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Bermudes-Contreras JD, Gutiérrez-Velázquez MV, Delgado-Alvarado EA, Torres-Ricario R, Cornejo-Garrido J. Hypoglycemic and Hypolipidemic Effects of Triterpenoid Standardized Extract of Agave durangensis Gentry. PLANTS (BASEL, SWITZERLAND) 2025; 14:894. [PMID: 40265815 DOI: 10.3390/plants14060894] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Revised: 02/27/2025] [Accepted: 03/03/2025] [Indexed: 04/24/2025]
Abstract
Diabetes mellitus is a chronic, degenerative, and multifactorial disease characterized by hyperglycemia, and at least 537 million people suffered from diabetes in 2021. Agave durangensis Gentry, a species of agave native to the state of Durango, reports phenolic compounds, flavonols, flavonoids, and saponins and could be an alternative for the treatment of diabetes. The aim of this work was to identify the compounds in the leaves of Agave durangensis Gentry and their potential activity in diabetes. The leaf extract of Agave durangensis Gentry (EAD) was characterized by ultra-performance liquid chromatography-mass spectrometry (UPLC-MS), and different families of bioactive compounds were quantified by analytical methods. Probable pharmacological targets were identified in silico, and the inhibition of dipeptidyl peptidase-4 (DPP4) was validated in vitro. A model of hyperglycemia was established with streptozotocin in male Wistar rats, and we administered EAD intragastrically at a dose of 300 mg/kg, as well as combinations of the extract with metformin and sitagliptin over 30 days. Biochemical and histological parameters were analyzed. We identified thirty-six major compounds, where triterpenes represented 30% of the extract. Molecular docking showed that the extract could interact with α-glucosidases and DPP4 since a large number of compounds in the extract have a Δ G lower than that reported for the controls, and DPP4 inhibition was confirmed by in vitro assays. In vivo assays demonstrated that the administration of the extract was able to significantly decrease glucose levels by 56.75% and glycosylated hemoglobin by 52.28%, which is higher than that reported for sitagliptin with a decrease of 35.22%. In addition, the extract decreased triglycerides by 59.28% and very-low-density lipoprotein (VLDL) cholesterol by 60.27%, and when administered in combination with metformin, it decreased them more than when metformin was administered alone. For all the above reasons, Agave durangensis Gentry extract could be used for the development of phytomedicine for the treatment of diabetes.
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Affiliation(s)
- Juan David Bermudes-Contreras
- Laboratorio de Biología Celular y Productos Naturales, Escuela Nacional de Medicina y Homeopatía, Instituto Politécnico Nacional (IPN), Gustavo A. Madero 07320, Ciudad de Mexico, Mexico
| | - Marcela Verónica Gutiérrez-Velázquez
- Laboratorio de Biotecnología, Centro Interdisciplinario de Investigación para el Desarrollo Integral Regional (CIIDIR) Unidad Durango-IPN, Durango 34220, Durango, Mexico
| | - Eli Amanda Delgado-Alvarado
- Laboratorio de Biotecnología, Centro Interdisciplinario de Investigación para el Desarrollo Integral Regional (CIIDIR) Unidad Durango-IPN, Durango 34220, Durango, Mexico
| | - René Torres-Ricario
- Laboratorio de Biotecnología, Centro Interdisciplinario de Investigación para el Desarrollo Integral Regional (CIIDIR) Unidad Durango-IPN, Durango 34220, Durango, Mexico
| | - Jorge Cornejo-Garrido
- Laboratorio de Biología Celular y Productos Naturales, Escuela Nacional de Medicina y Homeopatía, Instituto Politécnico Nacional (IPN), Gustavo A. Madero 07320, Ciudad de Mexico, Mexico
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Harris DD, Stone C, Broadwin M, Kanuparthy M, Sabe SA, Nho JW, Hamze J, Abid MR, Sellke FW. Dipeptidyl peptidase-4 inhibitor linagliptin improves fibrosis, apoptosis, and cardiac function in a large animal model of chronic myocardial ischemia. J Pharmacol Exp Ther 2025; 392:100532. [PMID: 40023609 DOI: 10.1016/j.jpet.2024.100532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Accepted: 12/16/2024] [Indexed: 03/04/2025] Open
Abstract
Interest is increasing in using novel diabetic medications, such as glucagon-like peptide 1 (GLP-1) receptor agonists, to manage coronary artery disease. Dipeptidyl peptidase-4 (DPP-4) inhibitors enhance GLP-1 activity through the same pathway as GLP-1 agonists; however, DPP-4 inhibitors have not been fully evaluated in the setting of ischemic heart disease. We chose to study the DPP-4 inhibitor linagliptin (LIN) in a porcine model of chronic coronary ischemia. Seventeen Yorkshire swine underwent left thoracotomy and ameroid constrictor placement over the left circumflex coronary artery at age 11 weeks. Two weeks thereafter, swine received either vehicle without drug (n = 9) or LIN 2.5 mg (n = 8). Following the elapse of 5 weeks of treatment, swine underwent terminal harvest. LIN significantly increased stroke volume, ejection fraction, cardiac output, and ischemic myocardial perfusion, while decreasing Tau (all P < .05). Trichrome staining showed a marked reduction in ischemic myocardial interstitial and perivascular fibrosis, accompanied by decreased levels of transforming growth factor-β (all P < .05). Apoptosis, measured by terminal deoxynucleotidyl transferase-mediated digoxigenin-deoxyuridine nick-end labeling staining, was significantly reduced, and accompanied by decreases in apoptosis-inducing factor, BCL2-associated agonist of cell death, caspase-9, and cleaved caspase-9 (all P < .05). Additionally, there were significant increases in phosphoinositide 3-kinase, phospho-protein kinase B, 5' adenosine monophosphate-activated protein kinase, phospho-5' adenosine monophosphate-activated protein kinase, and endothelial nitric oxide synthase, and significant reductions in collagen 18 and angiostatin (all P < .05). LIN significantly improved left ventricular function, cellular survival, and attenuated adverse remodeling, all likely secondary to augmented perfusion ischemic myocardial perfusion. Given that this increased perfusion occurred independently of changes in vascular density, treatment likely resulted in enhanced microvascular reactivity. These benefits warrant further investigation of LIN to fully understand its potential as a therapy for ischemic heart disease. SIGNIFICANCE STATEMENT: Linagliptin significantly improved cardiac cellular survival, left ventricular function, and attenuated adverse myocardial remodeling in a clinically relevant, large animal model of chronic ischemic cardiomyopathy. This warrants further investigation of linagliptin to fully understand its therapeutic potential.
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Affiliation(s)
- Dwight Douglas Harris
- Division of Cardiothoracic Surgery, Cardiovascular Research Center, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island
| | - Christopher Stone
- Division of Cardiothoracic Surgery, Cardiovascular Research Center, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island
| | - Mark Broadwin
- Division of Cardiothoracic Surgery, Cardiovascular Research Center, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island
| | - Meghamsh Kanuparthy
- Division of Cardiothoracic Surgery, Cardiovascular Research Center, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island
| | - Sharif A Sabe
- Division of Cardiothoracic Surgery, Cardiovascular Research Center, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island
| | - Ju-Woo Nho
- Division of Cardiothoracic Surgery, Cardiovascular Research Center, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island
| | - Jad Hamze
- Division of Cardiothoracic Surgery, Cardiovascular Research Center, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island
| | - M Ruhul Abid
- Division of Cardiothoracic Surgery, Cardiovascular Research Center, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island
| | - Frank W Sellke
- Division of Cardiothoracic Surgery, Cardiovascular Research Center, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island.
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Zaki MK, Abed MN, Alassaf FA. Antidiabetic Agents and Bone Quality: A Focus on Glycation End Products and Incretin Pathway Modulations. J Bone Metab 2024; 31:169-181. [PMID: 39307518 PMCID: PMC11416877 DOI: 10.11005/jbm.2024.31.3.169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2024] [Revised: 05/01/2024] [Accepted: 05/18/2024] [Indexed: 09/26/2024] Open
Abstract
Diabetes mellitus is associated with inadequate bone health and quality and heightened susceptibility to fractures, even in patients with normal or elevated bone mineral density. Elevated advanced glycation end-products (AGEs) and a suppressed incretin pathway are among the mechanisms through which diabetes affects the bone. Accordingly, the present review aimed to investigate the effects of antidiabetic medications on bone quality, primarily through AGEs and the incretin pathway. Google Scholar, Cochrane Library, and PubMed were used to examine related studies until February 2024. Antidiabetic medications influence AGEs and the incretin pathway directly or indirectly. Certain antidiabetic drugs including metformin, glucagon-like peptide-1 receptor agonists (GLP-1RA), dipeptidyl-peptidase-4 (DDP-4) inhibitors, α-glucosidase inhibitors (AGIs), sodium-glucose co-transporter-2 inhibitors, and thiazolidinediones (TZDs), directly affect AGEs through multiple mechanisms. These mechanisms include decreasing the formation of AGEs and the expression of AGEs receptor (RAGE) in tissue and increasing serum soluble RAGE levels, resulting in the reduced action of AGEs. Similarly, metformin, GLP-1RA, DDP-4 inhibitors, AGIs, and TZDs may enhance incretin hormones directly by increasing their production or suppressing their metabolism. Additionally, these medications could influence AGEs and the incretin pathway indirectly by enhancing glycemic control. In contrast, sulfonylureas have not demonstrated any obvious effects on AGEs or the incretin pathway. Considering their favorable effects on AGEs and the incretin pathway, a suitable selection of antidiabetic drugs may facilitate more protective effects on the bone in diabetic patients.
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Affiliation(s)
- Muthanna K. Zaki
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Mosul, Mosul,
Iraq
| | - Mohammed N. Abed
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul,
Iraq
| | - Fawaz A. Alassaf
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Mosul, Mosul,
Iraq
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Harris DD, Sabe SA, Broadwin M, Stone C, Bellam K, Malhotra A, Abid MR, Sellke FW. Dipeptidyl peptidase 4 inhibitor sitagliptin decreases myocardial fibrosis and modulates myocardial insulin signaling in a swine model of chronic myocardial ischemia. PLoS One 2024; 19:e0307922. [PMID: 39074126 PMCID: PMC11285952 DOI: 10.1371/journal.pone.0307922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Accepted: 07/09/2024] [Indexed: 07/31/2024] Open
Abstract
Although both clinical data and animal models suggest cardiovascular benefits following administration of Dipeptidyl Peptidase 4 (DPP-4) inhibitors, the underlying mechanisms remain unclear. We therefore sought to evaluate the effect of the DPP-4 inhibitor sitagliptin on myocardial fibrosis, and insulin signaling in chronic myocardial ischemia using a swine model. An ameroid constrictor placement on the left coronary circumflex artery of thirteen Yorkshire swine to model chronic myocardial ischemia. After two weeks of recovery, swine were assigned to one of two groups: control (CON, n = 8), or sitagliptin 100mg daily (SIT, n = 5). After 5 weeks of treatment, the swine underwent terminal harvest with collection of myocardial tissue. Fibrosis was quantified using Masson's trichrome. Protein expression was quantified by Immunoblotting. Trichrome stain demonstrated a significant decrease in perivascular and interstitial fibrosis in the SIT group relative to CON (all p<0.05). Immunoblot showed a reduction in Jak2, the pSTAT3 to STAT 3 Ratio, pSMAD 2/3, and SMAD 2/3, and an increase in STAT 3 in the SIT group relative to CON (all p<0.05). SIT treatment was associated with increased expression of insulin receptor one and decreased expression of makers for insulin resistance, including phospho-PKC- alpha, RBP-4, SIRT1, and PI3K (p<0.05). Sitagliptin results in a reduction in perivascular and interstitial fibrosis and increased insulin sensitivity in chronically ischemic swine myocardium. This likely contributes to the improved cardiovascular outcomes seen with DPP-4 inhibitors.
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Affiliation(s)
- Dwight D. Harris
- Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI, United States of America
| | - Sharif A. Sabe
- Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI, United States of America
| | - Mark Broadwin
- Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI, United States of America
| | - Chris Stone
- Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI, United States of America
| | - Krishna Bellam
- Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI, United States of America
| | - Akshay Malhotra
- Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI, United States of America
| | - M. Ruhul Abid
- Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI, United States of America
| | - Frank W. Sellke
- Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI, United States of America
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Kamrul-Hasan A, Dutta D, Nagendra L, Sharma M, Patra S, Bhattacharya S. Role of anagliptin, a dipeptidyl peptidase-4 inhibitor, in managing type 2 diabetes: A systematic review and meta-analysis. Medicine (Baltimore) 2024; 103:e38870. [PMID: 38996148 PMCID: PMC11245198 DOI: 10.1097/md.0000000000038870] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Accepted: 06/19/2024] [Indexed: 07/14/2024] Open
Abstract
BACKGROUND No comprehensive meta-analysis has examined and consolidated the effectiveness and safety of anagliptin in treating type 2 diabetes mellitus (T2D). To bridge this knowledge gap, we undertook this meta-analysis. METHODS Randomized controlled trials involving patients with T2D receiving anagliptin were sought after through electronic databases. The control arm consisted of either an active comparator (active control group [ACG]) or a placebo (passive control group [PCG]). The primary outcome was glycated hemoglobin (HbA1c), with secondary outcomes including fasting plasma glucose (FPG) and lipid profiles and adverse events. RESULTS From the 226 articles first examined, 10 randomized controlled trials with 970 participants were analyzed. Reductions in HbA1c (mean difference [MD]: -0.03%, 95% confidence interval [CI]: -0.14 to 0.14, P = .51, I2 = 9%) and FPG (MD: 0.03 mmol/L, 95% CI: -0.30 to 0.35, P = .87, I2 = 42%) were similar in the anagliptin group and ACG. Anagliptin reduced FPG better than placebo (MD: -1.25 mmol/L, 95% CI: -1.87 to -0.64, P < .0001, I2 = 0%). Sufficient data were unavailable to analyze the HbA1c lowering with anagliptin versus placebo. Among the lipid parameters, changes in total cholesterol, high-density lipoprotein cholesterol, apolipoprotein B48, and apolipoprotein B100 were identical between the anagliptin and control groups (PCG and ACG). Anagliptin was better than ACG at lowering low-density lipoprotein cholesterol but not as good at lowering triglyceride. Adverse events were infrequent and similar in the anagliptin and control groups (PCG and ACG). CONCLUSION Anagliptin positively affects glucose control and is safe for managing T2D. Its low-density lipoprotein cholesterol-lowering effect warrants further investigation.
