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Tommerdahl KL, Kula AJ, Bjornstad P. Pharmacological management of youth with type 2 diabetes and diabetic kidney disease: a comprehensive review of current treatments and future directions. Expert Opin Pharmacother 2023; 24:913-924. [PMID: 37071054 PMCID: PMC10198950 DOI: 10.1080/14656566.2023.2203319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 04/12/2023] [Indexed: 04/19/2023]
Abstract
INTRODUCTION Diabetic kidney disease (DKD) is a leading cause of mortality in people with type 2 diabetes (T2D), and over 50% of individuals with youth-onset T2D will develop DKD as a young adult. Diagnosis of early-onset DKD remains a challenge in young persons with T2D secondary to a lack of available biomarkers for early DKD, while the injuries may still be reversible. Furthermore, multiple barriers exist to initiate timely prevention and treatment strategies for DKD, including a lack of Food and Drug Administration approval of medications in pediatrics; provider comfort with medication prescription, titration, and monitoring; and medication adherence. AREAS COVERED Therapies that have promise for slowing DKD progression in youth with T2D include metformin, renin-angiotensin-aldosterone system inhibitors, glucagon-like peptide-1 receptor agonists, sodium glucose co-transporter 2 inhibitors, thiazolidinediones, sulfonylureas, endothelin receptor agonists, and mineralocorticoid antagonists. Novel agents are also in development to act synergistically on the kidneys with the aforementioned medications. We comprehensively review the available pharmacologic strategies for DKD in youth-onset T2D including mechanisms of action, potential adverse effects, and kidney-specific effects, with an emphasis on published pediatric and adult trials. EXPERT OPINION Large clinical trials evaluating pharmacologic interventions targeting the treatment of DKD in youth-onset T2D are strongly needed.
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Affiliation(s)
- Kalie L. Tommerdahl
- Department of Pediatrics, Section of Pediatric Endocrinology, Children’s Hospital Colorado and University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, Colorado, USA
- Ludeman Family Center for Women’s Health Research, Division of General Internal Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Alexander J. Kula
- Department of Pediatrics, Section of Pediatric Nephrology, Lurie Children’s Hospital and Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Petter Bjornstad
- Department of Pediatrics, Section of Pediatric Endocrinology, Children’s Hospital Colorado and University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
- Ludeman Family Center for Women’s Health Research, Division of General Internal Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA
- Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
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Salman L, Martinez L, Faddoul G, Manning C, Ali K, Salman M, Vazquez-Padron R. Hyaluronan Inhibition as a Therapeutic Target for Diabetic Kidney Disease: What Is Next? KIDNEY360 2023; 4:e851-e860. [PMID: 37055910 PMCID: PMC10371374 DOI: 10.34067/kid.0000000000000126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Accepted: 03/17/2023] [Indexed: 04/15/2023]
Abstract
Diabetic kidney disease (DKD) is the leading cause of CKD and ESKD in the United States and worldwide. Pharmacotherapy and lifestyle modifications for glycemia, dyslipidemia, and BP control have shown success in slowing the progression of DKD. Traditional treatments, such as angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and more recently the use of sodium-glucose cotransporter 2 inhibitors, nonsteroidal selective mineralocorticoid receptor antagonists, such as finerenone, and glucagon-like peptide 1 receptor agonists, have led to added benefits on various outcomes. However, significant residual risk for DKD progression remains despite the current standard-of-care approaches. Arteriolar hyalinosis (AH) is among the key findings seen on kidney biopsies of patients with DKD. It results from the excessive accumulation of hyaluronan (HA) in the arterioles. AH has not been targeted specifically by any of the therapeutic methods currently being used. We discuss in this manuscript the potential use of a selective therapy targeting AH and the increased total renal HA deposits using a HA synthesis inhibitor in DKD.
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Affiliation(s)
- Loay Salman
- Division of Nephrology and Hypertension, Department of Medicine, Albany Med Health System, Albany, New York
| | - Laisel Martinez
- Division of Vascular Surgery, DeWitt Daughtry Family Department of Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, Florida
| | - Geovani Faddoul
- Division of Nephrology and Hypertension, Department of Medicine, Albany Med Health System, Albany, New York
| | - Christina Manning
- Division of Nephrology and Hypertension, Department of Medicine, Albany Med Health System, Albany, New York
| | - Karim Ali
- Division of Nephrology and Hypertension, Department of Medicine, Albany Med Health System, Albany, New York
| | - Maya Salman
- Faculty of Medicine, Damascus University, Damascus, Syria
| | - Roberto Vazquez-Padron
- Division of Vascular Surgery, DeWitt Daughtry Family Department of Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, Florida
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Shetty R, Basheer FT, Poojari PG, Thunga G, Chandran VP, Acharya LD. Adverse drug reactions of GLP-1 agonists: A systematic review of case reports. Diabetes Metab Syndr 2022; 16:102427. [PMID: 35217468 DOI: 10.1016/j.dsx.2022.102427] [Citation(s) in RCA: 62] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 02/08/2022] [Accepted: 02/09/2022] [Indexed: 12/29/2022]
Abstract
BACKGROUND AND AIM The importance of glucagon-like peptide-1 (GLP-1) agonists is increasing because of its blood sugar controlling and weight loss properties. The data regarding safety of GLP-1 agonists are limited. This study aims to review case reports and case series on adverse drug reactions (ADRs) of GLP-1 agonist. METHODOLOGY A comprehensive search was performed in PubMed/Medline, Scopus and Embase to identify literatures. Bibliographic search and open search in Google, Google Scholar, SpringerLink and ResearchGate was performed to identify additional studies. Case reports and case series published the ADRs by the use of GLP-1 agonists in type 2 diabetes patients were included in the study. Reviews, experimental studies, observational studies, grey literature and non English studies were excluded. RESULTS The study identified 120 cases of GLP-1 agonists associated ADRs (liraglutide - 46, exenatide - 46, dulaglutide - 20, semaglutide - 4, albiglutide - 2, lixisenatide - 2). The major ADRs reported was gastrointestinal disorders (n = 40) followed by renal (n = 23), dermatologic (n = 14), hepatic (n = 10), immunologic (n = 13), endocrine/metabolic (n = 7), hematologic (n = 3), angioedema (n = 3), neurologic (n = 2), cardiovascular (n = 2) and 1 from each of psychiatric, reproductive, generalized edema problems. CONCLUSION Gastrointestinal problems, particularly pancreatitis was the more frequently reported adverse drug reaction associated with GLP-1 agonist. The most adverse drug reactions were observed with liraglutide and exenatide.
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Affiliation(s)
- Rashmi Shetty
- Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India.
| | - Fathima Thashreefa Basheer
- Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India.
| | - Pooja Gopal Poojari
- Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India.
| | - Girish Thunga
- Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India.
| | - Viji Pulikkel Chandran
- Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India.
| | - Leelavathi D Acharya
- Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India.
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4
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Dong S, Sun C. Can glucagon-like peptide-1 receptor agonists cause acute kidney injury? An analytical study based on post-marketing approval pharmacovigilance data. Front Endocrinol (Lausanne) 2022; 13:1032199. [PMID: 36583004 PMCID: PMC9792852 DOI: 10.3389/fendo.2022.1032199] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 11/25/2022] [Indexed: 12/15/2022] Open
Abstract
UNLABELLED Clinical studies after marketing have shown that the use of glucagon-like peptide-1 receptor agonist(GLP-1RA) may lead to acute kidney injury(AKI). However, few epidemiological studies have investigated the risk, clinical features, and outcomes of AKI caused by different GLP-1RA. In this study, Adverse Event Reporting System (FAERS) data were used to compare the association between different GLP-1RA and AKI in the real world. METHODS FAERS data from January 2004 to December 2021 were mined using disproportionality analysis and Bayesian analysis to determine the correlation between different GLP-1RA and AKI, and the onset time, mortality, and hospitalization rate of different GLP-1RA were analyzed. RESULTS We identified 2670 cases of AKI events associated with GLP-1RA, of which liraglutide was the most commonly reported (34.98%). The patients with AKI were mainly males (47.94%), and the age group was mainly 45-84 years old (73.15%). obese patients with weight more than 99kg (24.42%) were more likely to have AKI. According to different signal mining methods, reporting odds ratio (ROR) (1.50, 95% confidence interval =1.41-1.60) and Bayesian confidence Propagation neural network (0.57, 95% confidence interval =0.54), liraglutide was more strongly associated with AKI than other GLP-1RA. The median time to onset of AKI was 63 days [quartile range (IQR): 15-458.5 days]. In addition, the hospitalization rate and fatality rate of patients with GLP-1RA-related AKI were 45.28% and 4.23% respectively. CONCLUSIONS Based on the data in the FAERS database, we analyzed the risk, onset time, and adverse reaction outcomes of GLP-1RA-induced AKI in detail. The results showed that liraglutide had the highest risk of AKI. From the early stage of treatment, we need to monitor patients' renal function regularly, especially for patients with high kidney risks such as obesity and age.
