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Njei B, Al-Ajlouni Y, Lemos SY, Ugwendum D, Ameyaw P, Njei LP, Boateng S. Efficacy and Safety of GLP-1 Receptor Agonists in Patients With Metabolic Dysfunction-Associated Steatotic Liver Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Cureus 2024; 16:e71366. [PMID: 39534801 PMCID: PMC11556413 DOI: 10.7759/cureus.71366] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/11/2024] [Indexed: 11/16/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) poses a major global health challenge. glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown potential therapeutic benefits for MASLD patients, including improvements in liver function, inflammation, and fibrosis. This study aims to systematically review and meta-analyze randomized controlled trials (RCTs) to evaluate the efficacy and safety of GLP-1RAs in MASLD patients, focusing on hepatic outcomes, cardiovascular outcomes, anthropometric measurements, and mortality. Following PRISMA guidelines, a comprehensive database search was conducted to include RCTs assessing GLP-1RAs' effects on MASLD. Quality assessment was conducted using the Revised Cochrane Risk of Bias tool. Our meta-analysis used a random-effects model, calculating standardized mean differences for continuous outcomes to determine the agents' efficacy and safety. Additionally, funnel plots were generated to assess publication bias, ensuring the integrity of our meta-analytical findings. The review included 27 trials, revealing GLP-1RAs significantly improved hepatic function markers (alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, and liver fat content) and cardiovascular risk factors (fasting blood sugar, HbA1c levels, lipid profiles). Additionally, GLP-1RAs were associated with significant reductions in body weight, BMI, subcutaneous fat, and waist circumference. GLP-1RAs demonstrate a promising therapeutic role in managing MASLD, offering benefits that extend to improving liver function, mitigating cardiovascular risk, and promoting weight loss. Further research is needed to confirm these findings and optimize GLP-1RAs' usage in MASLD treatment.
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Affiliation(s)
- Basile Njei
- Department of Medicine, Yale School of Medicine, New Haven, USA
| | | | - Samira Y Lemos
- Department of Diabetes and Endocrinology, Yaoundé General Hospital, Yaoundé, CMR
| | - Derek Ugwendum
- Department of Internal Medicine, Richmond University Medical Center Affiliated with Mount Sinai Health System and Icahn School of Medicine at Mount Sinai, Staten Island, USA
| | - Prince Ameyaw
- Department of Internal Medicine, Bridgeport Hospital, Yale New Haven Health, Bridgeport, USA
| | - Lea-Pearl Njei
- Department of Biological Science, University of Maryland Baltimore County, Baltimore, USA
| | - Sarpong Boateng
- Department of Medicine, Bridgeport Hospital, Bridgeport, USA
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Ali II, D'Souza C, Tariq S, Adeghate EA. Adropin Is Expressed in Pancreatic Islet Cells and Reduces Glucagon Release in Diabetes Mellitus. Int J Mol Sci 2024; 25:9824. [PMID: 39337311 PMCID: PMC11432804 DOI: 10.3390/ijms25189824] [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: 07/22/2024] [Revised: 08/30/2024] [Accepted: 09/06/2024] [Indexed: 09/30/2024] Open
Abstract
Diabetes mellitus affects 537 million adults around the world. Adropin is expressed in different cell types. Our aim was to investigate the cellular localization in the endocrine pancreas and its effect on modulating pancreatic endocrine hormone release in streptozotocin (STZ)-induced diabetic rats. Adropin expression in the pancreas was investigated in normal and diabetic rats using immunohistochemistry and immunoelectron microscopy. Serum levels of insulin, glucagon pancreatic polypeptide (PP), and somatostatin were measured using a Luminex® χMAP (Magpix®) analyzer. Pancreatic endocrine hormone levels in INS-1 832/3 rat insulinoma cells, as well as pancreatic tissue fragments of normal and diabetic rats treated with different concentrations of adropin (10-6, 10-9, and 10-12 M), were measured using ELISA. Adropin was colocalized with cells producing either insulin, glucagon, or PP. Adropin treatment reduced the number of glucagon-secreting alpha cells and suppressed glucagon release from the pancreas. The serum levels of GLP-1 and amylin were significantly increased after treatment with adropin. Our study indicates a potential role of adropin in modulating glucagon secretion in animal models of diabetes mellitus.
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Affiliation(s)
- Ifrah I Ali
- Department of Anatomy, College of Medicine & Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
| | - Crystal D'Souza
- Department of Anatomy, College of Medicine & Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
| | - Saeed Tariq
- Department of Anatomy, College of Medicine & Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
| | - Ernest A Adeghate
- Department of Anatomy, College of Medicine & Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
- Zayed Foundation, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
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Pratap-Singh A, Guo Y, Baldelli A, Singh A. Concept for a Unidirectional Release Mucoadhesive Buccal Tablet for Oral Delivery of Antidiabetic Peptide Drugs Such as Insulin, Glucagon-like Peptide 1 (GLP-1), and their Analogs. Pharmaceutics 2023; 15:2265. [PMID: 37765234 PMCID: PMC10534625 DOI: 10.3390/pharmaceutics15092265] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 08/11/2023] [Accepted: 08/12/2023] [Indexed: 09/29/2023] Open
Abstract
Injectable peptides such as insulin, glucagon-like peptide 1 (GLP-1), and their agonists are being increasingly used for the treatment of diabetes. Currently, the most common route of administration is injection, which is linked to patient discomfort as well as being subjected to refrigerated storage and the requirement for efficient supply chain logistics. Buccal and sublingual routes are recognized as valid alternatives due to their high accessibility and easy administration. However, there can be several challenges, such as peptide selection, drug encapsulation, and delivery system design, which are linked to the enhancement of drug efficacy and efficiency. By using hydrophobic polymers that do not dissolve in saliva, and by using neutral or positively charged nanoparticles that show better adhesion to the negative charges generated by the sialic acid in the mucus, researchers have attempted to improve drug efficiency and efficacy in buccal delivery. Furthermore, unidirectional films and tablets seem to show the highest bioavailability as compared to sprays and other buccal delivery vehicles. This advantageous attribute can be attributed to their capability to mitigate the impact of saliva and inadvertent gastrointestinal enzymatic digestion, thereby minimizing drug loss. This is especially pertinent as these formulations ensure a more directed drug delivery trajectory, leading to heightened therapeutic outcomes. This communication describes the current state of the art with respect to the creation of nanoparticles containing peptides such as insulin, glucagon-like peptide 1 (GLP-1), and their agonists, and theorizes the production of mucoadhesive unidirectional release buccal tablets or films. Such an approach is more patient-friendly and can improve the lives of millions of diabetics around the world; in addition, these shelf-stable formulations ena a more environmentally friendly and sustainable supply chain network.
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Affiliation(s)
- Anubhav Pratap-Singh
- Food, Nutrition, and Health Program, Faculty of Land & Food Systems, The University of British Columbia, 2205 East Mall, Vancouver, BC V6T 1Z4, Canada
| | - Yigong Guo
- Food, Nutrition, and Health Program, Faculty of Land & Food Systems, The University of British Columbia, 2205 East Mall, Vancouver, BC V6T 1Z4, Canada
- Natural Health and Food Products Research Group, Centre for Applied Research & Innovation (CARI), British Columbia Institute of Technology, Burnaby, BC V5G 3H2, Canada
| | - Alberto Baldelli
- Food, Nutrition, and Health Program, Faculty of Land & Food Systems, The University of British Columbia, 2205 East Mall, Vancouver, BC V6T 1Z4, Canada
| | - Anika Singh
- Food, Nutrition, and Health Program, Faculty of Land & Food Systems, The University of British Columbia, 2205 East Mall, Vancouver, BC V6T 1Z4, Canada
- Natural Health and Food Products Research Group, Centre for Applied Research & Innovation (CARI), British Columbia Institute of Technology, Burnaby, BC V5G 3H2, Canada
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Vadmand AC, Nissen AA, Mathiesen S, Soerum ME, Gerbek T, Fridh MK, Sørensen K, Hartmann B, Holst JJ, Müller K. Metabolic Dysregulation in Adult Survivors of Pediatric Hematopoietic Stem Cell Transplantation: The Role of Incretins. J Clin Endocrinol Metab 2023; 108:453-462. [PMID: 36181459 DOI: 10.1210/clinem/dgac561] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 09/19/2022] [Indexed: 01/20/2023]
Abstract
CONTEXT Survivors of pediatric hematopoietic stem cell transplantation (HSCT) have increased risk of developing metabolic syndrome (MetS), but the mechanisms are poorly understood. OBJECTIVE We aimed to test the hypothesis that insufficient secretion of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) plays a pathogenetic role in HSCT survivors with MetS. METHODS This cross-sectional cohort study, conducted at the Danish national referral center for HSCT, studied 42 male HSCT survivors (median age 28.9 years) for a median 21.2 years from HSCT, along with 15 age- and sex-matched healthy controls. Main outcome measures were glucose metabolism and incretin hormones (by oral glucose tolerance test [OGTT]) and MetS criteria. The hypothesis was formulated before data collection. RESULTS GLP-1, GIP, and glucagon during an OGTT were similar in patients and controls, with no overall difference between survivors with (24%) and without MetS. However, fasting glucagon was significantly higher in patients with hypertriglyceridemia (mean difference [MD]: 6.1 pmol/L; 95% CI, 1.5-10.8; P = 0.01), and correlated with HDL (MD: 4.7 mmol/L; 95% CI, -0.6 to 9.9; P = 0.08), android-gynoid ratio (correlation coefficient [r] = 0.6, P = 0.0001) and waist-hip ratio (r = 0.5, P = 0.002). A similar pattern was seen for GIP, correlating positively with triglyceride (MD: 60%; 95% CI, 44-82; P = 0.002). GIP levels were significantly increased in patients treated with total body irradiation (TBI) (MD: 165%; 95% CI, 118-230; P = 0.004), which was found to be a significant risk factor for MetS. CONCLUSION This study demonstrates an altered production of incretin hormones in HSCT survivors previously treated with TBI, developing dyslipidemia and abdominal adiposity.
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Affiliation(s)
- Amalia Christina Vadmand
- Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, DK-2100 Copenhagen, Denmark
| | - Anne Anker Nissen
- Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, DK-2100 Copenhagen, Denmark
| | - Sidsel Mathiesen
- Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, DK-2100 Copenhagen, Denmark
| | - Maria Ebbesen Soerum
- Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, DK-2100 Copenhagen, Denmark
| | - Tina Gerbek
- Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, DK-2100 Copenhagen, Denmark
| | - Martin Kaj Fridh
- Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, DK-2100 Copenhagen, Denmark
| | - Kaspar Sørensen
- Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, DK-2100 Copenhagen, Denmark
| | - Bolette Hartmann
- The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, DK-2200 Copenhagen N, Denmark
- Department of Biomedical Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark
| | - Jens Juul Holst
- The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, DK-2200 Copenhagen N, Denmark
- Department of Biomedical Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark
| | - Klaus Müller
- Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, DK-2100 Copenhagen, Denmark
- Institute for Inflammation Research, University Hospital Rigshospitalet, DK-2100 Copenhagen, Denmark
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DeMarsilis A, Reddy N, Boutari C, Filippaios A, Sternthal E, Katsiki N, Mantzoros C. Pharmacotherapy of type 2 diabetes: An update and future directions. Metabolism 2022; 137:155332. [PMID: 36240884 DOI: 10.1016/j.metabol.2022.155332] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 10/07/2022] [Accepted: 10/07/2022] [Indexed: 11/06/2022]
Abstract
Type 2 diabetes (T2D) is a widely prevalent disease with substantial economic and social impact for which multiple conventional and novel pharmacotherapies are currently available; however, the landscape of T2D treatment is constantly changing as new therapies emerge and the understanding of currently available agents deepens. This review aims to provide an updated summary of the pharmacotherapeutic approach to T2D. Each class of agents is presented by mechanism of action, details of administration, side effect profile, cost, and use in certain populations including heart failure, non-alcoholic fatty liver disease, obesity, chronic kidney disease, and older individuals. We also review targets of novel therapeutic T2D agent development. Finally, we outline an up-to-date treatment approach that starts with identification of an individualized goal for glycemic control then selection, initiation, and further intensification of a personalized therapeutic plan for T2D.
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Affiliation(s)
- Antea DeMarsilis
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA
| | - Niyoti Reddy
- Department of Medicine, School of Medicine, Boston University, Boston, USA
| | - Chrysoula Boutari
- Second Propedeutic Department of Internal Medicine, Hippocration Hospital, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Andreas Filippaios
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA
| | - Elliot Sternthal
- Section of Endocrinology, VA Boston Healthcare System, Harvard Medical School, Boston, MA 02115, USA
| | - Niki Katsiki
- Department of Nutritional Sciences and Dietetics, International Hellenic University, Sindos, Greece; School of Medicine, European University Cyprus, Nicosia, Cyprus.
| | - Christos Mantzoros
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA; Section of Endocrinology, VA Boston Healthcare System, Harvard Medical School, Boston, MA 02115, USA
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Dubourg J, Fouqueray P, Quinslot D, Grouin J, Kaku K. Long-term safety and efficacy of imeglimin as monotherapy or in combination with existing antidiabetic agents in Japanese patients with type 2 diabetes (TIMES 2): A 52-week, open-label, multicentre phase 3 trial. Diabetes Obes Metab 2022; 24:609-619. [PMID: 34866306 PMCID: PMC9305103 DOI: 10.1111/dom.14613] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Revised: 11/17/2021] [Accepted: 12/01/2021] [Indexed: 12/01/2022]
Abstract
AIM To evaluate the safety and efficacy of imeglimin for 52 weeks as monotherapy or combination therapy with existing antidiabetic agents in Japanese patients with type 2 diabetes. MATERIALS AND METHODS TIMES 2 was a phase 3, pivotal, open-label trial including patients with type 2 diabetes inadequately controlled despite diet/exercise or despite treatment with a single agent from one of several available classes of antidiabetic drugs along with diet/exercise. All patients received imeglimin 1000 mg twice-daily orally for 52 weeks as monotherapy or combination therapy. The primary endpoint was safety (adverse events, laboratory results, ECG). The secondary endpoints were changes from baseline in HbA1c and fasting plasma glucose at week 52. RESULTS A total of 714 patients received the following treatments: imeglimin monotherapy (n = 134), combination with an α-glucosidase inhibitor (n = 64), biguanide (n = 64), dipeptidyl peptidase-4 inhibitor (DPP4-I; n = 63), glinide (n = 64), glucagon-like peptide-1 receptor agonist (GLP1-RA; n = 70), sodium-glucose co-transporter-2 inhibitor (n = 63), sulphonylurea (n = 127), or thiazolidinedione (n = 65). The percentage of patients experiencing at least one treatment emergent adverse event (TEAE) was 75.5%. Most of these events were mild or moderate in intensity. Serious TEAEs, none of them related to the study drug, occurred in 5.6% of all patients. No clinically significant changes in ECG, vital signs, physical examination, or laboratory tests were noted in any groups. At week 52, HbA1c decreased by 0.46% with imeglimin monotherapy, by 0.56%-0.92% with imeglimin as oral combination therapy, and by 0.12% with injectable GLP1-RA combination therapy. The greatest net HbA1c reduction (0.92%) occurred in patients receiving a DPP4-I in combination with imeglimin. CONCLUSIONS Imeglimin provides well-tolerated, long-term safety and efficacy in both monotherapy and oral combination therapy in Japanese patients with type 2 diabetes.