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Affiliation(s)
- A.B.M. Kamrul-Hasan
- Department of Endocrinology, Mymensingh Medical College, Mymensingh, Bangladesh
| | - Deep Dutta
- Department of Endocrinology, CEDAR Superspeciality Healthcare, Dwarka, New Delhi, India
| | - Lakshmi Nagendra
- Department of Endocrinology, JSS Medical College, JSS Academy of Higher Education and Research, Mysore, India
| | - Meha Sharma
- Department of Rheumatology, CEDAR Superspeciality Healthcare, Dwarka, New Delhi, India
| | - Shinjan Patra
- Department of Endocrinology and Metabolism, All India Institute of Medical Sciences, Nagpur, India
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Kamonsuwan K, Balmori V, Marnpae M, Chusak C, Thilavech T, Charoensiddhi S, Smid S, Adisakwattana S. Black Goji Berry ( Lycium ruthenicum) Juice Fermented with Lactobacillus rhamnosus GG Enhances Inhibitory Activity against Dipeptidyl Peptidase-IV and Key Steps of Lipid Digestion and Absorption. Antioxidants (Basel) 2024; 13:740. [PMID: 38929180 PMCID: PMC11200685 DOI: 10.3390/antiox13060740] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Revised: 06/14/2024] [Accepted: 06/15/2024] [Indexed: 06/28/2024] Open
Abstract
With the global increase in hyperglycemia and hyperlipidemia, there is an urgent need to explore dietary interventions targeting the inhibition of dipeptidyl peptidase-IV (DPP-IV) and lipid digestion and absorption. This study investigated how Lactobacillus rhamnosus GG (LGG) affects various aspects of black goji berry (BGB) (Lycium ruthenicum Murr.) juice, including changes in physicochemical and functional properties, as well as microbiological and sensory attributes. Throughout the fermentation process with 2.5-10% (w/v) BGB, significantly improved probiotic viability, lactic acid production, and decreased sugar content. While total flavonoids increase, anthocyanins decrease, with no discernible change in antioxidant activities. Metabolite profiling reveals elevated phenolic compounds post-fermentation. Regarding the inhibition of lipid digestion and absorption, fermented BGB exhibits improved bile acid binding, and disrupted cholesterol micellization by approximately threefold compared to non-fermented BGB, while also increasing pancreatic lipase inhibitory activity. Furthermore, a decrease in cholesterol uptake was observed in Caco-2 cells treated with fermented BGB (0.5 mg/mL), with a maximum reduction of 16.94%. Fermented BGB also shows more potent DPP-IV inhibition. Sensory attributes are significantly improved in fermented BGB samples. These findings highlight the potential of BGB as a bioactive resource and a promising non-dairy carrier for LGG, enhancing its anti-hyperglycemic and anti-hyperlipidemic properties.
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Affiliation(s)
- Kritmongkhon Kamonsuwan
- Center of Excellence in Phytochemical and Functional Food for Clinical Nutrition, Department of Nutrition and Dietetics, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok 10330, Thailand; (K.K.); (C.C.)
| | - Vernabelle Balmori
- Department of Food Science and Technology, Southern Leyte State University, Sogod 6606, Philippines;
| | - Marisa Marnpae
- The Halal Science Center, Chulalongkorn University, Bangkok 10330, Thailand;
| | - Charoonsri Chusak
- Center of Excellence in Phytochemical and Functional Food for Clinical Nutrition, Department of Nutrition and Dietetics, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok 10330, Thailand; (K.K.); (C.C.)
| | - Thavaree Thilavech
- Department of Food Chemistry, Faculty of Pharmacy, Mahidol University, Bangkok 10400, Thailand;
| | - Suvimol Charoensiddhi
- Department of Food Science and Technology, Faculty of Agro-Industry, Kasetsart University, Bangkok 10900, Thailand;
| | - Scott Smid
- Discipline of Pharmacology, School of Biomedicine, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide 5000, SA, Australia;
| | - Sirichai Adisakwattana
- Center of Excellence in Phytochemical and Functional Food for Clinical Nutrition, Department of Nutrition and Dietetics, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok 10330, Thailand; (K.K.); (C.C.)
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Pinheiro MM, Pinheiro FMM, Garo ML, Pastore D, Pacifici F, Ricordi C, Della-Morte D, Infante M. Prevention and treatment of type 1 diabetes: in search of the ideal combination therapy targeting multiple immunometabolic pathways. METABOLISM AND TARGET ORGAN DAMAGE 2024; 4. [DOI: 10.20517/mtod.2024.12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/12/2025]
Abstract
Type 1 diabetes (T1D) represents an autoimmune disease caused by the gradual immune-mediated destruction of the insulin-producing beta cells within the pancreatic islets of Langerhans, resulting in the lifelong need for exogenous insulin therapy. According to recent estimates, T1D currently affects about 8.4 million individuals worldwide. Since a definitive biological cure for this disease is not available yet, there is a great need for novel therapeutic strategies aimed at safely and effectively altering the natural history of the disease during its sequential stages. Ideal therapeutic goals in T1D include the prevention of autoimmune beta-cell destruction, the preservation of residual beta-cell mass and endogenous insulin secretion, the replacement and/or regeneration of beta cells, as well as automated insulin delivery through advanced closed-loop artificial pancreas systems. With this regard, an important research area focused on the identification of a definitive biological cure for T1D is represented by the investigation of immunotherapeutic and beta-cell-protective agents used as disease-modifying therapies to forestall or eliminate insulin dependence. In this commentary, we discuss the reasons why the use of combination therapies targeting the multiple immunometabolic dysfunctions associated with T1D (other than beta-cell autoimmunity) is likely to be more effective in preserving beta cell function in individuals at different stages of T1D, as compared to the use of single therapeutic agents.
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Kamrul-Hasan A, Alam MS, Talukder SK, Dutta D, Selim S. Efficacy and Safety of Omarigliptin, a Novel Once-Weekly Dipeptidyl Peptidase-4 Inhibitor, in Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis. Endocrinol Metab (Seoul) 2024; 39:109-126. [PMID: 38417828 PMCID: PMC10901664 DOI: 10.3803/enm.2023.1839] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Revised: 11/13/2023] [Accepted: 11/30/2023] [Indexed: 03/01/2024] Open
Abstract
BACKGRUOUND No recent meta-analysis has holistically analyzed and summarized the efficacy and safety of omarigliptin in type 2 diabetes mellitus (T2DM). We conducted a meta-analysis to address this knowledge gap. METHODS Electronic databases were searched to identify randomized controlled trials (RCTs) that included patients with T2DM who received omarigliptin in the intervention arm. The control arm consisted of either a placebo (passive control group [PCG]) or an active comparator (active control group [ACG]). The primary outcome assessed was changes in hemoglobin A1c (HbA1c), while secondary outcomes included variations in glucose levels, achievement of glycemic targets, adverse events (AEs), and hypoglycemic events. RESULTS From 332 initially screened articles, data from 16 RCTs involving 8,804 subjects were analyzed. Omarigliptin demonstrated superiority over placebo in reducing HbA1c levels (mean difference, -0.58%; 95% confidence interval, -0.75 to -0.40; P<0.00001; I2=91%). Additionally, omarigliptin outperformed placebo in lowering fasting plasma glucose, 2-hour postprandial glucose, and in the percentage of participants achieving HbA1c levels below 7.0% and 6.5%. The glycemic efficacy of omarigliptin was similar to that of the ACG across all measures. Although the omarigliptin group experienced a higher incidence of hypoglycemic events compared to the PCG, the overall AEs, serious AEs, hypoglycemia, and severe hypoglycemia were comparable between the omarigliptin and control groups (PCG and ACG). CONCLUSION Omarigliptin has a favorable glycemic efficacy and safety profile for managing T2DM.
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Affiliation(s)
- A.B.M. Kamrul-Hasan
- Department of Endocrinology, Mymensingh Medical College, Mymensingh, Bangladesh
| | - Muhammad Shah Alam
- Department of Medicine, Army Medical College Cumilla, Cumilla, Bangladesh
| | | | - Deep Dutta
- Department of Endocrinology, Center for Endocrinology, Diabetes, Arthritis and Rheumatism (CEDAR) Superspeciality Healthcare, New Delhi, India
| | - Shahjada Selim
- Department of Endocrinology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
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Wu MZ, Teng THK, Tsang CTW, Chan YH, Lee CH, Ren QW, Huang JY, Cheang IF, Tse YK, Li XL, Xu X, Tse HF, Lam CSP, Yiu KH. Risk of hyperkalaemia in patients with type 2 diabetes mellitus prescribed with SGLT2 versus DPP-4 inhibitors. EUROPEAN HEART JOURNAL. CARDIOVASCULAR PHARMACOTHERAPY 2024; 10:45-52. [PMID: 37942588 DOI: 10.1093/ehjcvp/pvad081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Revised: 10/17/2023] [Accepted: 11/03/2023] [Indexed: 11/10/2023]
Abstract
AIMS To investigate the risk of hyperkalaemia in new users of sodium-glucose cotransporter 2 (SGLT2) inhibitors vs. dipeptidyl peptidase-4 (DPP-4) inhibitors among patients with type 2 diabetes mellitus (T2DM). METHODS AND RESULTS Patients with T2DM who commenced treatment with an SGLT2 or a DPP-4 inhibitor between 2015 and 2019 were collected. A multivariable Cox proportional hazards analysis was applied to compare the risk of central laboratory-determined severe hyperkalaemia, hyperkalaemia, hypokalaemia (serum potassium ≥6.0, ≥5.5, and <3.5 mmol/L, respectively), and initiation of a potassium binder in patients newly prescribed an SGLT2 or a DPP-4 inhibitor. A total of 28 599 patients (mean age 60 ± 11 years, 60.9% male) were included after 1:2 propensity score matching, of whom 10 586 were new users of SGLT2 inhibitors and 18 013 of DPP-4 inhibitors. During a 2-year follow-up, severe hyperkalaemia developed in 122 SGLT2 inhibitor users and 325 DPP-4 inhibitor users. Use of SGLT2 inhibitors was associated with a 29% reduction in incident severe hyperkalaemia [hazard ratio (HR) 0.71, 95% confidence interval (CI) 0.58-0.88] compared with DPP-4 inhibitors. Risk of hyperkalaemia (HR 0.81, 95% CI 0.71-0.92) and prescription of a potassium binder (HR 0.74, 95% CI 0.67-0.82) were likewise decreased with SGLT2 inhibitors compared with DPP-4 inhibitors. Occurrence of incident hypokalaemia was nonetheless similar between those prescribed an SGLT2 inhibitor and those prescribed a DPP-4 inhibitor (HR 0.90, 95% CI 0.81-1.01). CONCLUSION Our study provides real-world evidence that compared with DPP-4 inhibitors, SGLT2 inhibitors were associated with lower risk of hyperkalaemia and did not increase the incidence of hypokalaemia in patients with T2DM.
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Affiliation(s)
- Mei-Zhen Wu
- Division of Cardiology, Department of Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518000, China
- Division of Cardiology, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, 999077, China
| | - Tiew-Hwa Katherine Teng
- National Heart Centre Singapore, National Heart Research Institute of Singapore, Singapore, 169609, Singapore
- Duke-NUS Medical School, Cardiovascular Sciences Academic Clinical Programme, Singapore, 169857, Singapore
- School of Allied Health, University of Western Australia, Perth, 6009, Australia
| | - Christopher Tze-Wei Tsang
- Division of Cardiology, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, 999077, China
| | - Yap-Hang Chan
- Division of Cardiology, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, 999077, China
| | - Chi-Ho Lee
- Division of Endocrinology, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, 999077, China
| | - Qing-Wen Ren
- Division of Cardiology, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, 999077, China
| | - Jia-Yi Huang
- Division of Cardiology, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, 999077, China
| | - Iok-Fai Cheang
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, Jiangsu, 210029, China
| | - Yi-Kei Tse
- Division of Cardiology, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, 999077, China
| | - Xin-Li Li
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, Jiangsu, 210029, China
| | - Xin Xu
- Division of Cardiology, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, 999077, China
| | - Hung-Fat Tse
- Division of Cardiology, Department of Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518000, China
- Division of Cardiology, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, 999077, China
| | - Carolyn S P Lam
- National Heart Centre Singapore, National Heart Research Institute of Singapore, Singapore, 169609, Singapore
- Duke-NUS Medical School, Cardiovascular Sciences Academic Clinical Programme, Singapore, 169857, Singapore
- Department of Cardiology, University Medical Center Groningen, Groningen, 9713, The Netherlands
| | - Kai-Hang Yiu
- Division of Cardiology, Department of Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518000, China
- Division of Cardiology, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, 999077, China
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10
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Shah V, Colletti T, Reau N. Could the answer to NAFLD be hidden in diabetic therapy? The impact of T2DM treatment on NAFLD. Clin Liver Dis (Hoboken) 2024; 23:e0100. [PMID: 38343636 PMCID: PMC10857655 DOI: 10.1097/cld.0000000000000100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Accepted: 09/28/2023] [Indexed: 01/04/2025] Open
Abstract
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Affiliation(s)
- Vicki Shah
- Department of Hepatology, Rush University, Chicago, Illinois, USA
| | - Thomas Colletti
- College of Medical Sciences, Lynchburg University, Lynchburg, Virginia, USA
| | - Nancy Reau
- Section-Chief of Hepatology, Rush University, Chicago, Illinois, USA
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11
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Wang CY, Liao KM, Wang YH, Chen KH, Chuang S, Liu CJ, Shu CC, Wang HC. Dipeptidyl peptidase IV inhibitors and the risk of mycobacterial pulmonary infections in type 2 diabetes mellitus. J Infect Public Health 2023; 16:1709-1715. [PMID: 37729686 DOI: 10.1016/j.jiph.2023.08.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2022] [Revised: 07/10/2023] [Accepted: 08/22/2023] [Indexed: 09/22/2023] Open
Abstract
BACKGROUND Type 2 diabetes mellitus (DM) is a risk factor for mycobacterial pulmonary infections (MPI), including tuberculosis (TB) and nontuberculous mycobacterial lung disease (NTM-LD). Dipeptidyl peptidase IV inhibitor (DPP4i), a common DM medication, has an immune-modulation effect that raises concerns about developing MPI. However, there is scarce research on the topic. METHODS This retrospective study was conducted in a tertiary-referral center in Taiwan from 2009 to 2016. Patients with type 2 DM who were receiving any DM medication were enrolled. TB and NTM-LD were defined by microbiological criteria. We analyzed the risk of MPI in DPP4i users using Cox proportional hazard regression with adjusted inverse probability of treatment weighting. RESULTS A total of 9963 patients were included. Among them, 3931 were classified as DPP4i users, and 6032 patients were DPP4i nonusers. DPP4i users had no increase in incidences of MPI (604 vs. 768 per 100,000 person-years, p = 0.776), NTM-LD (174 vs. 255 per 100,000 person-years, p = 0.228), and TB (542 vs. 449 per 100,000 person-years, p = 0.663) relative to those of DPP4i nonusers. After adjustment, the adjusted hazard ratios for MPI (aHR: 1.07, 95% CI: 0.79-1.45), TB (aHR: 1.15, 95% CI: 0.81-1.64) and NTM-LD (aHR: 0.85, 95% CI: 0.49-1.47) were not significantly increased relative to those of nonusers. The subgroup analysis also showed that DPP4i use did not increase the risk of MPI in different DM severities and comorbidities. CONCLUSIONS According to our large cohort study, DPP4i use is safe for patients with type 2 DM and might not increase the risk of MPI.
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Affiliation(s)
- Cheng-Yi Wang
- Department of Internal Medicine, Cardinal Tien Hospital and School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan
| | - Kuang-Ming Liao
- Department of Internal Medicine, Chi Mei Medical Center, Chiali, Taiwan
| | - Ya-Hui Wang
- Medical Research Center, Cardinal Tien Hospital and School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan
| | - Kuang-Hung Chen
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Shulin Chuang
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
| | - Chia-Jung Liu
- National Taiwan University College of Medicine, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital, Hsin-Chu Branch, Hsin-Chu country, Taiwan
| | - Chin-Chung Shu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; National Taiwan University College of Medicine, Taipei, Taiwan.
| | - Hao-Chien Wang
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; National Taiwan University College of Medicine, Taipei, Taiwan; National Taiwan University Cancer Center, Taipei, Taiwan
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12
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Ahmad BA, Sanghani IM, Sayabugari R, Biju H, Siddegowda A, Ittiachen Kinattingal M, Yartha SGR, Gaonkar PM, Andrabi SS, Vaghamashi YK, Korwar A. Beyond Blood Sugar: Investigating the Cardiovascular Effects of Antidiabetic Drugs. Cureus 2023; 15:e46373. [PMID: 37920618 PMCID: PMC10618835 DOI: 10.7759/cureus.46373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/30/2023] [Indexed: 11/04/2023] Open
Abstract
Cardiovascular disease is a major comorbidity associated with diabetes mellitus. Various antidiabetic drugs are currently used to treat type 2 diabetes mellitus and have varying effects on the cardiovascular system. Some drugs, such as glucagon-like peptide 1 (GLP-1) agonists and sodium-glucose cotransporter 2 (SGLT-2) inhibitors, are cardioprotective, whereas others, such as insulin, have deleterious effects on the cardiovascular system. This narrative review assessed the impact of antidiabetic drugs on cardiovascular health in the management of diabetes mellitus. It critically examines various classes of these medications, including conventional options such as metformin and newer agents such as incretin-based therapies and SGLT-2.
