type 2 diabetes mellitus owing to good antidiabetic efficacy, low risk of hypoglycemia, and relatively few other side effects. They also offer potential additional benefits such as weight neutrality or weight loss, positive effects on blood pressure and lipid levels, and potential cardio- and neuroprotectivity. Some experimental and clinical studies have raised concerns with respect to potential cardiovascular and pancreatic side effects of these therapies such as increased risk of heart failure with DPP-4 inhibitors as well as acute pancreatitis and pancreatic cancer with both classes. The available data are at present not robust enough to enable firm conclusions regarding these potential associations. Nevertheless, some recent data suggest a possibility of slightly increased risk of acute pancreatitis with GLP-1 RAs while they do not indicate increased risk of pancreatic cancer. Ongoing cardiovascular outcome trials will shed more light on the possible cardioprotective effects of incretin-based therapies as well as on the possible interconnection of DPP-4 inhibitors and heart failure.
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Affiliation(s)
- Martin Haluzík
- 3rd Dept. of Medicine, 1st Faculty of Medicine and General University Hospital, Charles University, U Nemocnice 1, 128 08, Prague 2, Czech Republic,
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39
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Guastamacchia E, Triggiani V, Aglialoro A, Aiello A, Ianni L, Maccario M, Zini M, Giorda C, Guglielmi R, Betterle C, Attanasio R, Borretta G, Garofalo P, Papini E, Castello R, Ceriello A. Italian Association of Clinical Endocrinologists (AME) & Italian Association of Clinical Diabetologists (AMD) Position Statement : Diabetes mellitus and thyroid disorders: recommendations for clinical practice. Endocrine 2015; 49:339-52. [PMID: 25403287 DOI: 10.1007/s12020-014-0474-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2014] [Accepted: 11/01/2014] [Indexed: 02/07/2023]
Abstract
Thyroid disease and diabetes mellitus, the most common disorders in endocrine practice, are not infrequently associated in the same subject. An altered thyroid function may affect glucose tolerance and worsen metabolic control in patients with diabetes. Thyrotoxicosis increases the risk of hyperglycemic emergencies, while a clinically relevant hypothyroidism may have a detrimental effect on glycemic control in diabetic patients. The association of alterations in thyroid function with diabetes mellitus may adversely affect the risk of cardiovascular and microvascular complications resulting from diabetes. Moreover, the treatments used for both diabetes and thyroid disease, respectively, can impact one other. Finally, multinodular goiter, but not thyroid carcinoma, was shown to be more prevalent in type 2 diabetes mellitus. Aim of the present Position Statement is to focus on the evidence concerning the association of thyroid disease and diabetes mellitus and to provide some practical suggestions for an updated clinical management.
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Affiliation(s)
- Edoardo Guastamacchia
- Endocrinology and Metabolic Diseases, Interdisciplinary Department of Internal Medicine, University of Bari "Aldo Moro", Bari, Italy
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40
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Thomsen RW, Pedersen L, Møller N, Kahlert J, Beck-Nielsen H, Sørensen HT. Incretin-based therapy and risk of acute pancreatitis: a nationwide population-based case-control study. Diabetes Care 2015; 38:1089-98. [PMID: 25633664 DOI: 10.2337/dc13-2983] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2013] [Accepted: 12/22/2014] [Indexed: 02/03/2023]
Abstract
OBJECTIVE To investigate whether the use of incretin-based drugs (GLP-1 receptor agonists and dipeptidyl peptidase 4 [DPP4] inhibitors) is associated with acute pancreatitis. RESEARCH DESIGN AND METHODS The study was a nationwide population-based case-control study using medical databases in Denmark. Participants were 12,868 patients with a first-time hospitalization for acute pancreatitis between 2005 and 2012 and a population of 128,680 matched control subjects. The main outcome measure was the odds ratio (OR) for acute pancreatitis associated with different antihyperglycemic drugs. We adjusted for history of gallstones, alcoholism, obesity, and other pancreatitis-associated comorbidities and medications. RESULTS