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Affiliation(s)
- Shichao Dong
- Department of Pharmacy, The Second Hospital of Tianjin Medical University, Tianjin, China
| | - Chuan Sun
- Department of Pharmacy, Children’s Hospital of Nanjing Medical University, Nanjing, China
- *Correspondence: Chuan Sun,
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Gilbert MP, Pratley RE. GLP-1 Analogs and DPP-4 Inhibitors in Type 2 Diabetes Therapy: Review of Head-to-Head Clinical Trials. Front Endocrinol (Lausanne) 2020; 11:178. [PMID: 32308645 PMCID: PMC7145895 DOI: 10.3389/fendo.2020.00178] [Citation(s) in RCA: 206] [Impact Index Per Article: 41.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Accepted: 03/12/2020] [Indexed: 12/15/2022] Open
Abstract
The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released from enteroendocrine cells in response to the presence of nutrients in the small intestines. These homones facilitate glucose regulation by stimulating insulin secretion in a glucose dependent manner while suppressing glucagon secretion. In patients with type 2 diabetes (T2DM), an impaired insulin response to GLP-1 and GIP contributes to hyperglycemia. Dipeptidyl peptidase-4 (DPP-4) inhibitors block the breakdown of GLP-1 and GIP to increase levels of the active hormones. In clinical trials, DPP-4 inhibitors have a modest impact on glycemic control. They are generally well-tolerated, weight neutral and do not increase the risk of hypoglycemia. GLP-1 receptor agonists (GLP-1 RA) are peptide derivatives of either exendin-4 or human GLP-1 designed to resist the activity of DPP-4 and therefore, have a prolonged half-life. In clinical trials, they have demonstrated superior efficacy to many oral antihyperglycemic drugs, improved weight loss and a low risk of hypoglycemia. However, GI adverse events, particularly nausea, vomiting, and diarrhea are seen. Both DPP-4 inhibitors and GLP-1 RAs have demonstrated safety in robust cardiovascular outcome trials, while several GLP-1 RAs have been shown to significantly reduce the risk of major adverse cardiovascular events in persons with T2DM with pre-existing cardiovascular disease (CVD). Several clinical trials have directly compared the efficacy and safety of DPP-4 inhibitors and GLP-1 RAs. These studies have generally demonstrated that the GLP-1 RA provided superior glycemic control and weight loss relative to the DPP-4 inhibitor. Both treatments were associated with a low and comparable incidence of hypoglycemia, but treatment with GLP-1 RAs were invariably associated with a higher incidence of GI adverse events. A few studies have evaluated switching patients from DPP-4 inhibitors to a GLP-1RA and, as expected, improved glycemic control and weight loss are seen following the switch. According to current clinical guidelines, GLP-1RA and DPP-4 inhibitors are both indicated for the glycemic management of patients with T2DM across the spectrum of disease. GLP-1RA may be preferred over DPP- 4 inhibitors for many patients because of the greater reductions in hemoglobin A1c and weight loss observed in the clinical trials. Among patients with preexisting CVD, GLP-1 receptor agonists with a proven cardiovascular benefit are indicated as add-on to metformin therapy.
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Affiliation(s)
- Matthew P. Gilbert
- Division of Endocrinology and Diabetes, Department of Medicine, Larner College of Medicine at the University of Vermont, Burlington, VT, United States
- *Correspondence: Matthew P. Gilbert
| | - Richard E. Pratley
- AdventHealth Diabetes Institute, Translational Research Institute for Metabolism and Diabetes, Orlando, FL, United States
- Richard E. Pratley
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Aldrich S, Ashjian E. Use of GLP-1 receptor agonists in patients with T2DM and chronic kidney disease. Nurse Pract 2019; 44:20-28. [PMID: 30695005 DOI: 10.1097/01.npr.0000553396.65976.bb] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
Diabetes mellitus is the leading cause of chronic kidney disease (CKD) in the US. An increasing number of glucagon-like peptide-1 receptor agonists are available for diabetes management. Differences between medications in this class, as well as limited data on patients with CKD, underscore the importance of a patient-centered approach to care.
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Affiliation(s)
- Sarah Aldrich
- Sarah Aldrich is an ambulatory care pharmacist and assistant lecturer at the University of Toledo College of Pharmacy and Pharmaceutical Sciences, Toledo, Ohio. Emily Ashjian is a clinical assistant professor at the University of Michigan College of Pharmacy, Ann Arbor, Mich
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Seufert J, Borck A, Bramlage P. Addition of a single short-acting insulin bolus to basal insulin-supported oral therapy: a systematic review of data on the basal-plus regimen. BMJ Open Diabetes Res Care 2019; 7:e000679. [PMID: 31641521 PMCID: PMC6777409 DOI: 10.1136/bmjdrc-2019-000679] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2019] [Revised: 06/28/2019] [Accepted: 09/12/2019] [Indexed: 12/01/2022] Open
Abstract
We summarize here clinical and trial data on a once-daily administration of a single bolus to the meal with the largest expected postprandial glucose excursion (basal-plus), and comment on its clinical utility in the treatment of type 2 diabetes. A PubMed search of data published until September 2018 was taken into consideration and PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines were followed. Eighteen reports representing 15 studies were identified (age: 18-80 years; 50-890 patients; follow-up: 8 days to 60 weeks). Data suggest basal-plus is efficacious for improving glycemic control, with a low incidence of (severe) hypoglycemia and minor increases in bodyweight. The timing of short-acting insulin administration and use of different monitoring/titration approaches appear to have minimal impact. When compared with premixed insulin, basal-plus results in largely comparable outcomes. Compared with basal-bolus, it may result in non-inferior glycemic improvements with less weight gain, less hypoglycemia and fewer daily injections. A basal insulin/glucagon-like peptide-1 receptor agonist fixed ratio combination may offer several advantages over the basal-plus regimen, at the cost of gastrointestinal side effects. We conclude that the stepwise introduction of short-acting insulin via the basal-plus strategy represents a viable alternative to a full basal-bolus regimen and may help to overcome barriers associated with multiple injections and anticipated complexity of the insulin regimen.
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Affiliation(s)
- Jochen Seufert
- Division of Endocrinology and Diabetoligy, Department of Medicine II, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | | | - Peter Bramlage
- Institute for Pharmacology and Preventive Medicine, Cloppenburg, Germany
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van Baar MJB, van der Aart AB, Hoogenberg K, Joles JA, Heerspink HJL, van Raalte DH. The incretin pathway as a therapeutic target in diabetic kidney disease: a clinical focus on GLP-1 receptor agonists. Ther Adv Endocrinol Metab 2019; 10:2042018819865398. [PMID: 31384419 PMCID: PMC6657126 DOI: 10.1177/2042018819865398] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Accepted: 07/01/2019] [Indexed: 12/13/2022] Open
Abstract
Diabetic kidney disease (DKD) remains the main cause for chronic kidney disease (CKD) and end-stage kidney disease (ESKD) worldwide. Both CKD and ESKD lead to major increases in risk of cardiovascular disease and death in people with diabetes. Despite optimal management of lifestyle, glucose levels and hypertension, residual risk remains high, indicating that additional therapies to mitigate the burden of the disease are desired. In past decades, new treatment options for the management of diabetes have emerged, of which some have showed promising renoprotective potential. This review discusses current understanding of the renal effects of glucagon-like peptide receptor agonists and their potential use in prevention and treatment of DKD.
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Affiliation(s)
- Michaël J. B. van Baar
- Department of Internal Medicine, Amsterdam University Medical Centers, VUMC, Amsterdam, The Netherlands
| | - Annemarie B. van der Aart
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, Groningen, The Netherlands
- Department of Clinical Pharmacy, Martini Hospital, Groningen, The Netherlands
| | - Klaas Hoogenberg
- Department of Internal Medicine, Martini Hospital, Groningen, The Netherlands
| | - Jaap A. Joles
- Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Hiddo J. L. Heerspink
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, Groningen, The Netherlands
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Taylor SR, Moody MT. Acute Kidney Injury Occurring in a Patient Initiated on Dulaglutide. J Pharm Technol 2018; 34:231-232. [DOI: 10.1177/8755122518782155] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Affiliation(s)
- Shawn R. Taylor
- Wingate University, Hendersonville Campus, Hendersonville, NC, USA
- Dale Fell Health Center, Appalachian Mountain Community Health Center, Asheville, NC, USA
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Lovre D, Shah S, Sihota A, Fonseca VA. Managing Diabetes and Cardiovascular Risk in Chronic Kidney Disease Patients. Endocrinol Metab Clin North Am 2018; 47:237-257. [PMID: 29407054 PMCID: PMC5806139 DOI: 10.1016/j.ecl.2017.10.006] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
We discuss mechanisms of increased cardiovascular disease (CVD) in patients with chronic kidney disease (CKD) and strategies for managing cardiovascular (CV) risk in these patients. Our focus was mainly on decreasing CV events and progression of microvascular complications by reducing levels of glucose and lipids. We searched PubMed with no limit on the date of the article. All articles were discussed among all authors. We chose pertinent articles, and searched their references in turn for additional relevant publications.
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Affiliation(s)
- Dragana Lovre
- Section of Endocrinology, Tulane University Health Sciences Center, 1430 Tulane Avenue, #8553, New Orleans, LA 70112, USA; Section of Endocrinology, Southeast Louisiana Veterans Health Care Systems, 2400 Canal Street, New Orleans, LA 70119, USA.
| | - Sulay Shah
- Section of Endocrinology, Tulane University Health Sciences Center, 1430 Tulane Avenue, #8553, New Orleans, LA 70112, USA
| | - Aanu Sihota
- Section of Endocrinology, Tulane University Health Sciences Center, 1430 Tulane Avenue, #8553, New Orleans, LA 70112, USA
| | - Vivian A Fonseca
- Section of Endocrinology, Tulane University Health Sciences Center, 1430 Tulane Avenue, #8553, New Orleans, LA 70112, USA; Section of Endocrinology, Southeast Louisiana Veterans Health Care Systems, 2400 Canal Street, New Orleans, LA 70119, USA
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Coppolino G, Leporini C, Rivoli L, Ursini F, di Paola ED, Cernaro V, Arturi F, Bolignano D, Russo E, De Sarro G, Andreucci M. Exploring the effects of DPP-4 inhibitors on the kidney from the bench to clinical trials. Pharmacol Res 2018; 129:274-294. [PMID: 29223646 DOI: 10.1016/j.phrs.2017.12.001] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2017] [Revised: 10/15/2017] [Accepted: 12/01/2017] [Indexed: 02/06/2023]
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Sharma T, Paixao R, Villabona C. GLP-1 agonist associated acute kidney injury: A case report and review. DIABETES & METABOLISM 2017; 45:489-491. [PMID: 29275947 DOI: 10.1016/j.diabet.2017.12.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/29/2017] [Revised: 11/25/2017] [Accepted: 12/03/2017] [Indexed: 01/15/2023]
Affiliation(s)
- T Sharma
- Department of Internal Medicine, University of Connecticut, 262, Farmington Avenue, Farmington, CT 06030, USA.
| | - R Paixao
- Department of Internal Medicine, University of Connecticut, 262, Farmington Avenue, Farmington, CT 06030, USA
| | - C Villabona
- Department of Internal Medicine, University of Connecticut, 262, Farmington Avenue, Farmington, CT 06030, USA
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Quan H, Zhang H, Wei W, Fang T, Chen D, Chen K. A crossover study of the combination therapy of metformin and exenatide or biphasic insulin aspart 30 in overweight or obese patients newly diagnosed with type 2 diabetes mellitus. Exp Ther Med 2017; 14:3279-3287. [PMID: 28912879 DOI: 10.3892/etm.2017.4863] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2015] [Accepted: 11/18/2016] [Indexed: 12/27/2022] Open
Abstract
The aim of the present study was to explore the effects of various combinations of exenatide, metformin (MET) and biphasic insulin aspart 30 (BIA30) on type 2 diabetes mellitus (T2DM). Two hundred overweight or obese patients newly diagnosed with T2DM were evenly randomized into two groups: A (twice daily for all: Phase I, 5 µg exenatide + 0.5 g MET for 4 weeks, then 10 µg exenatide + 0.5 g MET for 8 weeks; Phase II, 0.5 g MET for 12 weeks; Phase III, 0.3-0.4 U/kg/day BIA30 + 0.5 g MET for 12 weeks) and B (Phases I, II, III matched the phases III, II and I in group A). In groups A and B a significant decrease and increase, respectively, in glycated hemoglobin (HbAlc) and body mass index (BMI) was noted during Phase I. A 3.2±0.4-kg decrease in body weight in group A and a 2.6±0.3-kg increase in group B was observed. In Phase II, HbAlc was significantly increased in both groups (P<0.05). In Phase III, the BMI was increased in group A and reduced in group B (P<0.05). There was a 3.8±0.4-kg weight decrease in group B and 4.2±0.5-kg increase in group A (P<0.05). The combination of exenatide and MET promoted weight loss, glycemic control, β-cell function index, C peptide and adiponectin levels. These results suggested that the combination of exenatide and MET is better than the combination of BIA and MET for the therapy of overweight or obese patients newly diagnosed with T2DM.