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Affiliation(s)
| | | | | | | | - Kohei Kaku
- Department of Internal MedicineKawasaki Medical SchoolOkayamaJapan
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Hu S, Wang S, Qi C, Gu S, Shi C, Mao L, Fan G. Cost-Utility Analysis of Once-Weekly Semaglutide, Dulaglutide, and Exenatide for Type 2 Diabetes Patients Receiving Metformin-Based Background Therapy in China. Front Pharmacol 2022; 13:831364. [PMID: 35250578 PMCID: PMC8894868 DOI: 10.3389/fphar.2022.831364] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 01/31/2022] [Indexed: 11/18/2022] Open
Abstract
Introduction: The substantial financial burden associated with type 2 diabetes (T2D) over a lifetime cannot be neglected. Therefore, the objective of this study was to evaluate the pharmacoeconomic value of three once-weekly GLP-1 RAs, namely subcutaneous semaglutide (sc. SEMA), dulaglutide (DULA), and extended-release exenatide (e-r EXEN), in treating patients with T2D that cannot be controlled with metformin-based background therapy, and to find a suitable price reduction for non-cost-effective medications, to provide reasonable recommendations to the administration for adjusting drug prices. Methods: The baseline characteristics of the simulation patient cohort were sourced from a comprehensive meta-analysis synthesizing 453 trials evaluating 21 hypoglycemic agents from nine categories of drugs. The UKPDS OM2 was applied to project the long-term effectiveness and costs from a Chinese health care provider’s perspective. After cost-utility analysis, the reasonable price adjustment of non-cost-effective options was explored via binary search. Uncertainty was measured by means of sensitivity analysis. Results: After a 40-year simulation, the sc. SEMA, DULA, and e-r EXEN groups yielded 9.6315, 9.5968, and 9.5895 quality-adjusted life years (QALYs), respectively. In terms of expenditure, the total costs for the sc. SEMA, DULA, and e-r EXEN groups were $42012.47, $24931.27, and $40264.80, respectively. DULA was dominant over e-r EXEN due to the higher QALYs and lower total costs. The ICURs of sc. SEMA vs. DULA and sc. SEMA vs. e-r EXEN were $492994.72/QALY and $41622.69/QALY (ICUR > λ), respectively, indicating that sc. SEMA was not more cost-effective than DULA or e-r EXEN. The INMB and absolute NMB yielded the same conclusions which were robust to one-way, scenario, and probabilistic sensitivity analyses. After several assumptions in the binary search, sc. SEMA and e-r EXEN appear to become cost-effective when their annual costs are decreased by 57.67% and 70.34%, respectively, with DULA as a counterpart. Conclusion: From the cost-utility analysis, DULA appears to be the most cost-effective option among sc. SEMA, DULA, and e-r EXEN for the treatment of patients with T2D receiving metformin-based background therapy. With a 57.67% or 70.34% reduction in cost, sc. SEMA or e-r EXEN, respectively, would become as cost-effective as DULA in China.
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Çiçekli MN, Tiryaki ES, Altun A, Günaydın C. GLP-1 agonist liraglutide improves ouabain-induced mania and depressive state via GSK-3β pathway. J Recept Signal Transduct Res 2022; 42:486-494. [PMID: 35133924 DOI: 10.1080/10799893.2022.2032747] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Bipolar disorder (BD) is a severe mental illness characterized by aberrant mood changes between hypomania and mania or mixed states and depression. Metabolic changes also accompany disease progression and cause significant morbidity. Symptomatic treatment options are available, but asymptomatic patients and poor drug responders are significant problems. Based on the most common pharmacological agent that is used in the treatment, lithium and its main mechanisms of action, oxidative stress, and glycogen synthase kinase-3β (GSK-3β) signaling are extensively investigated. However, knowledge about the effects of compounds that positively affect oxidative stress and GSK-3β signaling, such as glucagon-like peptide-1 (GLP-1) mimetics, liraglutide, is still missing. Therefore, in this study, we aimed to investigate the effects of liraglutide on the ouabain-induced bipolar disease model in rats. After intracerebroventricular single dose ouabain administration, animals were treated with 100, 200, and 400 µg/kg liraglutide (s.c.) and valproic acid (200 mg/kg, i.p.) for 10 d. The locomotion and depressive states of animals were assessed by an open field, forced swimming test, and sucrose preference tests. Serum total antioxidant (TAS) and oxidant states (TOS) and glutathione, malonyl dialdehyde (MDA) levels in the brain tissue were determined. GSK-3β phosphorylation was evaluated by western blotting. Our results demonstrated that liraglutide attenuated ouabain-induced hyperlocomotion and depressive state. Additionally, liraglutide prevented oxidative stress after ouabain administration. Decreased GSK-3β phosphorylation due to the ouabain insult was alleviated by liraglutide treatment. These findings indicate that the manic and depressive-like behaviors are ameliorated by liraglutide, which exerted antioxidant action, possibly improving GSK-3β phosphorylation.
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Affiliation(s)
| | - Emre Soner Tiryaki
- Department of Physiology, School of Medicine, Ondokuz Mayıs University, Samsun, Turkey
| | - Ahmet Altun
- Department of Pharmacology, School of Medicine, Cumhuriyet University, Sivas, Turkey
| | - Caner Günaydın
- Department of Pharmacology, School of Medicine, Samsun University, Samsun, Turkey
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Quintilhano DL, Miksza DR, de Souza Galia WB, Ramalho MORC, Lucena CF, Valle MMR, Graciano MFR, de Souza HM, Bertolini GL. Insulin secretion decline in Walker-256 tumor-bearing rats is early, follows the course of cachexia, and is not improved by lixisenatide. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2021; 394:697-705. [PMID: 33128591 DOI: 10.1007/s00210-020-02006-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Accepted: 10/19/2020] [Indexed: 12/13/2022]
Abstract
Lixisenatide, a glucagon-like peptide-1 receptor agonist, is used to stimulate insulin secretion in patients with type 2 diabetes mellitus. However, its effect on insulin secretion in cancer patients, particularly during the cachexia course, has not yet been evaluated. The purpose of this study was to investigate the lixisenatide effect on INS secretion decline during the cachexia course (2, 6, and 12 days of tumor) in pancreatic islets isolated from Walker-256 tumor-bearing rats. Pancreatic islets of healthy and tumor-bearing rats were incubated in the presence or absence of lixisenatide (10 nM). Tumor-bearing rats showed reduction of body weight and fat and muscle mass, characterizing the development of cachexia, as well as reduction of insulinemia and INS secretion stimulated by glucose (5.6, 8.3, 11.1, 16.7, and 20 mM) on days 2, 6, and/or 12 of tumor. Lixisenatide increased the 16.7 mM glucose-stimulated insulin secretion, but not by 5.6 mM glucose, in the islets of healthy rats, without changing the insulin intracellular content. However, lixisenatide did not prevent the decreased 16.7 mM glucose-stimulated insulin secretion in the pancreatic islets of rats with 2, 6, and 12 days of tumor and neither the decreased insulin intracellular content of rats with 12 days of tumor. In consistency, in vivo treatment with lixisenatide (50 μg kg-1, SC, once daily, for 6 days) visually increased insulinemia of healthy fasted rats, but did not prevent hypoinsulinemia of tumor-bearing rats. In conclusion, Walker-256 tumor-bearing rats showed early decline (2 days of tumor) of insulin secretion, which followed the cachexia course (6 and 12 days of tumor) and was not improved by lixisenatide, evidencing that this insulin secretagogue, used to treat type 2 diabetes, does not have beneficial effect in cancer bearing-rats.
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Affiliation(s)
- Débora Luiza Quintilhano
- Department of Physiological Sciences, State University of Londrina, Londrina, PR, 86051-990, Brazil
| | - Daniele Romani Miksza
- Department of Physiological Sciences, State University of Londrina, Londrina, PR, 86051-990, Brazil
| | | | | | - Camila Ferraz Lucena
- Department of Physiology and Biophysics, University of São Paulo, Sao Paulo, PR, 05508-900, Brazil
| | | | | | - Helenir Medri de Souza
- Department of Physiological Sciences, State University of Londrina, Londrina, PR, 86051-990, Brazil
| | - Gisele Lopes Bertolini
- Department of Physiological Sciences, State University of Londrina, Londrina, PR, 86051-990, Brazil.
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Quintilhano DL, Miksza DR, Biazi GR, Frasson-Uemura IG, Graciano MFR, Mazzuco TL, Carpinelli ÂR, de Souza HM, Bertolini GL. Effects of lixisenatide treatment on mild cachexia and related metabolic abnormalities in Walker-256 tumour-bearing rats. Cell Biochem Funct 2020; 39:335-343. [PMID: 32911572 DOI: 10.1002/cbf.3588] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Revised: 08/03/2020] [Accepted: 08/16/2020] [Indexed: 11/07/2022]
Abstract
Lixisenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist, is used in the treatment of type 2 diabetes mellitus (T2DM). It increases insulin (INS) secretion and can decrease INS resistance, improving metabolic disorders in this disease. However, its effects on metabolic disturbances in cancer-bearing, which also exhibit decreased INS secretion and INS resistance, changes that may contribute to weight loss (cachexia), have not yet been evaluated. The purpose of this study was to investigate the lixisenatide treatment effects on mild cachexia and related metabolic abnormalities in Walker-256 tumour-bearing rats. Lixisenatide (50 μg kg-1 , SC) was administered once daily, for 6 days, after inoculation of Walker-256 tumour cells. Acute lixisenatide treatment did not improve hypoinsulinemia, INS secretion and INS resistance of tumour-bearing rats. It also did not prevent the reduced glucose and increased triacylglycerol and lactate in the blood and nor the loss of retroperitoneal and epididymal fat of these animals. However, acute lixisenatide treatment accentuated the body mass loss of tumour-bearing rats. Therefore, lixisenatide, unlike T2DM, does not improve hypoinsulinemia and INS resistance associated with cancer, evidencing that it does not have the same beneficial effects in these two diseases. In addition, lixisenatide aggravated weight loss of tumour-bearing rats, suggesting that its use for treatment of T2DM patients with cancer should be avoided. SIGNIFICANCE OF THE STUDY: Lixisenatide increases insulin secretion and appears to reduce insulin resistance in T2DM. However, lixisenatide treatment does not improve hypoinsulinemia and insulin resistance associated with cancer, as it does in T2DM, and aggravated weight loss, suggesting that its use for treatment of T2DM patients with cancer should be avoided.
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Affiliation(s)
- Débora L Quintilhano
- Department of Physiological Sciences, State University of Londrina, Londrina, Brazil
| | - Daniele R Miksza
- Department of Physiological Sciences, State University of Londrina, Londrina, Brazil
| | - Giuliana R Biazi
- Department of Physiological Sciences, State University of Londrina, Londrina, Brazil
| | | | | | - Tânia L Mazzuco
- Department of Clinical Medicine, State University of Londrina, Londrina, Brazil
| | - Ângelo R Carpinelli
- Department of Physiology and Biophysics, University of São Paulo, São Paulo, Brazil
| | - Helenir M de Souza
- Department of Physiological Sciences, State University of Londrina, Londrina, Brazil
| | - Gisele L Bertolini
- Department of Physiological Sciences, State University of Londrina, Londrina, Brazil
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Cornell S. A review of GLP-1 receptor agonists in type 2 diabetes: A focus on the mechanism of action of once-weekly agents. J Clin Pharm Ther 2020; 45 Suppl 1:17-27. [PMID: 32910490 PMCID: PMC7540167 DOI: 10.1111/jcpt.13230] [Citation(s) in RCA: 79] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 04/24/2020] [Accepted: 05/10/2020] [Indexed: 12/16/2022]
Abstract
WHAT IS KNOWN AND OBJECTIVE Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are one of the preferred approved treatment options for people with type 2 diabetes (T2D) and inadequate glycaemic control. The objective of this review is to provide a general clinical overview of the similarities and differences in the mechanisms of action (MoA) of the once-weekly GLP-1 RA class of medications, highlighting the role of pharmacists in providing optimal medication management, education and care for people with diabetes. METHODS This is a narrative review of the published literature regarding the MoA of the currently available once-weekly GLP-1 RAs in T2D. RESULTS AND DISCUSSION GLP-1 RAs have an established efficacy and safety profile. Their benefits derive from their blood glucose-lowering effects, which include pancreatic beta-cell-mediated glucose-dependent insulin secretion and suppressed glucagon release, and their ability to slow gastric emptying and promote satiety. GLP-1 RAs may also exert beneficial effects on multiple organ systems in which GLP-1 receptors are present, including the cardiovascular and renal systems. Differences between individual GLP-1 RAs with regard to their molecular size, structure and duration of action (short or longer acting) have led to differing pharmacodynamics and clinical effects such as degree of glycaemic control, weight loss abilities, cardiovascular effects and tolerability profiles. WHAT IS NEW AND CONCLUSION From the literature, this appears to be the first review of the evidence base supporting the MoA of once-weekly GLP-1 RAs in T2D aimed at pharmacists, with a particular emphasis on the expanding role of pharmacists in team-based diabetes management. As a class, GLP-1 RAs are an effective treatment option for people with T2D, shown to achieve multi-factorial clinical benefits. The results suggest that when selecting or advising about treatments, pharmacists should consider how the different once-weekly GLP-1 RAs and their MoA affect clinical outcomes in order to ensure optimal treatment for individuals.