A total of 89 pancreatitis patients (0.69%) and 684 control subjects (0.53%) were ever users of incretins. The crude OR for acute pancreatitis among incretin users was 1.36 (95% CI 1.08-1.69), while it was 1.44 (95% CI 1.34-1.54) among users of other antihyperglycemic drugs. After confounder adjustment, the risk of acute pancreatitis was not increased among incretin users (OR 0.95 [95% CI 0.75-1.21]), including DPP4 inhibitor users (OR 1.04 [95% CI 0.80-1.37]) or GLP-1 receptor agonist users (OR 0.82 [95% CI 0.54-1.23]), or among nonincretin antihyperglycemic drug users (OR 1.05 [95% CI 0.98-1.13]), compared with nonusers of any antihyperglycemic drugs. Findings were similar in current versus ever drug users and in patients with pancreatitis risk factors. The adjusted OR comparing incretin-based therapy with other antihyperglycemic therapy internally while also adjusting for diabetes duration and complications was 0.97 (95% CI 0.76-1.23). CONCLUSIONS Our findings suggest that the use of incretin-based drugs appears not to be associated with an increased risk of acute pancreatitis.
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Affiliation(s)
- Reimar Wernich Thomsen
- Department of Clinical Epidemiology, Institute of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Lars Pedersen
- Department of Clinical Epidemiology, Institute of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Niels Møller
- Medical Department M (Endocrinology and Diabetes) and Institute of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Johnny Kahlert
- Department of Clinical Epidemiology, Institute of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Henning Beck-Nielsen
- The Danish Centre for Strategic Research in Type 2 Diabetes, Diabetes Research Centre, Department of Endocrinology, Odense University Hospital, Odense, Denmark
| | - Henrik Toft Sørensen
- Department of Clinical Epidemiology, Institute of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark
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41
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Bailey CJ. Safety of antidiabetes medications: An update. Clin Pharmacol Ther 2015; 98:185-95. [DOI: 10.1002/cpt.125] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2014] [Accepted: 03/13/2015] [Indexed: 12/27/2022]
Affiliation(s)
- CJ Bailey
- Diabetes Research, Life and Health Sciences, Aston University; Birmingham UK
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ALVIM RAFAELO, CHEUHEN MARCELR, MACHADO SILMARAR, SOUSA ANDRÉGUSTAVOP, SANTOS PAULOC. General aspects of muscle glucose uptake. ACTA ACUST UNITED AC 2015; 87:351-68. [PMID: 25761221 DOI: 10.1590/0001-3765201520140225] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2014] [Accepted: 09/06/2014] [Indexed: 12/25/2022]
Abstract
Glucose uptake in peripheral tissues is dependent on the translocation of GLUT4 glucose transporters to the plasma membrane. Studies have shown the existence of two major signaling pathways that lead to the translocation of GLUT4. The first, and widely investigated, is the insulin activated signaling pathway through insulin receptor substrate-1 and phosphatidylinositol 3-kinase. The second is the insulin-independent signaling pathway, which is activated by contractions. Individuals with type 2 diabetes mellitus have reduced insulin-stimulated glucose uptake in skeletal muscle due to the phenomenon of insulin resistance. However, those individuals have normal glucose uptake during exercise. In this context, physical exercise is one of the most important interventions that stimulates glucose uptake by insulin-independent pathways, and the main molecules involved are adenosine monophosphate-activated protein kinase, nitric oxide, bradykinin, AKT, reactive oxygen species and calcium. In this review, our main aims were to highlight the different glucose uptake pathways and to report the effects of physical exercise, diet and drugs on their functioning. Lastly, with the better understanding of these pathways, it would be possible to assess, exactly and molecularly, the importance of physical exercise and diet on glucose homeostasis. Furthermore, it would be possible to assess the action of drugs that might optimize glucose uptake and consequently be an important step in controlling the blood glucose levels in diabetic patients, in addition to being important to clarify some pathways that justify the development of drugs capable of mimicking the contraction pathway.