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Affiliation(s)
- Binish A Ahmad
- Department of Internal Medicine, King Edward Medical University, Lahore, PAK
| | - Isha M Sanghani
- Department of Internal Medicine, Punyashlok Ahilyadevi Holkar Government Medical College, Baramati, IND
| | | | - Hannah Biju
- Department of Internal Medicine, Kristu Jayanti College, Bengaluru, IND
| | | | - Minnu Ittiachen Kinattingal
- Department of Internal Medicine, New Hope Clinical Research, Charlotte, USA
- Department of Internal Medicine, Karuna Medical College, Palakkad, IND
| | | | - Prajyoth M Gaonkar
- Department of Internal Medicine, Punyashlok Ahilyadevi Holkar Government Medical College, Baramati, IND
| | - Syed Shireen Andrabi
- Department of Internal Medicine, School of Medicne, Tehran University of Medical Sciences, Tehran, IRN
| | | | - Arunika Korwar
- Department of Internal Medicine, KJ Somaiya Medical College, Mumbai, IND
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Cañas JMH, Gutierrez MAG, Ossa AB. What is Glycaemic Variability and which Pharmacological Treatment Options are Effective? A Narrative Review. TOUCHREVIEWS IN ENDOCRINOLOGY 2023; 19:16-21. [PMID: 38046184 PMCID: PMC10688563 DOI: 10.17925/ee.2023.19.2.4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Accepted: 04/12/2023] [Indexed: 12/05/2023]
Abstract
Glycated haemoglobin is currently used for diagnosis and follow-up of diabetes mellitus. However, it has important limitations; as it only reflects the average glycaemia over the last 3 months, it does not allow the identification of crucial events, such as episodes of hypoglycaemia and hyperglycaemia. Strict control of hyperglycaemia can result in severe hypoglycaemia that can be life threatening and can have important sequelae. Recently, the concept of glycaemic variability has been developed to provide information about the magnitude of glycaemic excursions and the duration of these fluctuations. This new approach has the potential to improve outcomes, decrease the risk of hypoglycaemia, and decrease cardiovascular risk. This review describes the most commonly prescribed non-insulin anti-diabetic drugs for diabetes management, their mechanism of action, and the existing evidence about their effectiveness in improving glycaemic variability and diabetes control.
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14
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Lin WR, Liu KH, Ling TC, Wang MC, Lin WH. Role of antidiabetic agents in type 2 diabetes patients with chronic kidney disease. World J Diabetes 2023; 14:352-363. [PMID: 37122432 PMCID: PMC10130897 DOI: 10.4239/wjd.v14.i4.352] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Revised: 01/10/2023] [Accepted: 04/04/2023] [Indexed: 04/12/2023] Open
Abstract
Insulin resistance is a condition in which the target tissues have a decreased response to insulin signaling, resulting in glucose uptake defect, and an increased blood sugar level. Pancreatic beta cells thus enhance insulin production to compensate. This situation may cause further beta cell dysfunction and failure, which can lead diabetes mellitus (DM). Insulin resistance is thus an important cause of the development of type 2 DM. Insulin resistance has also been found to have a strong relationship with cardiovascular disease and is common in chronic kidney disease (CKD) patients. The mechanisms of insulin resistance in CKD are complex and multifactorial. They include physical inactivity, inflammation and oxidative stress, metabolic acidosis, vitamin D deficiency, adipose tissue dysfunction, uremic toxins, and renin-angiotensin-aldosterone system activation. Currently, available anti-diabetic agents, such as biguanides, sulfonylureas, thiazolidinediones, alfa-glucosidase inhibitors, glucagon-like peptide-1-based agents, and sodium-glucose co-transporter-2 inhibitors, have different effects on insulin resistance. In this short review, we describe the potential mechanisms of insulin resistance in CKD patients. We also review the interaction of currently available anti-diabetic medications with insulin resistance.
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Affiliation(s)
- Wei-Ren Lin
- Division of Nephrology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan 704, Taiwan
| | - Kuan-Hung Liu
- Division of Nephrology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan 704, Taiwan
| | - Tsai-Chieh Ling
- Division of Nephrology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan 704, Taiwan
| | - Ming-Cheng Wang
- Division of Nephrology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan 704, Taiwan
| | - Wei-Hung Lin
- Division of Nephrology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan 704, Taiwan
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15
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The Implication of Mechanistic Approaches and the Role of the Microbiome in Polycystic Ovary Syndrome (PCOS): A Review. Metabolites 2023; 13:metabo13010129. [PMID: 36677054 PMCID: PMC9863528 DOI: 10.3390/metabo13010129] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 01/09/2023] [Accepted: 01/10/2023] [Indexed: 01/18/2023] Open
Abstract
As a complex endocrine and metabolic condition, polycystic ovarian syndrome (PCOS) affects women's reproductive health. These common symptoms include hirsutism, hyperandrogenism, ovulatory dysfunction, irregular menstruation, and infertility. No one knows what causes it or how to stop it yet. Alterations in gut microbiota composition and disruptions in secondary bile acid production appear to play a causative role in developing PCOS. PCOS pathophysiology and phenotypes are tightly related to both enteric and vaginal bacteria. Patients with PCOS exhibit changed microbiome compositions and decreased microbial diversity. Intestinal microorganisms also alter PCOS patient phenotypes by upregulating or downregulating hormone release, gut-brain mediators, and metabolite synthesis. The human body's gut microbiota, also known as the "second genome," can interact with the environment to improve metabolic and immunological function. Inflammation is connected to PCOS and may be caused by dysbiosis in the gut microbiome. This review sheds light on the recently discovered connections between gut microbiota and insulin resistance (IR) and the potential mechanisms of PCOS. This study also describes metabolomic studies to obtain a clear view of PCOS and ways to tackle it.
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16
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Ansari P, Hannan JMA, Choudhury ST, Islam SS, Talukder A, Seidel V, Abdel-Wahab YHA. Antidiabetic Actions of Ethanol Extract of Camellia sinensis Leaf Ameliorates Insulin Secretion, Inhibits the DPP-IV Enzyme, Improves Glucose Tolerance, and Increases Active GLP-1 (7-36) Levels in High-Fat-Diet-Fed Rats. MEDICINES (BASEL, SWITZERLAND) 2022; 9:medicines9110056. [PMID: 36422117 PMCID: PMC9698069 DOI: 10.3390/medicines9110056] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/23/2022] [Revised: 11/04/2022] [Accepted: 11/09/2022] [Indexed: 05/14/2023]
Abstract
Camellia sinensis (green tea) is used in traditional medicine to treat a wide range of ailments. In the present study, the insulin-releasing and glucose-lowering effects of the ethanol extract of Camellia sinensis (EECS), along with molecular mechanism/s of action, were investigated in vitro and in vivo. The insulin secretion was measured using clonal pancreatic BRIN BD11 β cells, and mouse islets. In vitro models examined the additional glucose-lowering properties of EECS, and 3T3L1 adipocytes were used to assess glucose uptake and insulin action. Non-toxic doses of EECS increased insulin secretion in a concentration-dependent manner, and this regulatory effect was similar to that of glucagon-like peptide 1 (GLP-1). The insulin release was further enhanced when combined with isobutylmethylxanthine (IBMX), tolbutamide or 30 mM KCl, but was decreased in the presence of verapamil, diazoxide and Ca2+ chelation. EECS also depolarized the β-cell membrane and elevated intracellular Ca2+, suggesting the involvement of a KATP-dependent pathway. Furthermore, EECS increased glucose uptake and insulin action in 3T3-L1 cells and inhibited dipeptidyl peptidase IV (DPP-IV) enzyme activity, starch digestion and protein glycation in vitro. Oral administration of EECS improved glucose tolerance and plasma insulin as well as inhibited plasma DPP-IV and increased active GLP-1 (7-36) levels in high-fat-diet-fed rats. Flavonoids and other phytochemicals present in EECS could be responsible for these effects. Further research on the mechanism of action of EECS compounds could lead to the development of cost-effective treatments for type 2 diabetes.
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Affiliation(s)
- Prawej Ansari
- Department of Pharmacy, School of Pharmacy and Public Health, Independent University, Bangladesh (IUB), Dhaka 1229, Bangladesh
- School of Biomedical Sciences, Ulster University, Coleraine BT52 1SA, UK
- Correspondence:
| | - J. M. A. Hannan
- Department of Pharmacy, School of Pharmacy and Public Health, Independent University, Bangladesh (IUB), Dhaka 1229, Bangladesh
| | - Samara T. Choudhury
- Department of Pharmacy, School of Pharmacy and Public Health, Independent University, Bangladesh (IUB), Dhaka 1229, Bangladesh
| | - Sara S. Islam
- Department of Pharmacy, School of Pharmacy and Public Health, Independent University, Bangladesh (IUB), Dhaka 1229, Bangladesh
| | - Abdullah Talukder
- Department of Pharmacy, School of Pharmacy and Public Health, Independent University, Bangladesh (IUB), Dhaka 1229, Bangladesh
| | - Veronique Seidel
- Natural Products Research Laboratory, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, UK
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Ferrari F, Moretti A, Villa RF. Incretin-based drugs as potential therapy for neurodegenerative diseases: current status and perspectives. Pharmacol Ther 2022; 239:108277. [DOI: 10.1016/j.pharmthera.2022.108277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 08/26/2022] [Accepted: 08/29/2022] [Indexed: 10/14/2022]
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Chellappan DK, Bhandare RR, Shaik AB, Prasad K, Suhaimi NAA, Yap WS, Das A, Banerjee P, Ghosh N, Guith T, Das A, Balakrishnan S, Candasamy M, Mayuren J, Palaniveloo K, Gupta G, Singh SK, Dua K. Vaccine for Diabetes-Where Do We Stand? Int J Mol Sci 2022; 23:ijms23169470. [PMID: 36012735 PMCID: PMC9409121 DOI: 10.3390/ijms23169470] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Revised: 08/18/2022] [Accepted: 08/19/2022] [Indexed: 11/16/2022] Open
Abstract
Diabetes is an endocrinological disorder with a rapidly increasing number of patients globally. Over the last few years, the alarming status of diabetes has become a pivotal factor pertaining to morbidity and mortality among the youth as well as middle-aged people. Current developments in our understanding related to autoimmune responses leading to diabetes have developed a cause for concern in the prospective usage of immunomodulatory agents to prevent diabetes. The mechanism of action of vaccines varies greatly, such as removing autoreactive T cells and inhibiting the interactions between immune cells. Currently, most developed diabetes vaccines have been tested in animal models, while only a few human trials have been completed with positive outcomes. In this review, we investigate the undergoing clinical trial studies for the development of a prototype diabetes vaccine.
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Affiliation(s)
- Dinesh Kumar Chellappan
- Department of Life Sciences, School of Pharmacy, International Medical University, Kuala Lumpur 57000, Malaysia
- Correspondence: (D.K.C.); (R.R.B.); Tel.: +60-12-636-1308 (D.K.C.); +971-6-705-6227 (R.R.B.)
| | - Richie R. Bhandare
- Department of Pharmaceutical Sciences, College of Pharmacy & Health Sciences, Ajman University, Al-Jruf, Ajman P.O. Box 346, United Arab Emirates
- Center of Medical and Bio-Allied Health Sciences Research, Ajman University, Al-Jruf, Ajman P.O. Box 346, United Arab Emirates
- Correspondence: (D.K.C.); (R.R.B.); Tel.: +60-12-636-1308 (D.K.C.); +971-6-705-6227 (R.R.B.)
| | - Afzal B. Shaik
- St. Mary’s College of Pharmacy, St. Mary’s Group of Institutions Guntur, Chebrolu, Guntur 522212, India
| | - Krishna Prasad
- Department of Clinical Sciences, College of Dentistry, Centre of Medical and Bio-Allied Health Science Research, Ajman University, Al-Jruf, Ajman P.O. Box 346, United Arab Emirates
| | | | - Wei Sheng Yap
- School of Health Sciences, International Medical University, Kuala Lumpur 57000, Malaysia
| | - Arpita Das
- Department of Biotechnology, Adamas University, Kolkata 700126, India
| | - Pradipta Banerjee
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Nandini Ghosh
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Tanner Guith
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Amitava Das
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | | | - Mayuren Candasamy
- Department of Life Sciences, School of Pharmacy, International Medical University, Kuala Lumpur 57000, Malaysia
| | - Jayashree Mayuren
- Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Kuala Lumpur 57000, Malaysia
| | - Kishneth Palaniveloo
- C302, Institute of Ocean and Earth Sciences, University of Malaya, Kuala Lumpur 50603, Malaysia
| | - Gaurav Gupta
- School of Pharmacy, Suresh Gyan Vihar University, Jaipur 302017, India
- Department of Pharmacology, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai 600077, India
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun 248007, India
| | - Sachin Kumar Singh
- School of Pharmaceutical Sciences, Lovely Professional University, Jalandhar-Delhi G.T Road, Phagwara 144411, India
- Australian Research Centre in Complementary and Integrative Medicine, Faculty of Health, University of Technology Sydney, Sydney, NSW 2007, Australia
| | - Kamal Dua
- Australian Research Centre in Complementary and Integrative Medicine, Faculty of Health, University of Technology Sydney, Sydney, NSW 2007, Australia
- Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Sydney, NSW 2007, Australia
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García-Compeán D, Kumar R, Cueto-Aguilera ÁND, Maldonado-Garza HJ, Villarreal-Pérez JZ. Body weight loss and glycemic control on the outcomes of patients with NAFLD. The role of new antidiabetic agents. Ann Hepatol 2022:100751. [PMID: 36002119 DOI: 10.1016/j.aohep.2022.100751] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 08/09/2022] [Accepted: 08/12/2022] [Indexed: 02/08/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is currently the most common cause of chronic liver disease worldwide affecting a third of adults and 12% of children in Western countries. In around 50-60%% of cases, NAFLD and type 2 diabetes mellitus (T2DM) coexist and act synergistically to increase the risk of adverse hepatic and extra-hepatic outcomes. T2DM is a strong risk factor for rapid progression of NAFLD to nonalcoholic steatohepatitis (NASH), cirrhosis or hepatocellular carcinoma (HCC), which have become frequent indications of liver transplantation. The pathophysiology of NAFLD is complex and its relationship with T2DM is bidirectional, where lipotoxicity and insulin resistance (IR), act as the strongest pillars. To date, no pharmacological treatment has been approved for NAFLD. However, there is an intense research with numerous drugs focused on reversing inflammation and liver fibrosis through modulation of molecular targets without good results. It has been known for some time that weight reduction >10% is associated to histological improvement of NAFLD. Recently, glycemic control has been shown to induce similar results. Diet and physical exercise for weight reduction have limitations, so alternative methods (pharmacologic, endoscopic or surgical) may be required. Currently, new antidiabetic drugs inducing weight loss, have been recently approved for the treatment of obesity. Nevertheless, their therapeutic effects on NAFLD have not been extensively studied. We will review here, recently published data on the effects of weight loss and glycemic control on the histological and metabolic parameters of NAFLD and recent published data on therapeutic studies of NAFLD with new antidiabetic drugs.