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Affiliation(s)
- Susan Cornell
- Chicago College of PharmacyMidwestern UniversityDowners GroveILUSA
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12
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He Z, Gao Y, Lieu L, Afrin S, Cao J, Michael NJ, Dong Y, Sun J, Guo H, Williams KW. Direct and indirect effects of liraglutide on hypothalamic POMC and NPY/AgRP neurons - Implications for energy balance and glucose control. Mol Metab 2019; 28:120-134. [PMID: 31446151 PMCID: PMC6822260 DOI: 10.1016/j.molmet.2019.07.008] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2019] [Revised: 07/22/2019] [Accepted: 07/25/2019] [Indexed: 12/15/2022] Open
Abstract
OBJECTIVE The long-acting glucagon-like peptide-1 receptor (GLP-1R) agonist, liraglutide, stimulates insulin secretion and efficiently suppresses food intake to reduce body weight. As such, liraglutide is growing in popularity in the treatment of diabetes and chronic weight management. Within the brain, liraglutide has been shown to alter the activity of hypothalamic proopiomelanocortin (POMC) and Neuropeptide Y/Agouti-related peptide (NPY/AgRP) neurons. Moreover, the acute activities of POMC and NPY neurons have been directly linked to feeding behavior, body weight, and glucose metabolism. Despite the increased usage of liraglutide and other GLP-1 analogues as diabetic and obesity interventions, the cellular mechanisms by which liraglutide alters the activity of metabolically relevant neuronal populations are poorly understood. METHODS In order to resolve this issue, we utilized neuron-specific transgenic mouse models to identify POMC and NPY neurons for patch-clamp electrophysiology experiments. RESULTS We found that liraglutide directly activated arcuate POMC neurons via TrpC5 channels, sharing a similar mechanistic pathway to the adipose-derived peptide leptin. Liraglutide also indirectly increases excitatory tone to POMC neurons. In contrast, liraglutide inhibited NPY/AgRP neurons through post-synaptic GABAA receptors and enhanced activity of pre-synaptic GABAergic neurons, which required both TrpC5 subunits and K-ATP channels. In support of an additive role of leptin and liraglutide in suppressing food intake, leptin potentiated the acute effects of liraglutide to activate POMC neurons. TrpC5 subunits in POMC neurons were also required for the intact pharmacological effects of liraglutide on food intake and body weight. Thus, the current study adds to recent work from our group and others, which highlight potential mechanisms to amplify the effects of GLP-1 agonists in vivo. Moreover, these data highlight multiple sites of action (both pre- and post-synaptic) for GLP-1 agonists on this circuit. CONCLUSIONS Taken together, our results identify critical molecular mechanisms linking GLP-1 analogues in arcuate POMC and NPY/AgRP neurons with metabolism.
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Affiliation(s)
- Zhenyan He
- The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China; Division of Hypothalamic Research, the University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA
| | - Yong Gao
- Division of Hypothalamic Research, the University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA; National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China
| | - Linh Lieu
- Division of Hypothalamic Research, the University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA
| | - Sadia Afrin
- Division of Hypothalamic Research, the University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA
| | - Jianhong Cao
- Division of Hypothalamic Research, the University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA; Pi-wei Institute, Guangzhou University of Chinese Medicine, 12 Jichang Road, Guangzhou 510405, China
| | - Natalie J Michael
- Division of Hypothalamic Research, the University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA
| | - Yanbin Dong
- Division of Hypothalamic Research, the University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA; Pi-wei Institute, Guangzhou University of Chinese Medicine, 12 Jichang Road, Guangzhou 510405, China
| | - Jia Sun
- Division of Hypothalamic Research, the University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA
| | - Hongbo Guo
- The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
| | - Kevin W Williams
- Division of Hypothalamic Research, the University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA.
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Rasalam R, Barlow J, Kennedy M, Phillips P, Wright A. GLP-1 Receptor Agonists for Type 2 Diabetes and Their Role in Primary Care: An Australian Perspective. Diabetes Ther 2019; 10:1205-1217. [PMID: 31183762 PMCID: PMC6612351 DOI: 10.1007/s13300-019-0642-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Indexed: 02/08/2023] Open
Abstract
The ever-increasing number of drugs available to treat type 2 diabetes and the complexity of patients with this condition present a constant challenge when it comes to identifying the most appropriate treatment approach. The more recent glucagon-like peptide-1 receptor agonists (GLP-1RAs) are non-insulin injectable options for the management of type 2 diabetes. Effective at improving glycaemic control with a low intrinsic risk of hypoglycaemia and the potential for weight reduction, this agent class is an important addition to the prescribing armamentarium. However, understanding their place in therapy may prove confusing for many primary care practitioners, especially given the common belief that 'injectables' are a last-resort treatment option, which puts them at risk of being niched alongside insulin. This review summarises the clinical evidence for GLP-1RAs and how they compare to other glucose-lowering agents in managing type 2 diabetes. It also provides practical and case-driven opinions and recommendations on the optimal use of GLP-1RAs by discussing important patient factors and clinical considerations that will help to identify those who are most likely to benefit from this class of agents.Funding: Eli Lilly Australia.
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Affiliation(s)
- Roy Rasalam
- James Cook University, Douglas, QLD, Australia.
| | - John Barlow
- Bankstown Medical Centre, Bankstown, NSW, Australia
| | | | - Pat Phillips
- Queen Elizabeth Specialist Centre, Woodville South, SA, Australia
| | - Alan Wright
- Lakes Medical Centre, South Lake, WA, Australia
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Hershon KS, Hirsch BR, Odugbesan O. Importance of Postprandial Glucose in Relation to A1C and Cardiovascular Disease. Clin Diabetes 2019; 37:250-259. [PMID: 31371856 PMCID: PMC6640888 DOI: 10.2337/cd18-0040] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
IN BRIEF This article reviews the evidence regarding the impact of postprandial glucose (PPG) on overall A1C and its relation to cardiovascular disease (CVD). To date, four randomized, controlled trials have evaluated the impact of PPG reduction on CVD; however, only one of these successfully demonstrated a positive effect. Despite this, epidemiological evidence does indicate a cardiovascular benefit of PPG reduction, and agents that can be used to manage PPG in people with type 2 diabetes are also discussed.
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Affiliation(s)
| | | | - Ola Odugbesan
- North Atlanta Endocrinology and Diabetes, Lawrenceville, GA
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15
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Schmider W, Belder R, Lee M, Niemoeller E, Souhami E, Frias JP. Impact of dose capping in insulin glargine/lixisenatide fixed-ratio combination trials in patients with type 2 diabetes. Curr Med Res Opin 2019; 35:1081-1089. [PMID: 30550345 DOI: 10.1080/03007995.2018.1558852] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
OBJECTIVE The LixiLan clinical trials of insulin glargine (iGlar)/lixisenatide fixed-ratio combination (iGlarLixi) investigated the safety and efficacy of iGlarLixi versus iGlar: LixiLan-O (NCT02058147) in patients with type 2 diabetes (T2D) inadequately controlled on oral antidiabetes drugs (OADs) and LixiLan-L (NCT02058160) in patients with T2D inadequately controlled on basal insulin ± OADs. In these two trials, both iGlar and iGlarLixi were titrated to a maximum (capped) dose of 60 units. We evaluated whether this may have affected the reported glycemic efficacy of iGlar, and the glycemic differences observed between treatment with iGlarLixi and iGlar. METHODS The efficacy of iGlar under uncapped conditions was simulated in a two-step approach. First, a model characterizing the relationship between iGlar dose and fasting self-measured plasma glucose (f-SMPG) was developed. Then, the relationship between glycated hemoglobin A1c (A1C) and f-SMPG was established to translate simulated f-SMPG responses to A1C responses. RESULTS Most patients achieved stable f-SMPG at ∼60 units/day, with no further reduction with increasing insulin dose. In comparisons of observed/capped and simulated/uncapped changes in mean A1C from baseline to Week 30, iGlarLixi consistently demonstrated treatment benefit compared with iGlar. Uncapping resulted in a slightly higher mean iGlar dose in both LixiLan-O (+0.72 units) and LixiLan-L (+2.1 units), without marked impact on f-SMPG or A1C change from baseline. CONCLUSION Uncapping the iGlar dose in LixiLan-O and LixiLan-L would not have led to significant improvements in mean A1C reduction in the iGlar arm, supporting the conclusion that iGlarLixi provides additional, clinically relevant glycemic control versus iGlar alone.
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Affiliation(s)
| | | | | | | | | | - Juan P Frias
- d National Research Institute , Los Angeles , CA , USA
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Nagai Y, Mukai K, Otsuki M, Kimura T, Kozawa J, Nishizawa H, Maeda N, Matsuoka TA, Iwahashi H, Imagawa A, Shimomura I. Suppression Failure of Cortisol Secretion by Dexamethasone May Occur in Glucagon-like Peptide-1 Receptor Agonist-treated Patients with Diabetic Autonomic Neuropathy. Intern Med 2019; 58:949-953. [PMID: 30568127 PMCID: PMC6478970 DOI: 10.2169/internalmedicine.1585-18] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Two diabetic women (case 1, 75 years old; case 2, 49 years old) being treated with glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1 RAs) showed no suppression of cortisol secretion on a dexamethasone suppression test (DST). However, its secretion was suppressed after switching from GLP-1 RAs to insulin. We also checked the cortisol secretion by a DST in five consecutive inpatients (case 3-7) being treated with GLP-1 RAs. The coefficients of R-R interval variation at rest and during deep breathing were lower in the two false-positive cases (case 1 and 2) than in the five true-negative cases (case 3-6). GLP-1 RAs can be switched to insulin in order to eliminate the slow absorption effect of dexamethasone by GLP-1 RAs if a DST is planned in diabetic patients receiving GLP-1 RAs.
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Affiliation(s)
- Yasuki Nagai
- Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Japan
| | - Kosuke Mukai
- Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Japan
| | - Michio Otsuki
- Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Japan
| | - Takekazu Kimura
- Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Japan
| | - Junji Kozawa
- Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Japan
| | - Hitoshi Nishizawa
- Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Japan
| | - Norikazu Maeda
- Department of Metabolism and Atherosclerosis, Osaka University Graduate School of Medicine, Japan
| | - Taka-Aki Matsuoka
- Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Japan
| | - Hiromi Iwahashi
- Department of Diabetes Care Medicine, Osaka University Graduate School of Medicine, Japan
| | - Akihisa Imagawa
- Department of Internal Medicine (I), Osaka Medical College, Japan
| | - Iichiro Shimomura
- Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Japan
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Dailey G, Bajaj HS, Dex T, Groleau M, Stager W, Vinik A. Post hoc efficacy and safety analysis of insulin glargine/lixisenatide fixed- ratio combination in North American patients compared with the rest of world. BMJ Open Diabetes Res Care 2019; 7:e000581. [PMID: 31114694 PMCID: PMC6501856 DOI: 10.1136/bmjdrc-2018-000581] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Revised: 12/07/2018] [Accepted: 12/09/2018] [Indexed: 01/20/2023] Open
Abstract
Objective To assess the efficacy and safety of iGlarLixi (titratable fixed-ratio combination of insulin glargine (iGlar) and lixisenatide) in patients with type 2 diabetes (T2D) living in North America (NA; USA and Canada) compared with the rest of the world (RoW). Research design and methods Post hoc analysis included patient-level data from 509 sites/centers across two phase III trials: LixiLan-O (NCT02058147; insulin-naive patients; NA, n=371; RoW, n=796) and LixiLan-L (NCT02058160; inadequately controlled patients on basal insulin; NA, n=196; RoW, n=535). Efficacy outcomes were: change from baseline to Week 30 in glycated hemoglobin (HbA1c), postprandial glucose (PPG), PPG excursions, fasting plasma glucose (FPG) and body weight; proportion of patients achieving HbA1c <42 mmol/mol (<7.0%); proportion of patients achieving composite endpoint: HbA1c <42 mmol/mol (<7.0%), no weight gain or symptomatic hypoglycemia (blood glucose ≤3.9 mmol/L (≤70 mg/dL)). Safety endpoints included incidence of documented symptomatic hypoglycemia and gastrointestinal (GI) adverse events. Results Significantly larger reductions (p≤0.003) in HbA1c from baseline to Week 30 were achieved with iGlarLixi, compared with iGlar or lixisenatide, in NA and RoW patients in LixiLan-O (iGlarLixi vs iGlar: -0.31 and -0.29, respectively; iGlarLixi vs lixisenatide: -0.84 and -0.69, respectively) and in LixiLan-L (iGlarLixi vs iGlar: -0.5 and -0.51, respectively). Documented symptomatic hypoglycemia was similar between NA and RoW patients. iGlarLixi resulted in significant weight benefits versus iGlar (change from baseline -1.58 and -1.29 kg for NA and RoW patients, respectively; p<0.001). GI adverse events were similar for iGlarLixi and iGlar, but significantly higher for lixisenatide. Conclusions iGlarLixi improved glycemic parameters versus iGlar or lixisenatide alone in both NA and RoW patients, with beneficial weight effects versus iGlar. iGlarLixi treatment responses, hypoglycemia risk and GI adverse events in NA patients were comparable with patients in the RoW. Trial registry Clinicaltrials.gov NCT02058147 and NCT02058160.