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Affiliation(s)
- Huibiao Quan
- Department of Endocrinology, People's Hospital of Hainan, Haikou, Hainan 570311, P.R. China
| | - Huachuan Zhang
- Department of Endocrinology, People's Hospital of Hainan, Haikou, Hainan 570311, P.R. China
| | - Weiping Wei
- Department of Endocrinology, People's Hospital of Hainan, Haikou, Hainan 570311, P.R. China
| | - Tuanyu Fang
- Department of Endocrinology, People's Hospital of Hainan, Haikou, Hainan 570311, P.R. China
| | - Daoxiong Chen
- Department of Endocrinology, People's Hospital of Hainan, Haikou, Hainan 570311, P.R. China
| | - Kaining Chen
- Department of Endocrinology, People's Hospital of Hainan, Haikou, Hainan 570311, P.R. China
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Tuttle KR, McKinney TD, Davidson JA, Anglin G, Harper KD, Botros FT. Effects of once-weekly dulaglutide on kidney function in patients with type 2 diabetes in phase II and III clinical trials. Diabetes Obes Metab 2017; 19:436-441. [PMID: 27766728 PMCID: PMC5347883 DOI: 10.1111/dom.12816] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2016] [Revised: 10/06/2016] [Accepted: 10/17/2016] [Indexed: 01/07/2023]
Abstract
Dulaglutide is a once-weekly glucagon-like peptide-1 receptor agonist approved for the treatment of type 2 diabetes (T2D). Integrated data from 9 phase II and III trials in people with T2D (N = 6005) were used to evaluate the effects of dulaglutide on estimated glomerular filtration rate (eGFR [Chronic Kidney Disease Epidemiology Collaboration]), urine albumin-to-creatinine ratio (UACR) and kidney adverse events (AEs). No significant differences in eGFR were observed during treatment for dulaglutide vs placebo, active comparators or insulin glargine (mean ± standard deviation values: dulaglutide vs placebo: 87.8 ± 17.7 vs 88.2 ± 17.9 mL/min/1.73 m2 , P = .075; dulaglutide vs active comparators: 89.9 ± 16.7 vs 88.8 ± 16.3 mL/min/1.73 m2 , P = .223; and dulaglutide vs insulin glargine: 85.9 ± 18.2 vs 83.9 ± 18.6 mL/min/1.73 m2 , P = .423). Lower UACR values were observed for dulaglutide vs placebo, active comparators and insulin glargine (at 26 weeks, median [Q1-Q3] values were: dulaglutide vs placebo: 8.0 [4.4-20.4] vs 8.0 [4.4-23.9] mg/g, P = .023; dulaglutide vs active comparators: 8.0 [4.4-21.2] vs 8.9 [4.4-27.4] mg/g, P = .013; and dulaglutide vs insulin glargine: 8.9 [4.4-29.2] vs 12.4 [5.3-50.5] mg/g, P = .029). AEs reflecting potential acute renal failure were 3.4, 1.7 and 7.0 events/1000 patient-years for dulaglutide, active comparators and placebo, respectively. In conclusion, dulaglutide treatment of clinical trial participants with T2D did not affect eGFR and slightly decreased albuminuria.
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Affiliation(s)
| | | | - Jaime A. Davidson
- Touchstone Diabetes CenterUniversity of Texas Southwestern Medical CenterDallasTexas
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15
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Jendle J, Grunberger G, Blevins T, Giorgino F, Hietpas RT, Botros FT. Efficacy and safety of dulaglutide in the treatment of type 2 diabetes: a comprehensive review of the dulaglutide clinical data focusing on the AWARD phase 3 clinical trial program. Diabetes Metab Res Rev 2016; 32:776-790. [PMID: 27102969 DOI: 10.1002/dmrr.2810] [Citation(s) in RCA: 112] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2015] [Revised: 03/18/2016] [Accepted: 04/13/2016] [Indexed: 01/24/2023]
Abstract
Dulaglutide (DU) is a once weekly glucagon-like peptide-1 receptor agonist (GLP-1 RA) approved for the treatment of type 2 diabetes mellitus (T2DM). Glycaemic efficacy and safety characteristics of dulaglutide have been assessed in six Phase 3 studies in the AWARD program. The objective of this review article is to summarize these results from the six completed AWARD studies. At the primary endpoint, in five of the six studies, once weekly dulaglutide 1.5 mg was superior to the active comparator [exenatide, insulin glargine (two studies), metformin, and sitagliptin], with a greater proportion of patients reaching glycated hemoglobin A1c (HbA1c) targets of <7.0% (53.0 mmol/mol) and ≤6.5% (47.5 mmol/mol). Dulaglutide 1.5 mg was non-inferior to liraglutide in AWARD-6. Once weekly dulaglutide 0.75 mg was evaluated in five of these trials and demonstrated superiority to the active comparator in four of five AWARD studies (exenatide, glargine, metformin, and sitagliptin), and non-inferiority to glargine in the AWARD-2 study. Similar to other GLP-1 receptor agonists, treatment with dulaglutide was associated with weight loss or attenuation of weight gain and low rates of hypoglycaemia when used alone or with non-insulin-secretagogue therapy. The most frequently reported adverse events were gastrointestinal, including nausea, vomiting, and diarrhea. The incidence of dulaglutide antidrug antibody formation was 1-2.8% with rare injection site reactions. In conclusion, dulaglutide is an effective treatment for T2DM and has an acceptable tolerability and safety profile. Copyright © 2016 John Wiley & Sons, Ltd.
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Affiliation(s)
- Johan Jendle
- School of Medical Sciences, Örebro University, Örebro, Sweden.
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16
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Offurum A, Wagner LA, Gooden T. Adverse safety events in patients with Chronic Kidney Disease (CKD). Expert Opin Drug Saf 2016; 15:1597-1607. [PMID: 27648959 DOI: 10.1080/14740338.2016.1236909] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Chronic kidney disease (CKD) confers a higher risk of adverse safety events as a result of many factors including medication dosing errors and use of nephrotoxic drugs, which can cause kidney injury and renal function decline. CKD patients may also have comorbidities such as hypertension and diabetes for which they require more frequent care from different providers, and for which standard, but countervailing treatments, may put them at risk for adverse safety events. Areas covered: In addition to the well-known agents such as iodinated radiocontrast, antimicrobials, diuretics and angiotensin converting enzyme (ACE) inhibitors which can directly affect renal function, safety considerations in the treatment of common CKD complications such as anemia, diabetes, analgesia and thrombosis will also be discussed. Expert opinion: Better outcomes in CKD may be achieved by alerting care providers to the special care needs of kidney patients and encouraging patients to self-manage their disease with the decision support of multidisciplinary patient care teams.
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Affiliation(s)
- Ada Offurum
- a General Internal Medicine , University of Maryland Medical System Ringgold standard institution , Baltimore , MD , USA
| | - Lee-Ann Wagner
- a General Internal Medicine , University of Maryland Medical System Ringgold standard institution , Baltimore , MD , USA
| | - Tanisha Gooden
- a General Internal Medicine , University of Maryland Medical System Ringgold standard institution , Baltimore , MD , USA
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Marín-Peñalver JJ, Martín-Timón I, Sevillano-Collantes C, del Cañizo-Gómez FJ. Update on the treatment of type 2 diabetes mellitus. World J Diabetes 2016; 7:354-95. [PMID: 27660695 PMCID: PMC5027002 DOI: 10.4239/wjd.v7.i17.354] [Citation(s) in RCA: 368] [Impact Index Per Article: 40.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2016] [Revised: 07/02/2016] [Accepted: 07/20/2016] [Indexed: 02/05/2023] Open
Abstract
To achieve good metabolic control in diabetes and keep long term, a combination of changes in lifestyle and pharmacological treatment is necessary. Achieving near-normal glycated hemoglobin significantly, decreases risk of macrovascular and microvascular complications. At present there are different treatments, both oral and injectable, available for the treatment of type 2 diabetes mellitus (T2DM). Treatment algorithms designed to reduce the development or progression of the complications of diabetes emphasizes the need for good glycaemic control. The aim of this review is to perform an update on the benefits and limitations of different drugs, both current and future, for the treatment of T2DM. Initial intervention should focus on lifestyle changes. Moreover, changes in lifestyle have proven to be beneficial, but for many patients is a complication keep long term. Physicians should be familiar with the different types of existing drugs for the treatment of diabetes and select the most effective, safe and better tolerated by patients. Metformin remains the first choice of treatment for most patients. Other alternative or second-line treatment options should be individualized depending on the characteristics of each patient. This article reviews the treatments available for patients with T2DM, with an emphasis on agents introduced within the last decade.