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Bethel MA, Xu W, Theodorakis MJ. Pharmacological interventions for preventing or delaying onset of type 2 diabetes mellitus. Diabetes Obes Metab 2015; 17:231-44. [PMID: 25312701 DOI: 10.1111/dom.12401] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2013] [Revised: 10/07/2014] [Accepted: 10/09/2014] [Indexed: 01/11/2023]
Abstract
Prevention or delay of onset of type 2 diabetes in individuals at varying risk across the dysglycaemia continuum before overt diabetes becomes clinically manifest constitutes a leading objective of global disease prevention schemes. Pharmacological intervention has been suggested as a means to help prevent diabetes and reduce the global burden of this chronic condition. However, there is no credible evidence that early pharmacological intervention leads to long-term benefit in reducing diabetes-related complications or preventing early mortality, compared to treating people with diagnosed diabetes who have crossed the glycaemic threshold. In this review, we examine published evidence from trials using pharmacological agents to delay or prevent progression to diabetes. We also explore the benefit/risk impact of such therapies, safety issues and relevant off-target effects. Current evidence suggests none of the drugs currently available sustainably lower cumulative diabetes incidence, none provides a durable delay in diabetes diagnosis and none provides a convincing concomitant excess benefit for microvascular or macrovascular risk.
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Affiliation(s)
- M A Bethel
- Diabetes Trials Unit, University of Oxford, Churchill Hospital, Oxford, UK; Division of Endocrinology, Department of Medicine, Duke University Medical Center, Durham, NC, USA
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Li X, Zhang Z, Duke J. Glucagon-like peptide 1-based therapies and risk of pancreatitis: a self-controlled case series analysis. Pharmacoepidemiol Drug Saf 2015; 23:234-9. [PMID: 24741695 DOI: 10.1002/pds.3542] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
PURPOSE Previous studies have suggested a link between glucagon-like peptide 1 (GLP-1)-based therapies and acute pancreatitis, while other studies have found no association. Because differences in diabetes severity may confound this relationship, a self-controlled case series (SCCS) analysis has been suggested as a means to control for individual-level confounding. METHODS We evaluated the relationship between GLP-1-based therapies and pancreatitis by SCCS method using a large observational database. We calculated the incidence density ratio of pancreatitis for exposure versus non-exposure to each drug. To examine the robustness of our findings, we performed sensitivity analyses by varying risk windows, using two pancreatitis definitions and including incident pancreatitis or all occurrences. RESULTS From dispensing data on 1.2 million patients, we found 7992 sitagliptin-exposed patients and 3552 exenatide-exposed patients between 2004 and 2009. Using an ICD9/CPT-based case definition of pancreatitis, we identified 207 sitagliptin and 82 exenatide cases. Augmenting this definition with laboratory criteria increased our cohort to 245 sitagliptin and 96 exenatide cases. For sitagliptin and exenatide cases, respectively, the mean duration of observation was 5.2 and 5.5 years, and the mean duration of drug exposure was 0.7 and 0.5 years. For all analyses (including different pancreatitis definitions, risk periods, and incident or recurrent events), the incidence density ratios for development of pancreatitis during exposure versus non-exposure ranged from 0.68 to 1.46, with all having 95% confidence intervals containing 1. CONCLUSIONS We found no association between the use of GLP-1-based therapies and pancreatitis using SCCS analysis in a large observational database.