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Affiliation(s)
- George Dailey
- Division of Diabetes and Endocrinology, Scripps Whittier Diabetes Institute, San Diego, California, USA
| | - Harpreet S Bajaj
- LMC Diabetes and Endocrinology, Brampton, Ontario, Canada
- Leadership Sinai Centre for Diabetes, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Terry Dex
- Sanofi US, Bridgewater, New Jersey, USA
| | | | | | - Aaron Vinik
- Eastern Virginia Medical School, Norfolk, Virginia, USA
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Liu J, Yang K, Yang J, Xiao W, Le Y, Yu F, Gu L, Lang S, Tian Q, Jin T, Wei R, Hong T. Liver-derived fibroblast growth factor 21 mediates effects of glucagon-like peptide-1 in attenuating hepatic glucose output. EBioMedicine 2019; 41:73-84. [PMID: 30827929 PMCID: PMC6443026 DOI: 10.1016/j.ebiom.2019.02.037] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2018] [Revised: 01/30/2019] [Accepted: 02/18/2019] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Glucagon-like peptide-1 (GLP-1) and its based agents improve glycemic control. Although their attenuating effect on hepatic glucose output has drawn our attention for decades, the potential mechanisms remain unclear. METHODS Cytokine array kit was used to assess cytokine profiles in db/db mice and mouse primary hepatocytes treated with exenatide (exendin-4). Two diabetic mouse models (db/db and Pax6m/+) were treated with a GLP-1 analog exenatide or liraglutide. The expression and secretion of fibroblast growth factor 21 (FGF21) in the livers of diabetic mice, primary mouse and human hepatocytes, and the human hepatic cell line HepG2 treated with or without GLP-1 analog were measured. Blockage of FGF21 with neutralizing antibody or siRNA, or hepatocytes isolated from Fgf21 knockout mice were used, and the expression and activity of key enzymes in gluconeogenesis were analyzed. Serum FGF21 level was evaluated in patients with type 2 diabetes (T2D) receiving exenatide treatment. FINDINGS Utilizing the cytokine array, we identified that FGF21 secretion was upregulated by exenatide (exendin-4). Similarly, FGF21 production in hepatocytes was stimulated by exenatide or liraglutide. FGF21 blockage attenuated the inhibitory effects of the GLP-1 analogs on hepatic glucose output. Similar results were also observed in primary hepatocytes from Fgf21 knockout mice. Furthermore, exenatide treatment increased serum FGF21 level in patients with T2D, particularly in those with better glucose control. INTERPRETATION We identify that function of GLP-1 in inhibiting hepatic glucose output is mediated via the liver hormone FGF21. Thus, we provide a new extra-pancreatic mechanism by which GLP-1 regulates glucose homeostasis. FUND: National Key Research and Development Program of China, the National Natural Science Foundation of China, the Natural Science Foundation of Beijing and Peking University Medicine Seed Fund for Interdisciplinary Research.
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Affiliation(s)
- Junling Liu
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China; Clinical Stem Cell Research Center, Peking University Third Hospital, Beijing, China
| | - Kun Yang
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China
| | - Jin Yang
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China; Clinical Stem Cell Research Center, Peking University Third Hospital, Beijing, China
| | - Wenhua Xiao
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China
| | - Yunyi Le
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China
| | - Fei Yu
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China; Clinical Stem Cell Research Center, Peking University Third Hospital, Beijing, China
| | - Liangbiao Gu
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China; Clinical Stem Cell Research Center, Peking University Third Hospital, Beijing, China
| | - Shan Lang
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China; Clinical Stem Cell Research Center, Peking University Third Hospital, Beijing, China
| | - Qing Tian
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China
| | - Tianru Jin
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada; Banting and Best Diabetes Center, University of Toronto, Toronto, Ontario, Canada
| | - Rui Wei
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China; Clinical Stem Cell Research Center, Peking University Third Hospital, Beijing, China.
| | - Tianpei Hong
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China; Clinical Stem Cell Research Center, Peking University Third Hospital, Beijing, China.
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Handelsman Y, Chovanes C, Dex T, Giorgino F, Skolnik N, Souhami E, Stager W, Niemoeller E, Frias JP. Efficacy and safety of insulin glargine/lixisenatide (iGlarLixi) fixed-ratio combination in older adults with type 2 diabetes. J Diabetes Complications 2019; 33:236-242. [PMID: 30600136 DOI: 10.1016/j.jdiacomp.2018.11.009] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Revised: 11/02/2018] [Accepted: 11/23/2018] [Indexed: 12/11/2022]
Abstract
AIMS This study assessed the efficacy and safety of iGlarLixi (a titratable, fixed-ratio combination of insulin glargine [iGlar] plus lixisenatide) in older patients with type 2 diabetes. METHODS This post hoc analysis used patient-level data from patients aged ≥65 years from the phase III LixiLan-O and LixiLan-L studies, which compared iGlarLixi with iGlar and lixisenatide (LixiLan-O only). Efficacy endpoints were changes in glycated hemoglobin A1C, fasting plasma glucose, postprandial glucose, weight, and achievement of A1C <7.0% (53 mmol/mol). Safety measures included incidence of documented symptomatic hypoglycemia (defined as typical symptoms of hypoglycemia plus self-measured plasma glucose ≤70 mg/dL [3.9 mmol/L]), severe hypoglycemia (requiring assistance of another person), and incidence of gastrointestinal adverse events. Results were compared with those from patients aged <65 years. RESULTS In both trials, older patients treated with iGlarLixi achieved significantly greater reductions in A1C at Week 30 than comparators. Treatment with iGlarLixi mitigated insulin-associated weight gain and lixisenatide-associated gastrointestinal events. Results were largely comparable between patients aged ≥65 versus <65 years. CONCLUSIONS iGlarLixi provides significant improvements in glycemic control in patients aged ≥65 years without increasing hypoglycemia risk. As a once-daily injection, it simplifies treatment regimens and may contribute to improved adherence in this patient population.
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Affiliation(s)
- Yehuda Handelsman
- Metabolic Institute of America, 18372 Clark St. Suite 212, Tarzana, CA 91356, USA.
| | - Christina Chovanes
- Abington Memorial Hospital, 500 York Rd Suite 108, Jenkintown, PA 19046, USA.
| | - Terry Dex
- Sanofi US, Inc., 55 Corporate Drive, Bridgewater, NJ 08807, USA.
| | - Francesco Giorgino
- University of Bari Aldo Moro, Piazza Giulio Cesare 11, Bari 70124, Italy.
| | - Neil Skolnik
- Abington Memorial Hospital, 500 York Rd Suite 108, Jenkintown, PA 19046, USA.
| | | | - William Stager
- Sanofi US, Inc., 55 Corporate Drive, Bridgewater, NJ 08807, USA.
| | | | - Juan Pablo Frias
- National Research Institute, 2010 Wilshire Blvd #302, Los Angeles, 90057, CA, USA.
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20
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Frias JP, Dex T, Roberts M, Kaplan A. A Review of the Safety and Adverse Event Profile of the Fixed-Ratio Combination of Insulin Glargine and Lixisenatide. Diabetes Ther 2019; 10:21-33. [PMID: 30539523 PMCID: PMC6349286 DOI: 10.1007/s13300-018-0547-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Indexed: 02/07/2023] Open
Abstract
INTRODUCTION iGlarLixi is a titratable, fixed-ratio combination of insulin glargine (100 units/mL) and lixisenatide (33 μg/mL). This review evaluates the overall safety and adverse event (AE) profile of iGlarLixi in patients with type 2 diabetes. METHODS We collated patient-level data from the phase 2 LixiLan proof-of-concept trial and the phase 3 LixiLan-L (insulin-experienced patients) and LixiLan-O (insulin-naïve patients) trials to evaluate AEs associated with iGlarLixi. We also describe data from the ELIXA study to examine pancreatitis and pancreatic cancer, and the ELIXA and ORIGIN studies for cardiovascular safety data. RESULTS Patients treated with iGlarLixi had improved glycemic control with a similar incidence of documented symptomatic hypoglycemia (plasma glucose ≤ 70 mg/dL) compared with iGlar. Incidence of severe hypoglycemia (an event requiring third-party assistance) was low in all treatment arms in both LixiLan-L and LixiLan-O. Rates of gastrointestinal AEs in patients treated with iGlarLixi tended to be lower compared with lixisenatide alone, but higher than those treated with iGlar alone. Gastrointestinal AEs were generally mild to moderate in intensity and transient. Antibodies formed in response to iGlarLixi did not have any significant clinical impact, with similar safety observed for antibody-positive and antibody-negative populations. Rates of allergic reactions, malignancy, renal impairment, and cardiovascular events were low and comparable between treatment groups. Older age (≥ 65 years) and gender did not affect efficacy or safety. CONCLUSION iGlarLixi has a safety profile that is consistent with that of its two active components insulin glargine and lixisenatide, with no signals for pancreatitis or thyroid C cell tumors, and no black-box warning for iGlarLixi. There were no unexpected safety findings; iGlarLixi had beneficial effects on glycemic control, with no increased risk of hypoglycemia, despite a greater glycated hemoglobin A1c reduction. In addition, there were also fewer gastrointestinal AEs associated with iGlarLixi compared with lixisenatide alone. FUNDING Sanofi US Inc.
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Affiliation(s)
- Juan P Frias
- National Research Institute, Los Angeles, CA, USA.
| | | | | | - Allen Kaplan
- Medical University of South Carolina, Charleston, SC, USA
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Gentilella R, Pechtner V, Corcos A, Consoli A. Glucagon-like peptide-1 receptor agonists in type 2 diabetes treatment: are they all the same? Diabetes Metab Res Rev 2019; 35:e3070. [PMID: 30156747 DOI: 10.1002/dmrr.3070] [Citation(s) in RCA: 153] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2017] [Revised: 07/30/2018] [Accepted: 08/18/2018] [Indexed: 02/06/2023]
Abstract
Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) are an important class of drugs with a well-established efficacy and safety profile in patients with type 2 diabetes mellitus. Agents in this class are derived from either exendin-4 (a compound present in Gila monster venom) or modifications of human GLP-1 active fragment. Differences among these drugs in duration of action (ie, short-acting vs long-acting), effects on glycaemic control and weight loss, immunogenicity, tolerability profiles, and administration routes offer physicians several options when selecting the most appropriate agent for individual patients. Patient preference is also an important consideration. The aim of this review is to discuss the differences between and similarities of GLP-1 RAs currently approved for clinical use, focusing particularly on the properties characterising the single short-acting and long-acting GLP-1 RAs rather than on their individual efficacy and safety profiles. The primary pharmacodynamic difference between short-acting (ie, exenatide twice daily and lixisenatide) and long-acting (ie, albiglutide, dulaglutide, exenatide once weekly, liraglutide, and semaglutide) GLP-1 RAs is that short-acting agents primarily delay gastric emptying (lowering postprandial glucose) and long-acting agents affect both fasting glucose (via enhanced glucose-dependent insulin secretion and reduced glucagon secretion in the fasting state) and postprandial glucose (via enhanced postprandial insulin secretion and inhibition of glucagon secretion). Other advantages of long-acting GLP-1 RAs include smaller fluctuations in plasma drug concentrations, improved gastrointestinal tolerability profiles, and simpler, more convenient administration schedules (once daily for liraglutide and once weekly for albiglutide, dulaglutide, the long-acting exenatide formulation, and semaglutide), which might improve treatment adherence and persistence.
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Affiliation(s)
| | - Valeria Pechtner
- Lilly Diabetes, Eli Lilly and Company, Neuilly-sur-Seine, France
| | | | - Agostino Consoli
- Department of Medicine and Ageing Sciences and CeSI-Met, University D'Annunzio, Chieti, Italy
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Wei ZG, Wang MC, Zhang HH, Wang ZY, Wang GN, Wei FX, Zhang YW, Xu XD, Zhang YC. PRISMA-efficacy and safety of lixisenatide for type 2 diabetes mellitus: A meta-analysis of randomized controlled trials. Medicine (Baltimore) 2018; 97:e13710. [PMID: 30572502 PMCID: PMC6320179 DOI: 10.1097/md.0000000000013710] [Citation(s) in RCA: 2] [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] [Indexed: 11/26/2022] Open
Abstract
OBJECTIVE We aimed to systematically evaluate the efficacy and safety of lixisenatide in patients with type 2 diabetes mellitus. METHODS PubMed, EMBASE, Cochrane Library, ClinicalTrials.gov, Google, Web of Science and the Chinese Science Citation Database were searched up to March 2018. Randomized controlled trials determining the efficacy and safety of lixisenatide in patients with type 2 diabetes mellitus were eligible for inclusion. Two authors independently extracted the data in a prespecified Microsoft Excel spreadsheet. A meta-analysis was performed using Review Manager 5.3 software. Weighted mean difference (WMD) and relative risk (RR) together with their corresponding 95% confidence intervals (CIs) were estimated, and only the random effects model was used in order to achieve a more conservative estimate of the efficacy and safety. RESULTS Fourteen multicenter randomized controlled trials involving 11,947 patients were eligible for inclusion. Compared to placebo, lixisenatide could more significantly reduce the level of HbA1c (WMD=-0.44; 95% confidence interval [CI] [-0.55,-0.33]), and a higher proportion of lixisenatide-treated patients achieved the HbA1c level of < 7.0% (RR = 1.89, 95% CI [1.75-2.03]) and < 6.5% (RR = 3.03, 95% CI [2.54-3.63]) than the placebo-treated patients. Lixisenatide was also associated with a significant reduction in fasting plasma glucose and 2-hour postprandial plasma glucose levels. The risks for any adverse events, gastrointestinal adverse events, and symptomatic hypoglycemia significantly increased in the lixisenatide-treatedment group compared to those in the placebo group. However, lixisenatideit did not increase the risks of serious adverse events, death, or severe hypoglycemia. CONCLUSIONS Lixisenatide was more effective than placebo in patients with type 2 diabetes mellitus, and the mild-to-moderate adverse events were found to be tolerated during the follow-up.