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Abstract
OBJECTIVE To review the use of GLP-1 agonists in patients with type 1 diabetes mellitus (T1DM). DATA SOURCES A search using the MEDLINE database, EMBASE, and Cochrane Database was performed through March 2016 using the search terms glucagon-like peptide 1 (GLP-1) agonists, incretin, liraglutide, exenatide, albiglutide, dulaglutide, type 1 diabetes mellitus STUDY SELECTION AND DATA EXTRACTION All English-language trials that examined glycemic end points using GLP-1 agonists in humans with T1DM were included. DATA SYNTHESIS A total of 9 clinical trials examining the use of GLP-1 agonists in T1DM were identified. On average, hemoglobin A1C (A1C) was lower than baseline, with a maximal lowering of 0.6%. This effect was not significant when tested against a control group, with a relative decrease in A1C of 0.1% to 0.2%. In all trials examined, reported hypoglycemia was low, demonstrating no difference when compared with insulin monotherapy. Weight loss was seen in all trials, with a maximum weight loss of 6.4 kg over 24 weeks. Gastrointestinal adverse effects are potentially limiting, with a significant number of patients in trials reporting nausea. CONCLUSION The use of GLP-1 agonists should be considered in T1DM patients who are overweight or obese and not at glycemic goals despite aggressive insulin therapy; however, tolerability of these agents is a potential concern. Liraglutide has the strongest evidence for use and would be the agent of choice for use in overweight or obese adult patients with uncontrolled T1DM.
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Affiliation(s)
- Kristin M Janzen
- Butler University College of Pharmacy and Health Sciences, Indianapolis, IN, USA Indiana University Health, Indianapolis, IN, USA
| | - Taylor D Steuber
- Butler University College of Pharmacy and Health Sciences, Indianapolis, IN, USA Indiana University Health, Indianapolis, IN, USA
| | - Sarah A Nisly
- Butler University College of Pharmacy and Health Sciences, Indianapolis, IN, USA Indiana University Health, Indianapolis, IN, USA
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19
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Affiliation(s)
- Amar Puttanna
- Department of Diabetes and Endocrinology; City Hospital; Birmingham UK
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20
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Phase III Study on Efficacy and Safety of Triple Combination (Exenatide/Metformin/Biphasic Insulin Aspart) Therapy for Type 2 Diabetes Mellitus. Am J Ther 2016; 25:e609-e616. [PMID: 26844723 DOI: 10.1097/mjt.0000000000000431] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Exenatide, metformin (MET), and biphasic insulin aspart 30 (BIA30) have been widely used in the treatment of patients with type 2 diabetes mellitus (T2DM); however, each of these medications has significant adverse effects, which limit their utilization. This study aimed to evaluate the efficacy and safety of triple combination (exenatide/metformin/biphasic insulin aspart) therapy for T2DM. Two hundred patients with poorly controlled T2DM were randomly divided into the low-dose (0.5 μg exenatide, 0.05 U·kg·d BIA30, and 0.01 g MET twice daily) and normal-dose (2 μg exenatide, 0.2 U·kg·d BIA30, and 0.05 g MET twice daily) groups for 48 weeks of treatment. Of note, 82 and 90 individuals from the low-dose and normal-dose groups, respectively, completed the study. The levels of adiponectin, C-reactive protein, tumor necrosis factor-α, and resistin were measured. The normal-dose treatment was more effective at lowering hemoglobin A1c levels than the low-dose therapy (HbA1c changes of -2.5 ± 0.19% and -0.8 ± 0.07%, respectively) after 48 weeks. The maximum weight decrease was 0.9 kg in the low-dose group and 4.0 kg in the normal-dose group. The triple combination therapy increased the levels of insulin sensitivity and adiponectin and reduced the levels of C-reactive protein, resistin, and tumor necrosis factor-α. No significant difference in the adverse effects was found between the low-dose and normal-dose groups (P > 0.05). In conclusion, the investigated triple combination therapy for T2MD is therefore an effective and safe therapeutic strategy.
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Smits MM, Tonneijck L, Muskiet MHA, Hoekstra T, Kramer MHH, Pieters IC, Cahen DL, Diamant M, van Raalte DH. Cardiovascular, renal and gastrointestinal effects of incretin-based therapies: an acute and 12-week randomised, double-blind, placebo-controlled, mechanistic intervention trial in type 2 diabetes. BMJ Open 2015; 5:e009579. [PMID: 26586327 PMCID: PMC4654309 DOI: 10.1136/bmjopen-2015-009579] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
INTRODUCTION Incretin-based therapies, that is, glucagon-like peptide (GLP)-1 receptor agonists and dipeptidyl peptidase (DPP)-4 inhibitors, are relatively novel antihyperglycaemic drugs that are frequently used in type 2 diabetes management. Apart from glucose-lowering, these agents exhibit pleiotropic actions that may have favourable and unfavourable clinical consequences. Incretin-based therapies have been associated with heart rate acceleration, heart failure, acute renal failure and acute pancreatitis. Conversely, these agents may reduce blood pressure, glomerular hyperfiltration, albuminuria and hepatic steatosis. While large-sized cardiovascular safety trials can potentially identify the clinical significance of some of these pleiotropic actions, small-sized mechanistic studies are important to understand the (patho)physiological rationale of these findings. The current protocol describes a mechanistic study to assess cardiovascular, renal and gastrointestinal effects, and mechanisms of incretin-based therapies in type 2 diabetes. METHODS AND ANALYSES 60 patients with type 2 diabetes will undergo acute and prolonged randomised, double-blind, intervention studies. The acute intervention will consist of intravenous administration of the GLP-1 receptor agonist exenatide or placebo. For the prolonged intervention, patients will be randomised to 12-week treatment with the GLP-1 receptor agonist liraglutide, the DPP-4 inhibitor sitagliptin or matching placebos. For each examined organ system, a primary end point is defined. Primary cardiovascular end point is change in resting heart rate variability assessed by beat-to-beat heart rate monitor and spectral analyses software. Primary renal end point is change in glomerular filtration rate assessed by the classic inulin clearance methodology. Primary gastrointestinal end points are change in pancreatic exocrine function assessed by MRI-techniques (acute intervention) and faecal elastase-1 levels (12-week intervention). Secondary end points include systemic haemodynamics, microvascular function, effective renal plasma flow, renal tubular function, pancreatic volume and gallbladder emptying-rate. MEDICAL ETHICS AND DISSEMINATION The study is approved by the local Ethics Review Board (VU University Medical Center, Amsterdam) and conducted in accordance with the Declaration of Helsinki and Good Clinical Practice. TRIAL REGISTRATION NUMBER NCT01744236.
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Affiliation(s)
- Mark M Smits
- Department of Internal Medicine, Diabetes Centre, VU University Medical Center, Amsterdam, The Netherlands
| | - Lennart Tonneijck
- Department of Internal Medicine, Diabetes Centre, VU University Medical Center, Amsterdam, The Netherlands
| | - Marcel H A Muskiet
- Department of Internal Medicine, Diabetes Centre, VU University Medical Center, Amsterdam, The Netherlands
| | - Trynke Hoekstra
- Department of Health Sciences, EMGO Institute for Health and Care Research, VU University Amsterdam, Amsterdam, The Netherlands
- Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands
| | - Mark H H Kramer
- Department of Internal Medicine, Diabetes Centre, VU University Medical Center, Amsterdam, The Netherlands
| | - Indra C Pieters
- Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands
| | - Djuna L Cahen
- Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Michaela Diamant
- Department of Internal Medicine, Diabetes Centre, VU University Medical Center, Amsterdam, The Netherlands
| | - Daniël H van Raalte
- Department of Internal Medicine, Diabetes Centre, VU University Medical Center, Amsterdam, The Netherlands
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Scheen AJ. Pharmacokinetics and clinical use of incretin-based therapies in patients with chronic kidney disease and type 2 diabetes. Clin Pharmacokinet 2015; 54:1-21. [PMID: 25331711 DOI: 10.1007/s40262-014-0198-2] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The prevalence of chronic kidney disease (CKD) of stages 3-5 (glomerular filtration rate [GFR] <60 mL/min) is about 25-30 % in patients with type 2 diabetes mellitus (T2DM). While most oral antidiabetic agents have limitations in patients with CKD, incretin-based therapies are increasingly used for the management of T2DM. This review analyses (1) the influence of CKD on the pharmacokinetics of dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists; and (2) the efficacy/safety profile of these agents in clinical practice when prescribed in patients with both T2DM and CKD. Most DPP-4 inhibitors (sitagliptin, vildagliptin, saxagliptin, alogliptin) are predominantly excreted by the kidneys. Thereby, pharmacokinetic studies showed that total exposure to the drug is increased in proportion to the decline of GFR, leading to recommendations for appropriate dose reductions according to the severity of CKD. In these conditions, clinical studies reported a good efficacy and safety profile in patients with CKD. In contrast, linagliptin is eliminated by a predominantly hepatobiliary route. As a pharmacokinetic study showed only minimal influence of decreased GFR on total exposure, no dose adjustment of linagliptin is required in the case of CKD. The experience with GLP-1 receptor agonists in patients with CKD is more limited. Exenatide is eliminated by renal mechanisms and should not be given in patients with severe CKD. Liraglutide is not eliminated by the kidney, but it should be used with caution because of the limited experience in patients with CKD. Only limited pharmacokinetic data are also available for lixisenatide, exenatide long-acting release (LAR) and other once-weekly GLP-1 receptor agonists in current development. Several case reports of acute renal failure have been described with GLP-1 receptor agonists, probably triggered by dehydration resulting from gastrointestinal adverse events. However, increasing GLP-1 may also exert favourable renal effects that could contribute to reducing the risk of diabetic nephropathy. In conclusion, the already large reassuring experience with DPP-4 inhibitors in patients with CKD offers new opportunities to the clinician, whereas more caution is required with GLP-1 receptor agonists because of the limited experience in this population.