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Affiliation(s)
- Diego García-Compeán
- Gastroenterology Service and Internal Medicine Department, Faculty of Medicine, University Hospital "Dr. José E. González", Universidad Autónoma de Nuevo León, Monterrey 64700, Nuevo León, Mexico.
| | - Ramesh Kumar
- Department of Gastroenterology, All India Institute of Medical Sciences, Patna 801507, India
| | - Ángel Noe Del Cueto-Aguilera
- Gastroenterology Service and Internal Medicine Department, Faculty of Medicine, University Hospital "Dr. José E. González", Universidad Autónoma de Nuevo León, Monterrey 64700, Nuevo León, Mexico
| | - Héctor Jesús Maldonado-Garza
- Gastroenterology Service and Internal Medicine Department, Faculty of Medicine, University Hospital "Dr. José E. González", Universidad Autónoma de Nuevo León, Monterrey 64700, Nuevo León, Mexico
| | - Jesús Zacarías Villarreal-Pérez
- Endocrinology Service and Internal Medicine Department, University Hospital. Autonomous University of Nuevo León, México. Madero y Gonzalitos Colonia Mitras CP 64700 Monterrey Nuevo León, México., Monterrey 64700, Mexico
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Insulin Secretory Actions of Ethanol Extract of Eucalyptus citriodora Leaf, including Plasma DPP-IV and GLP-1 Levels in High-Fat-Fed Rats, as Well as Characterization of Biologically Effective Phytoconstituents. Metabolites 2022; 12:metabo12080757. [PMID: 36005629 PMCID: PMC9414540 DOI: 10.3390/metabo12080757] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 08/13/2022] [Accepted: 08/15/2022] [Indexed: 12/30/2022] Open
Abstract
Due to the numerous adverse effects of synthetic drugs, researchers are currently studying traditional medicinal plants to find alternatives for diabetes treatment. Eucalyptus citriodora is known to be used as a remedy for various illnesses, including diabetes. This study aimed to explore the effects of ethanol extract of Eucalyptus citriodora (EEEC) on in vitro and in vivo systems, including the mechanism/s of action. The methodology used involved the measurement of insulin secretion from clonal pancreatic β-cells, BRIN BD11, and mouse islets. Other in vitro systems further examined EEEC’s glucose-lowering properties. Obese rats fed a high-fat-fed diet (HFF) were selected for in vivo evaluation, and phytoconstituents were detected via RP-HPLC followed by LC-MS. EEEC induced insulin secretion in a concentration-dependent manner with modulatory effects, similar to 1 µM glucagon-like peptide 1 (GLP-1), which were partly declined in the presence of Ca2+-channel blocker (Verapamil), KATP-channel opener (Diazoxide), and Ca2+ chelation. The insulin secretory effects of EEEC were augmented by isobutyl methylxanthine (IBMX), which persisted in the context of tolbutamide or a depolarizing concentration of KCl. EEEC enhanced insulin action in 3T3-L1 cells and reduced glucose absorption, and protein glycation in vitro. In HFF rats, it improved glucose tolerance and plasma insulin, attenuated plasma DPP-IV, and induced active GLP-1 (7-36) levels in circulation. Rhodomyrtosone B, Quercetin-3-O-β-D-glucopyranoside, rhodomyrtosone E, and quercitroside were identified as possible phytoconstituents that may be responsible for EEEC effects. Thus, these findings revealed that E. citriodora could be used as an adjunct nutritional supplement to manage type 2 diabetes.
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Hussain F, Hafeez J, Khalifa AS, Naeem M, Ali T, Eed EM. In vitro and in vivo study of inhibitory potentials of α-glucosidase and acetylcholinesterase and biochemical profiling of M. charantia in alloxan-induced diabetic rat models. Am J Transl Res 2022; 14:3824-3839. [PMID: 35836841 PMCID: PMC9274573] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Accepted: 05/12/2022] [Indexed: 06/15/2023]
Abstract
OBJECTIVES Diabetes mellitus is a multifactorial chronic disease that affects the human population and it is the third most common cause of death worldwide. Momordica charantia is used as popular folk medicine and its action against diabetes mellitus remains unclear. We investigated the inhibitory potentials of α-glucosidase, acetylcholinesterase, and biochemical profiling of M. charantia in alloxan-induced diabetic rat models. METHODS An In vivo study was carried out by using twenty male albino Wistar rats randomly divided into five groups each comprising four rats. Diabetes mellitus was induced by single intraperitoneal administration of 80 mg/kg body weight of alloxan and treatment with plant extract was conducted for a period of thirty days to check their impact on body weight and differentblood values. Biochemical profiling and characterization were performed by in vitro assays and HPLC, and FTIR. Histopathologic effects of M. charantia were examined through automated image analysis. Results were analyzed through Tukey's test, a complete randomized design and two factorial designs under CRD. RESULTS Methanolic extract demonstrated potent alpha-glucosidase (72.30 ± 1.17%) and acetylcholinesterase (50.12 ± 0.82%) inhibitory activities. HPLC analysis confirmed the existence of vital flavonoids, antioxidants, and saponins. FTIR revealed the presence of hydroxyl groups, esters, alkanes, alkenes, alkynes, ketones, alcohols, amines and carboxylic acids as major functional groups. Results of in vivo study demonstrated that co-administration of alloxan and methanolic extract of M. charantia significantly improved the levels of fasting blood glucose, glycated hemoglobin and insulin in diabetic rats. CONCLUSION M. charantia can be recommended as a therapeutic adjunct for diabetic patients as it can provide favorable remedial action in the context of the diabetes continuum of metabolic syndrome.
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Affiliation(s)
- Fatma Hussain
- Clinico-Molecular Biochemistry Laboratory, Department of Biochemistry, University of AgricultureFaisalabad 38000, Pakistan
| | - Javaria Hafeez
- Clinico-Molecular Biochemistry Laboratory, Department of Biochemistry, University of AgricultureFaisalabad 38000, Pakistan
| | - Amany S Khalifa
- Department of Clinical Pathology and Pharmaceutics, College of Pharmacy, Taif UniversityP.O. Box 11099, Taif 21944, Saudi Arabia
| | - Muhammad Naeem
- College of Life Science, Hebei Normal UniversityShijiazhuang 050024, Hebei, China
| | - Tayyab Ali
- Clinico-Molecular Biochemistry Laboratory, Department of Biochemistry, University of AgricultureFaisalabad 38000, Pakistan
| | - Emad M Eed
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif UniversityP.O. Box 11099, Taif 21944, Saudi Arabia
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22
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Attimarad M, Venugopala KN, Chohan MS, David M, Molina EIIP, Sreeharsha N, Nair AB, Tratrat C, Altaysan AI, Balgoname AA. An Experimental Design Approach to Quantitative Expression for Quality Control of a Multicomponent Antidiabetic Formulation by the HILIC Method. Molecules 2022; 27:3135. [PMID: 35630608 PMCID: PMC9148089 DOI: 10.3390/molecules27103135] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 05/12/2022] [Accepted: 05/12/2022] [Indexed: 12/13/2022] Open
Abstract
A rapid and reproducible hydrophilic liquid chromatography (HILIC) process was established for concomitant determination of remogliflozin etabonate (RE), vildagliptin (VD), and metformin (MF) in a formulation. A face-centered central composite experimental design was employed to optimize and predict the chromatographic condition by statistically studying the surface response model and design space with desirability close to one. A HILIC column with a simple mobile phase of acetonitrile (65% v/v) and 20 mM phosphate buffer (35% v/v, pH 6, controlled with orthophosphoric acid) was used to separate RE, VD, and MF. RE, VD, and MF were separated in 3.6 min using an isocratic mode mobile phase flow at a flow rate of 1.4 mL at room temperature, and the analytes were examined by recording the absorption at 210 nm. The developed HILIC method was thoroughly validated for all parameters recommended by ICH, and linearity was observed in the ranges 20−150 µg/mL, 10−75 µg/mL, and 50−750 µg/mL for RE, VD, and MF, respectively, along with excellent regression coefficients (r2 > 0.999). The calculated percentage relative deviation and relative error ascertained the precision and accuracy of the method. The selectivity and accuracy were further confirmed by the high percentage recovery of added standard drugs to the formulation using the standard addition technique. The robustness of the HILIC processes was confirmed by developing a half-normal probability plot and Pareto chart, as the slight variation of a single factor had no significant influence on the assay outcomes. Utilization of the optimized HILIC procedure for concurrent quantification of RE, VD, and MF in solid dosage forms showed accurate and reproducible results. Hence, the fast HILIC method can be regularly employed for the quality assurance of pharmaceutical preparations comprising RE, VD, and MF.
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Affiliation(s)
- Mahesh Attimarad
- Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi Arabia; (K.N.V.); (N.S.); (A.B.N.); (C.T.); (A.I.A.); (A.A.B.)
| | - Katharigatta Narayanaswamy Venugopala
- Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi Arabia; (K.N.V.); (N.S.); (A.B.N.); (C.T.); (A.I.A.); (A.A.B.)
- Department of Biotechnology and Food Technology, Faculty of Applied Sciences, Durban University of Technology, Durban 4000, South Africa
| | - Muhammad S. Chohan
- Department of Biomedical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi Arabia;
| | - Marysheela David
- Department of Nursing, College of Applied Medical Sciences, King Faisal University, Al-Ahsa 31982, Saudi Arabia;
| | - Efren II Plaza Molina
- Department of Pharmacy Practice, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi Arabia;
| | - Nagaraja Sreeharsha
- Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi Arabia; (K.N.V.); (N.S.); (A.B.N.); (C.T.); (A.I.A.); (A.A.B.)
- Department of Pharmaceutics, Vidya Siri College of Pharmacy, Off Sarjapura Road, Bangalore 560035, India
| | - Anroop Balachandran Nair
- Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi Arabia; (K.N.V.); (N.S.); (A.B.N.); (C.T.); (A.I.A.); (A.A.B.)
| | - Christophe Tratrat
- Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi Arabia; (K.N.V.); (N.S.); (A.B.N.); (C.T.); (A.I.A.); (A.A.B.)
| | - Abdulrahman Ibrahim Altaysan
- Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi Arabia; (K.N.V.); (N.S.); (A.B.N.); (C.T.); (A.I.A.); (A.A.B.)
| | - Abdulmalek Ahmed Balgoname
- Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi Arabia; (K.N.V.); (N.S.); (A.B.N.); (C.T.); (A.I.A.); (A.A.B.)
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23
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The Role of Endometrial Stem/Progenitor Cells in Recurrent Reproductive Failure. J Pers Med 2022; 12:jpm12050775. [PMID: 35629197 PMCID: PMC9143189 DOI: 10.3390/jpm12050775] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 05/06/2022] [Accepted: 05/09/2022] [Indexed: 02/06/2023] Open
Abstract
Recurrent implantation failure (RIF) and recurrent pregnancy loss (RPL), collectively referred to as recurrent reproductive failure (RRF), are both challenging conditions with many unanswered questions relating to causes and management options. Both conditions are proposed to be related to an aberrant endometrial microenvironment, with different proposed aetiologies related to a restrictive or permissive endometrium for an invading embryo. The impressive regenerative capacity of the human endometrium has been well-established and has led to the isolation and characterisation of several subtypes of endometrial stem/progenitor cells (eSPCs). eSPCs are known to be involved in the pathogenesis of endometrium-related disorders (such as endometriosis) and have been proposed to be implicated in the pathogenesis of RRF. This review appraises the current knowledge of eSPCs, and their involvement in RRF, highlighting the considerable unknown aspects in this field, and providing avenues for future research to facilitate much-needed advances in the diagnosis and management of millions of women suffering with RRF.
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24
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Experimental Design Approach for Quantitative Expressions of Simultaneous Quantification of Two Binary Formulations Containing Remogliflozin and Gliptins by RP-HPLC. SEPARATIONS 2022. [DOI: 10.3390/separations9020023] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
The aim of this study was to develop a fast RP-HPLC method for simultaneous measurement of two antidiabetic formulations (vildagliptin + remogliflozin and teneligliptin + remogliflozin) under identical experimental conditions. Using the Box–Behnken approach and response surface design, the interaction and quadratic influence of three variable parameters, acetonitrile %, pH of the mobile phase, and flow rate, on resolution between the peaks were optimized. To forecast the resolution of peaks (2.7 and 6.5) for the three anti-diabetic medications, the design space with desirability function was used to find the optimal chromatographic conditions. Isocratic elution with 58:42 acetonitrile and phosphate buffer (20 mM KH2PO4, pH adjusted to 4.9 with orthophosphoric acid) over a Zorabx C18 HPLC column with a flow rate of 1.2 mL min−1 separated all three analytes in 2.5 min. In addition, the optimized HPLC process was validated using ICH recommendations. The devised HPLC method’s precision and accuracy were proven by the low percent relative standard deviation (0.60–1.65%), good percentage recovery (98.18–101.50%), and low percentage relative errors (0.20–1.82%). The method’s robustness was also proven by slightly varying the five separate parameters. Finally, the accuracy of the proposed HPLC approach was confirmed using a standard addition method for simultaneous determination of vildagliptin + remogliflozin and teneligliptin + remogliflozin from formulations. Furthermore, the findings demonstrated that experimental design can be successfully used to optimize chromatographic conditions with fewer runs. The devised HPLC method for simultaneous quantification of two binary combinations utilizing the same chromatographic conditions is fast, accurate, precise, and easy, and it might be utilized in laboratories for routine quality control investigations on both formulations.
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25
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Narimani R, Kachuei A, Rezvanian H, Feizi A, Poorpoone M. Effect of sitagliptin on proteinuria in patients with type 2 diabetes - A renoprotective effect of sitagliptin. JOURNAL OF RESEARCH IN MEDICAL SCIENCES 2021; 26:35. [PMID: 34484367 PMCID: PMC8383993 DOI: 10.4103/jrms.jrms_78_20] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 08/15/2020] [Accepted: 01/04/2021] [Indexed: 12/12/2022]
Abstract
Background: Diabetic nephropathy, the leading cause of chronic renal failure, is related to diabetes poor control. Some antihyperglycemic drugs like dipeptidyl peptidase-4 inhibitors have shown to prevent diabetic nephropathy. This study endeavors to assess the effect of sitagliptin on proteinuria in Iranian type 2 diabetics. Materials and Methods: A total of 90 type 2 diabetic patients aged between 30 and 80 years with glycated hemoglobin (HbA1C) <8.5 and normotensive under treatment of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers were randomly assigned into two groups. One group received 50 mg sitagliptin per day and the other group received placebo. The two groups were evaluated for albumin–creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR) at baseline and 3 months later. Results: Eighty-four patients, 38 (45%) males and 46 (55%) females, were enrolled in this study. The mean age was 58.47 ± 7.33. The two groups did not differ in baseline characteristics. After 3 months, in the sitagliptin group, HbA1C (7.89 ± 0.39 to 7.37 ± 0.61, P < 0.001), fasting blood sugar (FBS) (136.86 ± 22.51 to 130.53, P = 0.04), systolic blood pressure (BP) (124.39 ± 9.70 mmHg to 119.32 ± 9 mmHg), diastolic BP (76.44 ± 6.53 to 73.13 ± 5.34 mmHg, P < 0.001), and ACR (314.40 ± 414.64 to 293.49 ± 400.71, P < 0.001) were significantly decreased and eGFR was significantly increased (73.35 ± 10.73 to 76.86 ± 10.59, P < 0.001) at 3 months compared to the placebo group. ACR reduction was higher in macroalbuminuric (Ma) patients compared to microalbuminuric (Mi) patients in the sitagliptin group (−30.25 ± 35.57 vs. −11.12 ± 14.01, P = 0.02). No significant difference was observed between the Ma and Mi subgroups regarding changes in eGFR. Univariate analysis showed that changes in ACR correlated with FBS (r = 0.68, P < 0.0001), insulin (r = 0.44, P = 0.03), and homeostatic model assessment for insulin resistance (r = 0.69, P < 0.0001) and did not correlate with eGFR and BP. Conclusion: In conclusion, sitagliptin is a well-tolerated drug that improves glycemic control, lowers BP, and reduces urinary albumin excretion, especially in Ma type 2 diabetic patients.