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Affiliation(s)
- Zhen-gang Wei
- Department of General Surgery, Lanzhou University Second Hospital
- Hepatobiliary and pancreatic surgery laboratory, Lanzhou University Second Hospital
- Gansu Provincial-level Key Laboratory of Digestive System Tumors, Lanzhou 730030, China
| | - Man-cai Wang
- Department of General Surgery, Lanzhou University Second Hospital
- Hepatobiliary and pancreatic surgery laboratory, Lanzhou University Second Hospital
- Gansu Provincial-level Key Laboratory of Digestive System Tumors, Lanzhou 730030, China
| | - Hui-han Zhang
- Department of General Surgery, Lanzhou University Second Hospital
- Hepatobiliary and pancreatic surgery laboratory, Lanzhou University Second Hospital
- Gansu Provincial-level Key Laboratory of Digestive System Tumors, Lanzhou 730030, China
| | - Zhe-yuan Wang
- Department of General Surgery, Lanzhou University Second Hospital
- Hepatobiliary and pancreatic surgery laboratory, Lanzhou University Second Hospital
- Gansu Provincial-level Key Laboratory of Digestive System Tumors, Lanzhou 730030, China
| | - Gen-nian Wang
- Department of General Surgery, Lanzhou University Second Hospital
- Hepatobiliary and pancreatic surgery laboratory, Lanzhou University Second Hospital
- Gansu Provincial-level Key Laboratory of Digestive System Tumors, Lanzhou 730030, China
| | - Feng-xian Wei
- Department of General Surgery, Lanzhou University Second Hospital
- Hepatobiliary and pancreatic surgery laboratory, Lanzhou University Second Hospital
- Gansu Provincial-level Key Laboratory of Digestive System Tumors, Lanzhou 730030, China
| | - Ya-wu Zhang
- Department of General Surgery, Lanzhou University Second Hospital
- Hepatobiliary and pancreatic surgery laboratory, Lanzhou University Second Hospital
- Gansu Provincial-level Key Laboratory of Digestive System Tumors, Lanzhou 730030, China
| | - Xiao-dong Xu
- Department of General Surgery, Lanzhou University Second Hospital
- Hepatobiliary and pancreatic surgery laboratory, Lanzhou University Second Hospital
- Gansu Provincial-level Key Laboratory of Digestive System Tumors, Lanzhou 730030, China
| | - You-cheng Zhang
- Department of General Surgery, Lanzhou University Second Hospital
- Hepatobiliary and pancreatic surgery laboratory, Lanzhou University Second Hospital
- Gansu Provincial-level Key Laboratory of Digestive System Tumors, Lanzhou 730030, China
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Trujillo JM, Roberts M, Dex T, Chao J, White J, LaSalle J. Low incidence of gastrointestinal adverse events over time with a fixed-ratio combination of insulin glargine and lixisenatide versus lixisenatide alone. Diabetes Obes Metab 2018; 20:2690-2694. [PMID: 29923298 PMCID: PMC6221077 DOI: 10.1111/dom.13444] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Revised: 06/08/2018] [Accepted: 06/16/2018] [Indexed: 12/14/2022]
Abstract
This post hoc analysis of gastrointestinal (GI) adverse events (AEs) from the phase 3 LixiLan-L (NCT02058160) and LixiLan-O (NCT02058147) trials aimed to determine the frequency and timing of nausea, vomiting, and diarrhoea for iGlarLixi, a titratable, fixed-ratio combination of insulin glargine 100 units/mL (iGlar) and lixisenatide, versus iGlar alone or iGlar and lixisenatide alone, in patients with type 2 diabetes uncontrolled with oral antidiabetes drugs (OADs) or basal insulin ± OADs. In iGlarLixi-treated patients, the rate of GI AEs during the initial weeks of treatment was lower versus patients treated with lixisenatide alone (9.6% and 11.7% of iGlarLixi-treated patients in LixiLan-L and LixiLan-O, respectively, vs. 27.5% of lixisenatide-treated patients in LixiLan-O). Beyond day 60, these rates were generally low and similar to those of lixisenatide. These lower rates are likely due to the gradual titration of lixisenatide in iGlarLixi. Median durations of intermittent GI AEs in the iGlarLixi arms were 6.0, 2.0 and 2.5 days (LixiLan-L), and 5.0, 1.0 and 3.5 days (LixiLan-O), respectively. iGlarLixi-associated GI AEs were transient, mostly mild or moderate in severity, and occurred mainly during initial titration.
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Affiliation(s)
- Jennifer M. Trujillo
- Department of Clinical Pharmacy, Skaggs School of Pharmacy and Pharmaceutical SciencesUniversity of ColoradoAuroraColorado
| | | | - Terry Dex
- Sanofi US, Inc.BridgewaterNew Jersey
| | | | - John White
- Department of PharmacyWashington State UniversitySpokaneWashington
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24
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de Bem GF, Costa CA, Santos IB, Cristino Cordeiro VDS, de Carvalho LCRM, de Souza MAV, Soares RDA, Sousa PJDC, Ognibene DT, Resende AC, de Moura RS. Antidiabetic effect of Euterpe oleracea Mart. (açaí) extract and exercise training on high-fat diet and streptozotocin-induced diabetic rats: A positive interaction. PLoS One 2018; 13:e0199207. [PMID: 29920546 PMCID: PMC6007924 DOI: 10.1371/journal.pone.0199207] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Accepted: 06/04/2018] [Indexed: 12/17/2022] Open
Abstract
A growing body of evidence suggests a protective role of polyphenols and exercise training on the disorders of type 2 diabetes mellitus (T2DM). We aimed to assess the effect of the açaí seed extract (ASE) associated with exercise training on diabetic complications induced by high-fat (HF) diet plus streptozotocin (STZ) in rats. Type 2 diabetes was induced by feeding rats with HF diet (55% fat) for 5 weeks and a single dose of STZ (35 mg/kg i.p.). Control (C) and Diabetic (D) animals were subdivided into four groups each: Sedentary, Training, ASE Sedentary, and ASE Training. ASE (200 mg/kg/day) was administered by gavage and the exercise training was performed on a treadmill (30min/day; 5 days/week) for 4 weeks after the diabetes induction. In type 2 diabetic rats, the treatment with ASE reduced blood glucose, insulin resistance, leptin and IL-6 levels, lipid profile, and vascular dysfunction. ASE increased the expression of insulin signaling proteins in skeletal muscle and adipose tissue and plasma GLP-1 levels. ASE associated with exercise training potentiated the reduction of glycemia by decreasing TNF-α levels, increasing pAKT and adiponectin expressions in adipose tissue, and IR and pAMPK expressions in skeletal muscle of type 2 diabetic rats. In conclusion, ASE treatment has an antidiabetic effect in type 2 diabetic rats by activating the insulin-signaling pathway in muscle and adipose tissue, increasing GLP-1 levels, and an anti-inflammatory action. Exercise training potentiates the glucose-lowering effect of ASE by activating adiponectin-AMPK pathway and increasing IR expression.
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Affiliation(s)
- Graziele Freitas de Bem
- Department of Pharmacology, Institute of Biology, Rio de Janeiro State University, Rio de Janeiro, RJ, Brazil
| | - Cristiane Aguiar Costa
- Department of Pharmacology, Institute of Biology, Rio de Janeiro State University, Rio de Janeiro, RJ, Brazil
| | - Izabelle Barcellos Santos
- Department of Pharmacology, Institute of Biology, Rio de Janeiro State University, Rio de Janeiro, RJ, Brazil
| | | | | | | | - Ricardo de Andrade Soares
- Department of Pharmacology, Institute of Biology, Rio de Janeiro State University, Rio de Janeiro, RJ, Brazil
| | | | - Dayane Teixeira Ognibene
- Department of Pharmacology, Institute of Biology, Rio de Janeiro State University, Rio de Janeiro, RJ, Brazil
| | - Angela Castro Resende
- Department of Pharmacology, Institute of Biology, Rio de Janeiro State University, Rio de Janeiro, RJ, Brazil
- * E-mail: ,
| | - Roberto Soares de Moura
- Department of Pharmacology, Institute of Biology, Rio de Janeiro State University, Rio de Janeiro, RJ, Brazil
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25
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Abstract
UNLABELLED As the number of people living with type 2 diabetes (T2D) continues to rise, managing their complex needs presents an increasing challenge to physicians. While treatment guidelines provide evidence-based guidance, they are not prescriptive-rather they emphasize individualization of management based on a patient's clinical needs and preferences. Physicians, therefore, need to be fully aware of the advantages and disadvantages of the multiple and increasing treatment options available to them at each stage of the disease. The progressive nature of T2D means that treatment with basal insulin will become inevitable for many patients, while for some patients basal insulin alone will eventually be insufficient for maintaining glycemic targets. Recent guidelines recommend two basic approaches for intensifying basal insulin: the use of rapid-acting insulin, either as additional prandial injections or as part of premix (biphasic) insulin; and the addition of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) to the insulin therapy, which can be administered via subcutaneous injection once or twice daily, or weekly depending on formulation. More recently, two fixed-ratio combinations of basal insulin and a GLP-1 RA that allow for once-daily dosing have been approved. Each of these approaches has potential benefits and drawbacks, particularly in terms of risk for hypoglycemia, weight change, convenience, and side effects. Understanding these differences is central to guiding patient and physician choice. This article discusses the rationale, advantages, disadvantages, and implementation of currently available strategies for basal insulin treatment intensification in patients with T2D. FUNDING Sanofi US, Inc.
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Affiliation(s)
- Jerry Meece
- Clinical Services, Plaza Pharmacy and Wellness Center, Gainesville, TX, USA.
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26
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Yu M, Benjamin MM, Srinivasan S, Morin EE, Shishatskaya EI, Schwendeman SP, Schwendeman A. Battle of GLP-1 delivery technologies. Adv Drug Deliv Rev 2018; 130:113-130. [PMID: 30009885 PMCID: PMC6843995 DOI: 10.1016/j.addr.2018.07.009] [Citation(s) in RCA: 93] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Revised: 06/26/2018] [Accepted: 07/09/2018] [Indexed: 12/25/2022]
Abstract
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) belong to an important therapeutic class for treatment of type 2 diabetes. Six GLP-1 RAs, each utilizing a unique drug delivery strategy, are now approved by the Food and Drug Administration (FDA) and additional, novel GLP-1 RAs are still under development, making for a crowded marketplace and fierce competition among the manufacturers of these products. As rapid elimination is a major challenge for clinical application of GLP-1 RAs, various half-life extension strategies have been successfully employed including sequential modification, attachment of fatty-acid to peptide, fusion with human serum albumin, fusion with the fragment crystallizable (Fc) region of a monoclonal antibody, sustained drug delivery systems, and PEGylation. In this review, we discuss the scientific rationale of the various half-life extension strategies used for GLP-1 RA development. By analyzing and comparing different approved GLP-1 RAs and those in development, we focus on assessing how half-life extending strategies impact the pharmacokinetics, pharmacodynamics, safety, patient usability and ultimately, the commercial success of GLP-1 RA products. We also anticipate future GLP-1 RA development trends. Since similar drug delivery strategies are also applied for developing other therapeutic peptides, we expect this case study of GLP-1 RAs will provide generalizable concepts for the rational design of therapeutic peptides products with extended duration of action.
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Affiliation(s)
- Minzhi Yu
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, 428 Church St, Ann Arbor, MI 48109, United States of America
| | - Mason M Benjamin
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, 428 Church St, Ann Arbor, MI 48109, United States of America
| | | | - Emily E Morin
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, 428 Church St, Ann Arbor, MI 48109, United States of America
| | - Ekaterina I Shishatskaya
- Siberian Federal University, 79 Svobodnuy Ave, Krasnoyarsk 660041, Russian Federation; Institute of Biophysics SBRAS, 50 Akademgorodok, 660036, Russian Federation
| | - Steven P Schwendeman
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, 428 Church St, Ann Arbor, MI 48109, United States of America; Biointerfaces Institute, NCRC, 2800 Plymouth Rd, Ann Arbor, MI 48109, United States of America; Department of Biomedical Engineering, 2200 Bonisteel Blvd, Ann Arbor, MI 48109, United States of America.
| | - Anna Schwendeman
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, 428 Church St, Ann Arbor, MI 48109, United States of America; Biointerfaces Institute, NCRC, 2800 Plymouth Rd, Ann Arbor, MI 48109, United States of America.
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27
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Skolnik N, Hinnen D, Kiriakov Y, Magwire ML, White JR. Initiating Titratable Fixed-Ratio Combinations of Basal Insulin Analogs and Glucagon-Like Peptide-1 Receptor Agonists: What You Need to Know. Clin Diabetes 2018; 36:174-182. [PMID: 29686457 PMCID: PMC5898172 DOI: 10.2337/cd17-0048] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
IN BRIEF Titratable fixed-ratio combinations (FRCs) of a basal insulin and a glucagon-like peptide-1 (GLP-1) receptor agonist are new therapeutic options for people with type 2 diabetes. Two FRCs-insulin degludec/liraglutide and insulin glargine/lixisenatide-have been approved for use in the United States. The two components in these FRCs target different aspects of diabetes pathophysiology, working in a complementary manner to decrease blood glucose while mitigating the side effects associated with each component (hypoglycemia and weight gain with insulin and gastrointestinal side effects with GLP-1 receptor agonists). This article reviews these products and key considerations for their use.