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Affiliation(s)
- André J Scheen
- Division of Clinical Pharmacology, Centre for Interdisciplinary Research on Medicines (CIRM), University of Liège, Liège, Belgium,
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23
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Candeias EM, Sebastião IC, Cardoso SM, Correia SC, Carvalho CI, Plácido AI, Santos MS, Oliveira CR, Moreira PI, Duarte AI. Gut-brain connection: The neuroprotective effects of the anti-diabetic drug liraglutide. World J Diabetes 2015; 6:807-827. [PMID: 26131323 PMCID: PMC4478577 DOI: 10.4239/wjd.v6.i6.807] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2014] [Revised: 01/30/2015] [Accepted: 05/18/2015] [Indexed: 02/05/2023] Open
Abstract
Long-acting glucagon-like peptide-1 (GLP-1) analogues marketed for type 2 diabetes (T2D) treatment have been showing positive and protective effects in several different tissues, including pancreas, heart or even brain. This gut secreted hormone plays a potent insulinotropic activity and an important role in maintaining glucose homeostasis. Furthermore, growing evidences suggest the occurrence of several commonalities between T2D and neurodegenerative diseases, insulin resistance being pointed as a main cause for cognitive decline and increased risk to develop dementia. In this regard, it has also been suggested that stimulation of brain insulin signaling may have a protective role against cognitive deficits. As GLP-1 receptors (GLP-1R) are expressed throughout the central nervous system and GLP-1 may cross the blood-brain-barrier, an emerging hypothesis suggests that they may be promising therapeutic targets against brain dysfunctional insulin signaling-related pathologies. Importantly, GLP-1 actions depend not only on the direct effect mediated by its receptor activation, but also on the gut-brain axis involving an exchange of signals between both tissues via the vagal nerve, thereby regulating numerous physiological functions (e.g., energy homeostasis, glucose-dependent insulin secretion, as well as appetite and weight control). Amongst the incretin/GLP-1 mimetics class of anti-T2D drugs with an increasingly described neuroprotective potential, the already marketed liraglutide emerged as a GLP-1R agonist highly resistant to dipeptidyl peptidase-4 degradation (thereby having an increased half-life) and whose systemic GLP-1R activity is comparable to that of native GLP-1. Importantly, several preclinical studies showed anti-apoptotic, anti-inflammatory, anti-oxidant and neuroprotective effects of liraglutide against T2D, stroke and Alzheimer disease (AD), whereas several clinical trials, demonstrated some surprising benefits of liraglutide on weight loss, microglia inhibition, behavior and cognition, and in AD biomarkers. Herein, we discuss the GLP-1 action through the gut-brain axis, the hormone’s regulation of some autonomic functions and liraglutide’s neuroprotective potential.
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MacConell L, Gurney K, Malloy J, Zhou M, Kolterman O. Safety and tolerability of exenatide once weekly in patients with type 2 diabetes: an integrated analysis of 4,328 patients. Diabetes Metab Syndr Obes 2015; 8:241-53. [PMID: 26056482 PMCID: PMC4445788 DOI: 10.2147/dmso.s77290] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Exenatide once weekly (QW) is a glucagon-like peptide-1 receptor agonist (GLP-1RA) for the treatment of type 2 diabetes. Safety and tolerability are key considerations in treatment selection. This analysis examines the safety and tolerability profile of exenatide QW, other approved GLP-1RAs (exenatide twice daily and liraglutide once daily), and a pooled population of commonly used non-GLP-1RA treatments. METHODS Intent-to-treat populations from eight randomized Phase III trials with 24-week and 30-week comparator-controlled periods were analyzed. Data were pooled for exenatide QW, exenatide twice daily, and non-GLP-1RA comparator groups; comparisons between exenatide QW and liraglutide were analyzed separately to better match study groups. The incidence of treatment-emergent adverse events with 95% confidence intervals and exposure-adjusted incidence were calculated. Duration and recurrence were analyzed for gastrointestinal adverse events and adverse events of special interest. RESULTS Incidences of serious adverse events did not differ between treatments. Discontinuations due to adverse events occurred numerically less frequently with exenatide QW than with other GLP-1RAs but numerically more frequently than with non-GLP-1RA comparators. The most frequent adverse events in the GLP-1RA groups were gastrointestinal and generally mild, with decreasing incidence over time. Gastrointestinal adverse event incidences appeared lower with exenatide QW versus other GLP-1RAs and greater than with non-GLP-1RA comparators. Injection site-related adverse events seemed highest with exenatide QW, but generally did not lead to withdrawal and abated over time. Hypoglycemia was infrequent overall, but occurred numerically more frequently in the non-GLP-1RA comparator group and increased with concomitant sulfonylurea use. Pancreatitis, thyroid cancer, renal failure, and gallbladder disease were rarely reported. CONCLUSION The overall safety and tolerability profile of exenatide QW was similar to that of other GLP-1RAs, with improved gastrointestinal tolerability. The safety and tolerability profile of exenatide QW compared with non-GLP-1RA comparators was similar overall, with the exception of a lower incidence of hypoglycemia and anticipated differences in gastrointestinal and injection site-related adverse events.
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Affiliation(s)
- Leigh MacConell
- Clinical Development, Bristol-Myers Squibb, San Diego, CA, USA
| | - Kate Gurney
- Medical Writing, Bristol-Myers Squibb, San Diego, CA, USA
| | - Jaret Malloy
- Clinical Development, Bristol-Myers Squibb, San Diego, CA, USA
| | - Ming Zhou
- Biostatistics, Bristol-Myers Squibb, Princeton, NJ, USA
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Alsahli M, Gerich JE. Hypoglycemia in Patients with Diabetes and Renal Disease. J Clin Med 2015; 4:948-64. [PMID: 26239457 PMCID: PMC4470208 DOI: 10.3390/jcm4050948] [Citation(s) in RCA: 80] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2015] [Revised: 04/19/2015] [Accepted: 04/28/2015] [Indexed: 12/11/2022] Open
Abstract
This article summarizes our current knowledge of the epidemiology, pathogenesis, and morbidity of hypoglycemia in patients with diabetic kidney disease and reviews therapeutic limitations in this situation.
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Affiliation(s)
- Mazen Alsahli
- Department of Medicine, Southlake Health Center and University of Toronto Faculty of Medicine, 531 Davis Dr, Newmarket, Ontario L3Y 6P5, Canada.
| | - John E Gerich
- Department of Medicine, University of Rochester School of Medicine, 601 Elmwood Ave, Rochester, NY 14642, USA.
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Roche-Recinos A, Charlap E, Markell M. Management of glycemia in diabetic patients with stage IV and V chronic kidney disease. Curr Diab Rep 2015; 15:25. [PMID: 25772643 DOI: 10.1007/s11892-015-0600-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Diabetic kidney disease is a leading cause of end-stage kidney disease worldwide. Data suggest that prevention of progression to end-stage may lie in excellent blood glucose control; however, as kidney disease progresses, the risk of hypoglycemia increases, due to unpredictable insulin kinetics and altered pharmacokinetics of hypoglycemic agents. In addition, whole classes of hypoglycemic agents become contraindicated and regimens must be adjusted for declining kidney function. There is no consensus regarding the best therapy for the patient with advanced chronic kidney disease. In the best of circumstances, the care of these patients will involve intensive monitoring, with the input of a team of health care providers creating a coordinated care plan, including dietary advice and a drug regimen tailored to the specific issues faced by the individual patient. An open dialogue is necessary at all times, as patients may become frustrated and attempt self-treatment using over the counter alternatives.
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Affiliation(s)
- Andrea Roche-Recinos
- Division of Nephrology, SUNY Downstate Medical Center, Box 52, Brooklyn, NY, 11203, USA
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27
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Jenssen T, Hartmann A. Emerging treatments for post-transplantation diabetes mellitus. Nat Rev Nephrol 2015; 11:465-77. [PMID: 25917553 DOI: 10.1038/nrneph.2015.59] [Citation(s) in RCA: 65] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Post-transplantation diabetes mellitus (PTDM), also known as new-onset diabetes mellitus (NODM), occurs in 10-15% of renal transplant recipients and is associated with cardiovascular disease and reduced lifespan. In the majority of cases, PTDM is characterized by β-cell dysfunction, as well as reduced insulin sensitivity in liver, muscle and adipose tissue. Glucose-lowering therapy must be compatible with immunosuppressant agents, reduced glomerular filtration rate (GFR) and severe arteriosclerosis. Such therapy should not place the patient at risk by inducing hypoglycaemic episodes or exacerbating renal function owing to adverse gastrointestinal effects with hypovolaemia. First-generation and second-generation sulphonylureas are generally avoided, and caution is currently advocated for the use of metformin in patients with GFR <60 ml/min/1.73 m(2). DPP-4 inhibitors do not interact with immunosuppressant drugs and have demonstrated safety in small clinical trials. Other therapeutic options include glinides and glitazones. Evidence-based treatment regimens used in patients with type 2 diabetes mellitus cannot be directly implemented in patients with PTDM. Studies investigating the latest drugs are required to direct the development of improved treatment strategies for patients with PTDM. This Review outlines the modern principles of glucose-lowering treatment in PTDM with specific reference to renal transplant recipients.
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Affiliation(s)
- Trond Jenssen
- Research Group of Nephrology and Metabolism, Department of Clinical Medicine, UIT Arctic University of Norway, Hansine Hansens Veg 18, PO Box 6050 Langnes, 9037 Tromsø, Norway
| | - Anders Hartmann
- Department of Transplant Medicine, Section of Nephrology, Oslo University Hospital Rikshospitalet, Sognsvannvegen 20, PO Box 4950, Nydalen, Oslo 0424, Norway
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28
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Filippatos TD, Panagiotopoulou TV, Elisaf MS. Adverse Effects of GLP-1 Receptor Agonists. Rev Diabet Stud 2015; 11:202-30. [PMID: 26177483 DOI: 10.1900/rds.2014.11.202] [Citation(s) in RCA: 283] [Impact Index Per Article: 28.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Glucagon-like peptide-1 (GLP-1) receptor agonists are a class of injective anti-diabetic drugs that improve glycemic control and many other atherosclerosis-related parameters in patients with type 2 diabetes (T2D). However, the use of this relatively new class of drugs may be associated with certain adverse effects. Concerns have been expressed regarding the effects of these drugs on pancreatic and thyroid tissue, since animal studies and analyses of drug databases indicate an association of GLP-1 receptor agonists with pancreatitis, pancreatic cancer, and thyroid cancer. However, several meta-analyses failed to confirm a cause-effect relation between GLP-1 receptor agonists and the development of these adverse effects. One benefit of GLP-1 receptor agonists is that they do not cause hypoglycemia when combined with metformin or thiazolidinediones, but the dose of concomitant sulphonylurea or insulin may have to be decreased to reduce the risk of hypoglycemic episodes. On the other hand, several case reports have linked the use of these drugs, mainly exenatide, with the occurrence of acute kidney injury, primarily through hemodynamic derangement due to nausea, vomiting, and diarrhea. The most common symptoms associated with the use of GLP-1 receptor agonists are gastrointestinal symptoms, mainly nausea. Other common adverse effects include injection site reactions, headache, and nasopharyngitis, but these effects do not usually result in discontinuation of the drug. Current evidence shows that GLP-1 receptor agonists have no negative effects on the cardiovascular risk of patients with T2D. Thus, GLP-1 receptor agonists appear to have a favorable safety profile, but ongoing trials will further assess their cardiovascular effects. The aim of this review is to analyze critically the available data regarding adverse events of GLP-1 receptor agonists in different anatomic systems published in Pubmed and Scopus. Whenever possible, certain differences between GLP-1 receptor agonists are described. The review also provides the reader with structured data that compare the rates of the most common adverse effects for each of the various GLP-1 receptor agonists.