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Affiliation(s)
- Rouhollah Narimani
- Isfahan Endocrine and Metabolism Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Ali Kachuei
- Isfahan Endocrine and Metabolism Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Hassan Rezvanian
- Isfahan Endocrine and Metabolism Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Awat Feizi
- Isfahan Endocrine and Metabolism Research Center, Isfahan University of Medical Sciences, Isfahan, Iran.,Department of Epidemiology and Biostatistics, School of Health, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mohadese Poorpoone
- Isfahan Hematology and Oncology Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
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26
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Phillips J, Chen JHC, Ooi E, Prunster J, Lim WH. Global Epidemiology, Health Outcomes, and Treatment Options for Patients With Type 2 Diabetes and Kidney Failure. FRONTIERS IN CLINICAL DIABETES AND HEALTHCARE 2021; 2:731574. [PMID: 36994340 PMCID: PMC10012134 DOI: 10.3389/fcdhc.2021.731574] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Accepted: 07/29/2021] [Indexed: 12/15/2022]
Abstract
The burden of type 2 diabetes and related complications has steadily increased over the last few decades and is one of the foremost global public health threats in the 21st century. Diabetes is one of the leading causes of chronic kidney disease and kidney failure and is an important contributor to the cardiovascular morbidity and mortality in this population. In addition, up to one in three patients who have received kidney transplants develop post-transplant diabetes, but the management of this common complication continues to pose a significant challenge for clinicians. In this review, we will describe the global prevalence and temporal trend of kidney failure attributed to diabetes mellitus in both developing and developed countries. We will examine the survival differences between treated kidney failure patients with and without type 2 diabetes, focusing on the survival differences in those on maintenance dialysis or have received kidney transplants. With the increased availability of novel hypoglycemic agents, we will address the potential impacts of these novel agents in patients with diabetes and kidney failure and in those who have developed post-transplant diabetes.
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Affiliation(s)
- Jessica Phillips
- Department of Renal Medicine, Sir Charles Gairdner Hospital, Perth, WA, Australia
- *Correspondence: Jessica Phillips,
| | - Jenny H. C. Chen
- School of Medicine, University of Wollongong, Wollongong, NSW, Australia
- Depatment of Nephrology, Wollongong Hospital, Wollongong, NSW, Australia
| | - Esther Ooi
- School of Biomedical Sciences, University of Western Australia, Perth, WA, Australia
| | - Janelle Prunster
- Department of Renal Medicine, Cairns Hospital, Cairns, QLD, Australia
| | - Wai H. Lim
- Department of Renal Medicine, Sir Charles Gairdner Hospital, Perth, WA, Australia
- Medical School, University of Western Australia, Perth, WA, Australia
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27
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Campos C, Unger J. Primary care management of type 2 diabetes: a comparison of the efficacy and safety of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. Postgrad Med 2021; 133:843-853. [PMID: 34416133 DOI: 10.1080/00325481.2021.1971461] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dipeptidyl peptidase-4 inhibitors (DPP4is) exert their effects via the incretin system, which augments glucose-dependent insulin secretion in response to nutrient intake (the 'incretin effect'). Both classes are well-established pharmacologic options for the management of glycemic control in individuals with type 2 diabetes (T2D) after failure of first-line metformin; however, they have inherent differences in their mechanisms of action that are reflected in their clinical safety and efficacy profiles. GLP-1RAs have high glycemic efficacy and are associated with weight loss and, in some cases, cardioprotective effects, with a side-effect profile of predominantly transient gastrointestinal adverse events. Most GLP-1RAs are administered as subcutaneous injection, although an oral formulation of one GLP-1RA, semaglutide, has recently become available. DPP4is provide moderate glycemic control, are weight-neutral, and do not offer any cardiovascular benefits, but are generally well tolerated. DPP4is are all administered orally. This narrative review aims to provide guidance for a primary care audience on the similarities and differences between GLP-1RA and DPP4i therapies, with a focus on their mechanism of action, clinical safety, efficacy, and real-world effectiveness. The role of incretin-based therapies in the T2D treatment paradigm, including key considerations for guiding treatment decisions, will also be discussed.
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Affiliation(s)
- Carlos Campos
- Department of Family Medicine, University of Texas Health Science Center, San Antonio, USA
| | - Jeff Unger
- Unger Primary Care Concierge Medical Group, Rancho Cucamonga, USA
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28
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Wharton S, Yin P, Burrows M, Gould E, Blavignac J, Christensen RAG, Kamran E, Camacho F, Barakat M. Extended-release naltrexone/bupropion is safe and effective among subjects with type 2 diabetes already taking incretin agents: a post-hoc analysis of the LIGHT trial. Int J Obes (Lond) 2021; 45:1687-1695. [PMID: 34083744 PMCID: PMC8310797 DOI: 10.1038/s41366-021-00831-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 03/17/2021] [Accepted: 04/21/2021] [Indexed: 12/22/2022]
Abstract
BACKGROUND Extended-release naltrexone/bupropion (NB) is indicated for chronic weight management. Incretin agents are recommended for patients with type 2 diabetes. This analysis looked at the add-on of NB to incretins to see if weight loss could occur in patients already stabilized on incretin agents. METHODS This was a post-hoc analysis of NB vs. placebo (PL) among subjects with type 2 diabetes stable on an incretin agent prior to randomization in a double-blind, PL-controlled cardiovascular outcome trial (N = 1317). RESULTS Over 1 year, mean weight loss was significantly greater among NB patients vs. PL among those taking DPP-4i (mean absolute difference 4.6% [p < 0.0001]) and those taking GLP-1RAs (mean absolute difference 5.2%, p < 0.0001). Proportions of subjects achieving 5% weight loss were significantly greater for NB vs. PL at weeks 26 and 52 among those taking DPP-4is or GLP-1RAs. There were no significant differences in effectiveness observed between NB + DPP-4i and NB + GLP-1RA or between PL + DPP-4i and PL + GLP-1RA in any of the analyses. Serious adverse events were reported by 9.1% and 11.1% for PL + DPP-4i and PL + GLP-1RA, respectively, and 13.3% and 12.4% of NB + DPP-4i and NB + GLP-1RA, respectively. CONCLUSION NB appears to be effective in reducing weight in patients with T2DM and obesity/overweight who are taking DPP-4ihibitors or GLP-1RA. The SAE rates in all arms of this analysis were lower than have been reported in other cardiovascular outcome trials in type 2 diabetes.
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Affiliation(s)
- Sean Wharton
- The Wharton Medical Clinic, Toronto, ON, Canada.
| | | | | | - Errol Gould
- Currax Pharmaceuticals LLC, Morristown, NJ, USA
| | | | | | | | - Fernando Camacho
- Department of Statistics and Actuarial Sciences, University of Waterloo, Waterloo, ON, Canada
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29
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Dongiovanni P, Paolini E, Corsini A, Sirtori CR, Ruscica M. Nonalcoholic fatty liver disease or metabolic dysfunction-associated fatty liver disease diagnoses and cardiovascular diseases: From epidemiology to drug approaches. Eur J Clin Invest 2021; 51:e13519. [PMID: 33583033 DOI: 10.1111/eci.13519] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 02/10/2021] [Accepted: 02/11/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND A consensus of experts has proposed to replace the term nonalcoholic fatty liver disease (NAFLD), whose global prevalence is 25%, with metabolic dysfunction-associated fatty liver disease (MAFLD), to describe more appropriately the liver disease related to metabolic derangements. MAFLD is closely intertwined with type 2 diabetes, obesity, dyslipidaemia, all linked to a rise in the risk of cardiovascular disease (CVDs). Since controversy still stands on whether or not NAFLD/MAFLD raises the odds of CVD, the present review aims to evaluate the impact of NAFLD/MAFLD aetiologies on CV health and the potential correction by dietary and drug approaches. RESULTS Epidemiological studies indicate that NAFLD raises risk of fatal or non-fatal CVD events. NAFLD patients have a higher prevalence of arterial plaques and stiffness, coronary calcification, and endothelial dysfunction. Although genetic and environmental factors strongly contribute to NAFLD pathogenesis, a Mendelian randomization analysis indicated that the PNPLA3 genetic variant leading to NAFLD may not be causally associated with CVD risk. Among other genetic variants related to NAFLD, TM6SF2 appears to be protective, whereas MBOAT7 may favour venous thromboembolism. CONCLUSIONS NAFLD is correlated to a higher CVD risk which may be ameliorated by dietary interventions. This is not surprising, since new criteria defining MAFLD include other metabolic risk abnormalities fuelling development of serious adverse extrahepatic outcomes, for example CVD. The present lack of a targeted pharmacological approach makes the identification of patients with liver disease at higher CVD risk (eg diabetes, hypertension, obesity or high levels of C-reactive protein) of major clinical interest.
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Affiliation(s)
- Paola Dongiovanni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Erika Paolini
- General Medicine and Metabolic Diseases, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy.,Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
| | - Alberto Corsini
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy.,Multimedica IRCCS, Sesto San Giovanni (MI), Milan, Italy
| | - Cesare R Sirtori
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
| | - Massimiliano Ruscica
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
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30
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Pinheiro MM, Pinheiro FMM, Diniz SN, Fabbri A, Infante M. Combination of vitamin D and dipeptidyl peptidase-4 inhibitors (VIDPP-4i) as an immunomodulation therapy for autoimmune diabetes. Int Immunopharmacol 2021; 95:107518. [PMID: 33756226 DOI: 10.1016/j.intimp.2021.107518] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 02/15/2021] [Accepted: 02/16/2021] [Indexed: 12/18/2022]
Abstract
Type 1 diabetes (T1D) and latent autoimmune diabetes in adults (LADA) represent the most common types of autoimmune diabetes and are characterized by different age of onset, degrees of immune-mediated destruction of pancreatic beta cells and rates of disease progression towards insulin dependence. Several immunotherapies aimed to counteract autoimmune responses against beta cells and preserve beta-cell function are currently being investigated, particularly in T1D. Preliminary findings suggest a potential role of combination therapy with vitamin D and dipeptidyl peptidase-4 (DPP-4) inhibitors (VIDPP-4i) in preserving beta-cell function in autoimmune diabetes. This manuscript aims to provide a comprehensive overview of the immunomodulatory properties of vitamin D and DPP-4 inhibitors, as well as the rationale for investigation of their combined use as an immunomodulation therapy for autoimmune diabetes.
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Affiliation(s)
- Marcelo Maia Pinheiro
- UNIVAG, University Center, Dom Orlando Chaves Ave, 2655 - Cristo Rei, Várzea Grande, 78118-000 Mato Grosso, Brazil; Universidade Anhanguera de São Paulo - SP, 3305, Raimundo Pereira de Magalhães Ave., Pirituba, São Paulo, 05145-200 São Paulo, Brazil.
| | - Felipe Moura Maia Pinheiro
- Hospital de Base, Faculdade de Medicina de São José do Rio Preto FAMERP - SP, 5546, Brigadeiro Faria Lima Ave, Vila São Pedro, São José do Rio Preto, 15015-500 São Paulo, Brazil
| | - Susana Nogueira Diniz
- Universidade Anhanguera de São Paulo - SP, 3305, Raimundo Pereira de Magalhães Ave., Pirituba, São Paulo, 05145-200 São Paulo, Brazil
| | - Andrea Fabbri
- Diabetes Research Institute Federation (DRIF), Division of Endocrinology and Diabetes, CTO Andrea Alesini Hospital, ASL Roma 2, Department of Systems Medicine, University of Rome Tor Vergata, Via San Nemesio 21, 00145 Rome, Italy
| | - Marco Infante
- Diabetes Research Institute Federation (DRIF), Division of Endocrinology and Diabetes, CTO Andrea Alesini Hospital, ASL Roma 2, Department of Systems Medicine, University of Rome Tor Vergata, Via San Nemesio 21, 00145 Rome, Italy; UniCamillus, Saint Camillus International University of Health Sciences, Via di Sant'Alessandro, 8, 00131 Rome, Italy; Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Via San Nemesio 21, 00145 Rome, Italy.
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31
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Pringle NA, van de Venter M, Koekemoer TC. Comprehensive in vitro antidiabetic screening of Aspalathus linearis using a target-directed screening platform and cellomics. Food Funct 2021; 12:1020-1038. [PMID: 33416070 DOI: 10.1039/d0fo02611e] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
The antidiabetic potential of Aspalathus linearis has been investigated for over a decade, however, its characterisation remains incomplete with results scattered across numerous journals making the information difficult to compare and integrate. To explore whether any potential antidiabetic mechanisms for A. linearis have been neglected and to compare the suitability of extracts of green and "fermented" A. linearis as potential antidiabetic treatment strategies, this study utilised a comprehensive in vitro antidiabetic target-directed screening platform in combination with high content screening and analysis/cellomics. The antidiabetic screening platform consisted of 20 different screening assays that incorporated 5 well-characterised antidiabetic targets i.e. the intestine, liver, skeletal muscle, adipose tissue/obesity and pancreatic β-cells. Both the green and fermented extracts of A. linearis demonstrated very broad antidiabetic mechanisms as they revealed several promising activities that could be useful in combatting insulin resistance, inflammation, oxidative stress, protein glycation and pancreatic β-cell dysfunction and death - with a strong tendency to attenuate postprandial hyperglycaemia and the subsequent metabolic dysfunction which arises as a result of poor glycaemic control. The green extract was more successful at combatting oxidative stress in INS-1 pancreatic β-cells and enhancing intracellular calcium levels in the absence of glucose. Conversely, the fermented extract demonstrated a greater ability to inhibit α-glucosidase activity as well as palmitic acid-induced free fatty acid accumulation in C3A hepatocytes and differentiated L6 myotubes, however, further studies are required to clarify the potentially toxic and pro-inflammatory nature of the fermented extract.
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Affiliation(s)
- Nadine A Pringle
- Department of Biochemistry and Microbiology, Nelson Mandela University, Port Elizabeth, South Africa.
| | - Maryna van de Venter
- Department of Biochemistry and Microbiology, Nelson Mandela University, Port Elizabeth, South Africa.
| | - Trevor C Koekemoer
- Department of Biochemistry and Microbiology, Nelson Mandela University, Port Elizabeth, South Africa.