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Affiliation(s)
| | - Debbie Hinnen
- Memorial Hospital Diabetes Center, Colorado Springs, CO
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28
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Johnson EL, Frias JP, Trujillo JM. Anticipatory guidance in type 2 diabetes to improve disease management; next steps after basal insulin. Postgrad Med 2018; 130:365-374. [PMID: 29569978 DOI: 10.1080/00325481.2018.1452515] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
The alarming rise in the number of people living with type 2 diabetes (T2D) presents primary care physicians with increasing challenges associated with long-term chronic disease care. Studies have shown that the majority of patients are not achieving or maintaining glycemic goals, putting them at risk of a wide range of diabetes-related complications. Disease- and self-management programs have been shown to help patients improve their glycemic control, and are likely to be of particular benefit for patients with diabetes dealing with these issues. Anticipatory guidance is an individualized, proactive approach to patient education and counseling by a health-care professional to support patients in better coping with problems before they arise. It has been shown to improve disease outcomes in a variety of chronic conditions, including diabetes. While important at all stages, anticipatory guidance may be of particular importance during changes in treatment regimens, and especially during transition to, and escalation of, insulin-based regimens. The aim of this article is to provide advice to physicians on anticipatory guidance for basal-insulin dosing, focusing on appropriate basal-insulin-dose increase and prevention of potentially deleterious basal-insulin doses, so called overbasalization. It also provides an overview of new treatment options for patients with T2D who are not well controlled on basal-insulin therapy, fixed-ratio combinations of basal insulin and glucagon-like peptide-1 receptor agonists, and advice on the type of anticipatory guidance needed to ensure safe and appropriate switching to these therapies.
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Affiliation(s)
- Eric L Johnson
- a Department of Family and Community Medicine , University of North Dakota , Grand Forks , ND , USA
| | - Juan P Frias
- b National Research Institute , Los Angeles , CA , USA
| | - Jennifer M Trujillo
- c Skaggs School of Pharmacy and Pharmaceutical Sciences , University of Colorado , Aurora , CO , USA
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Cersosimo E, Johnson EL, Chovanes C, Skolnik N. Initiating therapy in patients newly diagnosed with type 2 diabetes: Combination therapy vs a stepwise approach. Diabetes Obes Metab 2018; 20:497-507. [PMID: 28862799 DOI: 10.1111/dom.13108] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2017] [Revised: 08/18/2017] [Accepted: 08/26/2017] [Indexed: 12/13/2022]
Abstract
There is clear evidence that achieving glycaemic targets reduces the risk of developing complications as a result of type 2 diabetes (T2D). Many patients, however, continue to have suboptimal glycaemic control because of issues that include unclear advice on how to achieve these targets as well as clinical inertia. The two management approaches recommended for patients newly diagnosed with T2D are stepwise and combination therapy, each of which has advantages and disadvantages. Stepwise therapy may result in good patient adherence and allow greater individualization of therapy, and minimization of side effects and cost, and so may be appropriate for patients who are closer to goal. Stepwise therapy, however, may also lead to frequent delays in achieving glycaemic goals and longer exposure to hyperglycaemia. Combination therapy, which is now emerging as an important therapy option, has a number of potential advantages over stepwise therapy, including reduction in clinical inertia and earlier and more frequent achievement of glycated haemoglobin goals by targeting multiple pathogenic mechanisms simultaneously, which may more effectively delay disease progression. Compared with stepwise therapy, the disadvantages of combination therapy include reduced patient adherence resulting from complex, multi-drug regimens, difficulty determining the cause of poor efficacy and/or side effects, patient refusal to accept disease, and higher cost. Fixed-dose and fixed-ratio combinations are novel therapeutic approaches which may help address several issues of treatment complexity and patient burden associated with combination therapy comprising individual drugs. The choice of which drugs to administer and the decision to use stepwise vs combination therapy, however, should always be made on an individualized basis.
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Affiliation(s)
- Eugenio Cersosimo
- Department of Medicine, University of Texas Health Science Center, San Antonio, Texas
| | - Eric L Johnson
- Department of Family and Community Medicine, University of North Dakota, Grand Forks, North Dakota
| | | | - Neil Skolnik
- Abington Family Medicine, Jenkintown, Pennsylvania
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Umpierrez GE, Bailey TS, Carcia D, Shaefer C, Shubrook JH, Skolnik N. Improving postprandial hyperglycemia in patients with type 2 diabetes already on basal insulin therapy: Review of current strategies. J Diabetes 2018; 10:94-111. [PMID: 28581207 DOI: 10.1111/1753-0407.12576] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Revised: 05/02/2017] [Accepted: 05/21/2017] [Indexed: 11/28/2022] Open
Abstract
A large number of patients with type 2 diabetes (T2D) on basal insulin do not reach their HbA1c goals and require additional therapy to address postprandial hyperglycemia. Guidelines from expert bodies have outlined several approaches to accomplish postprandial glucose (PPG) control, and recent literature suggests several more. This article provides strategies for primary care physicians caring for patients with T2D who do not achieve glycemic control with basal insulin alone. Current treatment guidelines and strategies for improving PPG control are reviewed, including the efficacy, safety, and cost-effectiveness of rapid-acting insulin (RAI) analogs, premixed insulin, glucagon-like peptide-1 (GLP-1) receptor agonists (RAs), dipeptidyl peptidase 4 inhibitors, sodium-glucose cotransporter 2 inhibitors, and α-glucosidase inhibitors. Other approaches, such as combinations of newer basal insulin plus RAI and a fixed-ratio combination of basal insulin and a GLP-1 RA, are also described.
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Affiliation(s)
| | | | - Danielle Carcia
- Abington Hospital Jefferson Health, Abington, Pennsylvania, USA
| | | | | | - Neil Skolnik
- Abington Hospital Jefferson Health, Abington, Pennsylvania, USA
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Upadhyay J, Polyzos SA, Perakakis N, Thakkar B, Paschou SA, Katsiki N, Underwood P, Park KH, Seufert J, Kang ES, Sternthal E, Karagiannis A, Mantzoros CS. Pharmacotherapy of type 2 diabetes: An update. Metabolism 2018; 78:13-42. [PMID: 28920861 DOI: 10.1016/j.metabol.2017.08.010] [Citation(s) in RCA: 139] [Impact Index Per Article: 19.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2017] [Revised: 08/24/2017] [Accepted: 08/26/2017] [Indexed: 12/22/2022]
Abstract
Type 2 diabetes (T2DM) is a leading cause of morbidity and mortality worldwide and a major economic burden. The prevalence of T2DM is rising, suggesting more effective prevention and treatment strategies are necessary. The aim of this narrative review is to summarize the pharmacologic treatment options available for patients with T2DM. Each therapeutic class is presented in detail, outlining medication effects, side effects, glycemic control, effect on weight, indications and contraindications, and use in selected populations (heart failure, renal insufficiency, obesity and the elderly). We also present representative cost for each antidiabetic category. Then, we provide an individualized guide for initiation and intensification of treatment and discuss the considerations and rationale for an individualized glycemic goal.
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Affiliation(s)
- Jagriti Upadhyay
- Section of Endocrinology, Diabetes and Metabolism, Boston VA Healthcare System, Boston, MA, USA; Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
| | - Stergios A Polyzos
- First Department of Pharmacology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Nikolaos Perakakis
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Divisions of Endocrinology and Diabetology, Department of Internal Medicine II, University Hospital of Freiburg, Freiburg, Germany
| | - Bindiya Thakkar
- Section of Endocrinology, Diabetes and Metabolism, Boston VA Healthcare System, Boston, MA, USA
| | - Stavroula A Paschou
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Niki Katsiki
- Second Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, Hippocration Hospital, Thessaloniki, Greece
| | - Patricia Underwood
- Section of Endocrinology, Diabetes and Metabolism, Boston VA Healthcare System, Boston, MA, USA
| | - Kyung-Hee Park
- Department of Family Medicine, Hallym University Sacred Heart Hospital, Gyeonggi-do, Republic of Korea
| | - Jochen Seufert
- Divisions of Endocrinology and Diabetology, Department of Internal Medicine II, University Hospital of Freiburg, Freiburg, Germany
| | - Eun Seok Kang
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Elliot Sternthal
- Section of Endocrinology, Diabetes and Metabolism, Boston VA Healthcare System, Boston, MA, USA
| | - Asterios Karagiannis
- First Department of Pharmacology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Christos S Mantzoros
- Section of Endocrinology, Diabetes and Metabolism, Boston VA Healthcare System, Boston, MA, USA; Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
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Božek T, Bilić-Ćurčić I, Berković MC, Gradišer M, Kurir TT, Majanović SK, Marušić S. The effectiveness of lixisenatide as an add on therapy to basal insulin in diabetic type 2 patients previously treated with different insulin regimes: a multi-center observational study. Diabetol Metab Syndr 2018; 10:16. [PMID: 29563974 PMCID: PMC5850977 DOI: 10.1186/s13098-018-0321-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Accepted: 03/08/2018] [Indexed: 01/10/2023] Open
Abstract
INTRODUCTION This observational study aimed to assess the effectiveness of lixisenatide as add on therapy to basal insulin in diabetic type 2 patients previously treated with different insulin regimes. METHODS Patients with diabetes type 2, prescribed with lixisenatide and basal insulin were divided in three groups (premixed insulin, basal bolus insulin and basal oral therapy (BOT). Difference in mean change in HbA1c, body mass index, total insulin doses, fasting blood glucose (FPG) and prandial blood glucose (PPG) were assessed after 3-6-months of follow-up. RESULTS The primary outcomes were assessed in 111 patients. Lixisenatide added to basal insulin, reduced HbA1c and body weight significantly in all three groups of patients (p < 0.001 for all), with the most prominent reduction in the basal bolus group of patients which had the highest baseline HbA1c compared to premix and BOT treatment groups. Regarding a difference in total insulin dose the reduction was statistically significant in the basal bolus (p = 0.006) and premix group (p < 0.001). FPG and PPG were also significantly reduced over time in all three groups (p < 0.001 for all). A composite outcome (reduction of HbA1c below 7% (53 mmol/mol) with any weight loss) was achieved in 27% of total patients included in the study, reduction of HbA1c below 7% was observed in 30% of patients, while 90% of patients experienced weight reduction. CONCLUSION These results indicate that lixisenatide add on basal insulin treatment (BIT) can improve glycemic control in a population with long-standing type 2 diabetes and previously uncontrolled on other insulin therapy.
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Affiliation(s)
- Tomislav Božek
- University Clinic for Diabetes Vuk Vrhovac, Zagreb, Croatia
| | - Ines Bilić-Ćurčić
- Department of Pharmacology, Faculty of Medicine, University J. J. Strossmayer Osijek, Clinical Hospital Center, Osijek, J. Huttlera 4, 31000 Osijek, Croatia
| | - Maja Cigrovski Berković
- Department for Endocrinology, Diabetes and Metabolism, University Hospital Centre “Sestre Milosrdnice”, Zagreb, Croatia
| | - Marina Gradišer
- Internal Medicine Ward, General Hospital Čakovec, Čakovec, Croatia
| | - Tina Tićinović Kurir
- Department for Endocrinology, Diabetes and Metabolism, University Hospital Center Split, Split, Croatia
| | - Sanja Klobučar Majanović
- Department for Endocrinology, Diabetes and Metabolism, University Hospital Center Rijeka, Rijeka, Croatia
| | - Srećko Marušić
- Department for Endocrinology, Diabetes and Metabolism, Clinical Hospital Dubrava, Zagreb, Croatia
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Wysham CH, Lin J, Kuritzky L. Safety and efficacy of a glucagon-like peptide-1 receptor agonist added to basal insulin therapy versus basal insulin with or without a rapid-acting insulin in patients with type 2 diabetes: results of a meta-analysis. Postgrad Med 2017; 129:436-445. [PMID: 28294702 DOI: 10.1080/00325481.2017.1297669] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVE To consolidate the evidence from randomized controlled trials evaluating the use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) as add-on to basal insulin therapy in type 2 diabetes (T2D) patients. RESEARCH DESIGN AND METHODS We searched the EMBASE® and NCBI PubMed (Medline) databases and relevant congress abstracts for randomized controlled trials evaluating the efficacy and safety of GLP-1 RAs as add-on to basal insulin compared with basal insulin with or without rapid-acting insulin (RAI) through 23 May 2016. The pooled data were analyzed using a random-effects meta-analysis model. A subanalysis was performed for trials investigating basal insulin plus GLP-1 RAs versus basal insulin plus RAI. RESULTS Of the 2617 retrieved records, 19 randomized controlled trials enrolling 7,053 patients with T2D were included. Compared with basal insulin ± RAI, reduction in glycated hemoglobin (HbA1c) from baseline (difference in means: -0.48% [95% confidence interval (CI), -0.67 to -0.30]; p < 0.0001) and weight loss (-2.60 kg [95% CI, -3.32 to -1.89]; p < 0.0001) were significantly greater with basal insulin plus GLP-1 RA. The subanalysis similarly showed significant results for change in HbA1c from baseline and for weight loss, as well as a significantly lower risk of symptomatic hypoglycemia in patients treated with basal insulin plus GLP-1 RA versus basal insulin plus RAI (odds ratio, 0.52 [95% CI, 0.42 to 0.64]; p < 0.0001). CONCLUSIONS Addition of GLP-1 RA to basal insulin provided improved glycemic control, led to weight reduction and similar hypoglycemia rates versus an intensified insulin strategy; however, symptomatic hypoglycemia rates were significantly lower when compared with a basal insulin plus RAI.