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Tseng CH, Lee KY, Tseng FH. An updated review on cancer risk associated with incretin mimetics and enhancers. JOURNAL OF ENVIRONMENTAL SCIENCE AND HEALTH. PART C, ENVIRONMENTAL CARCINOGENESIS & ECOTOXICOLOGY REVIEWS 2015; 33:67-124. [PMID: 25803196 DOI: 10.1080/10590501.2015.1003496] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
Incretin-based therapies, including the use of incretin mimetics of glucagon-like peptide-1 receptor (GLP-1R) agonists and incretin enhancers of dipeptidyl-peptidase 4 (DPP-4) inhibitors, are widely used by clinicians for glucose lowering in patients with type 2 diabetes mellitus. These agents have benefits of a lower risk of hypoglycemia, being neutral for body weight for DPP-4 inhibitors and having a potential for weight reduction with GLP-1R agonists. They may also have a neutral or beneficial cardiovascular effect. Despite these benefits, an increased risk of cancer (especially pancreatic cancer and thyroid cancer) associated with incretin-based therapies has been reported. In this article, we reviewed related literature of experimental animal and observational human studies, clinical trials, and meta-analyses published until December 15, 2014. Current studies suggested a probable role of GLP-1R activation on the development of pancreatic cancer and thyroid cancer in rodents, but such an effect in humans is not remarkable due to the lower or lack of expression of GLP-1R on human pancreatic ductal cells and thyroid tissues. Findings in human studies are controversial and inconclusive. In the analyses of the US Food and Drug Administration adverse events reporting system, a significantly higher risk of pancreatic cancer was observed for GLP-1R agonists and DPP-4 inhibitors, but a significantly higher risk of thyroid cancer was only observed for GLP-1R agonists. Such a higher risk of pancreatic cancer or thyroid cancer could not be similarly demonstrated in other human observational studies or analyses of data from clinical trials. With regards to cancers other than pancreatic cancer and thyroid cancer, available studies supported a neutral association in humans. Some preliminary studies even suggested a potentially beneficial effect on the development of other cancers with the use of incretins. Based on current evidence, continuous monitoring of the cancer issues related to incretin-based therapies is required, even though the benefits may outweigh the potential cancer risk in the general patients with type 2 diabetes mellitus.
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Affiliation(s)
- Chin-Hsiao Tseng
- a Department of Internal Medicine , National Taiwan University Hospital , Taipei , Taiwan
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Vasoactive Intestinal Peptide (VIP) Nanoparticles for Diagnostics and for Controlled and Targeted Drug Delivery. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2015; 98:145-68. [DOI: 10.1016/bs.apcsb.2014.11.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Fiorentino TV, Owston M, Abrahamian G, La Rosa S, Marando A, Perego C, Di Cairano ES, Finzi G, Capella C, Sessa F, Casiraghi F, Paez A, Adivi A, Davalli A, Fiorina P, Guardado Mendoza R, Comuzzie AG, Sharp M, DeFronzo RA, Halff G, Dick EJ, Folli F. Chronic continuous exenatide infusion does not cause pancreatic inflammation and ductal hyperplasia in non-human primates. THE AMERICAN JOURNAL OF PATHOLOGY 2015; 185:139-50. [PMID: 25447052 PMCID: PMC4278248 DOI: 10.1016/j.ajpath.2014.09.009] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/20/2014] [Revised: 08/26/2014] [Accepted: 09/09/2014] [Indexed: 12/16/2022]
Abstract
In this study, we aimed to evaluate the effects of exenatide (EXE) treatment on exocrine pancreas of nonhuman primates. To this end, 52 baboons (Papio hamadryas) underwent partial pancreatectomy, followed by continuous infusion of EXE or saline (SAL) for 14 weeks. Histological analysis, immunohistochemistry, Computer Assisted Stereology Toolbox morphometry, and immunofluorescence staining were performed at baseline and after treatment. The EXE treatment did not induce pancreatitis, parenchymal or periductal inflammatory cell accumulation, ductal hyperplasia, or dysplastic lesions/pancreatic intraepithelial neoplasia. At study end, Ki-67-positive (proliferating) acinar cell number did not change, compared with baseline, in either group. Ki-67-positive ductal cells increased after EXE treatment (P = 0.04). However, the change in Ki-67-positive ductal cell number did not differ significantly between the EXE and SAL groups (P = 0.13). M-30-positive (apoptotic) acinar and ductal cell number did not change after SAL or EXE treatment. No changes in ductal density and volume were observed after EXE or SAL. Interestingly, by triple-immunofluorescence staining, we detected c-kit (a marker of cell transdifferentiation) positive ductal cells co-expressing insulin in ducts only in the EXE group at study end, suggesting that EXE may promote the differentiation of ductal cells toward a β-cell phenotype. In conclusion, 14 weeks of EXE treatment did not exert any negative effect on exocrine pancreas, by inducing either pancreatic inflammation or hyperplasia/dysplasia in nonhuman primates.