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32
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Mahmood R, Kayani WK, Ahmed T, Malik F, Hussain S, Ashfaq M, Ali H, Rubnawaz S, Green BD, Calderwood D, Kenny O, Rivera GA, Mirza B, Rasheed F. Assessment of antidiabetic potential and phytochemical profiling of Rhazya stricta root extracts. BMC Complement Med Ther 2020; 20:293. [PMID: 32993632 PMCID: PMC7523044 DOI: 10.1186/s12906-020-03035-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Accepted: 07/24/2020] [Indexed: 12/17/2022] Open
Abstract
Background Diabetes mellitus is a chronic disease characterized by hyperglycemia that may occur due to genetic, environmental or lifestyle factors. Natural remedies have been used to treat diabetes since long and many antidiabetic compounds of varied efficacies have been isolated from medicinal plants. Rhazya stricta has been used for decades for the treatment of diabetes mellitus and associated ailments. Considering the folkloric use of R. stricta against diabetes, it was aimed to investigate the effectiveness of its root extracts against diabetes through in vitro assays and in vivo studies using animal model along with phytochemical profiling through GCMS. Methods Various fractions of Rhazya stricta obtained through column chromatography were evaluated for a variety of assays including α-glucosidase, Dipeptidyl peptidase-IV (DPP-IV), β-secretase and Glucagon-like peptide-1 (GLP-1) secretion studies. For the in vivo studies the alloxan-induced diabetic mice were treated with root extracts and blood glucose levels, HbA1C, and other biochemical markers along with the histological study of the liver were done. The phytochemical identification was performed using an Agilent 7890B GC coupled to a 7010 Triple Quadrupole (MS/MS) system. GraphPad Prism software version 5.01 was used for statistical analysis. Results Majority of the extract fractions showed excellent results against diabetes by inhibiting enzymes DPP-IV (Up to 61%) and β-secretase (Up to 83%) with IC50s 979 μg/ml and 169 μg/ml respectively with increase in the GLP1 secretion. The results of in vivo studies indicated a marked reduction in blood glucose and HbA1c levels along with positive effects on other parameters like lipid profile, liver functions and renal functions of extract-treated mice as compared to control. The histological examination of the liver demonstrated hepatoprotective effects against diabetes led changes and various classes of phytochemicals were also identified through GCMS in different fractions. Conclusion The results revealed strong antidiabetic activity of R. stricta root with the potential to protect body organs against diabetic changes. Moreover, a variety of phytochemicals has also been identified through GCMS that might be responsible for the antidiabetic potential of Rhazya stricta root. Graphical abstract ![]()
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Affiliation(s)
- Rashid Mahmood
- Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.,Drugs Control & Traditional Medicines Division, National Institute of Health, Islamabad, Pakistan
| | - Waqas Khan Kayani
- Department of Plant Breeding, Swedish University of Agricultural Sciences, Växtskyddsvägen 1, SE-230 53 Alnarp, Uppsala, Sweden
| | - Tanveer Ahmed
- Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Farnaz Malik
- Drugs Control & Traditional Medicines Division, National Institute of Health, Islamabad, Pakistan
| | - Shahzad Hussain
- Drugs Control & Traditional Medicines Division, National Institute of Health, Islamabad, Pakistan
| | - Muhammad Ashfaq
- Drugs Control & Traditional Medicines Division, National Institute of Health, Islamabad, Pakistan
| | - Hussain Ali
- Animal House, National Institute of Health, Islamabad, Pakistan
| | - Samina Rubnawaz
- Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Brian D Green
- Institute for Global Food Security, School of Biological Sciences, Queen's University Belfast, Belfast, Northern Ireland
| | - Danielle Calderwood
- Institute for Global Food Security, School of Biological Sciences, Queen's University Belfast, Belfast, Northern Ireland
| | - Owen Kenny
- Institute for Global Food Security, School of Biological Sciences, Queen's University Belfast, Belfast, Northern Ireland
| | - Gerardo A Rivera
- Institute for Global Food Security, School of Biological Sciences, Queen's University Belfast, Belfast, Northern Ireland
| | - Bushra Mirza
- Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Faiza Rasheed
- KTH Royal Institute of Technology, School of Chemical Science and Engineering, SE-100 44, Stockholm, Sweden.
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Kaneto H, Koshida R, Baxter M. Fixed-ratio combination of basal insulin and glucagon-like peptide-1 receptor agonists in the treatment of Japanese people with type 2 diabetes: An innovative solution to a complex therapeutic challenge. Diabetes Obes Metab 2020; 22 Suppl 4:24-34. [PMID: 32436323 DOI: 10.1111/dom.14095] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 05/12/2020] [Accepted: 05/19/2020] [Indexed: 12/13/2022]
Abstract
Over 10 million people in Japan have known or suspected type 2 diabetes (T2D), and this number is expected to rise. Although many people require therapy escalation because of the progressive nature of T2D, this appears to be suboptimal in Japanese real-world clinical practice. Insulin therapy tends to be introduced only when glycaemic control is very poor (mean glycated haemoglobin >9%). Although basal insulin therapy is effective in reducing fasting plasma glucose (FPG), postprandial plasma glucose often remains uncontrolled. Basal-bolus insulin regimens are complex and carry the risk of weight gain and hypoglycaemia. Recently, fixed-ratio combinations (FRCs) of BI and glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown efficacy in reducing both FPG and postprandial plasma glucose with a single injection and without increased risk of hypoglycaemia or weight gain. IDegLira, a titratable FRC of insulin degludec (100 U/mL) and liraglutide, is currently available in Japan and the United States/European Union at a ratio of 1 U (unit):0.036 mg. iGlarLixi (insulin glargine 100 U/mL and lixisenatide at a ratio of 1:1 (20 U/20 μg) has recently been approved in Japan. Phase 3 trials in Japan for IDegLira (DUAL Japan) and iGlarLixi (LixiLan JP) have shown that both FRCs are efficacious. This review provides an overview of IDegLira and iGlarLixi (Japanese formulation) and considers their potential use as new therapeutic options to address the clinical need for early glycaemic control in Japanese people with T2D.
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Affiliation(s)
- Hideaki Kaneto
- Division of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, Kurashiki, Japan
| | | | - Mike Baxter
- Medical Affairs, Sanofi, Reading, UK
- Department of Diabetes and Endocrinology, University of Swansea, Swansea, UK
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Mak WY, Nagarajah JR, Abdul Halim H, Ramadas A, Mohd Pauzi Z, Pee LT, Jagan N. Dipeptidyl Peptidase-4 inhibitors use in type II diabetic patients in a tertiary hospital. J Pharm Policy Pract 2020; 13:34. [PMID: 32566235 PMCID: PMC7301996 DOI: 10.1186/s40545-020-00238-y] [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] [Indexed: 12/17/2022] Open
Abstract
Background In Malaysia, for more than a decade, dipeptidyl peptidase-4 inhibitors (DPP-4i) are among the oral antidiabetic medications used as monotherapy or in combination to manage type II diabetes mellitus (T2DM). These medications are known for the efficacy in glycated haemoglobin (HbA1c) reduction and weight neutral effect with minimal hypoglycaemia occurrence. This study aimed to identify the outcomes of DPP-4i use in one of the largest tertiary public hospital in Southeast Asia. Methods This is a retrospective cross sectional study conducted in 2016, where stratified sampling method was used. Patients with T2DM treated with available DPP-4i; namely Linagliptin, Saxagliptin, Sitagliptin and Vildagliptin, for at least 3 months were identified from the pharmacy record. Medical records from Physician Clinic in Hospital Kuala Lumpur (HKL) were reviewed. Data on demographic, anthropometric, antidiabetic treatment modalities, laboratory and documented outcomes were collected. Outcomes endpoints which include changes in HbA1c, fasting blood glucose (FBG), and body weight were recorded and analysed. Adverse drug reactions (ADR) documented were also reported. Results and discussion A total of one hundred and five patients were recruited. The patients were 49.5% men (n = 52), with a mean age of 57 years, mean HbA1c of 8.5% (69 mmol/mol) and mean BMI of 29.5 kg/m2. At least 50% of the patients had T2DM for more than 10 years and more than two third of these patients had both T2DM and hypertension. Thirty nine patients were on Vildagliptin, 32 on Sitagliptin, 26 on Saxagliptin and the remaining on Linagliptin. The most commonly prescribed DPP-4i were Vildagliptin and Sitagliptin. Majority of the patients (90.4%) were prescribed with Metformin, with 62.8% of patients on fixed-dose combination, and the remaining on add-on Metformin therapy. Use of DPP-4i as an adjunct was associated with a mean reduction of 0.9% (9 mmol/mol) in HbA1c (p < 0.0001) and 1.15 mmol/L (19.82 mg/dL) in FBG (p = 0.001) without significant weight changes (p = 0.745). Sitagliptin had the highest reduction in HbA1c (1.66%,19 mmol/mol; p-value< 0.0001). Twelve ADRs were reported with the highest report on gastrointestinal intolerance (n = 7). None of the ADR reported caused any significant harm to the patients. Conclusion Overall, use of these DPP-4i as an adjunct antidiabetic was associated with reduction in HbA1c.
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Affiliation(s)
- Woh Yon Mak
- Department of Pharmacy, Hospital Kuala Lumpur, Kuala Lumpur, Malaysia
| | | | | | - Anitha Ramadas
- Department of Pharmacy, Hospital Kuala Lumpur, Kuala Lumpur, Malaysia
| | | | - Lay Ting Pee
- Department of Pharmacy, Hospital Kuala Lumpur, Kuala Lumpur, Malaysia
| | - Nirmala Jagan
- Department of Pharmacy, Hospital Kuala Lumpur, Kuala Lumpur, Malaysia
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Ferrari F, Moretti A, Villa RF. The treament of hyperglycemia in acute ischemic stroke with incretin-based drugs. Pharmacol Res 2020; 160:105018. [PMID: 32574826 DOI: 10.1016/j.phrs.2020.105018] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 05/21/2020] [Accepted: 06/10/2020] [Indexed: 12/14/2022]
Abstract
Stroke is a major cause of mortality and morbidity worldwide. Considerable experimental and clinical evidence suggests that both diabetes mellitus (DM) and post-stroke hyperglycemia are associated with increased mortality rate and worsened clinical conditions in acute ischemic stroke (AIS) patients. Insulin treatment does not seem to provide convincing benefits for these patients, therefore prompting a change of strategy. The selective agonists of Glucagon-Like Peptide-1 Receptors (GLP-1Ras) and the Inhibitors of Dipeptidyl Peptidase-IV (DPP-IVIs, gliptins) are two newer classes of glucose-lowering drugs used for the treatment of DM. This review examines in detail the rationale for their development and the physicochemical, pharmacokinetic and pharmacodynamic properties and clinical activities. Emphasis will be placed on their neuroprotective effects at cellular and molecular levels in experimental models of acute cerebral ischemia. In perspective, an adequate basis does exist for a novel therapeutic approach to hyperglycemia in AIS patients through the additive treatment with GLP-1Ras plus DPP-IVIs.
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Affiliation(s)
- Federica Ferrari
- Department of Advanced Diagnostic and Therapeutic Technologies, Section of Neuroradiology, ASST Grande Ospedale Metropolitano Niguarda, Piazza Ospedale Maggiore 3, 20162 Milano, Italy; Departments of Biology-Biotechnology and Chemistry, Laboratory of Pharmacology and Molecular Medicine of Central Nervous System, University of Pavia, Via Ferrata 9, 27100 Pavia, Italy
| | - Antonio Moretti
- Departments of Biology-Biotechnology and Chemistry, Laboratory of Pharmacology and Molecular Medicine of Central Nervous System, University of Pavia, Via Ferrata 9, 27100 Pavia, Italy
| | - Roberto Federico Villa
- Departments of Biology-Biotechnology and Chemistry, Laboratory of Pharmacology and Molecular Medicine of Central Nervous System, University of Pavia, Via Ferrata 9, 27100 Pavia, Italy.
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Culturally based pre-Ramadan education increased benefits and reduced hazards of Ramadan fasting for type 2 diabetic patients. J Diabetes Metab Disord 2020; 19:179-186. [PMID: 32550167 DOI: 10.1007/s40200-020-00489-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Accepted: 01/05/2020] [Indexed: 10/25/2022]
Abstract
Objectives In the current study, we aimed at evaluating the effect of a culturally-based pre-Ramadan education program (PREP) on glycemic control, weight, adherence to post-sunset physical activity, perception of hypoglycemia, and anti-diabetic medication dose adjustment during Ramadan fasting in type 2 diabetics. Study design A total of 1008 type 2 Diabetes patients were offered a culturally-based PREP in addition to the standard of care, two months before Ramadan. A retrospective interview one month after Ramadan compared the fasting experience of PREP attendees (470 patients) with those who merely received standard of care (538 patients) (Non-PREP). Results Ramadan fasting improved glycemic control with a correlation between HbA1c percent reduction and the number of fasting days (r = -0.290, p = 0.007). More HbA1c and weight percent reduction were observed in PREP attendees compared to the Non-PREP group (-14.8% ± 9.3 vs. -5.4% ± 5.4; p < 0.001; and - 1.96% ± 5.4 vs. -0.39% ± 2.8; p < 0.001, respectively). More commitment to night prayers in the PREP attendees compared to the Non-PREP group, (85.5% prayed >20 nights vs 28.4%; p < 0.001) with more HbA1c and weight percent reduction in the those who performed the prayers more than 20 nights compared to those who performed no prayers (-11.69% ± 8.8 vs -6.28% ± 6.4, p < 0.001; and - 2.76% ±5.1 vs 1.35% ±1.8, p < 0.001, respectively). More perception of true hypoglycemia was associated with PREP attendance (p0.046), insulin treatment (p0.000), and reduction of antidiabetic medication dosage (p0.004). Repeated lowering of antidiabetic medications doses with sequential downsizing of meals' portions, and appetite was reported. Conclusion Ramadan fasting was beneficial for people with type 2 diabetes with reduction of HbA1c in correlation with the number of fasting days. Contrasting PREP with Non-PREP participants discovered better HbA1c and weight reduction in the former group even with equal number of fasting days. PREP participants performed more Taraweeh night prayers. The more the prayer nights the more decline of HbA1c and weight was observed. PREP improved perception and response to hypoglycemia with low-dosing of antidiabetic medications, especially insulin.
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Vasculoprotective Effects of Vildagliptin. Focus on Atherogenesis. Int J Mol Sci 2020; 21:ijms21072275. [PMID: 32218354 PMCID: PMC7177465 DOI: 10.3390/ijms21072275] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 03/19/2020] [Accepted: 03/23/2020] [Indexed: 12/13/2022] Open
Abstract
Vildagliptin is a representative of Dipeptidyl Peptidase-4 (DPP-4) inhibitors, antihyperglycemic drugs, approved for use as monotherapy and combination therapy in type 2 diabetes mellitus. By inhibiting enzymatic decomposition, DPP-4 inhibitors increase the half-life of incretins such as GLP-1 (Glucagon-like peptide-1) and GIP (Gastric inhibitors polypeptide) and prolong their action. Some studies present results suggesting the anti-sclerotic and vasculoprotective effects of vildagliptin reaching beyond glycemic control. Vildagliptin is able to limit inflammation by suppression of the NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) signaling pathway and proinflammatory agents such as TNF-α (tumor necrosis factor α), IL-1β (Interleukin-1β), and IL-8 (Interleukin 8). Moreover, vildagliptin regulates lipid metabolism; attenuates postprandial hypertriglyceridemia; and lowers serum triglycerides, apolipoprotein B, and blood total cholesterol levels. This DPP-4 inhibitor also reduces macrophage foam cell formation, which plays a key role in atheromatous plaque formation and stability. Vildagliptin reduces vascular stiffness via elevation of nitric oxide synthesis, improves vascular relaxation, and results in reduction in both systolic and diastolic blood pressure. Treatment with vildagliptin lowers the level of PAI-1 presenting possible antithrombotic effect. By affecting the endothelium, inflammation, and lipid metabolism, vildagliptin may affect the development of atherosclerosis at its various stages. The article presents a summary of the studies assessing vasculoprotective effects of vildagliptin with special emphasis on atherogenesis.