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Affiliation(s)
| | - Jay Lin
- b Novosys Health , Green Brook , NJ , USA
| | - Louis Kuritzky
- c Department of Community Health and Family Medicine , University of Florida , Gainesville , FL , USA
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Olurishe C, Kwanashie H, Zezi A, Danjuma N, Mohammed B. Chronic administration of ethanol leaf extract of Moringa oleifera Lam. (Moringaceae) may compromise glycaemic efficacy of Sitagliptin with no significant effect in retinopathy in a diabetic rat model. JOURNAL OF ETHNOPHARMACOLOGY 2016; 194:895-903. [PMID: 27789327 DOI: 10.1016/j.jep.2016.10.065] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/11/2016] [Revised: 10/10/2016] [Accepted: 10/22/2016] [Indexed: 06/06/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Moringa oleifera Lam. (Moringaceae) has gained awareness for its antidiabetic effect, and is used as alternative therapy or concurrently with orthodox medicines such as sitagliptin in diabetes mellitus. This is without ascertaining the possibility of drug-herb interactions, which could either lead to enhanced antidiabetic efficacy, increased toxicity, or compromised glycaemic control with negative consequence in diabetic retinopathy. AIM OF THE STUDY To investigate the effect, of sitagliptin (50mg/kg), Moringa oleifera (300mg/kg) leaf extract, and a combination of both on glycaemic control parameters, lenticular opacity and changes in retinal microvasculature in alloxan (150mg/kg i.p) induced diabetic rat model. MATERIALS AND METHOD Seven groups of eight rats per group were used, with groups I, II and VII as normal (NC), diabetic (DC) and post-prandial controls (PPC). Groups III to VI were diabetic rats on sitagliptin (III), M. oleifera (IV), sitagliptin and M. oleifera (SM) (V), for 42 days with 2 weeks delayed treatment in a post-prandial hyperglycaemic group (PPSM) (VI). Glycaemic control parameters, insulin levels, body weights, and effects of retinal microvasculature on lenticular opacity/morphology were investigated. RESULTS A significant decrease in fasting blood glucose (FBG) levels was displayed in SM group from day 14(60%) (p<0.01) to day 28 (38%) (p<0.01) of treatment, compared to day 1. Thereafter, a steady increase of up to 57% on day 42 compared to day 28 was observed. A significant decrease in random blood glucose (RBG) levels, were demonstrated on day 42 (24%) (p<0.001), compared to day 1. No significant difference was seen in mean serum levels of insulin across groups. No significant changes in body weights. Evidence of mild lenticular opacity was observed, with no significant effect in pathologic lesions in the retina. CONCLUSION The chronic co-administration of sitagliptin and M. oleifera showed a progressive decrease in anti-hyperglycaemic effect of sitagliptin, and although it delayed the onset of lenticular opacity (i.e. cataract-like changes) it did not prevent the progression nor ameliorated pathologic lesions in the retina.
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Affiliation(s)
- Comfort Olurishe
- Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Ahmadu Bello University, Zaria, Nigeria.
| | - Helen Kwanashie
- Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Ahmadu Bello University, Zaria, Nigeria
| | - Abdulkadiri Zezi
- Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Ahmadu Bello University, Zaria, Nigeria
| | - Nuhu Danjuma
- Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Ahmadu Bello University, Zaria, Nigeria
| | - Bisalla Mohammed
- Department of Veterinary Pathology, Faculty of Veterinary Medicine, Ahmadu Bello University, Zaria, Nigeria
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Abstract
OBJECTIVE Diabetes is a well-established pro-inflammatory state with an increased risk for cardiovascular (CV) diseases. In recent years, the number of different classes of agents for the treatment of type 2 diabetes has increased substantially, and while glycemic control is the major focus of these medications, CV safety has become of interest. Two incretin-based therapies are currently available: glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors. METHODS The literature was reviewed for information regarding the incretin-based therapies and their effects on the CV system. RESULTS Independent of their glucose-lowering action, incretin-based therapies may have incretin-dependent mechanisms that positively affect blood pressure, weight, and other markers of CV disease risk, and, in the case of DPP-4 inhibition, nonincretin-dependent actions such as improving endothelial function. Several CV outcomes trials (CVOTs) with incretin-based therapies have recently completed with no excess CV risk observed, and positive effects have been reported in at least 1 trial of GLP-1 RAs, with more studies ongoing. Results for the risk for heart failure with DPP-4 inhibitor use are mixed, but no increase has been demonstrated with GLP-1 RAs. CONCLUSION Future CVOTs will need to be redesigned to help address these questions in the context of the emerging scope of the underlying mechanisms of cardio-metabolic disease in populations with diabetes. ABBREVIATIONS A1C = hemoglobin A1C ACS = acute coronary syndrome CHD = coronary heart disease CI = confidence interval CV = cardiovascular CVOT = Cardiovascular Outcome Trial DPP-4 = dipeptidyl peptidase 4 FDA = U.S. Food and Drug Administration GIP = glucose-dependent insulinotropic polypeptide GLP-1 = glucagon-like protein 1 GLP-1 RA = glucagon-like protein 1 receptor agonist HF = heart failure HR = hazard ratio LVEF = left ventricular ejection fraction MACE = major adverse cardiovascular events MI = myocardial infarction T2D = type 2 diabetes.
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Denney WS, Sonnenberg GE, Carvajal-Gonzalez S, Tuthill T, Jackson VM. Pharmacokinetics and pharmacodynamics of PF-05190457: The first oral ghrelin receptor inverse agonist to be profiled in healthy subjects. Br J Clin Pharmacol 2016; 83:326-338. [PMID: 27621150 DOI: 10.1111/bcp.13127] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2016] [Revised: 08/25/2016] [Accepted: 09/08/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate safety, tolerability and pharmacokinetics of oral PF-05190457, an oral ghrelin receptor inverse agonist, in healthy adults. METHODS Single (SAD) and multiple ascending dose (MAD) studies were randomised, placebo-controlled, double-blind studies. Thirty-five healthy men (age 38.2 ± 10.4 years; body mass index 24.8 ± 3.1 kg m-2 [mean ± standard deviation]) received ≥1 dose (2, 10, 40 [divided], 50, 100, 150, and 300 [single or divided] mg) of PF-05190457 and/or placebo in the SAD. In the MAD study, 35 healthy men (age 39.7 ± 10.1 years; body mass index 25.9 ± 3.3 kg m-2 ) received ≥1 dose (2, 10, 40 and 100 mg twice daily) of PF-05190457 and/or placebo daily for 2 weeks. RESULTS PF-05190457 absorption was rapid with a Tmax of 0.5-3 hours and a half-life between 8.2-9.8 hours. PF-05190457 dose-dependently blocked ghrelin (1 pmol kg-1 min-1 )-induced growth hormone (GH) release with (mean [90% confidence interval]) 77% [63-85%] inhibition at 100 mg. PF-05190457 (150 mg) delayed gastric emptying lag time by 30% [7-58%] and half emptying time by 20% [7-35%] with a corresponding decrease in postprandial glucose by 9 mg dL-1 . The most frequent adverse event reported by 30 subjects at doses ≥50 mg was somnolence. PF-05190457 plasma concentrations also increased heart rate up to 13.4 [4.8-58.2] beats min-1 and, similar to the effect on glucose and ghrelin-induced GH, was lost within 2 weeks. CONCLUSIONS PF-05190457 is a well-tolerated first-in-class ghrelin receptor inverse agonist with acceptable pharmacokinetics for oral daily dosing. Blocking ghrelin receptors inhibits ghrelin-induced GH, and increases heart rate, effects that underwent tachyphylaxis with chronic dosing. PF-051940457 has the potential to treat centrally-acting disorders such as insomnia.
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Affiliation(s)
- William S Denney
- Biotherapeutics Clinical Pharmacology, Pfizer Worldwide Research and Development, Cambridge, Massachusetts, 02139, USA
| | - Gabriele E Sonnenberg
- Cardiovascular, Metabolic, and Endocrine Diseases Research Unit, Pfizer Worldwide Research and Development, Cambridge, Massachusetts, 02139, USA
| | - Santos Carvajal-Gonzalez
- Cardiovascular, Metabolic, and Endocrine Diseases Research Unit, Pfizer Worldwide Research and Development, Cambridge, Massachusetts, 02139, USA
| | - Theresa Tuthill
- Cardiovascular, Metabolic, and Endocrine Diseases Research Unit, Pfizer Worldwide Research and Development, Cambridge, Massachusetts, 02139, USA
| | - V Margaret Jackson
- Cardiovascular, Metabolic, and Endocrine Diseases Research Unit, Pfizer Worldwide Research and Development, Cambridge, Massachusetts, 02139, USA
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Chatterjee S, Ghosal S, Chatterjee S. Glucagon-like peptide-1 receptor agonists favorably address all components of metabolic syndrome. World J Diabetes 2016; 7:441-448. [PMID: 27795818 PMCID: PMC5065664 DOI: 10.4239/wjd.v7.i18.441] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2016] [Revised: 07/28/2016] [Accepted: 08/06/2016] [Indexed: 02/05/2023] Open
Abstract
Cardiovascular death is the leading cause of mortality for patients with type 2 diabetes mellitus. The etiology of cardiovascular disease in diabetes may be divided into hyperglycemia per se and factors operating through components of metabolic syndrome (MetS). Hyperglycemia causes direct injury to vascular endothelium and possibly on cardiac myocytes. MetS is a cluster of risk factors like obesity, hyperglycemia, hypertension and dyslipidemia. The incidence of this syndrome is rising globally. Glucagon-like peptide-1 receptor agonists (GLP-1RA) are a group of drugs, which address all components of this syndrome favorably. Experimental evidence suggests that they have favorable actions on myocardium as well. Several compounds belonging to GLP-1RA class are in market now and a large number awaiting their entry. Although, originally this class of drugs emerged as a treatment for type 2 diabetes mellitus, more recent data generated revealed beneficial effects on multiple metabolic parameters. We have studied literature published between 2000 and 2016 to look into effects of GLP-1RA on components of MetS. Results from recently concluded clinical trials suggest that some of the molecules in this class may have favorable effects on cardiovascular outcome.
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Gilor C, Rudinsky AJ, Hall MJ. New Approaches to Feline Diabetes Mellitus: Glucagon-like peptide-1 analogs. J Feline Med Surg 2016; 18:733-43. [PMID: 27562982 PMCID: PMC11148896 DOI: 10.1177/1098612x16660441] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
CLINICAL RELEVANCE Incretin-based therapies are revolutionizing the field of human diabetes mellitus (DM) by replacing insulin therapy with safer and more convenient long-acting drugs. MECHANISM OF ACTION Incretin hormones (glucagon-like peptide-1 [GLP-1] and glucose-dependent insulinotropic peptide [GIP]) are secreted from the intestinal tract in response to the presence of food in the intestinal lumen. GLP-1 delays gastric emptying and increases satiety. In the pancreas, GLP-1 augments insulin secretion and suppresses glucagon secretion during hyperglycemia in a glucose-dependent manner. It also protects beta cells from oxidative and toxic injury and promotes expansion of beta cell mass. ADVANTAGES Clinical data have revealed that GLP-1 analog drugs are as effective as insulin in improving glycemic control while reducing body weight in people suffering from type 2 DM. Furthermore, the incidence of hypoglycemia is low with these drugs because of their glucose-dependent mechanism of action. Another significant advantage of these drugs is their duration of action. While insulin injections are administered at least once daily, long-acting GLP-1 analogs have been developed as once-a-week injections and could potentially be administered even less frequently than that in diabetic cats. OUTLINE This article reviews the physiology of incretin hormones, and the pharmacology and use of GLP-1 analogs, with emphasis on recent research in cats. Further therapies that are based on incretin hormones, such as DPP-4 inhibitors, are also briefly discussed, as are some other treatment modalities that are currently under investigation.
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Affiliation(s)
- Chen Gilor
- University of California School of Veterinary Medicine, 2118A Tupper Hall, Davis, CA 95616, USA
| | - Adam J Rudinsky
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210, USA
| | - Melanie J Hall
- Sheridan Animal Hospital & Veterinary Specialists of Western New York, 2288 Sheridan Drive, Buffalo, NY 14223, USA
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Tomlinson B, Hu M, Zhang Y, Chan P, Liu ZM. Investigational glucagon-like peptide-1 agonists for the treatment of obesity. Expert Opin Investig Drugs 2016; 25:1167-79. [PMID: 27563838 DOI: 10.1080/13543784.2016.1221925] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Obesity is a worldwide problem predisposing to type 2 diabetes mellitus (T2DM), hypertension, cardiovascular disease, cancer and other comorbidities. Lifestyle modification is the first line intervention but adjunctive pharmacotherapy is often required. The GLP-1 receptor agonists (GLP-1RAs) were developed primarily for T2DM and they also reduce body weight. Liraglutide was approved for the treatment of obesity and other GLP-1RAs are likely to be suitable for this indication. AREAS COVERED This review describes the GLP-1RAs that have been approved for the treatment of T2DM as potential candidates for the treatment of obesity and the new agents currently under development which may have advantages in patient adherence. EXPERT OPINION The GLP-1RAs offer a welcome addition to obesity pharmacotherapy. They appear to be free of serious adverse effects although uncertainty remains about possible risks of pancreatitis and neoplasms. However, they have frequent gastrointestinal side effects, particularly nausea, which limits their tolerability. Cardiovascular outcome studies in T2DM support their use and this is likely to increase in both T2DM and obesity. Other GLP-1RAs which can be given by subcutaneous injection once weekly or less frequently or by oral administration would have advantages especially if nausea is less frequent than with liraglutide.
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Affiliation(s)
- Brian Tomlinson
- a Research Center for Translational Medicine , Shanghai East Hospital Affiliated to Tongji University School of Medicine , Shanghai , China.,b Department of Medicine & Therapeutics , The Chinese University of Hong Kong , Shatin , Hong Kong
| | - Miao Hu
- b Department of Medicine & Therapeutics , The Chinese University of Hong Kong , Shatin , Hong Kong
| | - Yuzhen Zhang
- a Research Center for Translational Medicine , Shanghai East Hospital Affiliated to Tongji University School of Medicine , Shanghai , China
| | - Paul Chan
- c Division of Cardiology, Department of Internal Medicine, Wan Fang Hospital , Taipei Medical University , Taipei City , Taiwan
| | - Zhong-Min Liu
- d Department of Cardiac Surgery, Shanghai East Hospital , Tongji University , Shanghai , China
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Monnier L, Bonnet F, Colette C. Tailoring nutrient sequence and content to improve glucose tolerance: Why and how to do it. DIABETES & METABOLISM 2016; 42:211-4. [PMID: 27184768 DOI: 10.1016/j.diabet.2016.04.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/08/2016] [Accepted: 04/08/2016] [Indexed: 12/22/2022]
Affiliation(s)
- L Monnier
- Institute of Clinical Research, 641, avenue du Doyen-Giraud, 34093 Montpellier cedex 5, France.
| | - F Bonnet
- Departement of Endocrinology and Diabetology, University Hospital, Rennes, France
| | - C Colette
- Institute of Clinical Research, 641, avenue du Doyen-Giraud, 34093 Montpellier cedex 5, France
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Shaefer CF. Lixisenatide: A New Member of the Glucagon-Like Peptide 1 Receptor Agonist Class of Incretin Therapies. Clin Diabetes 2016; 34:81-5. [PMID: 27092017 PMCID: PMC4833487 DOI: 10.2337/diaclin.34.2.81] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
In Brief In the past decade, various incretin-based therapies have emerged in clinical practice. These drugs, including dipeptidyl peptidase-4 inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists lower A1C with weight-neutral or weight-lowering effects and a relatively lower risk of hypoglycemia. This article provides a review of lixisenatide, a once-daily GLP-1 receptor agonist for the treatment of type 2 diabetes.