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Affiliation(s)
- Theodosios D Filippatos
- Department of Internal Medicine, School of Medicine, University of Ioannina, 45110 Ioannina, Greece
| | - Thalia V Panagiotopoulou
- Department of Internal Medicine, School of Medicine, University of Ioannina, 45110 Ioannina, Greece
| | - Moses S Elisaf
- Department of Internal Medicine, School of Medicine, University of Ioannina, 45110 Ioannina, Greece
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Alsahli M, Gerich JE. Hypoglycemia, chronic kidney disease, and diabetes mellitus. Mayo Clin Proc 2014; 89:1564-71. [PMID: 25305751 DOI: 10.1016/j.mayocp.2014.07.013] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2014] [Revised: 07/12/2014] [Accepted: 07/25/2014] [Indexed: 12/21/2022]
Abstract
Hypoglycemia is a major problem associated with substantial morbidity and mortality in patients with diabetes and is often a major barrier to achieving optimal glycemic control. Chronic kidney disease not only is an independent risk factor for hypoglycemia but also augments the risk of hypoglycemia that is already present in people with diabetes. This article summarizes our current knowledge of the epidemiology, pathogenesis, and morbidity of hypoglycemia in patients with diabetes and chronic kidney disease and reviews therapeutic considerations in this situation. PubMed and MEDLINE were searched for literature published in English from January 1989 to May 2014 for diabetes mellitus, hypoglycemia, chronic kidney disease, and chronic renal insufficiency.
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MESH Headings
- Albuminuria/etiology
- Biomarkers/urine
- Databases, Bibliographic
- Diabetes Mellitus, Type 1/complications
- Diabetes Mellitus, Type 1/drug therapy
- Diabetes Mellitus, Type 1/epidemiology
- Diabetes Mellitus, Type 2/complications
- Diabetes Mellitus, Type 2/drug therapy
- Diabetes Mellitus, Type 2/epidemiology
- Glomerular Filtration Rate/physiology
- Humans
- Hypoglycemia/chemically induced
- Hypoglycemia/epidemiology
- Hypoglycemia/etiology
- Hypoglycemia/therapy
- Hypoglycemic Agents/adverse effects
- Hypoglycemic Agents/therapeutic use
- Insulin/adverse effects
- Insulin/therapeutic use
- Renal Insufficiency, Chronic/complications
- Renal Insufficiency, Chronic/drug therapy
- Renal Insufficiency, Chronic/epidemiology
- Risk Factors
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Affiliation(s)
- Mazen Alsahli
- Faculty of Medicine, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - John E Gerich
- Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY.
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Abstract
Glucagon-like peptide-1 (GLP-1) stimulates insulin secretion and inhibits glucagon secretion in the pancreatic islets of Langerhans under hyperglycaemia. In type 2 diabetes (T2DM), GLP-1 improves glycaemic control without a hypoglycaemia risk. GLP-1 receptors have also been found in extra-pancreatic tissues, e.g., the cardiovascular system, the gastrointestinal system, and the central nervous system. Since cardiovascular comorbidities and degenerative neurological changes are associated with T2DM, the interest in the extrapancreatic effects of GLP-1 has increased. GLP-1-based therapies with either GLP-1 receptor agonists (GLP-1 RA) or DPP-4 inhibitors (that delay the degradation of endogenous GLP-1) have become widely used therapeutic options in T2DM. In clinical studies, GLP-1 RA have demonstrated a significant lowering of blood pressure that is independent of body weight changes. Preclinical data and small short-term studies with GLP-1 and GLP-1 RA have shown cardioprotective effects in ischaemia models. GLP-1 as well as a treatment with GLP-1 RA also induces a stable body weight loss by affecting GLP-1 signaling in the hypothalamus and by slowing gastric emptying. Regarding neuroprotective actions in degenerative neurological disease models for Parkinson's- or Alzheimer's disease or neurovascular complications like stroke, animal studies have shown positive results. In this article, a summary of the extrapancreatic effects of GLP-1 and GLP-1-based therapies is presented.
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Affiliation(s)
- Baptist Gallwitz
- Department of Medicine IV, Eberhard-Karls-University, Otfried-Müller-Str. 10, 72076, Tübingen, Germany,
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31
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MacCallum L. Optimal Medication Dosing in Patients with Diabetes Mellitus and Chronic Kidney Disease. Can J Diabetes 2014; 38:334-43. [DOI: 10.1016/j.jcjd.2014.04.006] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2014] [Revised: 04/24/2014] [Accepted: 04/28/2014] [Indexed: 01/14/2023]
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Young MA, Wald JA, Matthews JE, Yang F, Reinhardt RR. Effect of renal impairment on the pharmacokinetics, efficacy, and safety of albiglutide. Postgrad Med 2014; 126:35-46. [PMID: 24918790 DOI: 10.3810/pgm.2014.05.2754] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Chronic kidney disease is frequently present in patients with type 2 diabetes mellitus (T2DM). New therapeutic options in this patient subpopulation are needed. OBJECTIVES Assess the effect of renal impairment on the pharmacokinetics (PK), efficacy, and safety of albiglutide in single- and multiple-dose studies. METHODS Pharmacokinetics, safety, and efficacy of once weekly albiglutide in patients with T2DM was assessed from a single-dose (30 mg), nonrandomized, open-label study (N = 41) including subjects with normal and varying degrees of renal impairment, including hemodialysis, and a pooled analysis of 4 phase 3, randomized, double-blind (1 open-label), active or placebo-controlled multiple-dose studies. The pooled analysis of the latter 4 studies (N = 1113) was part of the population PK analysis, which included subjects with normal and varying degrees of renal impairment (mild, moderate, severe) treated with albiglutide (30 to 50 mg) to primary end points of 26 to 52 weeks. RESULTS Single-dose PK showed area-under-the-curve ratios (and 90% CIs) of 1.32 (0.96-1.80), 1.39 (1.03-1.89), and 0.99 (0.63-1.57) for the moderate, severe, and hemodialysis groups, respectively, relative to the normal group. Results indicate that modest increases in plasma concentration of albiglutide were observed with the severity of renal impairment. There was a trend for more glycemic lowering as the estimated glomerular filtration rate decreased. The severe group had a higher frequency of gastrointestinal (eg, diarrhea, constipation, nausea, and vomiting) and hypoglycemic (with background sulfonylurea use) events compared with patients with mild or moderate renal impairment. CONCLUSION The PK, efficacy, and safety data indicate that albiglutide has a favorable benefit/risk ratio in patients with T2DM and varying degrees of renal impairment, and the need for a dose adjustment is not suggested. Experience in patients with more severe renal impairment is very limited, so the recommendation is to use albiglutide carefully in this population. CLINICAL TRIAL REGISTRATION (ClinicalTrials.gov):NCT00938158, NCT00849017, NCT00838916, NCT00839527, NCT0198539.
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Affiliation(s)
- Malcolm A Young
- Senior Director, Clinical Pharmacology, Modeling and Simulation, GlaxoSmithKline, Research Triangle Park, NC.
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Schwartz S. Evidence-based practice use of incretin-based therapy in the natural history of diabetes. Postgrad Med 2014; 126:66-84. [PMID: 24918793 DOI: 10.3810/pgm.2014.05.2757] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
The incretin class of anti-hyperglycemic agents, including glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-inhibitors, is an important addition to the therapeutic armamentarium for the management of appropriate patients with type 2 diabetes mellitus as an adjunct to diet and exercise and/or with the agents metformin, sulfonylureas, thiazolidinediones, or any combination thereof. More recently, US Food and Drug Administration (FDA)-approved indications for incretins were expanded to include use with basal insulin. This review article takes an evidence-based practice approach in discussing the importance of aggressive treatment for diabetes, the principles of incretin physiology and pathophysiology, use of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors, and patient types and contexts where incretin therapy has been found beneficial, from metabolic syndrome to overt diabetes.
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Affiliation(s)
- Stanley Schwartz
- Affiliate, Main Line Health System, Ardmore, PA; Emeritus, Clinical Associate Professor of Medicine, University of Pennsylvania, Philadelphia, PA.
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34
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Abstract
The incretin hormone, glucagon-like peptide-1 (GLP-1), stimulates insulin secretion and forms the basis of a new drug class for diabetes treatment. GLP-1 has several extra-pancreatic properties which include effects on kidney function. Although renal GLP-1 receptors have been identified, their exact localization and physiological role are incompletely understood. GLP-1 increases natriuresis through inhibition of the sodium-hydrogen ion exchanger isoform 3 in the proximal tubule. This may in part explain why GLP-1 receptor agonists have antihypertensive effects. Glomerular filtration rate is regulated by GLP-1, but the mechanisms are complex and may depend on e.g. glycaemic conditions. Atrial natriuretic peptide or the renin-angiotensin system may be involved in the signalling of GLP-1-mediated renal actions. Several studies in rodents have shown that GLP-1 therapy is renoprotective beyond metabolic improvements in models of diabetic nephropathy and acute kidney injury. Inhibition of renal inflammation and oxidative stress probably mediate this protection. Clinical studies supporting GLP-1-mediated renal protection exist, but they are few and with limitations. However, acute and chronic kidney diseases are major global health concerns and measures improving renal outcome are highly needed. Therefore, the renoprotective potential of GLP-1 therapy need to be thoroughly investigated in humans.