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Affiliation(s)
- Teresa Vanessa Fiorentino
- Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas; Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Michael Owston
- Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, Texas
| | - Gregory Abrahamian
- Department of Surgery, Transplant Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas
| | - Stefano La Rosa
- Department of Pathology, Ospedale di Circolo and Department of Surgical and Morphological Sciences, University of Insubria, Varese, Italy
| | - Alessandro Marando
- Department of Pathology, Ospedale di Circolo and Department of Surgical and Morphological Sciences, University of Insubria, Varese, Italy
| | - Carla Perego
- Department of Pharmacology and Biomolecular Science, Universitádegli Studi di Milano, Milan, Italy
| | - Eliana S Di Cairano
- Department of Pharmacology and Biomolecular Science, Universitádegli Studi di Milano, Milan, Italy
| | - Giovanna Finzi
- Department of Pathology, Ospedale di Circolo and Department of Surgical and Morphological Sciences, University of Insubria, Varese, Italy
| | - Carlo Capella
- Department of Pathology, Ospedale di Circolo and Department of Surgical and Morphological Sciences, University of Insubria, Varese, Italy
| | - Fausto Sessa
- Department of Pathology, Ospedale di Circolo and Department of Surgical and Morphological Sciences, University of Insubria, Varese, Italy
| | - Francesca Casiraghi
- Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas; Department of Biomedical Sciences for Health, Universitádegli Studi di Milano, Milan, Italy
| | - Ana Paez
- Department of Pediatrics, University of Texas Health Science Center at San Antonio, San Antonio, Texas
| | - Ashwin Adivi
- Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas
| | - Alberto Davalli
- Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas; Department of Internal and Specialized Medicine, Ospedale San Raffaele, Milan, Italy
| | - Paolo Fiorina
- Department of Pediatrics, Children's Hospital Harvard Medical School, Boston, Massachusetts
| | - Rodolfo Guardado Mendoza
- Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas; Division of Health Sciences, Department of Medicine and Nutrition, University of Guanajuato, Campus León, México, and the Research Department, Hospital Regional de Alta Especialidad del Bajío, León, Mexico
| | - Anthony G Comuzzie
- Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas
| | - Mark Sharp
- Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, Texas
| | - Ralph A DeFronzo
- Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas
| | - Glenn Halff
- Department of Surgery, Transplant Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas
| | - Edward J Dick
- Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, Texas
| | - Franco Folli
- Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas; Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas; Faculdade de Ciencias Medicas (FCM), Departamento de Clinica Medica, Obesity and Comorbidities Research Center (O.C.R.C.), Universidade Estadual de Campinas (UNICAMP), Campinas, Brazil.