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Affiliation(s)
- Charles F Shaefer
- University Health Systems-Primary Care and Medical College of Georgia, Augusta University, Augusta, GA
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Madsbad S. Review of head-to-head comparisons of glucagon-like peptide-1 receptor agonists. Diabetes Obes Metab 2016; 18:317-32. [PMID: 26511102 PMCID: PMC5064617 DOI: 10.1111/dom.12596] [Citation(s) in RCA: 216] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2015] [Revised: 08/16/2015] [Accepted: 10/22/2015] [Indexed: 12/11/2022]
Abstract
Currently, six glucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for treating type 2 diabetes. These fall into two classes based on their receptor activation: short-acting exenatide twice daily and lixisenatide once daily; and longer-acting liraglutide once daily, exenatide once weekly, albiglutide once weekly and dulaglutide once weekly. The phase III trial of a seventh GLP-1RA, taspoglutide once weekly, was stopped because of unacceptable adverse events (AEs). Nine phase III head-to-head trials and one large phase II study have compared the efficacy and safety of these seven GLP-1RAs. All trials were associated with notable reductions in glycated haemoglobin (HbA1c) levels, although liraglutide led to greater decreases than exenatide formulations and albiglutide, and HbA1c reductions did not differ between liraglutide and dulaglutide. As the short-acting GLP-1RAs delay gastric emptying, they have greater effects on postprandial glucose levels than the longer-acting agents, whereas the longer-acting compounds reduced plasma glucose throughout the 24-h period studied. Liraglutide was associated with weight reductions similar to those with exenatide twice daily but greater than those with exenatide once weekly, albiglutide and dulaglutide. The most frequently observed AEs with GLP-1RAs were gastrointestinal disorders, particularly nausea, vomiting and diarrhoea. Nauseaoccurred less frequently, however, with exenatide once weekly and albiglutide than exenatide twice daily and liraglutide. Both exenatide formulations and albiglutide may be associated with higher incidences of injection-site reactions than liraglutide and dulaglutide. GLP-1RA use in clinical practice should be customized for individual patients, based on clinical profile and patient preference. Ongoing assessments of novel GLP-1RAs and delivery methods may further expand future treatment options.
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Affiliation(s)
- Sten Madsbad
- Department of EndocrinologyHvidovre Hospital, University of CopenhagenHvidovreDenmark
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Srinivasan DK, Ojo OO, Owolabi BO, Conlon JM, Flatt PR, Abdel-Wahab YHA. [I10W]tigerinin-1R enhances both insulin sensitivity and pancreatic beta cell function and decreases adiposity and plasma triglycerides in high-fat mice. Acta Diabetol 2016; 53:303-15. [PMID: 26138324 DOI: 10.1007/s00592-015-0783-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2015] [Accepted: 05/31/2015] [Indexed: 12/11/2022]
Abstract
AIMS We have previously described the insulinotropic activities of [I10W]tigerinin-1R (RVCSAIPLPWCH.NH2) in vitro. In this study, we investigated the effects of the peptide on nutrient homoeostasis in mice with diet-induced obesity and insulin resistance. METHODS Male NIH Swiss mice were maintained on a high-fat diet for 12 weeks prior to the study. Twice-daily intraperitoneal injections of [I10W]tigerinin-1R (75 nmol/kg body weight) were administered for 28 days. Body weight, energy intake, body fat content, and plasma concentrations of triglyceride, cholesterol, non-fasting glucose and insulin were monitored. Effects of the peptide on glycaemic control were measured by glucose tolerance and insulin sensitivity tests. Pancreatic hormone content and insulin secretory responses of islets isolated from treated and untreated mice were examined. Immunohistochemical analysis was performed to study possible changes in islet morphology. RESULTS Administration of [I10W]tigerinin-1R to high-fat-fed mice produced significant (P < 0.05) decreases in plasma glucose, glucagon and triglyceride concentrations and an increase in plasma insulin compared to high-fat-fed controls. No changes in body weight or energy intake were observed with peptide treatment, but glycaemic control was significantly improved in response to oral or intraperitoneal glucose. Insulin sensitivity and secretory responses of islets to established insulin secretagogues were also significantly improved in peptide-treated mice. Total body fat, pancreatic insulin and glucagon contents, islet, beta and alpha cell areas were all significantly decreased in treated mice. CONCLUSIONS This study shows that [I10W]tigerinin-1R improves insulin sensitivity, islet function and glycaemic control in high-fat-fed mice and has potential as a template for development of novel anti-diabetic agents.
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Affiliation(s)
- Dinesh K Srinivasan
- SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, BT52 1SA, Northern Ireland, UK
| | - Opeolu O Ojo
- SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, BT52 1SA, Northern Ireland, UK
| | - Bosede O Owolabi
- SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, BT52 1SA, Northern Ireland, UK
| | - J Michael Conlon
- SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, BT52 1SA, Northern Ireland, UK
| | - Peter R Flatt
- SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, BT52 1SA, Northern Ireland, UK
| | - Yasser H A Abdel-Wahab
- SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, BT52 1SA, Northern Ireland, UK.
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Østergaard L, Frandsen CS, Madsbad S. Treatment potential of the GLP-1 receptor agonists in type 2 diabetes mellitus: a review. Expert Rev Clin Pharmacol 2016; 9:241-65. [PMID: 26573176 DOI: 10.1586/17512433.2016.1121808] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Over the last decade, the discovery of glucagon-like peptide 1 receptor agonists (GLP-1 RAs) has increased the treatment options for patients with type 2 diabetes mellitus (T2DM). GLP-1 RAs mimic the effects of native GLP-1, which increases insulin secretion, inhibits glucagon secretion, increases satiety and slows gastric emptying. This review evaluates the phase III trials for all approved GLP-1 RAs and reports that all GLP-1 RAs decrease HbA1c, fasting plasma glucose, and lead to a reduction in body weight in the majority of trials. The most common adverse events are nausea and other gastrointestinal discomfort, while hypoglycaemia is rarely reported when GLP-1 RAs not are combined with sulfonylurea or insulin. Treatment options in the near future will include co-formulations of basal insulin and a GLP-1 RA.
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Affiliation(s)
- L Østergaard
- a Department of Endocrinology, Hvidovre Hospital , University of Copenhagen , Copenhagen , Denmark
| | - Christian S Frandsen
- a Department of Endocrinology, Hvidovre Hospital , University of Copenhagen , Copenhagen , Denmark
| | - S Madsbad
- a Department of Endocrinology, Hvidovre Hospital , University of Copenhagen , Copenhagen , Denmark
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Guo XH. The value of short- and long-acting glucagon-like peptide-1 agonists in the management of type 2 diabetes mellitus: experience with exenatide. Curr Med Res Opin 2016; 32:61-76. [PMID: 26439329 DOI: 10.1185/03007995.2015.1103214] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
BACKGROUND Only about half of patients with type 2 diabetes treated with antihyperglycemic drugs achieve glycemic control (HbA1c <7%), most commonly due to poor treatment adherence. Glucagon-like peptide-1 (GLP-1) receptor agonists act on multiple targets involved in glucose homeostasis and have a low risk of causing hypoglycemia. While GLP-1 receptor (GLP-1R) agonists share the same mechanism of action, clinical profiles of individual agents differ, particularly between short- and long-acting agents. In this article, recent findings regarding the pharmacology of GLP-1 agonists are reviewed, and the clinical effects of short- versus long-acting agents are compared. DATA SOURCES Relevant articles were identified through a search of PubMed using the keywords glucagon-like peptide-1, GLP-1, glucagon-like peptide-1 receptor agonist, GLP-1R agonist, and exenatide for publications up to 22 May 2015. Supporting data were obtained from additional searches for albiglutide, dulaglutide, liraglutide and lixisenatide as well as from the bibliographies of key articles. FINDINGS Short-acting GLP-1R agonists produce greater reductions in postprandial glucose levels by slowing gastric emptying, whereas long-acting GLP-1R agonists produce greater reductions in fasting blood glucose by stimulating insulin secretion from the pancreas. These characteristics can be exploited to provide individualized treatment to patients. A large body of evidence supports the benefits of short- and long-acting exenatide as add-on therapy in patients with inadequate glycemic control despite maximum tolerated doses of metformin and/or sulfonylurea. Exenatide is generally well tolerated and no new safety concerns were identified during long-term follow-up of up to 5 years. A limitation of this review of short-and long-acting GLP-1 receptor agonists is that it focuses on exenatide rather than all the drugs in this class. However, the focus on a single molecule helps to avoid any confusion that may be introduced as a result of differences in molecular structure and size. CONCLUSIONS Short-acting GLP-1R agonists including exenatide are well suited to patients with type 2 diabetes with exaggerated postprandial glucose excursions and for co-administration with basal insulin therapy. Long-acting GLP-1R agonists including once weekly exenatide offer greater convenience and are well suited to patients who require specific control of fasting hyperglycemia.
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Affiliation(s)
- Xiao-Hui Guo
- a Endocrinology Department , Peking University First Hospital , Beijing , China
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Chen Z, Ning M, Zou Q, Cao H, Ye Y, Leng Y, Shen J. Discovery and Structure–Activity Relationship Study of 4-Phenoxythiazol-5-carboxamides as Highly Potent TGR5 Agonists. Chem Pharm Bull (Tokyo) 2016; 64:326-39. [DOI: 10.1248/cpb.c15-00905] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Affiliation(s)
- Zhixiang Chen
- College of Pharmacy, Nanchang University
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences
| | - Mengmeng Ning
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences
| | - Qingan Zou
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences
| | - Hua Cao
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences
| | - Yangliang Ye
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences
| | - Ying Leng
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences
| | - Jianhua Shen
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences
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Tomlinson B, Hu M, Zhang Y, Chan P, Liu ZM. An overview of new GLP-1 receptor agonists for type 2 diabetes. Expert Opin Investig Drugs 2015; 25:145-58. [DOI: 10.1517/13543784.2016.1123249] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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Hinnen DA. Therapeutic Options for the Management of Postprandial Glucose in Patients With Type 2 Diabetes on Basal Insulin. Clin Diabetes 2015; 33:175-80. [PMID: 26487791 PMCID: PMC4608276 DOI: 10.2337/diaclin.33.4.175] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
In Brief For patients with type 2 diabetes who require add-on therapy to metformin plus basal insulin, GLP-1 receptor agonists may be a favorable option because they effectively manage postprandial glucose, reduce body weight, and have an overall favorable safety profile compared to other agents. Given the wide range of treatment combinations available for type 2 diabetes management, health professionals must partner with patients to determine the best choices based on patients' individual lifestyle, resources, and treatment goals.
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Affiliation(s)
- Debbie A Hinnen
- Memorial Hospital Diabetes Center, University of Colorado Health, Colorado Springs, CO
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Oh S, Chon S, Ahn KJ, Jeong IK, Kim BJ, Kang JG. The Role of Glucagon-Like Peptide-1 Receptor Agonists in Type 2 Diabetes: Understanding How Data Can Inform Clinical Practice in Korea. Diabetes Metab J 2015; 39:177-87. [PMID: 26124987 PMCID: PMC4483602 DOI: 10.4093/dmj.2015.39.3.177] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduce glycosylated hemoglobin (HbA1c, 0.5% to 1.0%), and are associated with moderate weight loss and a relatively low risk of hypoglycemia. There are differences between Asian and non-Asian populations. We reviewed available data on GLP-1RAs, focusing on Korean patients, to better understand their risk/benefit profile and help inform local clinical practice. Control of postprandial hyperglycemia is important in Asians in whom the prevalence of post-challenge hyperglycemia is higher (vs. non-Asians). The weight lowering effects of GLP-1RAs are becoming more salient as the prevalence of overweight and obesity among Korean patients increases. The higher rate of gastrointestinal adverse events amongst Asian patients in clinical trials may be caused by higher drug exposure due to the lower body mass index of the participants (vs. non-Asian studies). Data on the durability of weight loss, clinically important health outcomes, safety and optimal dosing in Korean patients are lacking. Use of GLP-1RAs is appropriate in several patient groups, including patients whose HbA1c is uncontrolled, especially if this is due to postprandial glucose excursions and patients who are overweight or obese due to dietary problems (e.g., appetite control). The potential for gastrointestinal adverse events should be explained to patients at treatment initiation to facilitate the promotion of better compliance.
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Affiliation(s)
- Seungjoon Oh
- Department of Endocrinology and Metabolism, Kyung Hee University School of Medicine, Seoul, Korea
| | - Suk Chon
- Department of Endocrinology and Metabolism, Kyung Hee University School of Medicine, Seoul, Korea
| | - Kyu Jeong Ahn
- Department of Endocrinology and Metabolism, Kyung Hee University School of Medicine, Seoul, Korea
| | - In-Kyung Jeong
- Department of Endocrinology and Metabolism, Kyung Hee University School of Medicine, Seoul, Korea
| | - Byung-Joon Kim
- Department of Endocrinology, Gachon University College of Medicine, Incheon, Korea
| | - Jun Goo Kang
- Department of Endocrinology and Metabolism, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Korea
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