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Abdalla MA, Deshmukh H, Atkin S, Sathyapalan T. A review of therapeutic options for managing the metabolic aspects of polycystic ovary syndrome. Ther Adv Endocrinol Metab 2020; 11:2042018820938305. [PMID: 32670541 PMCID: PMC7338645 DOI: 10.1177/2042018820938305] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Accepted: 06/08/2020] [Indexed: 12/12/2022] Open
Abstract
Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women of reproductive age. Metabolic sequelae associated with PCOS range from insulin resistance to type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). Insulin resistance plays a significant role in the pathophysiology of PCOS and it is a reliable marker for cardiometabolic risk. Although insulin sensitising agents such as metformin have been traditionally used for managing metabolic aspects of PCOS, their efficacy is low in terms of weight reduction and cardiovascular risk reduction compared with newer agents such as incretin mimetics and SGLT2 inhibitors. With current pharmaceutical advances, potential therapeutic options have increased, giving patients and clinicians more choices. Incretin mimetics are a promising therapy with a unique metabolic target that could be used widely in the management of PCOS. Likewise, bariatric procedures have become less invasive and result in effective weight loss and the reversal of metabolic morbidities in some patients. Therefore, surgical treatment targeting weight loss becomes increasingly common in the management of obese women with PCOS. Newer emerging therapies, including twincretins, triple GLP-1 agonists, glucagon receptor antagonists and imeglemin, are promising therapeutic options for treating T2DM. Given the similarity of metabolic and pathological features between PCOS and T2DM and the variety of therapeutic options, there is the potential to widen our strategy for treating metabolic disorders in PCOS in parallel with current therapeutic advances. The review was conducted in line with the recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome 2018.
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Affiliation(s)
- Mohammed Altigani Abdalla
- Department of Academic Diabetes, Endocrinology
and Metabolism, Hull York Medical School, University of Hull, Hull, UK
| | - Harshal Deshmukh
- Department of Academic Diabetes, Endocrinology
and Metabolism, Hull York Medical School, University of Hull, Hull, UK
| | - Stephen Atkin
- School of Postgraduate Studies and Research,
RCSI Medical University of Bahrain, Kingdom of Bahrain
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Abdelaziz TS, Ali AY, Fatthy M. Efficacy and Safety of Dipeptidyl Peptidase-4 Inhibitors in Kidney Transplant Recipients with Post-transplant Diabetes Mellitus (PTDM)- a Systematic Review and Meta-Analysis. Curr Diabetes Rev 2020; 16:580-585. [PMID: 30907326 DOI: 10.2174/1573399815666190321144310] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Revised: 03/08/2019] [Accepted: 03/15/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND Kidney transplant recipients may develop post-transplant diabetes mellitus (PTDM). Dipeptidyl peptidase 4(DPP-4) inhibitors are evolving agents in the management of patients with diabetes mellitus. AIM To evaluate the efficacy and safety of DPP-4 inhibitors in the management of post-transplant diabetes mellitus (PTDM) in renal transplant recipients. METHODS We performed a systematic search of the electronic databases using keys words and Mesh terms. Data were extracted and reviewed using structured proforma. A comprehensive review of the eligible studies was performed independently by each of two reviewers; conflicts were resolved by the third reviewer. The primary efficacy endpoint was the difference in glycosylated hemoglobin (HbA1c) comparing any of the DPP-4 inhibitors to either placebo or other hypoglycaemic agent. The primary safety endpoints were the worsening of graft functions and change in Tacrolimus trough level. We performed the Random effect model using standardised mean difference. RESULTS We identified seven studies that were eligible for the systematic review; only one study compared Sitagliptin to insulin Glargine. One study involved head to head comparison of three DPP-4 inhibitors. The other five studies were pooled in the meta-analysis. DPP-4 inhibitors had a favourable glycemic effect as measured by HbA1c when compared to either placebo or oral anti-hyperglycemic medications (standardised mean difference in HbA1c = -0.993, 95% CI= -1.303 to -0.683, P=0.001). DPP-4 inhibitors use did not result in significant change in eGFR ((standardised mean difference = 0.147, 95% CI= -0.139 - 0.433, p=0.312).) nor Tacrolimus level (standardised Mean Difference= 0.152, 95% CI= -0.172 to 0.477, P=0.354). CONCLUSION Current evidence supports the short term efficacy and safety of DDP-4 inhibitor agents in the management of post transplantation diabetes mellitus (PTDM) in kidney transplant recipients. However, more RCTs are required to investigate the long-term safety and efficacy of these agents in kidney transplant recipients.
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Affiliation(s)
- Tarek Samy Abdelaziz
- Department of Renal Medicine, Kasr Alainy Hospitals, Cairo University hospitals, Cairo 14321, Egypt
| | - Ahmed Yamany Ali
- Department of Renal Medicine, Kasr Alainy Hospitals, Cairo University hospitals, Cairo 14321, Egypt
| | - Moataz Fatthy
- Department of Renal Medicine, Kasr Alainy Hospitals, Cairo University hospitals, Cairo 14321, Egypt
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Lee M, Sun J, Han M, Cho Y, Lee JY, Nam CM, Kang ES. Nationwide Trends in Pancreatitis and Pancreatic Cancer Risk Among Patients With Newly Diagnosed Type 2 Diabetes Receiving Dipeptidyl Peptidase 4 Inhibitors. Diabetes Care 2019; 42:2057-2064. [PMID: 31431452 DOI: 10.2337/dc18-2195] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Accepted: 07/29/2019] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Dipeptidyl peptidase 4 inhibitors (DPP-4i) are useful incretin-based antidiabetes drugs. However, there is a concern that DPP-4i may adversely impact the exocrine pancreas, owing to their pleiotropic effects. In this study, we investigated whether DPP-4i are associated with pancreatitis and pancreatic cancer using a nationwide population-based cohort study. RESEARCH DESIGN AND METHODS We included patients newly diagnosed with type 2 diabetes who were treated with antidiabetes drugs (n = 33,208) from 2007 to 2013. The data were obtained from the Korean National Health Insurance Service-Health Screening Cohort database (n = 514,866). Risk was estimated using a Cox proportional hazards model with time-dependent covariates. A 6-month lag time was used to account for a possible latency time. The risk across various time segments since the first prescription of DPP-4i was also analyzed. RESULTS Out of 33,208 subjects, 10,218 were new users of DPP-4i and 22,990 were new users of other antidiabetes drugs. DPP-4i significantly increased the risks of pancreatitis (adjusted hazard ratio [aHR] 1.24, 95% CI 1.01-1.52; P = 0.037) and pancreatic cancer (aHR 1.81, 95% CI 1.16-2.82; P = 0.009) with a 6-month drug use lag period. The risk of pancreatitis and pancreatic cancer was generally consistent in the first 12 months and 1 year after the initial prescription without showing an increasing trend according to exposure duration. CONCLUSIONS DPP-4i use is associated with increased risks of pancreatitis and pancreatic cancer in patients with newly diagnosed type 2 diabetes. However, the absence of increasing trend according to exposure duration suggests the chances of reverse causality, and long-term pancreatic safety of DPP-4i has to be further investigated.
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Affiliation(s)
- Minyoung Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jiyu Sun
- Biostatistics and Computing, Graduate School, Yonsei University, Seoul, Republic of Korea
| | - Minkyung Han
- Department of Public Health, Graduate School, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yongin Cho
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Ji-Yeon Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Chung Mo Nam
- Department of Preventive Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Eun Seok Kang
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea .,Institute of Endocrine Research, Yonsei University College of Medicine, Seoul, Republic of Korea
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A Randomized Pilot Study of the Effect of Trelagliptin and Alogliptin on Glycemic Variability in Patients with Type 2 Diabetes. Adv Ther 2019; 36:3096-3109. [PMID: 31562608 PMCID: PMC6822803 DOI: 10.1007/s12325-019-01097-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Indexed: 01/27/2023]
Abstract
INTRODUCTION This open-label, parallel-group, exploratory study examined the effects of two dipeptidyl peptidase 4 (DPP4) inhibitors on glycemic variability (GV) in patients with type 2 diabetes. METHODS Randomized patients with glycated hemoglobin A1c of at least 6.5% to less than 8.5% received trelagliptin 100 mg (n = 13) once weekly or alogliptin 25 mg (n = 14) once daily for 29 days. Continuous glucose monitoring was performed before the start of the treatment period (baseline) and from day 21 to 29, inclusive. The primary endpoint was change from baseline in the standard deviation (SD) of 24-h blood glucose values, measured daily for 7 days (day 22-28) of the treatment period. Secondary and additional efficacy endpoints included changes in glycemic parameters and the rate of DPP4 inhibition, respectively. Adverse events (AEs) were monitored to assess safety. RESULTS Mean change from baseline in the SD of 24-h blood glucose (95% confidence interval) at day 28 was - 7.35 (- 15.13, 0.44) for trelagliptin and - 11.63 (- 18.67, - 4.59) for alogliptin. In both treatment groups, glycemic parameters improved and the rate of DPP4 inhibition was maintained. Three patients reported AEs; no severe treatment-emergent AEs were reported in either group. CONCLUSION Once-weekly trelagliptin and once-daily alogliptin improved glycemic control and reduced GV without inducing hypoglycemia. TRIAL REGISTRATION ClinicalTrials.gov (NCT02771093) and JAPIC (JapicCTI-163250). FUNDING Takeda Pharmaceutical Company, Ltd.
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Neuroprotective Properties of Linagliptin: Focus on Biochemical Mechanisms in Cerebral Ischemia, Vascular Dysfunction and Certain Neurodegenerative Diseases. Int J Mol Sci 2019; 20:ijms20164052. [PMID: 31434198 PMCID: PMC6719127 DOI: 10.3390/ijms20164052] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 08/16/2019] [Accepted: 08/17/2019] [Indexed: 02/08/2023] Open
Abstract
Linagliptin is a representative of dipeptidyl peptidase 4 (DPP-4) inhibitors which are registered and used effectively in a treatment of diabetes mellitus type 2. They increase the levels of active forms of endogenous incretins such as GLP-1 and GIP by inhibiting their enzymatic decomposition. Scientific reports suggest beneficial effects of linagliptin administration via immunological and biochemical pathways involved in neuroprotective processes of CNS. Linagliptin’s administration leads to a decrease in the concentration of proinflammatory factors such as: TNF-α, IL-6 and increases the number of anti-inflammatory patrolling monocytes CX3CR1bright. Significant reduction in Aβ42 level has been associated with the use of linagliptin implying potential application in Alzheimer’s disease. Linagliptin improved vascular functions by increasing production of nitric oxide (NO) and limiting concentration of apolipoprotein B. Linagliptin-induced decrease in macrophages infiltration may provide improvement in atheromatous plaque stabilization. Premedication with linagliptin increases neuron’s survival after stroke and augments neuronal stem cells proliferation. It seems to be connected with SDF-1α/CXCR4 signaling pathway. Linagliptin prevented abnormal proliferation and migration of rat brain microvascular endothelial cells in a state of hypoperfusion via SIRT1/HIF-1α/VEGF pathway. The article presents a summary of the studies assessing neuroprotective properties of linagliptin with special emphasis on cerebral ischemia, vascular dysfunction and neurodegenerative diseases.
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Gou ZP, Wang ZL, Liang XF, Zheng L, Wang Y, Feng P. Single-dose escalation study of yogliptin in healthy Chinese volunteers. Eur J Pharm Sci 2019; 136:104950. [PMID: 31173870 DOI: 10.1016/j.ejps.2019.06.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Revised: 05/12/2019] [Accepted: 06/03/2019] [Indexed: 02/05/2023]
Abstract
BACKGROUND Yogliptin is a novel xanthine dipeptidyl peptidase-4 (DPP-4) inhibitor targeting type 2 diabetes. After promising preclinical pharmacological studies, the first human trial of yogliptin was designed. METHODS A randomized, double-blind, parallel, placebo-controlled phase I single-dose escalation study was designed to evaluate the pharmacokinetics, pharmacodynamics, and tolerability after single oral doses of yogliptin in healthy Chinese subjects. Healthy subjects were assigned to nine cohorts, which received a single dose of yogliptin at 2.5, 5, 10, 25, 50, 100, 200, 400, or 600 mg. Two subjects in each cohort received placebo. Blood samples were collected before dosing and up to 192 h afterwards. Urine samples were collected until 120 h after dosing. Plasma and urine drug concentrations were determined using liquid chromatography coupled with tandem mass spectrometry, and DPP-4 activity was measured using a semi-quantitative, fluorescence-based kinetic assay. RESULTS A total of 104 subjects were enrolled, 103 of whom completed the study (mean age, 25.3 years; mean weight, 58.8 kg; mean BMI, 21.8 kg/m2). A total of 27 adverse events (AEs) occurred in 25 of 86 yogliptin subjects (29.1%), and 3 AEs occurred in 3 of 18 placebo subjects (16.7%). Yogliptin was absorbed with a median time of maximum observed concentration (Tmax) of 3.0 h and was eliminated slowly with a t1/2 of 25.45-43.84 h. The maximum observed concentration (Cmax) and area under the curve (AUC) varied slightly more than dose-proportionally over the dose range from 2.5 to 400 mg. The fraction of drug excreted in urine ranged from 8.39% to 24.77%. Mean DPP-4 inhibition at 24 h after dosing ranged from 97.7% to 99.5%, and DPP-4 inhibition was >80% for 72 h at doses from 25 to 400 mg. DPP-4 inhibition was >80% for 1 week in the group receiving 400 mg. CONCLUSION Yogliptin was well tolerated in healthy subjects, with no dose-limiting toxicity observed in the range from 2.5 to 600 mg. Yogliptin inhibited plasma DPP-4 activity for 72 h at single doses of 25-200 mg and for 1 week at 400 mg, suggesting that once-weekly dosing of yogliptin is possible in type 2 diabetes patients. TRIAL REGISTRATION ChiCTR-IIR-17010311 (Chictr.org).
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Affiliation(s)
- Zhong-Ping Gou
- Institute of Drug Clinical Trials, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China
| | - Zhen-Lei Wang
- Institute of Drug Clinical Trials, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China
| | - Xiu-Fang Liang
- Institute of Drug Clinical Trials, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China
| | - Li Zheng
- Institute of Drug Clinical Trials, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China
| | - Ying Wang
- Institute of Drug Clinical Trials, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China
| | - Ping Feng
- Institute of Drug Clinical Trials, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China.