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Consoli A, Formoso G. Potential side effects to GLP-1 agonists: understanding their safety and tolerability. Expert Opin Drug Saf 2014; 14:207-18. [PMID: 25496749 DOI: 10.1517/14740338.2015.987122] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
INTRODUCTION Glucagon-like peptide 1 receptor (GLP-1Rx) agonists might elicit unwelcome side effects and concerns have recently been raised about their safety. AREAS COVERED Available evidence about safety, tolerability and potential adverse events relative to GLP-1Rx agonists presently used. We searched the MEDLINE database using the terms: 'GLP-1 receptor agonists', 'Incretin therapy side effects', 'exenatide', ' liraglutide', 'exenatide long-acting release', 'lixisenatide'. Articles were selected on the basis of the study design and importance, in the light of authors' clinical experience and personal judgment. The main safety concern about GLP-1Rx agonists use is the possible association with increased risk of pancreatitis and/or tumors. This concern stems mainly from limited observations in animal models not confirmed in similar studies. Furthermore, clinical studies reporting association between GLP-1Rx agonist use and pancreatitis/cancer are marred by several biases and both clinical trials and post-marketing analyses failed to demonstrate a significant association. EXPERT OPINION As stated by both FDA and EMA, the safety concerns emerged so far about GLP-1RX agonists should not affect present prescribing habits. Thus, although a strict data monitoring must be encouraged, they should not prevent access to the benefits of an innovative treatment, such as GLP-1Rx agonists use, to a large diabetic population still confronted with unmet needs.
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Affiliation(s)
- Agostino Consoli
- G. d'Annunzio University, Department of Medicine and Aging Sciences , Edificio CeSi, Room 271, Via Colle dell'Ara 1, 66100 Chieti , Italy +39 0871 541339 ; +39 0871 541307 ;
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Montilla S, Marchesini G, Sammarco A, Trotta MP, Siviero PD, Tomino C, Melchiorri D, Pani L. Drug utilization, safety, and effectiveness of exenatide, sitagliptin, and vildagliptin for type 2 diabetes in the real world: data from the Italian AIFA Anti-diabetics Monitoring Registry. Nutr Metab Cardiovasc Dis 2014; 24:1346-1353. [PMID: 25300980 DOI: 10.1016/j.numecd.2014.07.014] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2013] [Revised: 07/14/2014] [Accepted: 07/16/2014] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS In Italy, the reimbursed use of incretin mimetics and incretin enhancers was subject to enrollment of patients into a web-based system recording the general demographic and clinical data of patients. We report the utilization data of glucagon-like peptide 1 (GLP1) receptor agonists and dipeptidylpeptidase-4 (DPP4) inhibitors in clinical practice as recorded by the Italian Medicines Agency (AIFA) Monitoring Registry. METHODS AND RESULTS From February 2008 to August 2010, 75,283 patients with type 2 diabetes were entered into the registry and treated with exenatide, sitagliptin, or vildagliptin. The treatment was administered to patients in a wide range of ages (≥75 years, n = 6125 cases), body mass index (BMI) (≥35 kg/m(2), n = 22,015), and metabolic control (HbA(1c) ≥ 11% ((96 mmol/mol), n = 3151). Overall, 1116 suspected adverse drug reactions were registered, including 12 cases of acute pancreatitis (six on exenatide). Hypoglycemic episodes mainly occurred in combination with sulfonylureas. Treatment discontinuation for the three drugs (logistic regression analysis) was negatively associated with the male gender and positively with baseline HbA1c, diabetes duration, and, limitedly to DPP-4 inhibitors, with BMI. Treatment discontinuation (including loss to follow-up, accounting for 21-26%) was frequent. Discontinuation for treatment failure occurred in 7.7% of cases (exenatide), 3.8% (sitagliptin), and 4.1% (vildagliptin), respectively, corresponding to 27-40% of all discontinuations, after excluding lost to follow-up. HbA1c decreased on average by 0.9-1.0% (9 mmol/mol). Body weight decreased by 3.5% with exenatide and by 1.0-1.5% with DPP-4 inhibitors. CONCLUSIONS In the real world of Italian diabetes centers, prescriptions of incretins have been made in many cases outside the regulatory limits. Nevertheless, when appropriately utilized, incretins may grant results at least in line with pivotal trials.