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Affiliation(s)
- Jeppe Skov
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Norrebrogade 44, 8000, Aarhus, Denmark,
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35
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Dejager S, Schweizer A. Incretin therapies in the management of patients with type 2 diabetes mellitus and renal impairment. Hosp Pract (1995) 2014; 40:7-21. [PMID: 22615074 DOI: 10.3810/hp.2012.04.965] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Renal impairment (RI) is common among patients with type 2 diabetes mellitus (T2DM), and these patients also experience an age-related decline in renal function. At the same time, treatment options are more limited and treatment is more complex, particularly in patients with moderate or severe RI due to contraindications, need for dose adjustment and/or regular monitoring, and side effects, such as fluid retention and hypoglycemia, which are a more serious concern in this patient population. Incretin therapies, consisting of the injectable glucagon-like peptide-1 (GLP-1) receptor agonists and the oral dipeptidyl peptidase-4 (DPP-4) inhibitors, are a promising new class of antihyperglycemic drugs. In the overall population, they improve glycemic control in a glucose-dependent manner and are not likely to cause hypoglycemia, representing a clear advantage in at-risk populations. Data regarding use of these agents in renally impaired patients have started to emerge, and the objective of this article is to provide an overview of the currently available data and the potential role of these novel agents in the management of patients with T2DM and RI. Data for the GLP-1 receptor agonists in patients with moderate or severe RI are still limited, with no trials dedicated to these populations currently published. In addition, their potential to cause gastrointestinal side effects may limit use in patients with RI due to the risk of dehydration and hypovolemia. The use of GLP-1 receptor agonists in patients with moderate or severe RI is therefore, at present, underlying caution and/or restrictions. On the other hand, data from specific trials in patients with moderate or severe RI are now becoming available for most of the DPP-4 inhibitors. These studies demonstrate good efficacy and tolerability of the DPP-4 inhibitors in patients with moderate or severe RI, thus opening a place for these therapies in the treatment of populations with T2DM and RI. Several of the DPP-4 inhibitors are already approved for use in patients with moderate or severe RI, including for those with end-stage renal disease. While discussing the advantages related to their common mechanism of action, this article also describes differences among the DPP-4 inhibitors (eg, related to their pharmacokinetic properties and the available clinical data). In conclusion, while initial data for these new therapies are promising, further experience is needed to fully assess the risk-benefit balance and clinical positioning of these agents in RI populations.
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Giorda CB, Nada E, Tartaglino B. Pharmacokinetics, safety, and efficacy of DPP-4 inhibitors and GLP-1 receptor agonists in patients with type 2 diabetes mellitus and renal or hepatic impairment. A systematic review of the literature. Endocrine 2014; 46:406-19. [PMID: 24510630 DOI: 10.1007/s12020-014-0179-0] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2013] [Accepted: 01/16/2014] [Indexed: 12/14/2022]
Abstract
Renal or hepatic impairment, often encountered in patients with type 2 diabetes, influences the pharmacokinetics and bioavailability of antihyperglycemic agents. An emerging concern is whether pharmacotherapy with incretin-based agents, the most recent drug classes to be introduced for type 2 diabetes, can be safely used in patients with renal insufficiency or hepatic damage. This literature review examines the results of studies on these novel drug classes, with a view to provide the practitioner with a balanced, evidence-based position when considering incretin-based therapies in patients with type 2 diabetes and impaired kidney or liver function. All currently available dipeptidyl peptidase-4 (DPP-4) inhibitors appear to be appropriate pharmacotherapeutic choices in patients with declining renal function, with linagliptin affording the added advantage of not requiring dose adjustment or periodic monitoring of drug-related kidney function. In contrast, caution is warranted with the use of glucagon-like peptide-1 (GLP-1) receptor agonists in patients with moderate or severe renal impairment. The slightly wider evidence base for liraglutide than for exenatide or lixisenatide is not sufficient to support its use in severe renal impairment. What little evidence there is for incretin-based therapies in hepatic impairment has come from a few past hoc analysis of clinical trials, with most precautions and warnings reflecting the paucity of knowledge about incretin efficacy or safety in this condition.
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Affiliation(s)
- Carlo B Giorda
- Metabolism and Diabetes Unit, ASL TO5, Regione Piemonte, Chieri, Italy,
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37
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Seufert J, Gallwitz B. The extra-pancreatic effects of GLP-1 receptor agonists: a focus on the cardiovascular, gastrointestinal and central nervous systems. Diabetes Obes Metab 2014; 16:673-88. [PMID: 24373150 DOI: 10.1111/dom.12251] [Citation(s) in RCA: 106] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2013] [Revised: 08/09/2013] [Accepted: 12/13/2013] [Indexed: 01/03/2023]
Abstract
The glucagon-like peptide-1 receptor agonists (GLP-1RAs) exenatide, liraglutide and lixisenatide have been shown to improve glycaemic control and beta-cell function with a low risk of hypoglycaemia in people with type 2 diabetes. GLP-1 receptors are also expressed in extra-pancreatic tissues and trial data suggest that GLP-1RAs also have effects beyond their glycaemic actions. Preclinical studies using native GLP-1 or GLP-1RAs provide substantial evidence for cardioprotective effects, while clinical trial data have shown beneficial actions on hypertension and dyslipidaemia in people with type 2 diabetes. Significant weight loss has been reported with GLP-1RAs in both people with type 2 diabetes and obese people without diabetes. GLP-1RAs also slow down gastric emptying, but preclinical data suggest that the main mechanism behind GLP-1RA-induced weight loss is more likely to involve their effects on appetite signalling in the brain. GLP-1RAs have also been shown to exert a neuroprotective role in rodent models of stroke, Alzheimer's disease and Parkinson's disease. These extra-pancreatic effects of GLP-1RAs could provide multi-factorial benefits to people with type 2 diabetes. Potential adverse effects of GLP-1RA treatment are usually manageable but may include gastrointestinal effects, increased heart rate and renal injury. While extensive further research is still required, early data suggest that GLP-1RAs may also have the potential to favourably impact cardiovascular disease, obesity or neurological disorders in people without diabetes in the future.
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Affiliation(s)
- J Seufert
- Division of Endocrinology and Diabetology, Department of Medicine II, Albert-Ludwigs University Medical Center, Freiburg, Germany
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38
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Liles AM. Medication pitfalls in the CKD clinic: case presentations. Adv Chronic Kidney Dis 2014; 21:349-54. [PMID: 24969386 DOI: 10.1053/j.ackd.2014.03.014] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2014] [Revised: 03/11/2014] [Accepted: 03/18/2014] [Indexed: 01/14/2023]
Abstract
The kidney plays a major role in pharmacokinetics and pharmacodynamics of drugs; therefore, medication errors can result from failure to properly adjust medications in patients with CKD. It is the responsibility of all health-care providers to work collectively when reviewing medications, initiating new medications, and adjusting doses of current medications. Awareness of appropriate dosing recommendations can significantly decrease medication error-associated morbidity, mortality, and cost.
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Brunton S. GLP-1 receptor agonists vs. DPP-4 inhibitors for type 2 diabetes: is one approach more successful or preferable than the other? Int J Clin Pract 2014; 68:557-67. [PMID: 24499291 PMCID: PMC4238422 DOI: 10.1111/ijcp.12361] [Citation(s) in RCA: 88] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND In patients with type 2 diabetes (T2D), incretin-based therapies improve glycaemic control with low incidence of hypoglycaemia and without weight gain, both advantages over traditional add-ons to metformin. Dipeptidyl peptidase-4 (DPP-4) inhibitors are administered orally and provide a physiological increase in glucagon-like peptide-1 (GLP-1) levels, while GLP-1 receptor agonists (GLP-1RAs) are injectable and deliver pharmacological levels of GLP-1RA. This review aims to distinguish between GLP-1RAs and DPP-4 inhibitors, and discuss when each may be favoured in clinical practice. METHODS A MEDLINE search, limited to human clinical trials and using the search criteria 'GLP-1RA' or 'DPP-4 inhibitor', identified seven head-to-head studies and one relevant post hoc analysis (all a GLP-1RA vs. the DPP-4 inhibitor sitagliptin). In combination with treatment algorithms, product prescribing information and personal clinical experience, these studies were used to compare the efficacy and suitability of GLP-1RAs and DPP-4 inhibitors in patients with T2D. RESULTS In head-to-head clinical trials, GLP-1RAs provided greater glycaemic control, weight loss and overall treatment satisfaction vs. the DPP-4 inhibitor sitagliptin. Transient nausea was more frequent with GLP-1RAs and should be addressed through patient education and an incremental dosing approach. Current treatment algorithms recommend incretin-based therapy use after metformin failure, but local guidance may restrict their use. CONCLUSION GLP-1RAs provide superior glycaemic control and weight loss vs. DPP-4 inhibitors in patients with T2D. DPP-4 inhibitors may sometimes be preferred to a GLP-1RA if weight is not a concern, oral administration is a desirable feature or when a GLP-1RA cannot be tolerated.
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Affiliation(s)
- S Brunton
- Primary Care Metabolic Group, Charlotte, NC, USA
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40
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Umpierrez GE, Meneghini L. Reshaping diabetes care: the fundamental role of dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists in clinical practice. Endocr Pract 2014; 19:718-28. [PMID: 23512382 DOI: 10.4158/ep12292.ra] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
OBJECTIVE To update clinicians on the most recent safety and efficacy data on current incretin-based strategies for the treatment of type 2 diabetes (T2D). METHODS Title searches were conducted in the Pubmed database to identify literature pertaining to the safety and efficacy of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors. Product-specific title searches included the terms exenatide, liraglutide, linagliptin, saxagliptin, sitagliptin, and vildagliptin. RESULTS The recent literature has introduced us to newer DPP-4 inhibitors and longer-acting GLP-1RAs, updated meta-analyses assessing the safety and efficacy of incretin-based therapies, and studies exploring the use of incretin-based treatments in broader clinical settings such as combination therapy with insulin. Meta-analyses have demonstrated placebo-adjusted glycated hemoglobin (HbA1c) reductions of ~1% with GLP-1RAs and 0.6 to 0.8% with DPP-4 inhibitors and have suggested cardioprotective effects such as reduction of cardiovascular events and improvement of lipid profile. As a class, these agents have consistently demonstrated low risks of hypoglycemia relative to other agents. CONCLUSION Incretin-based therapies are characterized by an overall favorable safety profile and weight effect, a low risk of hypoglycemia, and clinically meaningful improvements in HbA1c. Based on an expanding and favorable literature describing their use in various patient populations, the guidelines of the American Association of Clinical Endocrinologists and the recently updated guidelines from the American Diabetes Association assign these agents a central role in the treatment of T2D.
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Affiliation(s)
- Guillermo E Umpierrez
- Department of Medicine, Division of Endocrinology and Metabolism, Emory University School of Medicine, Atlanta, Georgia 30303, USA.