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Liu Z, Yang B. Drug Development Strategy for Type 2 Diabetes: Targeting Positive Energy Balances. Curr Drug Targets 2019; 20:879-890. [DOI: 10.2174/1389450120666181217111500] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Revised: 12/07/2018] [Accepted: 12/10/2018] [Indexed: 12/22/2022]
Abstract
Newer classes of medications have been proven useful in glycemic control in type 2 diabetes
(T2D), but many do not appear capable to slow down the progressive loss of ß-cell function, or to
improve population-level glycemic control. Positive energy balance, e.g. surplus energy intake over
expenditure, is at the core for developing metabolic syndrome and T2D. Currently available glycemic
control drugs come to the market based on their 1-2 years risk-benefit profiles, but most of them do
not correct positive energy balance and lose efficacy in the long-term. This denouement is destined by
a positive energy balance of T2D. There is continuous endeavor/investment in new drugs for T2D. In
this review, we compared the effects of commonly used oral hypoglycemic agents on energy balance
and discussed several novel therapeutic targets/approaches for T2D that could potentially correct positive
energy balance: changing the composition of intestinal host-microbiota to alleviate excess caloric
consumption, controlling chylomicron uptake into intestinal lacteals to reduce excessive caloric intake,
and activating pyruvate kinase M2 (PKM2) to ameliorate glucose metabolism and increase energy
expenditure. We further reviewed how nicotine affects body weight and ameliorates positive energy
balance, and ways to encourage people to adopt a more healthy lifestyle by exercising more
and/or decreasing caloric intake. These potential targets/approaches may hopefully correct positive
energy balance, delay disease progression, reverse some pathophysiological changes, and eventually
prevent and/or cure the disease. Drug development strategies applying new insights into T2D process
and therapeutic index to correct positive energy balance need to be seriously considered.
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Affiliation(s)
- Zhenqi Liu
- Division of Endocrinology & Metabolism, Department of Medicine, University of Virginia School of Medicine, 450 Ray C. Hunt Dr. Charlottesville, VA 22903, United States
| | - Baichun Yang
- Division of Cardiovascular and Renal Products, Office of New Drugs I, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993, United States
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Varin EM, Mulvihill EE, Beaudry JL, Pujadas G, Fuchs S, Tanti JF, Fazio S, Kaur K, Cao X, Baggio LL, Matthews D, Campbell JE, Drucker DJ. Circulating Levels of Soluble Dipeptidyl Peptidase-4 Are Dissociated from Inflammation and Induced by Enzymatic DPP4 Inhibition. Cell Metab 2019; 29:320-334.e5. [PMID: 30393019 DOI: 10.1016/j.cmet.2018.10.001] [Citation(s) in RCA: 90] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Revised: 05/15/2018] [Accepted: 10/05/2018] [Indexed: 12/17/2022]
Abstract
Dipeptidyl peptidase-4 (DPP-4) controls glucose homeostasis through enzymatic termination of incretin action. We report that plasma DPP-4 activity correlates with body weight and fat mass, but not glucose control, in mice. Genetic disruption of adipocyte Dpp4 expression reduced plasma DPP-4 activity in older mice but did not perturb incretin levels or glucose homeostasis. Knockdown of hepatocyte Dpp4 completely abrogated the obesity-associated increase in plasma DPP-4 activity, reduced liver cytokine expression, and partially attenuated inflammation in adipose tissue without changes in incretin levels or glucose homeostasis. In contrast, circulating levels of soluble DPP4 (sDPP4) were dissociated from inflammation in mice with endothelial-selective or global genetic inactivation of Dpp4. Remarkably, inhibition of DPP-4 enzymatic activity upregulated circulating levels of sDPP4 originating from endothelial or hematopoietic cells without inducing systemic or localized inflammation. Collectively, these findings reveal unexpected complexity in regulation of soluble versus enzymatic DPP-4 and control of inflammation and glucose homeostasis.
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Affiliation(s)
- Elodie M Varin
- Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, LTRI, 600 University Avenue TCP5-1004, Toronto, ON M5G 1X5, Canada
| | - Erin E Mulvihill
- Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, LTRI, 600 University Avenue TCP5-1004, Toronto, ON M5G 1X5, Canada
| | - Jacqueline L Beaudry
- Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, LTRI, 600 University Avenue TCP5-1004, Toronto, ON M5G 1X5, Canada
| | - Gemma Pujadas
- Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, LTRI, 600 University Avenue TCP5-1004, Toronto, ON M5G 1X5, Canada
| | - Shai Fuchs
- Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, LTRI, 600 University Avenue TCP5-1004, Toronto, ON M5G 1X5, Canada
| | - Jean-François Tanti
- INSERM U1065, Mediterranean Center of Molecular Medicine, University Côte d'Azur, Faculty of Medicine, 06204 Nice, France
| | - Sofia Fazio
- INSERM U1065, Mediterranean Center of Molecular Medicine, University Côte d'Azur, Faculty of Medicine, 06204 Nice, France
| | - Kirandeep Kaur
- Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, LTRI, 600 University Avenue TCP5-1004, Toronto, ON M5G 1X5, Canada
| | - Xiemin Cao
- Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, LTRI, 600 University Avenue TCP5-1004, Toronto, ON M5G 1X5, Canada
| | - Laurie L Baggio
- Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, LTRI, 600 University Avenue TCP5-1004, Toronto, ON M5G 1X5, Canada
| | - Dianne Matthews
- Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, LTRI, 600 University Avenue TCP5-1004, Toronto, ON M5G 1X5, Canada
| | - Jonathan E Campbell
- Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, LTRI, 600 University Avenue TCP5-1004, Toronto, ON M5G 1X5, Canada
| | - Daniel J Drucker
- Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, LTRI, 600 University Avenue TCP5-1004, Toronto, ON M5G 1X5, Canada; Department of Medicine, University of Toronto, Toronto, ON M5S 2J7, Canada.
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Lundkvist P, Pereira MJ, Kamble PG, Katsogiannos P, Langkilde AM, Esterline R, Johnsson E, Eriksson JW. Glucagon Levels During Short-Term SGLT2 Inhibition Are Largely Regulated by Glucose Changes in Patients With Type 2 Diabetes. J Clin Endocrinol Metab 2019; 104:193-201. [PMID: 30137410 DOI: 10.1210/jc.2018-00969] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2018] [Accepted: 08/09/2018] [Indexed: 01/14/2023]
Abstract
CONTEXT The mechanism mediating sodium glucose cotransporter-2 (SGLT2) inhibitor-associated increase in glucagon levels is unknown. OBJECTIVE To assess short-term effects on glucagon, other hormones, and energy substrates after SGLT2 inhibition and whether such effects are secondary to glucose lowering. The impact of adding a dipeptidyl peptidase-4 inhibitor was addressed. DESIGN, SETTING, AND PATIENTS A phase 4, single-center, randomized, three-treatment crossover, open-label study including 15 patients with type 2 diabetes treated with metformin. INTERVENTIONS Patients received a single-dose of dapagliflozin 10 mg accompanied by the following in randomized order: isoglycemic clamp (experiment DG); saline infusion (experiment D); or saxagliptin 5 mg plus saline infusion (experiment DS). Directly after 5-hour infusions, a 2-hour oral glucose tolerance test (OGTT) was performed. RESULTS Glucose and insulin levels were stable in experiment DG and decreased in experiment D [P for difference (Pdiff) < 0.001]. Glucagon-to-insulin ratio (Pdiff < 0.001), and levels of glucagon (Pdiff < 0.01), nonesterified fatty acids (Pdiff < 0.01), glycerol (Pdiff < 0.01), and β-OH-butyrate (Pdiff < 0.05) were lower in DG vs D. In multivariate analysis, change in glucose level was the main predictor of change in glucagon level. In DS, glucagon and active GLP-1 levels were higher than in D, but glucose and insulin levels did not differ. During OGTT, glucose levels rose less and glucagon levels fell more in DS vs D. CONCLUSION The degree of glucose lowering markedly contributed to regulation of glucagon and insulin secretion and to lipid mobilization during short-term SGLT2 inhibition.
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Affiliation(s)
- Per Lundkvist
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Maria J Pereira
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Prasad G Kamble
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | | | | | | | - Eva Johnsson
- AstraZeneca Research and Development, Mölndal, Sweden
| | - Jan W Eriksson
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
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Xourgia E, Papazafiropoulou A, Melidonis A. Effects of antidiabetic drugs on epicardial fat. World J Diabetes 2018; 9:141-148. [PMID: 30254723 PMCID: PMC6153123 DOI: 10.4239/wjd.v9.i9.141] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2018] [Revised: 06/19/2018] [Accepted: 06/28/2018] [Indexed: 02/05/2023] Open
Abstract
Epicardial adipose tissue is defined as a deposit of adipocytes with pathophysiological properties similar to those of visceral fat, located in the space between the myocardial muscle and the pericardial sac. When compared with subcutaneous adipose tissue, visceral adipocytes show higher metabolic activity, lipolysis rates, increased insulin resistance along with more steroid hormone receptors. The epicardial adipose tissue interacts with numerous cardiovascular pathways via vasocrine and paracrine signalling comprised of pro- and anti-inflammatory cytokines excretion. Both the physiological differences between the two tissue types, as well as the fact that fat distribution and phenotype, rather than quantity, affect cardiovascular function and metabolic processes, establish epicardial fat as a biomarker for cardiovascular and metabolic syndrome. Numerous studies have underlined an association of altered epicardial fat morphology, type 2 diabetes mellitus (T2DM) and adverse cardiovascular events. In this review, we explore the prospect of using the epicardial adipose tissue as a therapeutic target in T2DM and describe the underlying mechanisms by which the antidiabetic drugs affect the pathophysiological processes induced from adipose tissue accumulation and possibly allow for more favourable cardiovascular outcomes though epicardial fat manipulation.
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Affiliation(s)
- Eleni Xourgia
- 1st Department of Internal Medicine and Diabetes Center, Tzaneio General Hospital of Piraeus, Athens 18536, Greece
| | - Athanasia Papazafiropoulou
- 1st Department of Internal Medicine and Diabetes Center, Tzaneio General Hospital of Piraeus, Athens 18536, Greece
| | - Andreas Melidonis
- 1st Department of Internal Medicine and Diabetes Center, Tzaneio General Hospital of Piraeus, Athens 18536, Greece
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Dawwas GK, Smith SM, Park H. Risk of heart failure hospitalization among users of dipeptidyl peptidase-4 inhibitors compared to glucagon-like peptide-1 receptor agonists. Cardiovasc Diabetol 2018; 17:102. [PMID: 30016946 PMCID: PMC6048850 DOI: 10.1186/s12933-018-0746-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2018] [Accepted: 07/07/2018] [Indexed: 12/19/2022] Open
Abstract
Background Incretin-based therapies including dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon like peptide-1 (GLP-1) receptor agonists are novel medications for type 2 diabetes management. Several studies have found cardioprotective effects of incretin-based therapies; however, it remains unclear whether there is any difference in heart failure (HF) risk between the two incretin-based therapies (DPP-4 inhibitors and GLP-1 receptor agonists). We aimed to assess the risk of hospitalization due to HF with the use of DPP-4 inhibitors compared to GLP-1 receptor agonists. Methods Using Truven Health Marketscan data, we conducted a retrospective cohort study of patients with type 2 diabetes, who were newly initiated on DPP-4 inhibitors or GLP-1 agonists. Follow-up continued from drug initiation until the first occurrence of: HF hospitalization (primary outcome), discontinuation of therapy (i.e. no fill for 7 days), switch to the comparator, end of enrollment, or end of study (December 2013). Cox proportional hazards models with propensity-score-matching were used to compare the risk of HF hospitalization between DPP-4 inhibitors and GLP-1 agonists. Results A total of 321,606 propensity score-matched patients were included in the analysis (n = 160,803 for DPP-4 inhibitors; n = 160,803 for GLP-1 agonists). After adjusting for baseline characteristics and disease risk factors, the use of DPP-4 inhibitors was associated with a 14% decreased risk of HF hospitalization compared to GLP-1 agonists use [hazard ratio (HR), 0.86; 95% confidence interval (CI) 0.83, 0.90]. The results were consistent in patients without baseline HF (HR, 0.85; 95% CI 0.82, 0.89), but the association was not statistically significant for patients with baseline HF (HR, 0.90; 95% CI 0.74, 1.07). Conclusion In this retrospective matched cohort of patients with type 2 diabetes, the use of DPP-4 inhibitors was associated with a reduced risk of HF hospitalization compared to GLP-1 agonists. However, the association was not statistically significant in patients who had HF prior to the use of DPP-4 inhibitors. Electronic supplementary material The online version of this article (10.1186/s12933-018-0746-4) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Ghadeer K Dawwas
- Department of Pharmaceutical Outcomes and Policy, College of Pharmacy, University of Florida, PO Box 100495, Gainesville, FL, 32610, USA
| | - Steven M Smith
- Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, PO Box 100486, Gainesville, FL, 32610, USA.,Department of Community Health and Family Medicine, College of Medicine, University of Florida, PO Box 100237, Gainesville, FL, 32610, USA
| | - Haesuk Park
- Department of Pharmaceutical Outcomes and Policy, College of Pharmacy, University of Florida, PO Box 100495, Gainesville, FL, 32610, USA.
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Molina-Vega M, Muñoz-Garach A, Fernández-García JC, Tinahones FJ. The safety of DPP-4 inhibitor and SGLT2 inhibitor combination therapies. Expert Opin Drug Saf 2018; 17:815-824. [DOI: 10.1080/14740338.2018.1497158] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Affiliation(s)
- María Molina-Vega
- Unidad de Gestión Clínica de Endocrinología y Nutrición, Hospital Universitario Virgen de la Victoria, Málaga, Spain
| | - Araceli Muñoz-Garach
- Unidad de Gestión Clínica de Endocrinología y Nutrición, Hospital Universitario Virgen de la Victoria, Málaga, Spain
- Instituto de Investigación Biomédica de Málaga (IBIMA), Málaga, Spain
| | - José C. Fernández-García
- Unidad de Gestión Clínica de Endocrinología y Nutrición, Hospital Universitario Virgen de la Victoria, Málaga, Spain
- Instituto de Investigación Biomédica de Málaga (IBIMA), Málaga, Spain
- Centro de Investigacion Biomedica en Red. Fisiopatologia de la Obesidad y Nutricion (CIBERObn CB06/003), Instituto de Salud Carlos III, Madrid, Spain
| | - Francisco J. Tinahones
- Unidad de Gestión Clínica de Endocrinología y Nutrición, Hospital Universitario Virgen de la Victoria, Málaga, Spain
- Instituto de Investigación Biomédica de Málaga (IBIMA), Málaga, Spain
- Centro de Investigacion Biomedica en Red. Fisiopatologia de la Obesidad y Nutricion (CIBERObn CB06/003), Instituto de Salud Carlos III, Madrid, Spain
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Abstract
OBJECTIVE To review therapeutic strategies for the management of patients with steroid-induced hyperglycemia. DATA SOURCES A literature search of MEDLINE/PubMed (1990 to June 2017) was conducted using the search terms steroid, glucocorticoid, corticosteroid, hyperglycemia, and diabetes as well via review of literature citations. STUDY SELECTION AND DATA EXTRACTION Relevant clinical trials and case studies focusing on pharmacological interventions in humans were reviewed for inclusion. Articles discussing islet cell transplant were excluded. DATA SYNTHESIS Hyperglycemia is a predictable adverse effect of glucocorticoid therapy, which is associated with negative outcomes, including an odds ratio of 1.36 for developing new-onset diabetes. A variety of strategies have been utilized for managing patients who are at risk of complications caused by steroid-induced hyperglycemia. Agents such as sulfonylureas, thiazolidinediones, meglitinides, metformin, dipeptidyl peptidase 4 (DPP-4) inhibitors, glucagon-like peptidase-1 agonists, and insulin have been evaluated in case studies and small clinical trials with varying degrees of success. CONCLUSIONS Since there are limited clinical data available to guide therapy, strategies that minimize the risk of adverse effects should be selected for the management of steroid-induced hyperglycemia. Therapies that may be safe and effective given current information include DPP-4 inhibitors, metformin, and weight-based neutral protamine Hagedorn insulin.
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Affiliation(s)
| | - Nicole L Metzger
- 1 Emory University Hospital, Atlanta, GA, USA.,2 Mercer University College of Pharmacy, Atlanta, GA, USA
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