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Affiliation(s)
- S Montilla
- Italian Medicines Agency (AIFA), Rome, Italy.
| | - G Marchesini
- Unit of Metabolic Diseases, S. Orsola-Malpighi University Hospital, Bologna, Italy
| | - A Sammarco
- Italian Medicines Agency (AIFA), Rome, Italy
| | - M P Trotta
- Italian Medicines Agency (AIFA), Rome, Italy
| | - P D Siviero
- Italian Medicines Agency (AIFA), Rome, Italy
| | - C Tomino
- Italian Medicines Agency (AIFA), Rome, Italy
| | - D Melchiorri
- Dept. Physiology and Pharmacology, University of Rome "La Sapienza", Rome, Italy
| | - L Pani
- Italian Medicines Agency (AIFA), Rome, Italy
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Gokhale M, Buse JB, Gray CL, Pate V, Marquis MA, Stürmer T. Dipeptidyl-peptidase-4 inhibitors and pancreatic cancer: a cohort study. Diabetes Obes Metab 2014; 16:1247-56. [PMID: 25109825 PMCID: PMC4227935 DOI: 10.1111/dom.12379] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2014] [Revised: 07/29/2014] [Accepted: 08/04/2014] [Indexed: 01/21/2023]
Abstract
AIM To compare pancreatic cancer incidence and diagnostic evaluation among patients initiating dipeptidyl-peptidase-4 (DPP-4) inhibitor treatment with those initiating sulfonylureas (SU) and thiazolidinediones (TZD). METHODS Medicare claims data were examined in a new-user active-comparator cohort study. Patients >65 years with no prescriptions for DPP-4 inhibitors, SU or TZD at baseline were included if they had at least two claims for the same drug within 180 days. Using an as-treated approach and propensity score-adjusted Cox models, we estimated the hazard ratios (HRs) and 95% confidence intervals (CIs) for pancreatic cancer. Diagnostic evaluations were compared using risk ratios. RESULTS In the DPP-4 inhibitor versus SU comparison, there were 18 179 patients who initiated treatment with DPP-4 inhibitors, of whom 26 developed pancreatic cancer (interquartile range follow-up 5-18 months). In the DPP-4 inhibitor versus TZD comparison there were 29 366 people initiating DPP-4 inhibitor treatment and 52 of these developed pancreatic cancer. The risk of pancreatic cancer with DPP-4 inhibitor treatment was lower relative to SU treatment (HR: 0.6, CI: 0.4-0.9) and similar to TZD treatment (HR: 1.0, 95% CI: 0.7-1.4). After the first 6 months of follow-up were excluded to reduce the potential for reverse causality, the results were not altered. The probability of diagnostic evaluation after commencing DPP-4 inhibitor treatment (79.3%) was similar to that for TZD (74.1%, risk ratio 1.06, 95% CI: 1.05-1.07) and SU (74.6%) (risk ratio 1.06, 95% CI: 1.05-1.07). The probability of diagnostic evaluation before the index date (date of initiating treatment) was ∼80% for all cohorts. CONCLUSION Although the present study was limited by sample size and the observed duration of treatment in the USA, our well-controlled population-based study suggests there is no higher short-term pancreatic cancer risk with DPP-4 inhibitor treatment relative to SU or TZD treatment.
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Affiliation(s)
- Mugdha Gokhale
- Department of Epidemiology, University of North Carolina at Chapel Hill
| | - John B. Buse
- Department of Medicine, University of North Carolina School of Medicine at Chapel Hill
| | - Christine L Gray
- Department of Epidemiology, University of North Carolina at Chapel Hill
| | - Virginia Pate
- Department of Epidemiology, University of North Carolina at Chapel Hill
| | - M. Alison Marquis
- Collaborative Studies Coordinating Center, Department of Biostatistics, University of North Carolina at Chapel Hill
| | - Til Stürmer
- Department of Epidemiology, University of North Carolina at Chapel Hill
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