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41
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Dubois-Laforgue D, Boutboul D, Lévy DJ, Joly D, Timsit J. Severe acute renal failure in patients treated with glucagon-like peptide-1 receptor agonists. Diabetes Res Clin Pract 2014; 103:e53-5. [PMID: 24447807 DOI: 10.1016/j.diabres.2013.11.014] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2013] [Revised: 09/30/2013] [Accepted: 11/12/2013] [Indexed: 01/14/2023]
Abstract
We report two patients with diabetes in whom acute renal failure requiring hemodialysis occurred while on treatment with glucagon-like peptide-1 receptor agonists. We discuss the mechanisms of this complication and the potential for its prevention.
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Affiliation(s)
- D Dubois-Laforgue
- Department of Immunology and Diabetology, Hôpital Cochin, 27 rue du Faubourg Saint-Jacques, 75014 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
| | - D Boutboul
- Department of Immunology and Diabetology, Hôpital Cochin, 27 rue du Faubourg Saint-Jacques, 75014 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France
| | - D J Lévy
- Department of Immunology and Diabetology, Hôpital Cochin, 27 rue du Faubourg Saint-Jacques, 75014 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France
| | - D Joly
- Department of Nephrology, Hôpital Necker, 149 rue de Sèvres, 75015 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France
| | - J Timsit
- Department of Immunology and Diabetology, Hôpital Cochin, 27 rue du Faubourg Saint-Jacques, 75014 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France
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Filippatos TD, Elisaf MS. Effects of glucagon-like peptide-1 receptor agonists on renal function. World J Diabetes 2013; 4:190-201. [PMID: 24147203 PMCID: PMC3797884 DOI: 10.4239/wjd.v4.i5.190] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2013] [Revised: 07/25/2013] [Accepted: 08/17/2013] [Indexed: 02/05/2023] Open
Abstract
Glucagon-like peptide-1 (GLP-1) receptor agonists result in greater improvements in glycemic control than placebo and promote weight loss with minimal hypoglycemia in patients with type 2 diabetes mellitus. A number of case reports show an association of GLP-1 receptor agonists, mainly exenatide, with the development of acute kidney injury. The present review aims to present the available data regarding the effects of GLP-1 receptor agonists on renal function, their use in subjects with chronic renal failure and their possible association with acute kidney injury. Based on the current evidence, exenatide is eliminated by renal mechanisms and should not be given in patients with severe renal impairment or end stage renal disease. Liraglutide is not eliminated by renal or hepatic mechanisms, but it should be used with caution since there are only limited data in patients with renal or hepatic impairment. There is evidence from animal studies that GLP-1 receptor agonists exert protective role in diabetic nephropathy with mechanisms that seem to be independent of their glucose-lowering effect. Additionally, there is evidence that GLP-1 receptor agonists influence water and electrolyte balance. These effects may represent new ways to improve or even prevent diabetic nephropathy.
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Davidson JA, Nikkel C, Grimm M. Exenatide once weekly: opportunities in the primary care setting. Postgrad Med 2013; 125:68-78. [PMID: 23748508 DOI: 10.3810/pgm.2013.05.2662] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Type 2 diabetes mellitus is a pandemic, with millions of new diagnoses made each year. In the United States, > 90% of patients with type 2 diabetes mellitus are cared for by primary care physicians who bear the primary responsibility of diagnosing and treating this disease. Building an optimal treatment regimen for a patient from the many choices available depends on many factors, including the ability of a given therapy to safely and effectively lower blood glucose levels, and potential benefits on body weight, cardiovascular risk factors, and hypoglycemia risk. With these considerations at the forefront, this article provides an overview of exenatide once weekly (EQW), a recently available antidiabetes therapy in the glucagon-like peptide-1 receptor agonist class designed to provide continuous glycemic control with once-weekly dosing. We discuss the clinical trials that have demonstrated the ability of EQW to effectively lower blood glucose levels and body weight with a minimal risk of hypoglycemia. In addition, we examine other issues likely to be relevant in a primary care setting, including safety and tolerability profiles, pharmacology and dosing, ease of use, recommended place in treatment, and patient perceptions of EQW.
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Affiliation(s)
- Jaime A Davidson
- Department of Medicine, Division of Endocrinology, Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
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Tuttle KR, Heilmann C, Hoogwerf BJ, Brown C, Anderson PW. Effects of Exenatide on Kidney Function, Adverse Events, and Clinical End Points of Kidney Disease in Type 2 Diabetes. Am J Kidney Dis 2013; 62:396-8. [DOI: 10.1053/j.ajkd.2013.03.026] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2012] [Accepted: 03/07/2013] [Indexed: 11/11/2022]
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Abstract
Type 2 diabetes (T2DM) is a multi-causal, heterogeneous and progressive cardiometabolic condition, with an increasing prevalence worldwide. T2DM is associated with multiple comorbidities that may impact patients' quality of life. Treatment is multifactorial, but pharmacologic treatment of hyperglycemia is still regarded as the mainstay of diabetes management. Current established therapies include metformin, sulfonylurea agents and insulin, the long-term use of which was associated with reduced micro- and macrovascular events in the United Kingdom Prospective Diabetes Study. Despite major recent advances in diabetes care, a large proportion of patients remain in poor glycemic control, necessitating the development of new therapeutic options. The recently published position statement of the American Diabetes Association and European Association for the Study of Diabetes for the management of hyperglycemia in T2DM has accommodated this wider range of therapy choices, as it is less prescriptive and advocates an individualized treatment approach, taking into account many relevant patient- and disease-related factors. This review summarizes the updates on various established agents as well as the recent developments with regard to incretin-based therapies, inhibitors of the renal tubular sodium-glucose-linked-transporter-2 and ultra-long acting basal insulin formulations.
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Bloomgarden ZT, Blonde L, Garber AJ, Wysham CH. Current issues in GLP-1 receptor agonist therapy for type 2 diabetes. Endocr Pract 2013; 18 Suppl 3:6-26; quiz 27-8. [PMID: 23315305 DOI: 10.4158/ep12300.ra] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The clinical management of hyperglycemia in patients with type 2 diabetes mellitus (T2DM) is guided not only by published treatment algorithms, but also by consideration of recent evidence and through consultation with colleagues and experts. Recent studies have dramatically increased the amount of information regarding the use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs). Topics that may be of particular interest to clinicians who treat T2DM patients include relative glycemic control efficacy of GLP-1 RAs, use of GLP-1 RAs across T2DM progression and in combination with insulin, recent data regarding GLP-1 RA safety, nonglycemic actions of GLP-1 RAs, including weight effects, and impact of GLP-1 RAs on patient quality of life and treatment satisfaction. The following review includes expert consideration of these topics with emphasis on recent, relevant reports to illustrate current perspectives.
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Affiliation(s)
- Zachary T Bloomgarden
- Department of Medicine, Division of Endocrinology, Diabetes and Bone Disease, Mount Sinai School of Medicine, New York, New York, USA.
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Avogaro A, Schernthaner G. Achieving glycemic control in patients with type 2 diabetes and renal impairment. Acta Diabetol 2013; 50:283-91. [PMID: 23212669 DOI: 10.1007/s00592-012-0442-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2012] [Accepted: 11/05/2012] [Indexed: 12/31/2022]
Abstract
Defining optimal regimens for the management of diabetes among patients with renal impairment is often clinically challenging, and guidance on the optimal management of these patients in clinical practice can vary considerably. Moreover, as many anti-diabetes agents are predominantly excreted renally, treatment options to control blood glucose levels are limited for patients with type 2 diabetes and concomitant chronic kidney disease. Many of the widely used and more established anti-diabetes drugs cannot be used in this population either or must be down-titrated to reduce the increased risk of severe hypoglycemic episodes. A number of more recently available anti-diabetes drugs are indicated for use in patients with type 2 diabetes and chronic kidney disease. Newer drugs that may improve the currently very limited treatment options for patients with type 2 diabetes and renal impairment include the glucagon-like peptide-1 receptor agonists and the dipeptidyl peptidase-4 inhibitors. This review paper, based on a literature search for both original and review articles (Medline), relevant clinical practice/regulatory guidelines and integrating our own knowledge of the field, provides an up-to-date examination of the current treatment options available. However, further studies with larger populations of patients with type 2 diabetes and chronic kidney disease are needed to clarify the efficacy and safety of the different treatment options, including newer drugs.
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Affiliation(s)
- Angelo Avogaro
- Department of Medicine, School of Medicine, University of Padova, Via Giustiniani 2, 35128, Padua, Italy.
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Thong KY, Walton C, Ryder REJ. Safety and efficacy of liraglutide 1.2mg in patients with mild and moderate renal impairment: the ABCD nationwide liraglutide audit. PRACTICAL DIABETES 2013. [DOI: 10.1002/pdi.1748] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
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Scheen AJ. Pharmacokinetic considerations for the treatment of diabetes in patients with chronic kidney disease. Expert Opin Drug Metab Toxicol 2013; 9:529-50. [PMID: 23461781 DOI: 10.1517/17425255.2013.777428] [Citation(s) in RCA: 68] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION People with chronic kidney disease (CKD) of stages 3 - 5 (creatinine clearance < 60 ml/min) represent ≈ 25% of patients with type 2 diabetes mellitus (T2DM), but the problem is underrecognized or neglected in clinical practice. However, most oral antidiabetic agents have limitations in case of renal impairment (RI), either because they require a dose adjustment or because they are contraindicated for safety reasons. AREAS COVERED The author performed an extensive literature search to analyze the influence of RI on the pharmacokinetics (PK) of glucose-lowering agents and the potential consequences for clinical practice. EXPERT OPINION As a result of PK interferences and for safety reasons, the daily dose should be reduced according to glomerular filtration rate (GFR) or even the drug is contraindicated in presence of severe CKD. This is the case for metformin (risk of lactic acidosis) and for many sulfonylureas (risk of hypoglycemia). At present, however, the exact GFR cutoff for metformin use is controversial. New antidiabetic agents are better tolerated in case of CKD, although clinical experience remains quite limited for most of them. The dose of DPP-4 inhibitors should be reduced (except for linagliptin), whereas both the efficacy and safety of SGLT2 inhibitors are questionable in presence of CKD.
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Affiliation(s)
- André J Scheen
- University of Liège, Division of Diabetes, Nutrition and Metabolic Disorders, Division of Clinical Pharmacology, Department of Medicine, CHU Sart Tilman (B35), Liège, Belgium.
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Rees DO, Price DE, Bain SC, Stephens JW. Response to Nandakoban et al. Acute tubulointerstitial nephritis following treatment with exenatide. Diabet Med 2013; 30:251-2. [PMID: 22998130 DOI: 10.1111/dme.12014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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